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Amyotrophic Lateral Sclerosis

  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
 
Updated: Mar 23, 2016
 

Practice Essentials

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. Although ALS is incurable and fatal, with median survival of 3 years, treatment can extend the length and meaningful quality of life for patients.

Signs and symptoms

In 75-80% of patients, symptoms begin with limb involvement. Initial complaints in patients with lower limb onset are often as follows:

  • Tripping, stumbling, or awkwardness when running
  • Foot drop; patients may report a "slapping" gait

Initial complaints with upper limb onset include the following:

  • Reduced finger dexterity, cramping, stiffness, and weakness or wasting of intrinsic hand muscles
  • Wrist drop interfering with work performance

With bulbar onset (20-25%), initial complaints are as follows:

  • Slurred speech, hoarseness, or decreased volume of speech
  • Aspiration or choking during a meal

Emotional and special cognitive difficulties in some ALS patients are as follows:

  • Involuntary laughing or crying
  • Depression
  • Impaired executive function
  • Maladaptive social behavior

Features of more-advanced disease are as follows:

  • Muscle atrophy becomes more apparent
  • Spasticity may compromise gait and manual dexterity
  • Muscle cramps are common
  • Rarely, painful joint contractures may result from immobility

Progression of bulbar disease leads to the following:

  • Voice changes: Hypernasality and development of a strained, strangled vocal quality; eventually, speech may be lost
  • Swallowing difficulties, usually starting with liquids
  • Drooling

The image below illustrates the 4 regions of the body.

The 4 regions or levels of the body. Bulbar (muscl The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).

See Clinical Presentation for more detail.

Diagnosis

Definitive diagnosis may not be possible with early ALS. Confirmation of the disease may require a period of observation to document its progressive nature and to exclude alternative diagnoses.

The World Federation of Neurology (WFN) has developed a diagnostic algorithm that combines the clinical and, in some cases, electrophysiologic findings.[1] The degree of certainty of diagnosis is increased by the number of body segments that demonstrate upper motor neuron (UMN) and lower motor neuron (LMN) signs. UMN signs are mild weakness, spasticity, and abnormally brisk reflexes; LMN signs are progressive weakness, wasting, and loss of reflexes and muscle tone. WFN categories are as follows:

  • Clinically definite ALS: UMN and LMN signs in at least 3 body segments
  • Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs
  • Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by electromyography (EMG) in at least 2 limbs
  • Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs
  • Clinically suspected ALS: Pure LMN syndrome with other causes of LMN disease adequately excluded

Hallmark findings in the electrodiagnosis of ALS are normal sensory nerve conduction studies and abnormal motor nerve conduction studies, with reduced motor compound muscle action potentials. The needle exam shows changes characteristic of ongoing denervation and reinnervation of muscles.

In patients with familial ALS, genetic testing may be requested after appropriate counseling. The results of genetic testing may affect not only the patient, but also family members. Tests for the SOD1, TARDBP (coding for TDP-43), FUS, ANG, C9orf72, and FIG4 genes and for the gene causing Kennedy disease are available commercially. Patients with other forms of familial ALS may be referred to centers with a research interest in familial ALS.

See Workup for more detail.

Management

American Academy of Neurology recommendations for management of patients with ALS can be summarized as follows[2, 3] :

  • Riluzole should be offered to all patients with ALS to slow disease progression
  • Enteral nutrition via percutaneous endoscopic gastrostomy (PEG) should be considered to stabilize body weight in patients with impaired oral intake; PEG placement probably prolongs survival to some degree; PEG placement when forced vital capacity (FVC) is still over 50% predicted minimizes risk of insertion
  • Noninvasive ventilation (NIV) should be offered to treat respiratory insufficiency to prolong survival and slow the decline of FVC; NIV may be considered at the earliest sign of nocturnal hypoventilation or respiratory insufficiency
  • Mechanical insufflation/exsufflation may be considered to clear secretions in patients with reduced peak cough flow, particularly during an acute lower respiratory infection
  • Creatine and high-dose vitamin E should not be used

Invasive ventilatory support, requiring tracheostomy, may be considered in the following cases:

  • Patients who present with respiratory failure and who are otherwise largely neurologically intact
  • Patients who want to be kept alive using long-term invasive ventilatory support as their disease progresses
  • Patients in whom secretions cannot be managed and who therefore cannot benefit from noninvasive ventilatory support (this occurs very rarely)
  • Muscle relaxants to relieve spasticity
  • The combination of dextromethorphan and quinidine (Nuedexta) to decrease emotional lability (pseudobulbar affect)
  • Anticholinergics and sympathomimetics for sialorrhea
  • Mucolytics for thickened secretions
  • Lorazepam for anxiety
  • Selective serotonin reuptake inhibitors (SSRIs) for depression
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or transdermal fentanyl for pain

See Treatment and Medication for more detail.

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Background

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. The disorder is named for its underlying pathophysiology, with “amyotrophy” referring to the atrophy of muscle fibers, which are denervated as their corresponding anterior horn cells degenerate. “Lateral sclerosis” refers to the changes seen in the lateral columns of the spinal cord as upper motor neuron (UMN) axons in these areas degenerate and are replaced by fibrous astrocytes (gliosis).

ALS is a fatal disease, with a median survival period of 3 years from onset of weakness.[4] (See Prognosis.) Aspiration pneumonia and medical complications of immobility contribute to morbidity in patients with the disease.

ALS was first described in 1869 by the French neurologist Jean-Martin Charcot and hence is also known as Charcot disease; however, it gained popular recognition and its best-known eponym in the United States after the baseball player Lou Gehrig announced his diagnosis with the disease in 1939.[5, 6, 7, 8, 9] ALS is also known as motor neuron disease (MND).

The cause of ALS is unknown, although a family history of the disease is obtained in about 5% of patients, and twin studies show a genetic contribution with heritability of about 61%.[10] In some cases, ALS overlaps clinically, pathologically, and biologically with frontotemporal dementia, and it may share common biologic mechanisms with Alzheimer disease, Parkinson disease, and other neurodegenerative diseases.[11, 12, 13, 14] (See Etiology.)

Degenerative effects of ALS

ALS is one of the system degeneration diseases, disorders that cause networks that work together in health to disintegrate together in an organized manner.[15, 16] ALS results from the systematic dismantling of the motor neuron system, with the clinical manifestations in each patient deriving from the site of onset and cell type involved; the relative affinity of the dismantling process for prefrontal, upper and lower motor neurons; and the rate of the disease’s spread within the network.[17]

In its classic form, ALS affects motor neurons at 2 or more levels of the motor neuron network supplying multiple regions of the body. It affects lower motor neurons (LMNs) that reside in the anterior horn of the spinal cord and in the brain stem, corticospinal UMNs that reside in the precentral gyrus, and, frequently, prefrontal motor neurons that are involved in planning or orchestrating the work of the upper and lower motor neurons.[18] (See Pathophysiology.)

Loss of LMNs leads to progressive muscle weakness, wasting (atrophy), and fasciculations, with loss of reflexes and muscle tone. Loss of corticospinal UMNs usually leads to milder weakness associated with stiffness (spasticity), which may be severe, and abnormally brisk reflexes.

Loss of prefrontal neurons may result in special forms of cognitive impairment that include, most commonly, executive dysfunction but that may also include an altered awareness of social implications of one’s circumstances and, consequently, maladaptive social behaviors.[19] In its fully expressed forms, the prefrontal dysfunction meets established criteria for frontotemporal dementia.[20, 21] Loss of ability to integrate motor function (apraxia), a premotor function, is seen at times. It is more noticeable in limbs that are not overly weak.

Types of motor neuron disease

Classic ALS

The term classic ALS is reserved for the form of disease that involves upper and lower motor neurons. The classic form of sporadic ALS usually starts as dysfunction or weakness in one part of the body and spreads gradually within that part and then to the rest of the body.[22] Ventilatory failure results in death 3 years, on average, after the onset of focal weakness. The rate of disease progression varies widely, however, with some patients dying a few months after experiencing their first symptom and others still walking 10 years afterward.

Progressive muscular atrophy and flail limb syndrome

The disease may be restricted to LMNs. When the pattern of LMN involvement is asymmetrical, the disorder is termed progressive muscular atrophy (PMA), and the course is usually indistinguishable from that of classic ALS. Patients with a symmetrical pattern, called flail limb syndrome, have a course that may be far longer.[23]

Primary lateral sclerosis

When only UMNs are involved, the disease is called primary lateral sclerosis (PLS). The course of PLS differs from that of ALS and is usually measured in decades.[24]

Progressive bulbar palsy

Rarely, the disease is restricted to bulbar muscles, in which case it is called progressive bulbar palsy (PBP). In most patients who present with initial involvement of bulbar muscles, the disease evolves to classic ALS.

Familial ALS

Worldwide, a family history of ALS is obtained in about 5% of cases; these patients have familial ALS. Most familial ALS is inherited in an autosomal dominant pattern,[18] often with reduced penetrance, but other patterns, such as X-linked or autosomal recessive inheritance, are seen (see Etiology.)

The fact that in most patients ALS is sporadic does not preclude a genetic contribution to the disease in these cases. ALS as a whole is best thought of as a disease showing complex inheritance.

Complications

Complications of ALS can include the following:

  • Progressive inability to perform activities of daily living (ADLs), including handling utensils for self feeding
  • Deterioration of ambulation
  • Aspiration pneumonia
  • Respiratory insufficiency
  • Complications from being wheelchair-bound or bedridden, including decubitus ulcers and skin infections (while rare in patients with ALS, these complications can emerge if appropriate padding is not used)
  • Deep vein thromboses and pulmonary emboli (these are rare in patients with ALS, but have been encountered with greater frequency in the active treatment arm of some clinical trials)

Diagnosis and treatment

The diagnosis of ALS is primarily clinical. Electrodiagnostic testing contributes to the diagnostic accuracy (see Clinical Presentation and Workup). Making a diagnosis is important to patients and families, allowing them to stop the search for alternative causes of a patient's disability and to focus their attention on treatment.

Although ALS is incurable, there are treatments that can extend the length and meaningful quality of life for patients (see Treatment).

Mechanism-specific treatments directed at the processes that cause the disease to evolve after it has expressed itself sufficiently to be diagnosed may, at best, have an ameliorative effect. Treatments that halt the spread of the disease may be more effective than those that try to salvage affected motor neurons. All of these have yet to be realized. Currently, the mainstay of ALS therapy is adaptive treatments directed at the clinical manifestations of the disease.

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Pathophysiology

ALS should not be considered a single disease entity, but rather a clinical diagnosis for different pathophysiologic cascades that share the common consequence of causing preferential progressive loss of motor neurons and the orderly dismantling of the motor neuron system.

ALS mechanisms

Previously, research into the mechanisms resulting in sporadic and familial types of ALS had examined several possibilities. For example, excitotoxicity was suggested to occur secondary to overactivation of glutamate receptors.

Oxidative stress linked to free radical formation was also explored as a cause of ALS, owing to the discovery of mutations in the free radical–scavenging enzyme superoxide dismutase 1 (SOD1).[25] Mitochondrial damage was implicated as a possible mechanism as well, as was autoimmunity to calcium ion channels.

The observation of cytoskeletal proteins in cellular inclusions led to consideration of neurofilament defects as another possible cause of ALS. Inclusions in general implicated defects in the proteasome system were considered as a possible unifying mechanism.

More recent research has focused on RNA processing, because several genetic risk factors for ALS are involved in this metabolic pathway, and aggregation of proteins involved in RNA metabolism has been seen in most forms of ALS. Apoptosis has emerged as a possible method of neuronal death, although this is not certain.

Despite such research, no direct mechanism for ALS has been identified. Most investigators and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of the disease.[26, 27]

If ALS is considered under the umbrella of neuronal system degenerative diseases, then the specificity for the motor system attacked by the disorder can be attributed to a pathologic process that arises within and spreads through the motor neuron system. Similarly, the focal onset (with subsequent spread) can be compared with the pathogenesis of prion disease (focal onset of a misfolded protein and its spread) or malignancy (a single DNA change or summative mutations, with a final one that confers the pathologic activity and its subsequent spread).

Prionlike propagation of misfolding of proteins—in particular, SOD1 and the 43 kDa transactive response DNA binding protein (TDP-43)—has been proposed as a mechanism for the regional spread of ALS symptoms.[25] The accumulation of misfolded proteins has parallels in other neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington disease.

Axonal degeneration

Motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones. This process occurs as a result of the death of the anterior horn cell body, leading to degeneration of the associated motor axon.

As the axon breaks down, surrounding Schwann cells catabolize the axon's myelin sheath and engulf the axon, breaking it into fragments. This forms small ovoid compartments containing axonal debris and surrounding myelin, termed myelin ovoids. Ovoids then are phagocytized by macrophages recruited into the area to clean up debris.

This type of axonal degeneration can be seen in the brain on biopsy as atrophy and pallor of myelinated motor axons in the corticospinal tracts. In cases in which the disease has been active for a long time, atrophy of the primary motor and premotor cortex may be seen as well. On biopsy of the spinal cord, degeneration of the myelinated motor axons with associated atrophy of the anterior motor roots of the spinal cord can be observed.

Wallerian degeneration also occurs peripherally, and collateral branches of surviving axons in the surrounding area can be seen attempting to reinnervate denervated muscle fibers. On muscle biopsy, various stages of atrophy are noted from this pattern of denervation and subsequent reinnervation of muscle fibers.

In typical ALS, certain motor neurons are spared until very late in the disease process. In the brain stem, these include the oculomotor, trochlear, and abducens nerves. In the spinal cord, the posterior columns, spinocerebellar tracts, nucleus of Onuf (which controls bowel and bladder function), and the Clarke column generally are spared, though the Clarke column can be affected in the familial form of the disease.

Pathways to cell death

Pathways that lead to cell death in ALS may be mediated by the following[28] :

  • Oxidative damage
  • Mitochondrial dysfunction
  • Caspase-mediated cell death (apoptosis)
  • Defects in axonal transport
  • Abnormal growth factor expression
  • Glial cell pathology
  • Glutamate excitotoxicity
  • Aggregation of abnormal proteins

Mutations in the copper/zinc superoxide dismutase 1 (SOD1) gene, which encodes an important antioxidant protein, have been seen in up to 20% of familial ALS patients.[29] Studies in transgenic mice carrying the human SOD1 mutation have provided important information on the pathophysiology of ALS.[28] Also, high levels of oxidative damage to proteins have been found in serum, urine, and cerebrospinal fluid samples from patients, as well as in postmortem samples of patients with both sporadic ALS and SOD1 -familial ALS.[30, 31, 32]

Inferences from animal models, including transgenic models of familial disease, to sporadic human disease are tenuous. However, recognition of the role of glutamate excitotoxicity in sporadic disease and in animal models paved the way to the testing and approval of riluzole, the only treatment that has been shown to ameliorate the course of sporadic ALS, extending patients’ lives by 2-3 months.[33, 34]

Derangements of RNA metabolism

The findings below have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS.

TARDBP gene

In 2006, ubiquitinated inclusions containing pathologic forms of TAR DNA-binding protein-43 (TDP-43) were identified in the cytoplasm of motor neurons of patients with sporadic ALS and in a subset of patients with frontotemporal dementia.[35, 36] TDP-43 is an RNA-processing protein that is normally localized predominantly in the nucleus.

Shortly after their identification in sporadic ALS, TDP-43–positive cytoplasmic inclusions were identified in patients with non-SOD1 familial ALS[37, 38] , and mutations in the gene on chromosome 1 coding for TDP-43 were identified in patients with sporadic and familial ALS.[39, 40, 41, 42, 43, 44]

Mutations in the TARDBP gene, which codes for TDP-43, account for 5% of patients with familial ALS. In addition, TDP-43 inclusions have been found in more than 90% of patients with sporadic ALS, in patients with Guamanian parkinsonism-dementia complex,[45] in the majority of patients with frontotemporal dementia, and in patients with familial British dementia.[46] A review of the continuum of multisystem TDP-43 proteinopathies concluded that the phenotypic expression is linked to the specific cells that are affected by the proteinopathy.[47]

FUS/TLS gene

In 2009, two groups[48, 49] reported that ALS-6, an autosomal dominant form of ALS, results from mutations in the gene for another RNA-processing protein, fused in sarcoma/translated in liposarcoma, or FUS/TLS. (The gene, FUS/TLS, is located on chromosome 16.) Patients these mutations have cytoplasmic inclusions containing FUS/TLS but not TDP-43. Usually, FUS/TLS, like TDP-43, is concentrated in the nucleus. Mutations in FUS/TLS account for 4% of patients with familial ALS.

Additional evidence

Further support for this idea has come from the following[50, 51] :

  • Association and functional studies of another RNA-processing protein, ELP3, in which variants apparently influencing expression alter the risk of ALS
  • The observation that other ALS genes, such as ANG, have a second role in RNA metabolism
  • The examination of genes implicated in related motor neuron diseases, such as SMN, GARS, and others that cause spinal muscular atrophy, which are also involved in this pathway

In 2011, researchers reported that a large hexanucleotide repeat expansion in the noncoding region adjacent to the C9orf72 gene, which is located on the short arm of chromosome 9, accounts for nearly 50% of familial ALS and frontotemporal dementia (FTD) in the Finnish population and more than a third of familial ALS in other groups of European ancestry.[13, 14]  It is the most common mutation seen in patients with sporadic ALS. One effect of this mutation is the formation of nuclear RNA foci containing antisense RNA repeats. In addition, a novel mechanism of poly-dipeptide production, repeat-associated non-ATG translation (RAN)[188] has been shown to occur in carriers of the hexanucleotide expansion.[189] The abnormal polypeptides form cytoplasmic deposits. It is unclear how these deposits cause disease. In particular, since median age of onset of C9orf72-associated ALS is the same as that of sporadic ALS, and the deposits precede clinical disease by years, it is unclear how the nuclear or cytoplasmic deposits cause ALS or FTD.

Disease onset (pathogenesis)

Making the distinction between the pathogenesis and pathophysiology of ALS matters because the mechanisms underlying each of these stages are probably different. This means that interfering with these mechanisms likely requires different approaches. The interventions to prevent disease onset are probably not the same as those required to slow or halt its progression after onset. Prevention of ALS requires modifying or removing factors that are part of disease pathogenesis. A precondition is identifying probable risk factors for ALS.[52]

In contrast to the advances in understanding the pathophysiology of ALS, however, the mechanisms that lead to disease onset (ie, pathogenesis) remain unknown. It is reasonable to assume that the abnormal gene or gene product plays a role in triggering disease onset in familial ALS and may have a role in disease propagation, but having an abnormal gene is neither necessary nor sufficient for developing ALS. Rarely, obligate familial gene carriers do not develop the disease. There is incomplete penetrance, or age-dependent penetrance, of the autosomal dominant genes.

Additional factors must be postulated to intervene between birth and disease onset even in patients who develop familial ALS, because the disease does not appear to start at birth, and within a given family there is great variability in the age of onset. Having normal copies of these genes does not prevent development of sporadic ALS.

Course of the disease

Loss of motor neurons bridges disease pathophysiology and its clinical expression. When advanced, this loss results in the characteristic picture seen in cross-sections of the spinal cord in ALS. At the level of the muscle, loss of discrete LMNs causes loss of innervation of individual motor units.

Early in the disease, surviving nerve fibers establish connections and reinnervate motor units that have lost their connection to axons that have died; as a result, larger motor units are formed. These large motor units manifest in histologic stains as fiber-type grouping. (See the image below.) They also have special characteristics on electromyographic testing. Later in the disease, when the motor neurons that supply the large motor units die, group atrophy ensues.

Muscle in nerve disease. Image courtesy of Dr. Fri Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.

As long as reinnervation can keep up with denervation, clinical weakness may not be detectable, although loss of dexterity may occur. However, as the motor units grow larger and their numbers decrease, the earliest consequence is that affected muscle may fatigue faster than muscle with normal motor units; consequently, one of the first symptoms of ALS may be fatigability of function in the region of onset (for example, “his speech would become muffled toward the end of his sermons”).

As the number of motor units innervating a muscle decreases further, reinnervation can no longer keep up with denervation, permanent weakness develops and progresses, and the affected muscles gradually atrophy. In general, loss of cortical neurons may also result in weakness, but spasticity manifesting as stiffness is a more prominent and disabling UMN symptom.

Risk factors and triggering of onset

Acquired nucleic acid changes may trigger disease onset in sporadic ALS.[53] The past 10 years have seen an increase in evidence supporting this hypothesis. This hypothesis relies on the observation that smoking is the only established risk factor for sporadic ALS[54, 55] and provides a mechanism by which smoking might cause the disease—namely, by induction of changes in nucleic acids. It is supported by clinical observation that age-specific incidence of ALS increases with age. It follows a similar logic that suggests that the alkylating components in the cycad are responsible for delayed onset of Western Pacific ALS/PDC.[56, 57]

Simultaneous initial involvement of cortical and spinal motor neurons responsible for the same body part in ALS and the independent spread of disease at spinal and cortical levels has been shown.[58] These observations have been replicated,[59] although other patterns of spread are sometimes seen. They establish an irrefutable role for corticospinal neurons in the early spread of ALS and provide an observational foundation for postulating the existence of a focus of onset and one or more "agents of spread."[60]

Further support for this hypothesis comes from a statistical examination of acquired somatic mutation rates in humans. Somatic mutations inevitably occur during the many cell divisions required for the single-cell zygote to develop into a full organism; those mutations result in genetic mosaicism, and a small focus of genetically altered cells could be a trigger for ALS.[61]

The increase, with age, of age-specific incidence of sporadic ALS suggests that as time passes there is greater chance for changes to accumulate in nucleic acids that will lead ultimately to the development of ALS. This observation has been recently subjected to confirmatory quantitative analysis.[190] This analysis showed that ALS incidence increases with age in a logarithmic fashion, and the slope of log incidence vs. log age is 5. This suggests a multi-step process, analogous to carcinogenesis,{ref 61} with 6 steps needed for ALS to be triggered.

An alternative trigger for disease onset might be appearance of a misfolded intracellular protein that induces other proteins to misfold, with cell-to-cell transmission of the misfolded protein within the motor network. The difference from classic prion disease is lack of transmissibility by inoculation to other organisms, and the confinement to a neuronal system, or network, with a common function. Hereditary or acquired nucleic acid changes may increase the likelihood that a gene product would be susceptible to misfolding, thus triggering disease onset.

The recent identification of the non-coding C9ORF72 hexanucleotide expansion in many familial and some sporadic ALS cases opens up a possibility that failure of regulation of a normal gene product may underlie ALS initiation and spread.[62, 63, 64, 65, 66, 67] In a broader sense, generation of a faulty regulatory gene product responsible for motor network maintenance, or failure to regulate such a product, may account for the specific disintegration of the motor network. MicroRNAs are particularly attractive candidates for this role.

The affirmation of spread substantiates the concept of a biologic focal onset for ALS. This in turn lends credibility to the concept of a focal trigger for ALS onset that generates the production of 1 or more agents of spread.[53]

Under this hypothesis, disease phenotype in each patient depends on the site of onset and the relative affinity of the specific agent of spread in that patient to motor neurons at the different hierarchical levels of the motor system (prefrontal, corticospinal, spinal/bulbar).[60] The concept of preferential affinity of the agent of spread may apply even to specific motor neurons within a given hierarchy, resulting, for example, in the special phenotypes in which LMNs are predominantly affected (flail arm syndrome, flail leg syndrome).[68]

Most of the biochemical changes found in the upper and lower motor neurons of diseased patients are probably downstream from those that initiate the disease and cause its spread. Some of these changes may represent the processes by which the motor neurons die, but others may reflect the efforts of the motor neurons to survive by compensating for, or “fighting,” the primary pathologic processes driving progression of ALS.

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Etiology

Most ALS cases are sporadic, and the specific cause of sporadic ALS is unknown. Many abnormal genes have been identified in familial cases and are considered causal, although the precise mechanism by which they cause ALS is unknown for most.

All of the mutated genes found to give rise to familial ALS have also been found in patients with sporadic ALS. This is to be expected, as the distinction between familial and apparently sporadic disease is based on obtaining a family history, which in turn depends on gene penetrance, family size, age of family members, and the level of knowledge of the person being interviewed.[69]

In addition, first-degree relatives of patients with apparently sporadic disease have an increased risk of ALS. The overall lifetime risk of ALS in these relatives is low, however (approximately 1 in 50).[70]

Familial cases

A family history of ALS is obtained in about 5% of cases and is often consistent with a Mendelian autosomal dominant pattern of inheritance. While most cases of familial ALS are indistinguishable from sporadic disease, others have unique phenotypes.[71]

Juvenile forms of ALS are more commonly familial. Mean age of onset is 10-20 years younger in patients with familial ALS than in patients with apparently sporadic disease, and variability in age of onset between families is greater than variability within families.[18] Age of onset may also be modified by genetic factors independent of the cause of ALS.[72, 73]

Many specific heritable gene mutations have been described in familial ALS (see Table 1, below).[8] A curated, up-to-date list that includes unpublished mutations, genotype-phenotype correlations, and tools for analysis is maintained on the ALSoD website.

Table 1. Familial Forms of ALS[74, 75, 76] (Open Table in a new window)

Gene Locus Protein Inheritance
SOD1



(ALS1)



21q22.11 Superoxide dismutase 1 (SOD1) AD*
ALS2 2q33 Alsin (ALS2) Juvenile/AR**
ALS3 18q21 Unknown AD
ALS4 9q34 SETX Juvenile/AD
ALSS 15q15 SPG11 Juvenile/AR
FUS (ALS6) 16p11.2 FUS AD
ALS7 20ptel-p13 Unknown AD
ALS8 20q13.3 VABP AD
ALS9 14q11.2 Angiogenin (ANG) AD
TARDBP (ALS10) 1p36.2 TAR DNA-binding protein (TARDBP) AD
ALS11 6q21 FIG4 AD
ALS12 10p13 OPTN AD; AR
ALS13 12q24 ATXN2 AD
ALSX Xp11 UBQLN2 X-linked
C9orf72 (ALS-FTD) 9q21-22 C9ORF72 AD
ALS-FTD 9p13.3 SIGMAR1 AD; Juvenile/AR
PFL1 17p13.2 Profilin 1 AD
*AD–autosomal dominant; **AR—autosomal recessive

About 10-20% of familial ALS cases result from a mutation in the copper/zinc superoxide dismutase 1 (SOD1) gene, also known as ALS1. In general, SOD1 ALS is a LMN form of the disease.[77] The other genes most commonly involved in familial ALS are C9orf72, FUS (ALS6) and TARDBP (ALS10).

SOD1 mutations

More than 140 allelic variations have been seen in SOD1. Some of these variations are characterized by a relatively predictable age of onset or rate of disease progression.

The traditionally used numbering of the amino acids in SOD1, which omits the start codon, is no longer in line with standard practice but will be used here. To translate to the modern numbering, an additional codon should be counted. For example, the D90A mutation frequent in Scandinavia should be p.D91A.

The most common SOD1 mutation in the United States is the A4V mutation, accounting for 50% of SOD1 ALS cases. It causes a rapidly progressive lower motor disease with a mean survival period of 1 year. The North American SOD1 A4V mutation descended from 2 founders (Amerindian and European) 400-500 years ago.[78]

Not all individuals with an SOD1 mutation develop ALS. SOD1 ALS has been shown to be a gain-of-function disease; knockout mice depleted of SOD1 do not develop ALS, and transgenic mice with 1 mutated and 2 normal genes have worse disease than those with 1 normal and 1 mutated gene. Misfolding and precipitation of the abnormal (and normal) SOD1 proteins are thought to be part of the pathophysiology of SOD1 ALS, but why the disease begins when it does and how it causes the LMN ALS phenotype is not clear.

Work in animal models suggests that silencing from birth of the expression of mutant SOD1 by silencing RNA molecules (siRNA) may prevent disease onset in transgenic mouse models.[79] This is an exciting direction for research in humans with SOD1 mutation, but major barriers need to be overcome first, including demonstration that this approach is effective in halting the disease after its clinical onset.[71, 74, 75, 80]

TARDBP and FUS mutations

Gene mutations resulting in abnormalities in proteins that regulate RNA processing have been discovered in patients with autosomal dominant familial ALS. Mutations in the TARDBP gene, which codes for TDP-43, have been found in 5% of patients with familial ALS.[37, 38, 39, 40, 41, 42, 43, 44] Mutations in the FUS gene are found in 3-4% of familial ALS cases.[71]

The mechanism by which these mutations cause ALS is distinct from that which takes place in SOD1 mutations. Although ubiquinated pathologic TDP-43 aggregates have been found in motor neuron cytoplasm of patients with sporadic ALS, they are not specific for this disease and have been found in affected nonmotor cells in patients with Guamanian parkinsonism-dementia complex,[45] British familial dementia,[46] and Alzheimer disease,[81] as well as in most patients with frontotemporal dementia.

Thus, formation of pathologic TDP-43 and its ubiquination may prove to be a mechanism of cell death that is not specific to ALS and is triggered by upstream processes, causing clinical pathology that depends on the cells affected. Conversely, TDP-43 deposition may prove to be a nonspecific defense mechanism involving an unsuccessful attempt to mitigate the action of the true instigators of cell death in a spectrum of neurodegenerative diseases, or it may be an epiphenomenon common to many forms of neurodegenerative diseases. Transgenic animal models with mutated TDP-43 do not develop ALS.

C9orf72 mutation

Studies of families with familial ALS in which some individuals also had frontotemporal dementia found linkage to a region on chromosome 9p21[82, 83, 84] Subsequently, a large genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) associated with apparently sporadic ALS in the same region. This was confirmed in a further GWAS-wide association study of patients with apparently sporadic ALS and controls from 8 countries,[85] as well as in a Finnish study[86] using family-based samples.

In 2011, two groups reported the discovery of a hexanucleotide (GGGGCC) repeat expansion in the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene­—the function of which is as yet unknown—as the cause of chromosome 9p21–associated ALS and frontotemporal dementia.[62, 63] This expansion of hexanucleotide repeats (from ≤23 in normal individuals to thousands in affected individuals) appears to be the most common genetic abnormality in ALS and in frontotemporal dementia.

The repeat expansion was found in 46.0% of patients with familial ALS, 21.1% with sporadic ALS, and 29.3% with familial frontotemporal dementia, in the Finnish population.[63] In their analysis of an extended North American clinical series, DeJesus-Hernandez et al found the C9orf72 expansion in 23.5% of patients with ALS cases and 11.7% of patients with familial frontotemporal dementia.[62]

More recent reports have found the C9ORF72 repeat expansion in 22-57% of familial ALS patients (depending in part on geographic origin) and in 3.6-7% of sporadic ALS patients.[64, 65, 66, 67] The frequency of the mutation varies widely even within Europe.[87]

Haplotype analysis of 5 European cohorts has shown that the hexanucleotide repeat expansion in C9orf72 had a single founder and arose around 6300 years ago.[87] The haplotype from which the mutation arose is intrinsically unstable, with an increased number of repeats.[87]

The phenotype of C9orf72 -mediated ALS shows distinct pathology, with p62-positive, TDP43-negative inclusions in the cerebellum and hippocampus.[88] Clinically, patients with this mutation have an earlier onset of disease and are more likely to have bulbar-onset disease, cognitive and behavioral impairment, and a family history of frontotemporal dementia than are ALS patients who carry other known mutations.

Other genes in familial ALS

Mutation in the ubiquilin 2 (UBQLN2) gene has been identified as a cause of X-linked dominant familial ALS and ALS with frontotemporal dementia.[89] This finding is of interest because it directly implicates the proteasome pathway in ALS pathogenesis.

Mutation in the profilin 1 (PFN1) gene has been identified in families with familial ALS.[76] The protein encoded by PFN1 plays a critical role in the conversion of monomeric (G)-actin to filamentous (F)-actin. Thus, the identification of this mutation provides further support for the role of the cytoskeleton and axonal transport in ALS pathogenesis.

Sporadic cases

The most widely accepted hypothesis regarding the cause of sporadic ALS posits that interactions between genetic, environmental, and age-dependent risk factors trigger disease onset. (See the image below.) ALS shows complex inheritance, which means that Mendelian, non-Mendelian, and apparently sporadic patterns of inheritance are seen. Smoking is the only environmental risk factor identified to date that may be considered “established.”[54, 55]

The genetic/environmental/age- and time-dependent The genetic/environmental/age- and time-dependent interactions hypothesis for amyotrophic lateral sclerosis (ALS). Risk factors operate upstream to a putative biochemical transformation (likely an acquired nucleic acid or protein change), which causes the appearance of altered proteins or nucleic acids or abnormal quantities of normal proteins or nucleid acids. These agents spread within the motor system and cause the downstream disintegration of the motor system and the downstream biochemical, histologic, and clinical consequences of ALS. (Adapted from Armon C. What is ALS? In: Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. Bedlack RS, Mitsumoto H, Eds. Demos Medical Publishing, New York, 2012:1-23)

Several lines of evidence support the hypothesis that genetic risk factors may influence disease initiation in apparently sporadic ALS, apart from finding known Mendelian gene mutations in patients with no family history. Twin studies show a genetic contribution to apparently sporadic ALS, with heritability of 0.61.[10] Increased risk for ALS and (in some studies) clustering of non-ALS neurodegenerative disease is found in relatives of patients with apparently sporadic ALS.[70, 90, 91, 92]

Environmental risk factors

Smoking

Cigarette smoking is the only exogenous risk factor that may be considered an established risk factor for ALS[54] (level A conclusion, based on 3 class II studies[93, 94, 95] and 1 class III study[96] ). In addition, a population-based study from the Netherlands demonstrated that current smokers are at increased risk for ALS, with an odds ratio of 1.38, and have shorter survival.[55]

Some aspects of the findings in these studies suggest that smoking may be implicated directly in causing the disease. Overall, studies have shown that active smokers have approximately double the risk of developing ALS compared with never smokers. Former smokers have an intermediate risk.

Identifying smoking as an established risk factor for ALS has the following major implications:

  • The findings provide a link between the environment and the occurrence of sporadic ALS; no link had previously been identified with this level of certainty
  • Since smoking has no redeeming features, avoidance of smoking may reduce the future occurrence of ALS
  • Future studies of risk factors in ALS need to be designed to precisely quantify active and passive smoking, to ensure that other putative risk factors confer a risk that is independent of their association with smoking
  • Since some of the mechanisms by which smoking causes other diseases in humans are understood fairly well, recognition of smoking’s role in the occurrence of ALS may help to pinpoint the biologic processes that initiate the disease

Focusing on processes at the initiation of sporadic ALS and close to its initiation, in order to account for its early spread within the motor system, may provide new avenues to treatments to stop its progression. This approach may augment the current focus on processes that occur relatively late in the course of the disease and cause the death of motor neurons directly.

No other risk factor has attained the level of certainty that smoking has with regard to its association with ALS. Trauma, physical activity, residence in rural areas, and alcohol consumption are probably not risk factors for ALS.[52] Indeed, in the population-based study from the Netherlands noted above, current alcohol consumption was associated with a reduced risk of ALS.[55]

Military service

Putative risk factors include service in the US military during World War II, the Korean War, and Vietnam,[97] as well as deployment to the Persian Gulf in the 1991 Persian Gulf War.[98] However, close scrutiny has cast doubt on the quality of the evidence supporting the role of these factors in triggering ALS.[98, 99, 100, 101, 102] More recently, a 13-year follow-up study found no excess of ALS among Gulf War veterans.[103]

Other putative exogenous risk factors have not risen to the level of probable. These include exposure to pesticides,[104] postmenopausal hormone use,[52, 105] and physical exercise.[106]

Sports

A possible increased risk of ALS in Italian professional soccer players was reported in 2005.[107, 108] Initially, it appeared that the apparent increase in risk may have resulted from underestimation of the expected number of cases of ALS.[109, 110, 111, 112, 113] However, a 5-year extension of the follow-up of this cohort showed an unambiguous excess of cases of ALS; 8 cases (including 3 new ones) were reported, even though the number of expected cases was 1.24.[114]

However, the ALS in the professional soccer players displayed atypical features; ie, 5 of the 8 cases had a bulbar onset, and 5 had been diagnosed between 2000 and 2006 (compared with 3 between 1980 and 1999 and none between 1970 and 1979). The authors concluded that the predilection for soccer players to develop ALS derives from a complex interplay between genetic predisposition for physical endurance and external factors such as drugs or herbicides.[114]

A subsequent report suggested that a form of motor neuron disease might develop in individuals, such as boxers, who have sustained repetitive injuries to the brain and developed chronic traumatic encephalopathy (CTE).[115] However, the claim that this was a novel form of motor neuron disease was challenged; instead, the possibility that these cases represented coincidental co-occurrence of ALS was proposed as more plausible.[116, 117, 118]

More recently, a study in retired US National Football League (NFL) players showed that, while their overall mortality was 50% less than expected, their mortality from neurodegenerative diseases was higher than expected. In particular, mortality from ALS and Alzheimer disease was 4-fold higher than expected.[119] These results are based on 7 individuals who died with Alzheimer disease and 7 individuals who died with ALS, out of a cohort of 3439 individuals.

The interpretation of this number as excessive appears to be a consequence of the method used to calculate the expected rate,[109] which may result in underestimation of that rate. In addition, when an apparent excess of neurodegenerative disease appears in the context of greatly reduced overall morality, the emergence of neurodegenerative deaths due to loss of competing causes of mortality needs to be considered.

These reports raised the question whether trauma to the head may be a risk factor for ALS. An evidence-based review of the literature concluded that for instances of isolated head trauma this was not the case.[120]

A subsequently published national population–based case-control study from Sweden found no association of ALS with severe head injury occurring more than 3 years before ALS diagnosis, nor was ALS associated with subtypes of head injury or repeated injuries occurring more than 3 years before diagnosis.[121] Exclusion of injuries occurring within 3 years of diagnosis is necessary to have some assurance that the injury occurred before biologic onset of the disease, which likely precedes clinical onset by several years.[122]

A population-based study from Rochester, Minnesota, showed no increased risk of neurodegenerative diseases among 438 players who played American football in high school between 1946 and 1956, despite poorer protective equipment and less regard for concussions compared with today, and no rules prohibiting head-first tackling.[123]

The balance of the evidence supports the conclusion that head trauma in general, including repetitive head trauma, is not a risk factor for ALS. The special circumstances of the Italian soccer players are uncertain, as their form of ALS was unusual, with most experiencing bulbar onset.

The special circumstances of the NFL players are also uncertain, as the data are sparse, and it is not clear that the numbers represent a true excess. Risk factors other than the sport itself may be involved, including local environmental risk factors or ingestion of testosterone, anabolic steroids, or other drugs.[114, 124]

One report indicated that head injury does not alter disease progression or neuropathological outcomes in patients with ALS.[191]

Western Pacific ALS

Most of the research on Western Pacific ALS has focused on Guam. Ingestion of food products derived from the false sago palm, Cycas micronesica (recently separated from Cycas circinalis), was proposed by nutritional anthropologist Marjorie Whiting as the process predisposing to the development of this form of ALS.[125] Despite the cycad nut being subjected to an elaborate preparation process to rid it of toxins before being used as a substrate for flour, some toxic factor was presumed to remain.[126]

In addition, the cycad nut is consumed by the flying fox (a type of bat), which used to be part of the Chamorro peoples' diet on Guam. Toxins from the cycad nut may have been concentrated (bioamplified) in the bat and delivered to the human consumer. The consumption of the flying fox was higher in the mid-20th century than it is now.[127] Most flying foxes consumed in Guam currently are imported.

An epidemiologic study in Guam provided evidence consistent with that hypothesis; its conclusions have been challenged,[127] but the challenges themselves have been questioned.[126]

The nature of the putative toxic component of cycad that may be responsible for delayed-onset neurodegenerative disease has also been a matter of intense debate. One hypothesis is that cycad contains excitotoxic amino acids that do not exert an effect until many years after they have been ingested.[128, 129, 130]

An alternative hypothesis is that alkylating components induce changes in nucleic acids[56, 57] that increase the likelihood that subsequent, additional, age-dependent nucleic acid changes trigger disease onset in Guamanian ALS/Parkinson-dementia complex (ALS/PDC).

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Epidemiology

Occurrence in the United States

Approximately 5600 people in the United States are diagnosed with ALS each year. The annual incidence is 2-3 per 100,000 population; this is about equal to that of multiple sclerosis and 5 times higher than that of Huntington disease. It is estimated that as many as 18,000 Americans may have ALS at any given time.

The lifetime risk for developing ALS for individuals aged 18 years has been estimated to be 1 in 350 for men and 1 in 420 for women.[109] These estimates are close to those reported from 4 European registries, using different methods.[131, 132, 133]

International occurrence

Age-adjusted European incidence data are similar to those for members of the US population who are of European descent.[131, 134] Most variability between countries has been attributed to different age composition or differences in case finding. More recent data, however, suggest that ethnic variability in disease incidence exists[135, 136] that may not be explained entirely by differences in case finding, with lower incidence in nonwhites or individuals of mixed ethnicity. Although this possibility is not supported by all studies, it merits further examination.[137]

Finland has one of the highest rates of ALS in the world; the disease occurs in the Finnish population nearly twice as frequently as it does in other populations of European ancestry.[86] A study from Finland found 2 clusters of cases based on geographic location at time of death and a cluster based on time of birth that closely matched one of the time-of-death clusters.[138] It was recognized that these results could be consistent with either a genetic or environmental cause. With the discovery of the hexanucleotide repeat expansion in C9orf72, most cases of ALS in Finland have been confirmed to be due to genetic factors.

Race-related demographics

In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.[135] Uncertainty surrounds this finding, however, as it has been considered to be an artifact of reduced case-finding in nonwhites. More convincing evidence for racial differences has come from an epidemiologic study in Cuba.[136]

Small population clusters have been identified that have higher rates of ALS. The Chamorro people of Guam and Marianas Island, residents of the Kii peninsula of Japan’s Honshu Island, and the Auyu and Jakai people of southwest New Guinea have a higher incidence of ALS than is found in populations elsewhere in the world.[8] The Chamorro population in Guam in the mid-20th century had an annual incidence of ALS (often in association with parkinsonism and dementia) as high as 70 cases per 100,000 (see Pathophysiology).[128] The incidence has since decreased to 7 cases per 100,000.

Sex- and age-related demographics

For most of the lifespan, the incidence of ALS is higher in men than in women, with an overall male-to-female ratio of 1.5-2:1.[18] Later in life, the incidence tends to equalize; this occurs at age 40-50 years in some populations and after the age of 65-70 years in others.[139]

Onset of ALS may occur from the teenage years to the late 80s; the incidence rises with increasing age until approximately age 75-80 years. Mean age of onset of sporadic ALS is 65 years; mean age of onset of familial ALS ranges from 46-55 years.

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Prognosis

ALS is a fatal disease. Median survival is 3 years from clinical onset of weakness. However, longer survival is not rare. About 15% of patients with ALS live 5 years after diagnosis, and about 5% survive for more than 10 years. Long-term survival is associated with a younger age at onset, being male, and limb (rather than bulbar) symptom onset. Rare reports of spontaneous remission exist.[140] In familial ALS that results from an alanine-to-valine mutation in codon 4 of the SOD1 gene (A4V mutation), average survival is 12 months from disease onset.[78]

Regionally limited forms of motor neuron disease (ie, brachial biplegia, lumbosacral biplegia, and progressive bulbar palsy [PBP] that remains restricted[141] ) progress slower than does classic ALS. Progressive muscular atrophy (PMA), distinct from classic ALS because of lack of upper motor neuron (UMN) findings, progresses at the same rate as classic ALS. UMN-predominant ALS progresses at a slower rate. Survival in cases of primary lateral sclerosis (PLS) is measured in decades. These observations suggest that it is the loss of LMNs that determines the prognosis.

Frontotemporal executive dysfunction may precede or follow the onset of ALS, but most patients with ALS do not have overt dementia, and cognitive impairment is usually subtle.[142] Approximately 15% of patients with ALS meet criteria for frontotemporal dementia (FTD). Patients with ALS associated with FTD have shorter survival than do those with ALS alone.[143, 144]

Measures of disease progression

The most effective predictor of survival is the rate of observed disease progression, estimated via the time between symptom onset and diagnosis or evaluated by employing measures such as the ALS Functional Rating Scale (ALSFRS).[145] Estimates derived as a ratio in which the numerator is a measurement of functional loss—as obtained using the ALSFRS-Revised (ALSFRS-R), the forced vital capacity (FVC) as percent of predicted, strength, or motor unit number estimates (MUNEs)—and the denominator is time elapsed from disease onset to the time of measurement, may provide more individualized prognostic information.[146, 147, 148, 149, 150]

Roche et al have proposed a system of stages, the timing of which is standardized as proportions of elapsed time through the course of ALS.[151] The milestones, and their typical time of occurrence, are as follows:

  • Stage 1: Symptom onset (involvement of first region)
  • Stage 2A: Diagnosis (35% of the way through the disease course)
  • Stage 2B: Involvement of second region (38%)
  • Stage 3: Involvement of third region (61%)
  • Stage 4A: Need for gastrostomy (77%)
  • Stage 4B: Need for noninvasive ventilation (80%)

It may be seen that most patients are diagnosed at a point at which ALS has extended to involve at least 2 regions and that the needs for gastrostomy and noninvasive ventilation (NIV) are usually recognized almost at the same time. These percentages are consistent with the figures of 12 months’ mean time from onset to diagnosis and 3 years’ mean duration of disease from onset to death.

Progressive muscular atrophy

Most patients with PMA have a course indistinguishable from that of patients with classic ALS (except for the absence of UMN findings). However, some patients may have a longer course, particularly those with flail arm or flail leg syndrome.[68]

Kim et al concluded that PMA should be considered a form of ALS.[152] Review of the medical records of 91 patients with PMA and 871 with ALS showed that patients with PMA were more likely to be male, to be older, and to live longer than those with ALS, but risk of death increased with age at onset in both patient groups and UMN signs developed in 22% of patients with PMA within 61 months after diagnosis.[152]

In the study, demographic and other clinical variables did not differ at diagnosis between patients who did or did not develop UMN signs. In PMA, as in ALS, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower FVC, and lower ALSFRS-R score.

Discussing prognosis with the patient

Patients the author has surveyed have indicated ambivalence about being offered individualized information early in the course of the disease (when it may matter most).[153] The author does not offer patients individualized prognostic information at the first visit. When patients do request it, he asks them to consider the possible implications of the answers they may receive and to ask him again at a subsequent visit. It is also helpful to discuss the implications of the rate of disease progression, based on the joint observations of the patient and the physician.

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Patient Education

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Contributor Information and Disclosures
Author

Carmel Armon, MD, MSc, MHS Chair, Department of Neurology, Assaf Harofeh Medical Center, Tel Aviv University Sackler Faculty of Medicine, Israel

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, Massachusetts Medical Society, American Academy of Sleep Medicine, American Stroke Association, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, Sigma Xi

Disclosure: Received research grant from: Neuronix Ltd, Yoqnea'm, Israel.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE Founding Editor-in-Chief, eMedicine Neurology; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc

Nicholas Lorenzo, MD, MHA, CPE is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American Academy of Neurology

Disclosure: Nothing to disclose.

Acknowledgements

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec. 1(5):293-9. [Medline].

  2. [Guideline] Miller RG, Jackson CE, Kasarskis EJ et al. Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Drug, nutritional, and respiratory therapies (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009. 73:1218-1226. [Medline]. [Full Text].

  3. [Guideline] Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: The care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13. 73(15):1227-1233. [Medline]. [Full Text].

  4. Hardiman O, van den Berg LH, Kiernan MC. Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Oct 11. 7(11):639-49. [Medline].

  5. King SJ, Duke MM, O'Connor BA. Living with amyotrophic lateral sclerosis/motor neurone disease (ALS/MND): decision-making about 'ongoing change and adaptation'. J Clin Nurs. 2009 Mar. 18(5):745-54. [Medline].

  6. Eisen A. Amyotrophic lateral sclerosis: A 40-year personal perspective. J Clin Neurosci. 2009 Apr. 16(4):505-12. [Medline].

  7. Phukan J, Hardiman O. The management of amyotrophic lateral sclerosis. J Neurol. 2009 Feb. 256(2):176-86. [Medline].

  8. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis. 2009 Feb 3. 4:3. [Medline]. [Full Text].

  9. Brooks BR. Managing amyotrophic lateral sclerosis: slowing disease progression and improving patient quality of life. Ann Neurol. 2009 Jan. 65 Suppl 1:S17-23. [Medline].

  10. Al-Chalabi A, Fang F, Hanby MF, Leigh PN, Shaw CE, Ye W, et al. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010 Dec. 81(12):1324-6. [Medline]. [Full Text].

  11. Hudson AJ. Clinical Neurology. The motor neuron diseases and related disorders. 1996. Vol. 4: 11-14.

  12. Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?. J Neurol Neurosurg Psychiatry. 2012 Jul. 83(7):739-45. [Medline]. [Full Text].

  13. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20. 72(2):257-68. [Medline]. [Full Text].

  14. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20. 72(2):245-56. [Medline]. [Full Text].

  15. Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009 Apr 16. 62(1):42-52. [Medline]. [Full Text].

  16. Armon C. What is ALS?. Bedlack RS, Mitsumoto H, Eds. Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. New York: Demos Medical Publishing; 2012. 1-23.

  17. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009 Sep 8. 73(10):805-11. [Medline]. [Full Text].

  18. Armon C. Epidemiology of ALS/MND. Shaw P and Strong M, eds. Motor Neuron Disorders. Elsevier Sciences: 2003. 167-206.

  19. Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families and friends. Fourth Edition. California: Published by the LLU Department of Neurology, Loma Linda; 2007. [Full Text].

  20. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998 Dec. 51(6):1546-54. [Medline].

  21. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry. 1994 Apr. 57(4):416-8. [Medline].

  22. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009 Sep 8. 73(10):805-11. [Medline]. [Full Text].

  23. Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009 Mar 24. 72(12):1087-94. [Medline]. [Full Text].

  24. Almeida V, de Carvalho M, Scotto M, Pinto S, Pinto A, Ohana B, et al. Primary lateral sclerosis: predicting functional outcome. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Mar. 14(2):141-5. [Medline].

  25. Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. 2010 Mar 1. 48(5):629-41. [Medline].

  26. Strong MJ. Progress in clinical neurosciences: the evidence for ALS as a multisystems disorder of limited phenotypic expression. Can J Neurol Sci. 2001 Nov. 28(4):283-98. [Medline].

  27. Shaw PJ. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry. 2005 Aug. 76(8):1046-57. [Medline]. [Full Text].

  28. Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 2009 Jan. 65 Suppl 1:S3-9. [Medline].

  29. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4. 362(6415):59-62. [Medline].

  30. Shaw PJ, Ince PG, Falkous G, Mantle D. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol. 1995 Oct. 38(4):691-5. [Medline].

  31. Simpson EP, Henry YK, Henkel JS, Smith RG, Appel SH. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology. 2004 May 25. 62(10):1758-65. [Medline].

  32. Mitsumoto H, Santella RM, Liu X, Bogdanov M, Zipprich J, Wu HC, et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler. 2008 Jun. 9(3):177-83. [Medline].

  33. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3. 330(9):585-91. [Medline].

  34. Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996 May 25. 347(9013):1425-31. [Medline].

  35. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6. 314(5796):130-3. [Medline].

  36. Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006 Dec 22. 351(3):602-11. [Medline].

  37. Tan CF, Eguchi H, Tagawa A, et al. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol. 2007 May. 113(5):535-42. [Medline].

  38. Mackenzie IR, Bigio EH, Ince PG, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007 May. 61(5):427-34. [Medline].

  39. Sreedharan J, Blair IP, Tripathi VB, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008 Mar 21. 319(5870):1668-72. [Medline].

  40. Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008 May. 40(5):572-4. [Medline].

  41. Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008 May. 7(5):409-16. [Medline].

  42. Yokoseki A, Shiga A, Tan CF, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008 Apr. 63(4):538-42. [Medline].

  43. Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 2008 Sep 19. 4(9):e1000193. [Medline].

  44. Del Bo R, Ghezzi S, Corti S, et al. TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur J Neurol. 2009 Jun. 16(6):727-32. [Medline].

  45. Hasegawa M, Arai T, Akiyama H, et al. TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain. 2007 May. 130:1386-94. [Medline].

  46. Schwab C, Arai T, Hasegawa M, Akiyama H, Yu S, McGeer PL. TDP-43 pathology in familial British dementia. Acta Neuropathol. 2009 Mar 13. [Medline].

  47. Geser F, Martinez-Lage M, Robinson J, et al. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 2009 Feb. 66(2):180-9. [Medline].

  48. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009 Feb 27. 323(5918):1205-8. [Medline].

  49. Vance C, Rogelj B, Hortobagyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009 Feb 27. 323(5918):1208-11. [Medline].

  50. Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PW, et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum Mol Genet. 2009 Feb 1. 18(3):472-81. [Medline]. [Full Text].

  51. Padhi AK, Kumar H, Vasaikar SV, Jayaram B, Gomes J. Mechanisms of loss of functions of human angiogenin variants implicated in amyotrophic lateral sclerosis. PLoS One. 2012. 7(2):e32479. [Medline]. [Full Text].

  52. Armon C. An evidence-based medicine approach to the evaluation of the role of exogenous risk factors in sporadic amyotrophic lateral sclerosis. Neuroepidemiology. 2003 Jul-Aug. 22(4):217-28. [Medline].

  53. Armon C. Acquired nucleic acid changes may trigger sporadic amyotrophic lateral sclerosis. Muscle Nerve. 2005 Sep. 32(3):373-7. [Medline].

  54. Armon C. Smoking may be considered an established risk factor for sporadic ALS. Neurology. November 17, 2009. 73 (20):1693-1698. [Medline]. [Full Text].

  55. de Jong SW, Huisman MH, Sutedja NA, van der Kooi AJ, de Visser M, Schelhaas HJ, et al. Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: a population-based study. Am J Epidemiol. 2012 Aug 1. 176(3):233-9. [Medline].

  56. Esclaire F, Kisby G, Spencer P, Milne J, Lesort M, Hugon J. The Guam cycad toxin methylazoxymethanol damages neuronal DNA and modulates tau mRNA expression and excitotoxicity. Exp Neurol. 1999 Jan. 155(1):11-21. [Medline].

  57. Kisby GE, Standley M, Park T, et al. Proteomic analysis of the genotoxicant methylazoxymethanol (MAM)-induced changes in the developing cerebellum. J Proteome Res. 2006 Oct. 5(10):2656-65. [Medline].

  58. Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology. 2007 May 8. 68(19):1571-5. [Medline].

  59. Körner S, Kollewe K, Fahlbusch M, et al. Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis. Muscle Nerve. 2011 May. 43(5):636-42. [Medline].

  60. Armon C. From clues to mechanisms: understanding ALS initiation and spread. Neurology. 2008 Sep 16. 71(12):872-3. [Medline].

  61. Frank SA. Evolution in health and medicine Sackler colloquium: Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration. Proc Natl Acad Sci U S A. 2010 Jan 26. 107 Suppl 1:1725-30. [Medline]. [Full Text].

  62. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20. 72(2):245-56. [Medline]. [Full Text].

  63. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20. 72(2):257-68. [Medline]. [Full Text].

  64. Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S, et al. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain. 2012 Mar. 135:751-64. [Medline]. [Full Text].

  65. Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012 Mar. 135:784-93. [Medline]. [Full Text].

  66. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012 Mar. 11(3):232-40. [Medline]. [Full Text].

  67. Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, et al. Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol. 2012 Mar. 123(3):409-17. [Medline]. [Full Text].

  68. Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, et al. Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology. 2009 Mar 24. 72(12):1087-94. [Medline].

  69. Al-Chalabi A, Lewis CM. Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Hum Hered. 2011. 71(4):281-8. [Medline].

  70. Hanby MF, Scott KM, Scotton W, Wijesekera L, Mole T, Ellis CE, et al. The risk to relatives of patients with sporadic amyotrophic lateral sclerosis. Brain. 2011 Dec. 134:3454-7. [Medline]. [Full Text].

  71. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006 Sep. 7(9):710-23. [Medline].

  72. Fogh I, Rijsdijk F, Andersen PM, Sham PC, Knight J, Neale B, et al. Age at onset in sod1-mediated amyotrophic lateral sclerosis shows familiality. Neurogenetics. 2007 Aug. 8(3):235-6. [Medline].

  73. Ahmeti KB, Ajroud-Driss S, Al-Chalabi A, Andersen PM, Armstrong J, et al. The Algen Consortium. Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1. Neurobiol Aging. 2013 Jan. 34(1):357.e7-19. [Medline].

  74. Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know?. Nat Rev Neurol. 2011 Oct 11. 7(11):603-15. [Medline].

  75. Ferraiuolo L, Kirby J, Grierson AJ, Sendtner M, Shaw PJ. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol. 2011 Nov. 7(11):616-30. [Medline].

  76. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Aug 23. 488(7412):499-503. [Medline]. [Full Text].

  77. Andersen PM. Amyotrophic lateral sclerosis genetics with Mendelian inheritance. Brown RH Jr, Swash M and Pasinelli P, eds. Amyotrophic Lateral Sclerosis. 2nd edition. Informa healthcare; 2006. 187-207.

  78. Saeed M, Yang Y, Deng HX, et al. Age and founder effect of SOD1 A4V mutation causing ALS. Neurology. 2009 May 12. 72(19):1634-9. [Medline].

  79. Saito Y, Yokota T, Mitani T, et al. Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model. J Biol Chem. 2005 Dec 30. 280(52):42826-30. [Medline].

  80. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012 Sep. 124(3):339-52. [Medline].

  81. Arai T, Mackenzie IR, Hasegawa M, et al. Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol. 2009 Feb. 117(2):125-36. [Medline].

  82. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology. 2006 Mar 28. 66(6):839-44. [Medline].

  83. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain. 2006 Apr. 129:868-76. [Medline].

  84. van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009 Oct. 41(10):1083-7. [Medline].

  85. Shatunov A, Mok K, Newhouse S, Weale ME, Smith B, Vance C. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 2010 Oct. 9(10):986-94. [Medline].

  86. Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, Myllykangas L. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 2010 Oct. 9(10):978-85. [Medline].

  87. Smith BN, Newhouse S, Shatunov A, Vance C, Topp S, Johnson L, et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet. 2013 Jan. 21(1):102-8. [Medline]. [Full Text].

  88. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 2011 Dec. 122(6):691-702. [Medline].

  89. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011 Aug 21. 477(7363):211-5. [Medline]. [Full Text].

  90. Majoor-Krakauer D, Ottman R, Johnson WG, Rowland LP. Familial aggregation of amyotrophic lateral sclerosis, dementia, and Parkinson's disease: evidence of shared genetic susceptibility. Neurology. 1994 Oct. 44(10):1872-7. [Medline].

  91. Fallis BA, Hardiman O. Aggregation of neurodegenerative disease in ALS kindreds. Amyotroph Lateral Scler. 2009 Apr. 10(2):95-8. [Medline].

  92. Cruz DC, Nelson LM, McGuire V, Longstreth WT Jr. Physical trauma and family history of neurodegenerative diseases in amyotrophic lateral sclerosis: a population-based case-control study. Neuroepidemiology. 1999. 18(2):101-10. [Medline].

  93. Nelson LM, McGuire V, Longstreth WT Jr, Matkin C. Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption. Am J Epidemiol. 2000 Jan 15. 151(2):156-63. [Medline].

  94. Kamel F, Umbach DM, Munsat TL, Shefner JM, Sandler DP. Association of cigarette smoking with amyotrophic lateral sclerosis. Neuroepidemiology. 1999. 18(4):194-202. [Medline].

  95. Gallo V, Bueno-De-Mesquita HB, Vermeulen R, Andersen PM, Kyrozis A, Linseisen J. Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort. Ann Neurol. 2009 Apr. 65(4):378-85. [Medline].

  96. Sutedja NA, Veldink JH, Fischer K, Kromhout H, Wokke JH, Huisman MH. Lifetime occupation, education, smoking, and risk of ALS. Neurology. 2007 Oct 9. 69(15):1508-14. [Medline].

  97. Weisskopf MG, O'Reilly EJ, McCullough ML, et al. Prospective study of military service and mortality from ALS. Neurology. 2005 Jan 11. 64(1):32-7. [Medline].

  98. Horner RD, Kamins KG, Feussner JR, et al. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003 Sep 23. 61(6):742-9. [Medline].

  99. Armon C. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2004 Mar 23. 62(6):1027; author reply 1027-9. [Medline].

  100. Armon C. Excess incidence of ALS in young Gulf War veterans. Neurology. 2004 Nov 23. 63(10):1986-7; author reply 1986-7. [Medline].

  101. Coffman CJ, Horner RD, Grambow SC, Lindquist J. Estimating the occurrence of amyotrophic lateral sclerosis among Gulf War (1990-1991) veterans using capture-recapture methods. Neuroepidemiology. 2005. 24(3):141-50. [Medline].

  102. Horner RD, Grambow SC, Coffman CJ, et al. Amyotrophic lateral sclerosis among 1991 Gulf War veterans: evidence for a time-limited outbreak. Neuroepidemiology. 2008. 31(1):28-32. [Medline].

  103. Barth SK, Kang HK, Bullman TA, Wallin MT. Neurological mortality among U.S. veterans of the Persian Gulf War: 13-year follow-up. Am J Ind Med. 2009 Sep. 52(9):663-70. [Medline].

  104. Sutedja NA, Veldink JH, Fischer K, Kromhout H, Heederik D, Huisman MH, et al. Exposure to chemicals and metals and risk of amyotrophic lateral sclerosis: a systematic review. Amyotroph Lateral Scler. 2009 Oct-Dec. 10(5-6):302-9. [Medline].

  105. Popat RA, Van Den Eeden SK, Tanner CM, et al. Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis. Neuroepidemiology. 2006. 27(3):117-21. [Medline].

  106. Beghi E, Logroscino G, Chiò A, Hardiman O, Millul A, Mitchell D, et al. Amyotrophic lateral sclerosis, physical exercise, trauma and sports: results of a population-based pilot case-control study. Amyotroph Lateral Scler. 2010 May 3. 11(3):289-92. [Medline]. [Full Text].

  107. Chiò A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005 Mar. 128:472-6. [Medline].

  108. Belli S, Vanacore N. Proportionate mortality of Italian soccer players: is amyotrophic lateral sclerosis an occupational disease?. Eur J Epidemiol. 2005. 20(3):237-42. [Medline].

  109. Armon C. Sports and trauma in amyotrophic lateral sclerosis revisited. J Neurol Sci. 2007 Nov 15. 262(1-2):45-53. [Medline].

  110. Chio A, Traynor BJ, Swingler R, eet al. Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings. J Neurol Sci. 2008 Jun 15. 269(1-2):187-8; author reply 188-9. [Medline].

  111. Belli S, Vanacore N. Sports and amyotrophic lateral sclerosis. J Neurol Sci. 2008 Jun 15. 269(1-2):191; author reply 191-2. [Medline].

  112. Armon C. Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings. J Neurol Sci. 2008. 269:188-189 (author reply).

  113. Armon C. Response to Belli and Vanacore. J Neurol Sci. 2008. 269:191192 (author reply).

  114. Chio A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G. ALS in Italian professional soccer players: the risk is still present and could be soccer-specific. Amyotroph Lateral Scler. 2009 Aug. 10(4):205-9. [Medline].

  115. McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010 Sep. 69(9):918-29. [Medline]. [Full Text].

  116. Appel SH, Cwik VA, Day JW. Trauma, TDP-43, and amyotrophic lateral sclerosis. Muscle Nerve. 2010 Dec. 42(6):851-2. [Medline].

  117. Bedlack RS, Genge A, Amato AA, Shaibani A, Jackson CE, Kissel JT, et al. Correspondence regarding: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 2010:69;918-29. J Neuropathol Exp Neurol. 2011 Jan. 70(1):96-7; author reply 98-100. [Medline].

  118. Armon C, Miller RG. Correspondence regarding: TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 2010:69;918-29. J Neuropathol Exp Neurol. 2011 Jan. 70(1):97-8; author reply 98-100. [Medline].

  119. Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012 Nov 6. 79(19):1970-4. [Medline].

  120. Armon C, Nelson LM. Is head trauma a risk factor for amyotrophic lateral sclerosis? An evidence based review. Amyotroph Lateral Scler. 2012 Jun. 13(4):351-6. [Medline].

  121. Peters TL, Fang F, Weibull CE, Sandler DP, Kamel F, Ye W. Severe head injury and amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 May. 14(4):267-72. [Medline].

  122. Kurland LT, Radhakrishnan K, Smith GE, Armon C, Nemetz PN. Mechanical trauma as a risk factor in classic amyotrophic lateral sclerosis: lack of epidemiologic evidence. J Neurol Sci. 1992 Dec. 113(2):133-43. [Medline].

  123. Savica R, Parisi JE, Wold LE, Josephs KA, Ahlskog JE. High school football and risk of neurodegeneration: a community-based study. Mayo Clin Proc. 2012. 87:335-340.

  124. Wicks P, Ganesalingham J, Collin C, Prevett M, Leigh NP, Al-Chalabi A. Three soccer playing friends with simultaneous amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2007 Jun. 8(3):177-9. [Medline].

  125. Whiting MG. Toxicity of Cycads: A Literature Review. Economic Botany. 1963. 68:270-302.

  126. Borenstein AR, Mortimer JA, Schellenberg GD, Galasko D. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2009 Feb 3. 72(5):473, 476; author reply 475-6. [Medline].

  127. Steele JC, McGeer PL. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology. 2008 May 20. 70(21):1984-90. [Medline].

  128. Borenstein AR, Mortimer JA, Schofield E, et al. Cycad exposure and risk of dementia, MCI, and PDC in the Chamorro population of Guam. Neurology. 2007 May 22. 68(21):1764-71. [Medline].

  129. Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A. 2003 Nov 11. 100(23):13380-3. [Medline].

  130. Khabazian I. Isolation of various forms of sterol B-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for the ALS-parkinsonian dementia complex. J Neurochem. 2002. 82:516-528.

  131. Chiò A, Mora G, Calvo A, Mazzini L, Bottacchi E, Mutani R. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. 2009 Feb 24. 72(8):725-31. [Medline].

  132. Alonso A, Logroscino G, Jick SS, Hernán MA. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. 2009 Jun. 16(6):745-51. [Medline].

  133. Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AH, Butt D, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006 Dec. 253(12):1642-3. [Medline].

  134. Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AH, Butt D, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006 Dec. 253(12):1642-3. [Medline].

  135. Cronin S, Hardiman O, Traynor BJ. Ethnic variation in the incidence of ALS: a systematic review. Neurology. 2007 Mar 27. 68(13):1002-7. [Medline].

  136. Zaldivar T, Gutierrez J, Lara G, Carbonara M, Logroscino G, Hardiman O. Reduced frequency of ALS in an ethnically mixed population: a population-based mortality study. Neurology. 2009 May 12. 72(19):1640-5. [Medline].

  137. Rojas-Garcia R, Scott KM, Roche JC, Scotton W, Martin N, Janssen A, et al. No evidence for a large difference in ALS frequency in populations of African and European origin: a population based study in inner city London. Amyotroph Lateral Scler. 2012 Jan. 13(1):66-8. [Medline].

  138. Sabel CE, Boyle PJ, Löytönen M, et al. Spatial clustering of amyotrophic lateral sclerosis in Finland at place of birth and place of death. Am J Epidemiol. 2003 May 15. 157(10):898-905. [Medline].

  139. Manjaly ZR, Scott KM, Abhinav K, Wijesekera L, Ganesalingam J, Goldstein LH, et al. The sex ratio in amyotrophic lateral sclerosis: A population based study. Amyotroph Lateral Scler. 2010 Oct. 11(5):439-42. [Medline].

  140. Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24. 66(2):265-7. [Medline].

  141. Turner MR, Scaber J, Goodfellow JA, Lord ME, Marsden R, Talbot K. The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis. J Neurol Sci. 2010 Jul 15. 294(1-2):81-5. [Medline].

  142. Murphy J, Henry R, Lomen-Hoerth C. Establishing subtypes of the continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol. 2007 Mar. 64(3):330-4. [Medline].

  143. Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012 Jan. 83(1):102-8. [Medline].

  144. Elamin M, Phukan J, Bede P, Jordan N, Byrne S, Pender N, et al. Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology. 2011 Apr 5. 76(14):1263-9. [Medline].

  145. Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, et al. Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler. 2009 Oct-Dec. 10(5-6):310-23. [Medline]. [Full Text].

  146. Kimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006. 66:265-267.

  147. Armon C, Moses D. Linear estimates of rates of disease progression as predictors of survival in patients with ALS entering clinical trials. J Neurol Sci. 1998 Oct. 160 Suppl 1:S37-41. [Medline].

  148. Armon C, Graves MC, Moses D, Forté DK, Sepulveda L, Darby SM, et al. Linear estimates of disease progression predict survival in patients with amyotrophic lateral sclerosis. Muscle Nerve. 2000 Jun. 23(6):874-82. [Medline].

  149. Armon C, Brandstater ME. Motor unit number estimate-based rates of progression of ALS predict patient survival. Muscle Nerve. 1999 Nov. 22(11):1571-5. [Medline].

  150. Czaplinski A, Yen AA, Appel SH. Amyotrophic lateral sclerosis: early predictors of prolonged survival. J Neurol. 2006 Nov. 253(11):1428-36. [Medline].

  151. Roche JC, Rojas-Garcia R, Scott KM, Scotton W, Ellis CE, Burman R, et al. A proposed staging system for amyotrophic lateral sclerosis. Brain. 2012 Mar. 135:847-52. [Medline]. [Full Text].

  152. Kim WK, Liu X, Sandner J, Pasmantier M, Andrews J, Rowland LP, et al. Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology. 2009 Nov 17. 73(20):1686-92. [Medline]. [Full Text].

  153. Armon C, Schultz JD. Preferences of patients with ALS for accurate prognostic information. Presented at the annual meeting of the International Alliance of Motor Neuron Disease Associations. Philadelphia. December 2004. [Full Text].

  154. Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A Manual for Patients, Families and Friends. Loma Linda University Department of Neurology, Loma Linda, California. Fourth Edition. 2007.

  155. Isaacs JD, Dean AF, Shaw CE, Al-Chalabi A, Mills KR, Leigh PN. Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder?. J Neurol Neurosurg Psychiatry. 2007 Jul. 78(7):750-3. [Medline]. [Full Text].

  156. Byrne S, Elamin M, Bede P, Hardiman O. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2012 Apr. 83(4):365-7. [Medline].

  157. Byrne S, Bede P, Elamin M, Kenna K, Lynch C, McLaughlin R, et al. Proposed criteria for familial amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2011 May. 12(3):157-9. [Medline].

  158. de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008 Mar. 119(3):497-503. [Medline].

  159. Bromberg MB, Swoboda KJ, Lawson VH. Counting motor units in chronic motor neuropathies. Exp Neurol. 2003 Nov. 184 Suppl 1:S53-7. [Medline].

  160. Armon C, Brandstater ME. Motor unit number estimate-based rates of progression of ALS predict patient survival. Muscle Nerve. 1999 Nov. 22(11):1571-5. [Medline].

  161. Cedarbaum JM, Stambler N. Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials. J Neurol Sci. 1997 Oct. 152 Suppl 1:S1-9. [Medline].

  162. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31. 169(1-2):13-21. [Medline].

  163. Instructions for completing the ALSFRS-R. (ALS Functional Rating Scale). ALS Connection. [Full Text].

  164. [Guideline] Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology. 1999 Apr 22. 52(7):1311-23. [Medline]. [Full Text].

  165. Bedlack RS, Mitsumoto H, Eds. Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. New York: Demos Medical Publishing; 2012.

  166. Amyotrophic Lateral Sclerosis Association. Available at http://www.alsa.org.

  167. Muscular Dystrophy Association. Available at http://als.mdausa.org/.

  168. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2007 Jan 24. CD001447. [Medline].

  169. Bensimon G, Lacomblez L, Delumeau JC, Bejuit R, Truffinet P, Meininger V. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol. 2002 May. 249(5):609-15. [Medline].

  170. Yanagisawa N, Tashiro K, Tohgi H, et al. Efficacy and safety of riluzole in patients with amyotrophic lateral sclerosis: double-blind placebo-controlled study in Japan. Igakuno Ayumi. 1997. 182:851-866. [Article in Japanese].

  171. Yanagisawa N, Shindo M. [Neuroprotective therapy for amyotrophic lateral sclerosis (ALS)]. Rinsho Shinkeigaku. 1996 Dec. 36(12):1329-30. [Medline].

  172. Armon C, Guiloff RJ, Bedlack R. Limitations of inferences from observational databases in amyotrophic lateral sclerosis: all that glitters is not gold. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Sep. 3(3):109-12. [Medline].

  173. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006. 5:140-147. [Medline].

  174. Jackson CE, Gronseth G, Rosenfeld J, et al. Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients. Muscle Nerve. 2009 Feb. 39(2):137-43. [Medline].

  175. Neppelberg E, Haugen DF, Thorsen L, Tysnes OB. Radiotherapy reduces sialorrhea in amyotrophic lateral sclerosis. Eur J Neurol. 2007 Dec. 14(12):1373-7. [Medline].

  176. Brooks BR, Thisted RA, Appel SH, et al. Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology. 2004 Oct 26. 63(8):1364-70. [Medline].

  177. Pioro EP, Brooks BR, Cummings J, Schiffer R, Thisted RA, Wynn D. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol. 2010 Nov. 68(5):693-702. [Medline].

  178. Baile WF, Buckman R, Lenzi R, Glober G, Beale EA, Kudelka AP. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist. 2000. 5(4):302-11. [Medline].

  179. VA Secretary Establishes ALS as a Presumptive Compensable Illness. September 23, 2008. VA Secretary Establishes ALS as a Presumptive Compensable Illness. September 23, 2008. [Full Text].

  180. Lo Coco D, Marchese S, Pesco MC, La Bella V, Piccoli F, Lo Coco A. Noninvasive positive-pressure ventilation in ALS: predictors of tolerance and survival. Neurology. 2006 Sep 12. 67(5):761-5. [Medline].

  181. Harding A. PET scans distinguish ALS patients from healthy controls. Reuters Health Information. March 11, 2014. [Full Text].

  182. Migliore L, Coppede F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res. 2008 Oct 31. [Medline].

  183. Valdmanis PN, Rouleau GA. Genetics of familial amyotrophic lateral sclerosis. Neurology. 2008 Jan 8. 70(2):144-52. [Medline].

  184. Van Laere K, Vanhee A, Verschueren J, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurol. 2014 Mar 10. [Medline].

  185. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci. 1994 Jul. 124 Suppl:96-107. [Medline].

  186. de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008 Mar. 119 (3):497-503. [Medline].

  187. Chiò A, Battistini S, Calvo A, Caponnetto C, Conforti FL, Corbo M, et al. Genetic counselling in ALS: facts, uncertainties and clinical suggestions. J Neurol Neurosurg Psychiatry. 2014 May. 85 (5):478-85. [Medline].

  188. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A. 2011 Jan 4. 108 (1):260-5. [Medline].

  189. Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013 Dec 17. 110 (51):E4968-77. [Medline].

  190. Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, et al. Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol. 2014 Nov. 13 (11):1108-13. [Medline].

  191. Fournier CN, Gearing M, Upadhyayula SR, Klein M, Glass JD. Head injury does not alter disease progression or neuropathologic outcomes in ALS. Neurology. 2015 Apr 28. 84 (17):1788-95. [Medline].

  192. Woolley SC, Strong MJ. Frontotemporal Dysfunction and Dementia in Amyotrophic Lateral Sclerosis. Neurol Clin. 2015 Nov. 33 (4):787-805. [Medline].

 
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The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).
The genetic/environmental/age- and time-dependent interactions hypothesis for amyotrophic lateral sclerosis (ALS). Risk factors operate upstream to a putative biochemical transformation (likely an acquired nucleic acid or protein change), which causes the appearance of altered proteins or nucleic acids or abnormal quantities of normal proteins or nucleid acids. These agents spread within the motor system and cause the downstream disintegration of the motor system and the downstream biochemical, histologic, and clinical consequences of ALS. (Adapted from Armon C. What is ALS? In: Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. Bedlack RS, Mitsumoto H, Eds. Demos Medical Publishing, New York, 2012:1-23)
Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.
Table 1. Familial Forms of ALS [74, 75, 76]
Gene Locus Protein Inheritance
SOD1



(ALS1)



21q22.11 Superoxide dismutase 1 (SOD1) AD*
ALS2 2q33 Alsin (ALS2) Juvenile/AR**
ALS3 18q21 Unknown AD
ALS4 9q34 SETX Juvenile/AD
ALSS 15q15 SPG11 Juvenile/AR
FUS (ALS6) 16p11.2 FUS AD
ALS7 20ptel-p13 Unknown AD
ALS8 20q13.3 VABP AD
ALS9 14q11.2 Angiogenin (ANG) AD
TARDBP (ALS10) 1p36.2 TAR DNA-binding protein (TARDBP) AD
ALS11 6q21 FIG4 AD
ALS12 10p13 OPTN AD; AR
ALS13 12q24 ATXN2 AD
ALSX Xp11 UBQLN2 X-linked
C9orf72 (ALS-FTD) 9q21-22 C9ORF72 AD
ALS-FTD 9p13.3 SIGMAR1 AD; Juvenile/AR
PFL1 17p13.2 Profilin 1 AD
*AD–autosomal dominant; **AR—autosomal recessive
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