Pathology of Motor Neuron Disorders 

Updated: Apr 28, 2014
  • Author: Hidehiro Takei, MD; Chief Editor: Adekunle M Adesina, MD, PhD  more...
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Definition

Motor neuron disorders (MNDs) are a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons; they include both sporadic and hereditary diseases. Either or both of the following 2 sets of motor neurons can be affected:

  • Upper motor neurons (UMNs), which originate from the primary motor cortex of the cerebrum (precentral gyrus) and possess long axons forming corticospinal and corticobulbar tracts
  • Lower motor neurons (LMNs), which originate in the brainstem (cranial nerve [CN] motor nuclei) and spinal cord (anterior horn cells) and directly innervate skeletal muscles

MNDs can be classified into those affecting primarily the UMNs, those affecting primarily the LMNs, and those affecting both, and the nomenclature is used accordingly. The patient’s symptoms vary, depending on which set of motor neurons is involved.

In this review, the following conditions will be discussed:

Amyotrophic lateral sclerosis

ALS, also known as Lou Gehrig disease, is the most common neurodegenerative disease of adult onset involving the motor neuron system. It is a fatal disorder and is characterized by progressive skeletal muscle weakness and wasting or atrophy (ie, amyotrophy), spasticity, and fasciculations as a result of degeneration of the UMNs and LMNs, culminating in respiratory paralysis. There are 3 types of ALS, as follows:

  • Sporadic ALS
  • Familial ALS
  • Western Pacific ALS with or without Parkinsonism-dementia complex (ALS/PDC)

Most ALS cases are sporadic, and only 5-10% of cases are considered to be familial. Mutations in the C9orf72 gene are responsible for 30-40% of familial ALS cases in the United States and Europe. Worldwide, approximately 20% of cases of familial ALS are due to a mutation in the Cu/Zn superoxide dismutase–1 gene (SOD1). Western Pacific ALS occurs on the islands of Guam (Guam ALS), on the Kii peninsula of Japan, and in Western New Guinea. It is now clear that a subset of ALS cases shows features of frontotemporal lobar degeneration (FTLD) (ie, FTLD-MND/ALS).

Primary lateral sclerosis

PLS is a rare, idiopathic neurodegenerative disorder that primarily involves the UMNs, resulting in progressive spinobulbar spasticity. Because substantial numbers of cases initially diagnosed as PLS would be reclassified as ALS as the disease progresses, Pringle et al suggest that a disease duration of at least 3 years is required to render this diagnosis clinically. [1] There is still debate regarding whether PLS is a distinct pathologic entity or whether it represents one end of a clinical spectrum of ALS.

Hereditary spastic paraparesis

HSP, also known as familial spastic paraplegias or Strumpell-Lorrain disease, comprises a clinically and genetically heterogeneous group of hereditary disorders characterized by slowly progressive spastic paraparesis. This condition is clinically classified as taking either a pure (uncomplicated) form or a complicated form, depending on whether the paraparesis exists in isolation or in conjunction with other major clinical features. There is significant overlap in clinical characteristics between pure HSP and PLS. [2]

Genetically, HSPs are classified by the mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and are subdivided by chromosomal locus or causative gene. Pure autosomal dominant HSP is the most common form.

Progressive bulbar palsy

PBP is a progressive degenerative disorder of the motor nuclei in the medulla (specifically involving the glossopharyngeal, vagus, and hypoglossal nerves) that produces atrophy and fasciculations of the lingual muscles, dysarthria, and dysphagia. In adults, because most of the cases presenting with these pure bulbar symptoms represent so-called bulbar-onset ALS and eventually develop widespread symptoms typically seen in ALS, some authors consider this disorder to be a subset of ALS.

Infantile PBP is a rare disorder that occurs in children and presents as the following 2 phenotypically associated forms:

  • Brown-Vialetto-Van Laere syndrome (pontobulbar palsy with deafness)
  • Fazio-Londe disease

Brown-Vialetto-Van Laere syndrome is characterized by bilateral sensorineural deafness that is followed by CN VII, CN IX, and CN XII palsies, whereas Fazio-Londe disease causes progressive bulbar palsy without deafness. Both disorders are genetically heterogeneous.

Spinal muscular atrophy

SMA comprises a large group of genetically determined neuromuscular disorders that are characterized by progressive degeneration of spinal LMNs (ie, alpha motor neurons in the anterior horns) accompanied by amyotrophy, with no evidence of sensory or pyramidal tract involvement. This condition is genetically heterogeneous, with autosomal recessive (most common), autosomal dominant, and X-linked recessive modes of inheritance.

The International SMA Consortium defined the following 4 clinical groups, depending on the age of onset and achieved motor abilities [3] :

  • Type I SMA (acute form, Werdnig-Hoffmann disease)
  • Type II SMA (intermediate form)
  • Type III SMA (juvenile form, Kugelberg-Welander disease)
  • Type IV SMA (adult form)

X-linked spinobulbar muscular atrophy (Kennedy disease)

First described in 1968 by Kennedy et al, [4] X-linked SBMA is an adult-onset, X-linked recessive trinucleotide, polyglutamine disorder that is caused by expansion of a polymorphic CAG tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12. [5]

This disorder is characterized by slowly progressive weakness of bulbar and limb muscles, associated with endocrinologic disturbances (androgen insensitivity). Because of X-linked transmission, this disorder almost exclusively affects males but is transmitted by female carriers.

Postpolio syndrome

PPS is a clinical diagnosis and essentially one of exclusion. This condition is characterized by late-onset muscle weakness and fatigue in skeletal or bulbar muscles, unrelated to any known cause, in individuals with a previous history of an acute attack of paralytic poliomyelitis. [6] Survivors of the polio epidemics that occurred worldwide in the mid-20th century constitute a population at risk for PPS.

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Epidemiology

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) develops with a uniform frequency in major Western countries; the annual incidence is about 2 per 100,000 population. [7] The estimated prevalence is 5 per 100,000 in the United States; approximately 30,000 Americans currently have the disease. Epidemiologic data suggest that smoking may be an established risk factor for sporadic ALS. [8] The peak age of onset is between 55 and 75 years. Men are affected more frequently than women; however, this sex discrepancy is not as pronounced in familial cases.

Primary lateral sclerosis

The incidence of primary lateral sclerosis (PLS) is difficult to determine, both because it occurs rarely and because there is a significant overlap with ALS.

Hereditary spastic paraparesis

The prevalence of hereditary spastic paraparesis (HSP) varies from study to study as a result of the marked differences in the classifications used and their included diagnoses. In Ireland, the prevalence of pure autosomal dominant HSP is 1.17/100,000 population, [9] whereas in southeast Norway, the HSP prevalence was estimated to be 7.4/100,000 population (pure autosomal dominant HSP, 4.5/100,000; complex autosomal dominant HSP, 1.0/100,000; and autosomal recessive HSP, 1.3/100,000). [10]

Progressive bulbar palsy

The prevalence of adult-onset progressive bulbar palsy (PBP) is difficult to determine because of the significant overlap with bulbar-onset ALS. For infantile PBP, approximately 60 cases of Brown-Vialetto-Van Laere syndrome have been reported to date, and around one half of those cases were sporadic. [11] The male-to-female ratio is approximately 1:3 in reported cases. Fewer than 40 cases of Fazio-Londe disease have been reported to date.

Spinal muscular atrophy

After cystic fibrosis, spinal muscular atrophy (SMA) is the second most common autosomal recessive disease in humans. The overall incidence of SMA is frequently cited as being about 1 in 6000 to 1 in 10,000 live births, and the carrier frequency is as high as 1 in 40. [12]

X-linked spinobulbar muscular atrophy (Kennedy disease)

Of the hereditary motor neuron diseases (MNDs), X-linked spinobulbar muscular atrophy(SBMA) is one of the least common, with a prevalence of approximately 1 per 40,000 males. Because of a founder effect, SBMA is more common among Japanese and Scandinavian men. [13] In the Vasa region of Western Finland, the prevalence of this condition is reportedly greater than that of ALS, with a prevalence of 13 in 85,000 among the male population. [14]

Postpolio syndrome

The prevalence of postpolio syndrome (PPS) has been reported to range from around 30% to 85%, depending on the population being studied and the diagnostic classification used. [15, 16, 17] According to a cross-sectional survey in Kitakyushu, Japan, the prevalence of PPS is 18.0 per 100,000 population (24.1 polio survivors per 100,000 population). [16]

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Etiology

Amyotrophic lateral sclerosis

The etiology of sporadic amyotrophic lateral sclerosis (ALS) remains uncertain, however, ALS is considered to be a multifactorial disease that is triggered by a complex interaction of internal factors (eg, genetic susceptibility to different neuronal insults and immunologic alterations) and external factors (eg, environmental variables).

The key theories proposed to date for the pathogenesis of ALS include glutamate-induced excitotoxicity, oxidative injury, altered mitochondrial function, cytoskeleton alterations, axonal transport dysregulation, neuroinflammation, immunomodulation, and autoimmunity. [18]

Of these, the leading theory is excitotoxicity induced by glutamate, the major excitatory neurotransmitter, which may disrupt intracellular calcium homeostasis, resulting in motor neuron death. Riluzole, a glutamate-release inhibitor, is licensed for the slowing of ALS progression, and randomized controlled trials have demonstrated a relatively mild effect, with a small positive effect on bulbar and limb function but not on muscle strength. [19]

An alternative hypothesis for which there are some current supporting data suggests that mitochondrial dysfunction acts with oxidative stress to cause abnormal neurodegeneration via calcium-mediated motor neuron injury. [20] As external or environmental factors, neurotoxicants such as various metals, chemicals, and foods have been proposed.

Primary lateral sclerosis

The etiology of primary lateral sclerosis (PLS) is unknown, but it may be similar to that proposed for ALS.

Hereditary spastic paraparesis

More than 40 genetic loci ascribed to the different types of hereditary spastic paraparesis (HSP) have been identified; however, a clear genetic basis for most HSP types remains uncertain.

Progressive bulbar palsy

The etiopathogenesis of Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease remains elusive.

Spinal muscular atrophy

Type I-III spinal muscular atrophy (SMA) is caused by alterations in the survival motor neuron gene (SMN). This gene becomes active in the healthy, mature fetus and functions in the stabilization of the neuronal population. In the absence of SMN, there is continued programmed cell death.

X-linked spinobulbar muscular atrophy (Kennedy disease)

X-linked spinobulbar muscular atrophy (SBMA) is caused by an expansion of a polymorphic tandem CAG repeat in the first exon of the androgen-receptor gene located on chromosome Xq11-q12, which encodes a polyglutamine stretch that may be a substrate for the caspases (cysteine protease cell death executioners).

Postpolio syndrome

The etiology of postpolio syndrome (PPS) remains controversial; however, the most widely accepted hypothesis involves distal degeneration of greatly enlarged motor units that developed through terminal axonal sprouting for the reinnervation of denervated fibers during recovery after acute poliomyelitis. The motor units undergo a continuous remodeling process with denervation and reinnervation, followed by an eventual loss of this balanced process, which results in permanent denervation. [21, 22]

Other hypotheses include immunologic mechanisms (autoimmune or related to persistent poliovirus infection), the normal aging process, overuse myopathy, and disuse. [23] The latter 3 processes are likely contributing factors.

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Clinical Features

Amyotrophic lateral sclerosis

The incidence of amyotrophic lateral sclerosis (ALS) increases with age until it peaks around the age of 75 years. In familial ALS, the onset is a decade earlier. Otherwise, familial and sporadic cases are clinically indistinguishable, and thus, a detailed family history and genetic studies are very important in discriminating between these 2 forms.

Approximately two thirds of patients with ALS initially present with focal muscle weakness in the upper or lower limbs (classic Charcot ALS), and approximately one fourth of patients presents with dysarthria, followed by progressive dysphagia (bulbar-onset ALS). Patients with ALS due to C9orf72 mutation present more frequently with bulbar onset; in addition, cognitive involvement is more common. [24]

In ALS with SOD1 mutations, extremity onset, particularly in the legs, is much more common than bulbar onset. About 5% of cases present with respiratory weakness without significant limb or bulbar symptoms. [25]

The flail arm and flail leg variants are initially localized forms with predominantly lower motor neuron (LMN) symptoms. [26] These are characterized by progressive weakness and severe wasting of the upper and lower limbs, bilaterally.

Regardless of the body part that is first affected by ALS disease, weakness and atrophy spread to other parts of body with varying degrees of upper motor neuron (UMN) symptoms (eg, spasticity) and eventually involve the muscles of all 4 extremities and the trunk, as well as bulbar muscles. Rectal and bladder sphincters and oculomotor muscles are usually spared. Sensory examination is usually unremarkable.

Approximately 5% of patients with ALS develop dementia of the frontotemporal type, characterized by behavioral changes with or without language dysfunction.

Primary lateral sclerosis

The age of onset for primary lateral sclerosis (PLS) is usually between 40 and 60 years, with spasticity in the legs accompanied by hyperactive deep tendon reflexes, clonus, and Babinski sign. Patients with spastic dysarthria as an initial symptom of PLS are also described. In contrast to ALS, the LMNs remain intact, and thus, no amyotrophy is observed. Rare cases of frontotemporal dementia with PLS have been reported. [27]

Hereditary spastic paraparesis

In pure (uncomplicated) hereditary spastic paraparesis (HSP), the age of disease onset ranges from infancy to the eighth decade, [28] and the disease severity varies; both reflect marked interfamilial variation. The essential clinical findings are slowly progressive and often include severe spasticity, hyperreflexia, and weakness in a pyramidal distribution, noticeably in both lower limbs, with extensor plantar responses.

Most patients with HSP present with difficulty in walking or a gait disturbance. In those with childhood onset, a delay in walking is not uncommon. Upper limb involvement is usually mild. Notably, as many as 25% of affected patients are asymptomatic. [29]

Sensory impairment is seen in 10-65% of cases and usually consists of diminished vibration sense and, less often, diminished joint-position sense in the lower extremities. [29] Urinary sphincter dysfunction occurs in up to 50% of patients, whereas anal sphincter involvement is unusual. [29] Important negative clinical findings include no cranial nerve (CN) involvement and no corticobulbar tract involvement.

In complicated HSP, spasticity is accompanied by a variety of conditions that are related to central and peripheral nervous system involvement, including muscle amyotrophy, optic atrophy, pigmentary retinopathy, mental retardation, extrapyramidal disease, ataxic syndrome, dementia, deafness, ichthyosis, peripheral neuropathy, and epilepsy. [29]

Progressive bulbar palsy

Brown-Vialetto-Van Laere syndrome typically presents with progressive sensorineural hearing loss. The age of onset of the initial symptoms reportedly ranges from infancy to the third decade of life. [11] The hearing loss is usually followed by other symptoms, including abnormalities of lower CNs VII-XII and LMN signs in the limbs, with an interval of several years. This interval has been reported to be shorter in males (mean, approximately 5 y) than in females (mean, almost 11 y). [11] Abnormalities of CNs II-VI occur much less frequently.

Fazio-Londe disease manifests itself in childhood as rapidly progressive weakness of the tongue, face, and pharyngeal muscles, as well as progressive upper limb weakness. No hearing impairment is seen.

Spinal muscular atrophy

The clinical picture of spinal muscular atrophy (SMA) is highly variable and represents a continuum. The age of onset ranges from before birth to adulthood. The International SMA Consortium has defined 4 clinical types of SMA (I-IV) on the basis of the age of onset and achieved motor functions. [3]

Type I SMA (Werdnig-Hoffmann disease)

Type I SMA is the most severe form. Patients present with profound hypotonia and generalized weakness (“floppy infants”) and never achieve the ability to sit. By definition, all patients present before age 6 months (sometimes with onset in the prenatal period). The diaphragm and the extraocular muscles tend to be spared (in contrast to SMA-plus disease types and severe congenital SMA). [30] No cardiac muscle involvement is seen. Creatine kinase is normal.

Type II SMA

The onset of type II SMA is before the age of 18 months. There may be some overlap with type I SMA, but the median age of onset is generally later than in type I. The clinical course of type II SMA is marked by periods of apparent arrest in clinical progression. Patients are able to sit independently, but they are never able to walk unaided. Spine deformities and contractures of all major joints often develop.

Type III SMA (Kugelberg-Welander disease)

Type III is a mild form of childhood and juvenile SMA. By definition, the disease onset is usually after the age of 18 months, but it may occur over a wide range, sometimes as late as the third decade of life. Patients gain the ability to walk without support. Spine deformities and contractures are frequent complications.

Type IV SMA

Type IV is an adult-onset type (age > 30 y) and represents the mildest form within the spectrum of SMA phenotypes. Patients present with pronounced proximal weakness, and the clinical picture is very similar to that of a limb-girdle muscular atrophy.

X-linked spinobulbar muscular atrophy (Kennedy disease)

X-linked spinobulbar atrophy (SBMA) is clinically characterized by adult-onset limb and bulbar weakness, muscular atrophy, and fasciculation, with frequent occurrence of endocrine disturbances such as gynecomastia, testicular atrophy, hypercholesterolemia, and diabetes mellitus. Asymptomatic patients are also present.

One clinical study reported that the mean age at first onset of muscle weakness was 41 years and that the most common presenting symptom was muscle cramps, followed by tremors and leg weakness. [31] Also reported was that muscle strength and function correlated directly with serum testosterone levels.

Postpolio syndrome

Most patients with postpolio syndrome (PPS) present with new, slowly progressive muscle weakness, frequently accompanied by muscle pain (myalgias) and fatigue, which can occur in both previously affected and unaffected muscles. This condition can also affect respiratory and bulbar muscles.

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Gross Findings

Amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS), the anterior nerve roots in the spinal cord are gray and thin or atrophic as compared with the posterior sensory roots (see the image below); this finding is more pronounced in the cervical and lumbar enlargements. The hypoglossal nerves are also affected. The bilateral pyramids in the medulla oblongata may be flattened.

Amyotrophic lateral sclerosis. Grossly, spinal cor Amyotrophic lateral sclerosis. Grossly, spinal cord shows gray and thin or atrophic anterior nerve roots.

The brain is usually unremarkable; however, the precentral gyrus (primary motor cortex) may be atrophic, especially in severe cases. In ALS cases with accompanying dementia, the brain may exhibit frontal (and temporal) lobe atrophy.

At autopsy, widespread muscle atrophy and wasting affecting the proximal and distal extremities, tongue, intercostal muscles, and diaphragm are noted. The skeletal muscle is grossly pale. Because of the loss of muscle bulk through atrophy, rigor mortis is usually absent in advanced stages of ALS disease.

Primary lateral sclerosis

No valid autopsy findings of pure primary lateral sclerosis (PLS), excluding upper motor neuron (UMN)–dominant ALS cases, have been reported to date. Theoretically, however, neither atrophy of the anterior nerve roots nor widespread muscle atrophy or wasting is seen.

Hereditary spastic paraparesis

Because of the few autopsy cases reported and the rarity of this condition, no characteristic gross pathology for hereditary spastic paraparesis (HSP) has been described.

Progressive bulbar palsy

Because of the few autopsy cases reported and the rarity of this condition, no characteristic gross pathology for progressive bulbar palsy (PBP) has been described.

Spinal muscular atrophy

In type I spinal muscular atrophy (SMA), atrophy of the anterior spinal nerve roots is seen in the spinal cord, whereas the posterior nerve roots are normal. [32] However, spinal cords in this affected age group are so small that evaluation is often difficult. The brain is unremarkable. No detailed gross neuropathologic findings have been reported in type II or III SMA.

X-linked spinobulbar muscular atrophy (Kennedy disease)

Although detailed microscopic descriptions have been reported in several autopsy cases of X-linked spinobulbar muscular atrophy (SBMA), no gross neuropathologic findings are described.

Postpolio syndrome

The spinal cord in postpolio syndrome (PPS) shows atrophic anterior nerve roots and normal dorsal roots. [33] The brain is unremarkable. Skeletal muscle atrophy of varying degree is noted.

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Microscopic Findings

Amyotrophic lateral sclerosis

The cardinal histologic change seen in amyotrophic lateral sclerosis (ALS) is loss of both upper motor neurons (UMNs) and lower motor neurons (LMNs) with associated astrogliosis. In the LMN system, there is loss or degeneration of the anterior horn cells (especially the large neurons) with anterior nerve root atrophy, as well as of the brainstem motor nuclei (eg, cranial nerve [CN] XII, motor VII, and motor V) (see the images below).

Amyotrophic lateral sclerosis. Histologic features Amyotrophic lateral sclerosis. Histologic features of markedly degenerated anterior spinal nerve root (cross section) with extensive demyelination. (Luxol fast blue-periodic acid-Schiff stain, ×40)
Amyotrophic lateral sclerosis. Histologic features Amyotrophic lateral sclerosis. Histologic features of unremarkable posterior nerve root. Compare with previous image showing markedly degenerated anterior spinal nerve root (cross-section) with extensive demyelination. (Luxol fast blue-periodic acid-Schiff stain, ×40)
Amyotrophic lateral sclerosis. Neurofilament prote Amyotrophic lateral sclerosis. Neurofilament protein (NFP) immunohistochemistry shows diffuse loss of both small- and large-diameter axons in this atrophic anterior nerve root. (NFP immunohistochemical stain, ×40)
Amyotrophic lateral sclerosis. Immunohistochemical Amyotrophic lateral sclerosis. Immunohistochemically, both small- and large-diameter axons are well-preserved in posterior nerve root, in contrast to previous image, where diffuse loss of both small- and large-diameter axons is seen in atrophic anterior nerve root. (Neurofilament protein immunohistochemical stain, ×40)

However, the brainstem nuclei controlling eye movements (CNs III, IV, and VI), the Clarke column (see the first image below), and the Onufrowicz nucleus (see the second image below) in the sacral spinal cord (involved in maintenance of micturition and fecal continence) are largely spared until late in ALS.

Amyotrophic lateral sclerosis. Histologic features Amyotrophic lateral sclerosis. Histologic features of spinal (lumbar) anterior horn, with loss of neurons and associated severe gliosis and well-preserved Clarke column (circle).
Amyotrophic lateral sclerosis. Neurons of Onufrowi Amyotrophic lateral sclerosis. Neurons of Onufrowicz nucleus in sacral cord are relatively well preserved. (Hematoxylin and eosin stain, ×40)

The anterior horns show varying degrees of astrogliosis, depending on the stage of the disease, and the surviving motor neurons usually show chromatolysis and cytoplasmic shrinkage with abundant lipofuscin granules in the soma (see the first image below). Axonal spheroids are frequently observed (see the second image below).

Amyotrophic lateral sclerosis. Histology shows res Amyotrophic lateral sclerosis. Histology shows residual anterior horn cells filled with abundant lipofuscin pigments (arrowhead) and of axonal spheroids (arrow) in very gliotic lumbar anterior horn. (Hematoxylin and eosin stain, ×200)
Amyotrophic lateral sclerosis. Neurofilament prote Amyotrophic lateral sclerosis. Neurofilament protein (NFP) immunohistochemistry labels rare residual neurons and scattered axonal spheroids (arrows) in lumbar anterior horn. (NFP immunohistochemical stain, ×400)

Neuronophagia and perivascular lymphocytic cuffing is occasionally seen in ALS. In the UMN system, the motor cortex is affected and shows loss or degeneration of neurons with astrogliosis mainly in the third and fifth layers (cell bodies of Betz cells), a feature that is more apparent in cases of longer duration (see the first image below). Superficial cortical spongiosis may also be seen (see the second image below).

Amyotrophic lateral sclerosis. Precentral gyrus (p Amyotrophic lateral sclerosis. Precentral gyrus (primary motor cortex) shows diffuse cortical gliosis highlighted with glial fibrillary acidic protein (GFAP) immunostain. (GFAP, ×40)
Amyotrophic lateral sclerosis. Precentral gyrus (p Amyotrophic lateral sclerosis. Precentral gyrus (primary motor cortex) shows diffuse superficial cortical spongiosis (arrowheads) and residual Betz cells (arrow). (Hematoxylin and eosin stain, ×20)

Other histologic findings reported in the precentral gyrus in ALS patients include clusters of astrocytes in the upper cortical layers (layers II and III), an increase in the size and number of subcortical white matter astrocytes, and astrocytosis in the gray-white matter junction (see the image below). [34]

Amyotrophic lateral sclerosis. Precentral gyrus (p Amyotrophic lateral sclerosis. Precentral gyrus (primary motor cortex) shows loss of neurons, associated astrogliosis, shrunken neuron (arrowhead), and features suggestive of neuronophagia (arrow). (Hematoxylin and eosin stain, ×400)

The cytopathology of the affected motor neurons in ALS is characterized by the following:

  • Bunina bodies (BBs)
  • Skeinlike inclusions (SLIs)
  • Round hyaline inclusions (RHIs), including Lewy body–like hyaline inclusions (LBHIs)
  • Basophilic inclusions (BIs)

BBs are currently considered to be a specific histologic hallmark of ALS and can be observed in frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) and Guam ALS. In contrast, these findings have not been reported in patients with SOD1 -mutated familial ALS.

BBs are small, eosinophilic (on hematoxylin and eosin [H&E] stain), and blue (on Luxol fast blue stain) granular perikaryal inclusions in the remaining LMNs, appearing either singly or in a group and sometimes arranged in small beaded chains (see the image below). They average 2-5 µm in diameter, and the number varies in each neuron.

Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Bunina bodies are small eosinophilic inclusions arranged in group or in small beaded chains that are present in residual neurons (arrows). (Hematoxylin and eosin stain, ×400)

BBs are seen predominantly in the somata and occasionally in the dendrites; however, they have not been found within the axoplasm. [35] BBs are seen more frequently in the lumbar cord than in the cervical and thoracic cords, are primarily distributed in the motor nuclei of the spinal cord and brainstem, but are rarely found in Betz cells, neurons of the oculomotor nuclei, and the Onufrowicz nuclei. [36]

Ultrastructurally, BBs are composed of electron-dense amorphous material containing tubules or vesicular structures, with a few central clear areas containing cytoplasmic components. [36] Although their morphologic structure is well known, their origin and nature remain unknown.

SLIs are intracytoplasmic filamentous structures that are found as aggregates of threadlike structures (see the images below). They are usually detected with immunohistochemical stains (see Immunohistochemistry); on H&E staining, they are barely visible or, sometimes, are detected as faintly eosinophilic linear or curvilinear structures. [35] SLIs are made of bundles of filaments 15-20 nm thick. They have been reported to be significantly related to neuronal loss, especially in the spinal cord. [37]

Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Skeinlike inclusions are intracytoplasmic filamentous structures found as threadlike aggregations in residual neurons. (Ubiquitin immunostain, ×200)
Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Skeinlike inclusions are intracytoplasmic filamentous structures found as threadlike aggregations in residual neurons. (Transactivation response DNA-binding protein 43 [TDP-43] immunostain, ×400)

RHIs are round, eosinophilic, hyaline structures in the remaining anterior horn neurons; some of them consist of cores and halos and are referred to as LBHIs. LBHIs are indistinguishable from the Lewy bodies seen in Parkinson disease on H&E staining. They range in size from quite small to as large as 20 µm in diameter or larger. [38] The somata usually contain a single inclusion. It should be kept in mind that there is confusion surrounding the definitions of these 2 very similar inclusions, and the 2 terms (RHI and LBHI) are often used interchangeably.

BIs are irregularly-shaped neuronal, cytoplasmic, light basophilic inclusions, initially described in patients with sporadic juvenile ALS. They are stained light red by methyl green-pyronin, which suggests that they have an RNA component. BIs are seen not only in the residual large anterior horn cells but also in the small anterior horn cells and neurons in the intermediolateral nuclei. [39] Generally, BBs and SLIs are not found in cases with BIs.

Widespread neuronal loss and degeneration can be seen with BIs in areas including the cerebral cortex, basal ganglia, and thalamus; thus, cases of ALS with BIs are considered to be within the spectrum of the most recently recognized entity, basophilic inclusion body disease (BIBD). [40]

In ALS, there is characteristic degeneration of the descending motor tracts (ie, anterior and lateral corticospinal tracts). This degeneration is most evident in the lower spinal segments, supporting the so-called dying back hypothesis. The posterior columns and spinocerebellar tracts are usually spared in the spinal cord. Some forms of familial ALS are known to show posterior column involvement. [34]

In the degenerated tracts, there is loss of large myelinated fibers, which can be highlighted with myelin stains (eg, Luxol fast blue), in association with infiltration of foamy macrophages and variable astrogliosis.

In FTLD-MND/ALS, spongiosis (microvacuolation) is observed in the frontal and temporal cortices, in addition to ALS features.

The striated muscles show neurogenic atrophy, characterized by clumps of pyknotic nuclei, small and large group atrophy, scattered angulated atrophic fibers, and fiber type grouping (see the images below).

Amyotrophic lateral sclerosis. This muscle biopsy Amyotrophic lateral sclerosis. This muscle biopsy shows neurogenic atrophic changes, with clumps of pyknotic nuclei, large group (fascicular) atrophy, hypertrophic fibers, and scattered angulated atrophic fibers. (Hematoxylin and eosin stain, ×100)
Amyotrophic lateral sclerosis. This muscle biopsy Amyotrophic lateral sclerosis. This muscle biopsy shows neurogenic atrophic changes with fiber type grouping. (Fast myosin heavy chain immunostain, ×100)

In the late stage of ALS disease, especially at autopsy, the muscles usually show marked atrophy with interstitial fibrosis and fatty infiltration (see the image below).

Amyotrophic lateral sclerosis. Markedly atrophic q Amyotrophic lateral sclerosis. Markedly atrophic quadriceps muscle obtained at autopsy shows end-stage myopathic changes with diffuse fatty infiltration. (Hematoxylin and eosin stain, ×200)

Primary lateral sclerosis

Degeneration in primary lateral sclerosis (PLS) is confined to UMNs, including their descending motor tracts (see the images below). No loss or degeneration of LMNs or gliosis is seen in the spinal anterior horns. No BBs are identified.

Primary lateral sclerosis. Histologic features of Primary lateral sclerosis. Histologic features of spinal cord with degenerated lateral column (arrows) are seen in this image. (Luxol fast blue stain, ×40)
Primary lateral sclerosis. Histologic features of Primary lateral sclerosis. Histologic features of spinal cord with well-preserved anterior horn neurons (arrowheads) are seen in this image. (Luxol fast blue plus eosin stain, ×100)

Hereditary spastic paraparesis

The pathways that are most severely affected in pure hereditary spastic paraparesis (HSP) are the crossed and uncrossed corticospinal tracts to the lower limbs and the fasciculus gracilis fibers from the lower limbs. The primary neuropathologic feature of pure HSP is axonal degeneration that is maximal in the terminal portions of the corticospinal tracts (descending tracts) and, to a lesser extent, of the dorsal column fibers (ascending tracts), suggesting a process of “dying back.”

Demyelination and gliosis can accompany the axonal loss. About 50% of HSP cases show spinocerebellar tract involvement. [29] Dorsal root ganglia, posterior roots, and peripheral nerves are unremarkable, as are the anterior horn cells.

Progressive bulbar palsy

Pathologic description of progressive bulbar palsy (PBP) is available in a few reported cases of Brown-Vialetto-Van Laere syndrome, which show neuronal injury and loss of neurons in the III, V, VI and lower CN (VII-XII) nuclei. [11]

Spinal muscular atrophy

Autopsy findings of spinal muscular atrophy (SMA) have mostly been reported from patients with SMA type I. The cardinal histologic feature of SMA type I is the paucity of motor neurons in the spinal cord and brainstem, with the few surviving motor neurons characterized by ballooning and chromatolysis. [41] In SMA type I, chromatolytic neurons tend to be markedly ballooned and spheroidal and to contain as yet ill-defined material inside them, in contrast to the neurons seen in other motor neuron disorders (MNDs), such as ALS. [42]

Chou and Wang described the following histopathologic tetrad of SMA type I [42] :

  • Central chromatolysis
  • Empty cell beds – These are empty (glial) shells or spaces that are still enclosed by the usual fiber network left by the previous occupants, motor neurons; they are easily visible with special stains (Bodian and others)
  • Migratory (heterotopic) motor neurons – These are seen along the distal pathways of their axons in the anterior spinal roots
  • Glial bundles of spinal roots – Outgrowth of birefringent glial bundles parallel to the spinal root axons is frequently seen in the anterior spinal nerve roots (proximal portion), which is apparent with polarizing microscopy

Other reported findings, especially in individuals with longer survival periods, include involvement of the dorsal root ganglia (with nodules of Nageotte), Clarke column, and lateral thalamic nucleus, with neuronal chromatolysis and ballooning. [41, 43]

An autopsy report on 2 patients with clinicogenetically confirmed SMA type II described severe reduction of motor neurons and gliosis in the spinal cord and brainstem. [43] However, in contrast to SMA type I, the Clark and lateral thalamic nuclei were spared, and ballooned and chromatolytic neurons were rarely seen. Additional findings were reduced Betz cells and large myelinated fibers in the lateral funiculus. [43]

The main histologic finding with SMA type III is a marked neuronal loss in the anterior horns throughout the spinal cord. The only autopsy report of a patient with clinicogenetically confirmed SMA type III noted inconspicuous empty cell bed formation, a small number of migratory (heterotopic) motor neurons, and prominent glial bundles in spinal roots in addition to the typical changes in the spinal anterior horns. [44]

Chromatolytic motor neurons were not as enlarged, were small in number, and were observed only in the anterior horn. [44] Changes other than those in motor neurons included moderate loss of myelinated fibers in the fasciculus gracilis and marked loss of neurons with severe gliosis in the dentate nucleus.

Because histopathologic features of muscle biopsies in SMA types I and II are essentially identical, the 2 types cannot be distinguished on the basis of muscle pathology alone. Characteristic features include atrophy affecting both type 1 and type 2 fibers, with type I fiber hypertrophy, and (in non–early onset cases) fiber type grouping (see the images below). The atrophic fibers are usually round in shape, in contrast to other forms of neurogenic atrophy, such as ALS. Excess endomysial connective tissue is not seen.

Spinal muscular atrophy type I (Werdnig-Hoffmann d Spinal muscular atrophy type I (Werdnig-Hoffmann disease). This muscle biopsy shows large group atrophy with fiber hypertrophy. (Hematoxylin and eosin stain, ×40)
Spinal muscular atrophy type I (Werdnig-Hoffmann d Spinal muscular atrophy type I (Werdnig-Hoffmann disease). This muscle biopsy shows large group atrophy with hypertrophic fibers identifiable as type I fibers. (ATPase pH 4.3, ×40)

The muscle pathology in SMA type III is variable, ranging from minimal changes to small or large group atrophy with fiber type grouping. Fatty infiltration of variable degree is noted. Hypertrophic type I fibers can be seen. A concomitant myopathic pattern can also be present.

X-linked spinobulbar muscular atrophy (Kennedy disease)

The cardinal histopathologic feature of X-linked spinobulbar muscular atrophy (SBMA) is loss of neurons in the anterior horns and motor nuclei in the spinal cord and brainstem. Motor nuclei of CNs III, IV, and VI are spared. Sensory neurons in the dorsal root ganglia are less severely affected, and large myelinated fibers demonstrate a distally accentuated sensory axonopathy in the peripheral nervous system. [45, 46]

The neurons in the Onufrowicz nuclei, intermediolateral columns, and Clarke columns of the spinal cord are generally well preserved, as is the case in ALS. [46] Muscle biopsy shows neurogenic atrophy of varying degree.

Postpolio syndrome

In postpolio syndrome (PPS), the spinal cord demonstrates active chronic inflammation with perivascular lymphoplasmacytic infiltrate in the anterior horns and leptomeninges. [47] The cord gray matter is gliotic, with axonal spheroids seen in the anterior horns. No degenerative changes are noted in the lateral columns, in contrast to the findings in ALS. These features are not specific to PPS: similar changes are seen in patients with stable postpoliomyelitis deficits. [47]

Miller noted focal, perivascular, intraparenchymal, chronic inflammatory infiltrates composed mostly of B cells with rare macrophages and no T cells in the spinal cord, suggesting an autoimmune etiology; he also noted neuronal loss with profound gliosis and scattered axonal spheroids in the anterior horns, moderate Wallerian degeneration in the lateral columns, and an unremarkable brain, specifically the internal capsule and precentral gyri. [33] Muscle biopsy showed neurogenic changes with secondary myopathic features of varying degree.

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Immunohistochemistry

Amyotrophic lateral sclerosis

The immunohistochemical profile of pathologic structures seen in amyotrophic lateral sclerosis (ALS) is shown in Table 1 below.

Table 1. Immunohistochemical Findings of Pathologic Structures Seen in Amyotrophic Lateral Sclerosis (Open Table in a new window)

  Cystatin C GFAP pNFP pTau α-Synuclein SOD-1 Ubiquitin TDP-43 FUS
Chromatolytic neurons - - + - - - -/+ - -
Axonal spheroids - - + - - -/+ - - -
Reactive astrocytes - + - - - -/+ - - -
Bunina bodies + - - - - - - - -
Skeinlike inclusions - - - - - - + +/- -
Round hyaline bodies - - - - - -/+ + +/- -
Lewy body–like hyaline inclusions - - + - - + + +/- -
Basophilic inclusions - - - - - - -/+ - +
FUS = fused-in-sarcoma protein; GFAP = glial fibrillary acidic protein; pNFP = phosphorylated neurofilament protein; pTau = phosphorylated tau; SOD-1 = superoxide dismutase–1; TDP-43 = transactive response DNA binding protein with molecular weight of 43 kd.

Ubiquitin immunohistochemical staining is very useful for highlighting neuronal cytoplasmic inclusions, which are a highly sensitive and specific marker for ALS. Notably, the Bunina body (BB), one of the pathognomonic features of ALS, is immunonegative for ubiquitin but immunoreactive for cystatin C.

The 43-kd transactive response (TAR) DNA–binding protein (TDP-43) is a major component of frontotemporal lobar degeneration (FTLD) with ubiquitin-only immunoreactive inclusions (FTLD-U). TDP-43 immunoreactivity is reported to be consistently colocalized with ubiquitinated inclusions observed in sporadic ALS (see the image below) and Guam ALS. [48, 49] However, in most familial ALS cases with SOD1 mutation, TDP-43 immunoreactive inclusions are absent despite the presence of ubiquitin immunoreactive inclusions. [48, 49]

Amyotrophic lateral sclerosis. Cytopathology of af Amyotrophic lateral sclerosis. Cytopathology of affected spinal motor neurons. Skeinlike inclusions are intracytoplasmic filamentous structures found as threadlike aggregations in residual neurons. (Transactivation response DNA-binding protein 43 [TDP-43] immunostain, ×400)

In addition to the neuronal cytoplasmic inclusions, TDP-43–immunoreactive and variably ubiquitin-immunoreactive glial (probably oligodendroglial) cytoplasmic inclusions are identified within the anterior horns and close to the white matter in the spinal cord in sporadic ALS cases. [50] Basophilic inclusions (BIs) are occasionally ubiquitin-immunoreactive; however, they have been found to be labeled with antibody against fused-in-sarcoma (FUS) protein. [50]

In Guam ALS with or without Parkinsonism-dementia complex (ALS/PDC), widespread tau-immunoreactive neurofibrillary tangles, especially in the isocortices and hippocampal formation, are known to be a characteristic feature.

In frontotemporal lobar degeneration with motor neuron disease (FTLD-MND)/ALS, ubiquitin- and TDP-43–immunoreactive, tau-negative inclusions and neurites are observed in the upper layers of the frontal cortex and the dentate fascia of the hippocampus in the brain.

As a sensitive method of detecting degeneration of white matter tracts, CD68 is very useful for highlighting macrophages within the degenerated tracts, especially in early degeneration (see the image below).

Amyotrophic lateral sclerosis. CD68 immunostaining Amyotrophic lateral sclerosis. CD68 immunostaining shows abundant histiocytes in lateral column (ie, corticospinal tract) of cervical cord. (CD68 immunohistochemical stain, ×20)

Primary lateral sclerosis

No characteristic immunohistochemical findings are noted in primary lateral sclerosis (PLS). When ubiquitin-immunoreactive inclusions are identified in the lower motor neurons (LMNs), ALS may be much more likely than PLS. No data on TDP-43 immunohistochemical findings have been reported to date.

Hereditary spastic paraparesis

No characteristic immunohistochemical findings are noted in hereditary spastic paraparesis (HSP).

Progressive bulbar palsy

No characteristic immunohistochemical findings are noted in Brown-Vialetto-Van Laere syndrome or Fazio-Londe disease.

Spinal muscular atrophy

In spinal muscular atrophy (SMA) type I, phosphorylated neurofilament protein (pNFP) and ubiquitin immunostains preferentially label the peripheral perikarya and proximal neuritis and the centers of the ballooned neurons, respectively [41, 42, 43] ; however, these features are not found reported in SMA type II. [43] Glial bundles invading the proximal portions of the anterior spinal roots are highlighted with glial fibrillary acidic protein (GFAP) immunostain. No data on TDP-43 immunohistochemical findings have been reported.

X-linked spinobulbar muscular atrophy (Kennedy disease)

As a pathologic hallmark of most polyglutamine-mediated neurodegenerative diseases, nuclear inclusions (NIs) containing the mutant androgen receptors are present in the residual motor neurons in the spinal cord and brainstem, as well as in the skin, testis, and some other visceral organs in X-linked spinobulbar muscular atrophy (SBMA). [46] These nuclear inclusions are detected by antibodies recognizing a small portion of the N-terminus of the androgen-receptor protein and the expanded polyglutamine tract (immunohistochemistry IC2 antibody).

No ubiquitin-immunoreactive cytoplasmic inclusions that are seen in ALS are noted in SBMA. No data on TDP-43 immunohistochemical findings have been reported to date. Abnormal pNFP expression in the somata is not seen.

Postpolio syndrome

No characteristic immunohistochemical findings are noted in postpolio syndrome (PPS). No ubiquitin-immunoreactive inclusions are identified in the LMNs in PPS.

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Molecular and Genetic Features

Amyotrophic lateral sclerosis

Most forms of amyotrophic lateral sclerosis (ALS) are sporadic and considered to be multifactorial diseases, but about 10% of patients have an inherited familial form of the disease with a clear family history. In many instances, however, the disease is not transmitted in a typical dominant or recessive manner. [51]

Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, DAO, OPTN, VCP,UBQLN2, and VAPB genes, are known to cause familial ALS.

Mutations in C9orf72, a gene of unknown function, are responsible for as many as 50% of familial ALS cases in individuals of European descent and approximately 5% of apparently sporadic ALS cases. This gene alteration is characterized by expanded GGGGCC hexanucleotide repeats in the promotor. The gene is autosomal dominantly inherited. [52, 53]

Dominant causative mutations in the Cu/Zn superoxide dismutase–1 gene (SOD1) on chromosome 21q22.11 are seen in about 20% of familial ALS cases (genetic nomenclature: ALS1) and 1% of sporadic cases. SOD1 mutations, which can occur at almost any position in the gene, result in a toxic gain-of-function pathology. The loss of normal SOD1 function is not the cause of ALS. [51] However, no consensus on the exact mechanisms as to how SOD1 mutations lead to selective premature death of motor neurons has yet emerged.

Homozygous loss-of-function mutations in the ALSIN gene on chromosome 2q33, which encodes the protein alsin, produce either an autosomal recessive juvenile-onset ALS or a juvenile-onset upper motor neuron (UMN)-predominant ALS (genetic nomenclature: ALS2). [54]

Mutations in the transactive response (TAR) DNA–binding protein gene (TARDBP) on chromosome 1 (1p36.22), which codes for TDP-43, have been identified in patients with both familial and sporadic ALS. A total of 30 different mutations are now known in 22 unrelated families (about 3% of familial ALS cases) and in 29 sporadic cases of ALS (about 1.5% of sporadic cases). [55] All TARDBP mutations exhibit an autosomal dominant pattern of inheritance.

Mutations in fused-in-sarcoma (FUS)/translocation in liposarcoma (TLS) protein have been identified. These mutations were reportedly detected in approximately 4% of familial ALS (about 0.4% of all ALS cases). [55] TDP-43 and FUS/TLS are DNA/RNA-binding proteins with striking structural and functional similarities, implicating alterations in RNA processing as a pathogenesis of ALS.

Primary lateral sclerosis

Primary lateral sclerosis (PLS) is typically sporadic with no family history; however, rare familial forms are seen. Mutations in the ALSIN gene on chromosome 2q33 (ALS2) cause juvenile PLS, which may overlap with the juvenile-onset UMN-predominant ALS. This condition is inherited in an autosomal recessive pattern. A unique locus (chromosome 4ptel-4p16.1) for an autosomal dominant form of adult-onset PLS in a large French-Canadian family has been mapped. [56]

Hereditary spastic paraparesis

Hereditary spastic paraparesis (HSP) comprises a large clinically and genetically heterogeneous group of inherited neurologic disorders and is transmitted as an autosomal dominant, autosomal recessive, or (rarely) X-linked recessive trait. Autosomal dominant inheritance accounts for 70-80% of all HSP cases and is most commonly associated with pure forms of HSP. Autosomal recessive HSPs are less common but exhibit greater phenotypic variability.

Of the 45 known gene loci, 20 have been identified as causative. [57] About 40% of autosomal dominant HSP cases are linked to the spastic paraplegia 4 (SPG4) locus on chromosome 2p21-p22. More than 150 mutations are scattered along the coding regions of the gene SPAST, encoding spastin, [57] and have been implicated in causing various types of DNA modification. [58, 59] About 10% are due to mutations in ATL1, encoding for atlastin, with an early-onset pure phenotype (SPG3A). [57, 59]

Of autosomal recessive HSP cases, SPG11 (SPG11, spatacsin) reportedly is the most common form, followed by SPG15 (ZFYVE26, spastizin). [60] Clinically, both forms are characterized by complicated HSP, cognitive deficits, a thin corpus callosum (seemingly the best phenotypic predictor for these 2 forms of HSP), peripheral neuropathy, and mild cerebellar ataxia. [61]

Progressive bulbar palsy

Around 50% of all reported cases of Brown-Vialetto-Van Laere syndrome are sporadic. The majority of familial cases have demonstrated an autosomal recessive inheritance. [11] There are no known molecular alterations.

Spinal muscular atrophy

The classic form of spinal muscular atrophy (SMA) (types I, II, and III) is an autosomal recessive motor neuron disorder (MND). All forms of SMA are associated with a locus on chromosome 5q13 that harbors the survival motor neuron gene (SMN1), and they are all caused by loss-of-function mutations or deletions of SMN1.

The SMN gene product is ubiquitously expressed, but it is detected at especially high levels in neuronal cells. This entity is a part of nuclear germ structures rich in heterogeneous nuclear ribonucleoproteins (hnRNPs). Some researchers have suggested that the SMN protein, as part of a large complex, plays a role in the assembly and regeneration of spliceosomal complexes.

The SMN gene exists in 2 copies, SMN1 and SMN2, which differ by only a single nucleotide in exon 7. The vast majority of the functional SMN protein is produced by SMN1, whereas SMN2 undergoes an alternative splicing pathway, producing primarily a transcript lacking exon 7 (SMN∆7) as the consequence of a single nucleotide transition (ie, C to T transition at position +6 of exon 7; c.840C>T). SMN∆7 is an unstable protein and is not functionally equivalent to full-length SMA.

About 10% of the mRNA transcript from SMN2 is spliced into the full-length transcript that codes for the fully functional SMN protein. Thus, the major factor influencing the severity of SMA phenotype (ie, SMA types I-III) is the number of SMN2 copies, which usually ranges from 1 to 4 and rarely may be as high as 8. [62] The underlying mechanism generating an increase in SMN2 copies and a reduction in or absence of SMN1 copies is gene conversion. [62]

Among 5q13-linked SMA patients, 96% of those with types I-III show homozygous absence of SMN1 exons 7 and 8 or exon 7 only because of deletions of SMN1 or conversion of SMN1 into SMN2. [62] The relatively uniform mutational spectrum in types I-III SMA has led to the availability of fast, reliable polymerase chain reaction (PCR)-based testing. SMN1 -targeted mutation analysis is used diagnostically to detect deletion of exons 7 and 8. SMN gene dosage analysis, determining the number of SMN1 copies, yields highly accurate SMA carrier detection.

X-linked spinobulbar muscular atrophy (Kennedy disease)

X-linked spinobulbar muscular atrophy (SBMA) is an adult-onset recessive disorder. Female carriers of the mutation usually are clinically unaffected. The molecular basis of SBMA is the expansion of a trinucleotide cytosine-adenine-guanine (CAG) repeat, which encodes the polyglutamine tract, in the exon 1 of the androgen receptor gene on chromosome Xq11-12.

The CAG repeat ranges in size from 11 to 35 in normal individuals but ranges from 40 to 62 in SBMA patients. [46] Expanded CAG-repeat size is inversely correlated with age at onset and has a slight tend3ncy to further expansion in successive generations (ie, anticipation). [5] Molecular genetic testing for the CAG trinucleotide repeat expansion is available on a clinical basis.

The pathogenesis of this polyglutamine disorder is still unclear; however, there are strong indications that aggregation of the mutant androgen receptors within the nucleus or cytoplasm of motor neurons and visceral cells results in disruption of cellular functions in SBMA patients. [5]

Postpolio syndrome

There are no known molecular alterations or significant genetic findings in postpolio syndrome (PPS).

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Prognosis and Predictive Factors

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is typically relentless in progression. About 50% of patients survive for less than 3 years after diagnosis, and about 20% survive for 5-10 years. [63] Patients with ALS invariably develop respiratory weakness, and most die of pulmonary complications.

Primary lateral sclerosis

Unlike ALS, clinically pure primary lateral sclerosis (PLS), defined by isolated upper motor neuron (UMN) signs 4 years after symptom onset, progresses slowly, and patients maintain high levels of independence for years or decades. [64] UMN-dominant ALS (ie, predominantly UMN disease with minor lower motor neuron [LMN] signs) presents with disability similar to that of ALS but progresses more slowly. [64]

Hereditary spastic paraparesis

Hereditary spastic paraparesis (HSP) is a disease that is compatible with a normal life expectancy. Most patients die in old age of coincidental diseases. [29]

Progressive bulbar palsy

Brown-Vialetto-Van Laere syndrome reportedly shows a variable clinical course, with fewer than 40% of reported cases demonstrating survival for 10 or more years after the initial appearance of symptoms. [11] Abrupt deterioration of the condition has also been reported in approximately one sixth of patients.

Spinal muscular atrophy

The mortality and morbidity of spinal muscular atrophy (SMA) are inversely correlated with the age at onset. In type I SMA, because bulbar and respiratory muscles become affected rapidly, two thirds of patients expire within the first 2 years. In type II SMA, survival into adolescence or adulthood is common. In type III SMA, the life expectancy is close to that of the normal population.

X-linked spinobulbar muscular atrophy (Kennedy disease)

The lifespan of individuals with X-linked spinobulbar muscular atrophy (SBMA) is not thought to be reduced.

Postpolio syndrome

Postpolio syndrome (PPS) is a slowly progressive disease that is rarely fatal. However, patients with PPS commonly develop new disabilities that cause significant morbidity, such as orthopedic complications (eg, progressive instability of joints, osteoporosis, fractures, osteoarthrosis, scoliosis, and spondylosis), respiratory insufficiency (eg, progressive nocturnal hypoventilation), and neurologic complications related to skeletal deformity and to the use of medical supporting devices (eg, peripheral neuropathy).

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Differential Diagnosis

Amyotrophic lateral sclerosis

Conditions that should be considered in the differential diagnosis of amyotrophic lateral sclerosis (ALS) include the following:

  • Other neurodegenerative disorders, such as primary lateral sclerosis (PLS), hereditary spastic paraparesis (HSP), spinal muscular atrophy (SMA), and X-linked spinobulbar muscular atrophy (SBMA)
  • Peripheral neuropathies, such as multifocal motor neuropathy, an acquired immune-mediated demyelinating neuropathy with frequently elevated anti-GM1 antibody titers that usually responds to treatment with intravenous immunoglobulin (IVIg)
  • Myopathies, including inclusion body myositis, which is characterized by wasting and weakness of deep finger flexors and the quadriceps femoris with typical rimmed vacuoles on muscle biopsy
  • Postpolio syndrome (PPS)
  • Monomeric amyotrophy (also known as Hirayama disease), a structural cervical cord disorder due to dynamic compression of the cord that is seen only at neck flexion with forward displacement of the posterior dura; young males in the second and third decades of life are mainly affected, the onset is insidious, and predominantly unilateral upper-extremity weakness and atrophy occur, with no sensory or upper motor neuron (UMN) symptoms [65]
  • Conditions listed in the PLS differential diagnosis (see below)

Primary lateral sclerosis

The major differential diagnosis for PLS is UMN-dominant ALS. According to Pringle et al, disease duration of at least 3 years is required to render this diagnosis [1] ; similarly, Gordon et al reported that clinically pure PLS can be defined by isolated UMN signs 4 years after symptom onset. [64] Differentiation between PLS and UMN-dominant ALS is reported to have prognostic significance. [64]

Other diseases that cause a slowly progressive pyramidal or pseudobulbar syndrome should be considered in the differential diagnosis of PLS. These include the following:

  • Structural spinal cord disorders (compressive lesions at the foramen magnum or cervical spinal cord), such as cervical spondylotic myelopathy, Arnold-Chiari malformation, or tumors
  • Pure (uncomplicated) HSP
  • Metabolic disorders, such as subacute combined degeneration of the cord (vitamin B-12 deficiency)
  • Viral infections, such as tropical spastic paraparesis (human T-lymphotropic virus type I) or HIV infection
  • Primary progressive multiple sclerosis (PPMS) – The most common presentation of PPMS (seen in 80% of patients) is progressive spastic paraparesis, mainly in the legs [66]

Hereditary spastic paraparesis

The main differential diagnosis for HSP is PLS. This distinction is important for genetic counseling of family members and for the patient’s prognosis, in that HSP generally carries a more favorable prognosis. [2] Other components of the differential diagnosis of HSP are similar to those of PLS. One study showed that in most patients with a sporadic adult-onset UMN syndrome, differentiation between HSP (with sporadic presentation) and PLS on the basis of clinical characteristics is unreliable and that genetic testing is therefore required. [2]

In addition, the differential diagnosis includes dopa-responsive dystonia and arginase deficiency. Given that both of these disorders are treatable, dopa-responsive dystonia should be excluded in a child with progressive gait disturbance and lower-extremity spasticity of unknown etiology, whereas arginase deficiency should be considered in a young child with progressive loss of developmental milestones and spasticity.

Progressive bulbar palsy

Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease are closely related conditions, and the only feature clearly distinguishing between them is the presence of deafness in patients with the former.

The differential diagnosis of Brown-Vialetto-Van Laere syndrome includes Fazio-Londe disease, Madras motor neuron disease (MMND), and Boltshauser syndrome (sensorineural hearing loss, distal muscular atrophy, and vocal cord paralysis, which is the only lower cranial nerve sign).

MMND has a unique geographic distribution (predominantly reported from Southern India) and clinically resembles Brown-Vialetto-Van Laere syndrome, except for the presence of UMN signs in addition to LMN signs in the majority of patients, a male predominance, and an uncommon familial inheritance (ie, mostly sporadic). [67]

In the differential diagnosis of Fazio-Londe disease, Roeleveld-Versteegh et al reported 2 pediatric cases of mitochondrial respiratory chain defects presenting as progressive bulbar paralysis. [68]

Spinal muscular atrophy

The differential diagnosis of SMA includes congenital muscular dystrophy, congenital myopathy, congenital neuropathy (eg, congenital hypomyelination neuropathy), disorders of carbohydrate metabolism, myasthenia gravis, and ALS (especially juvenile forms). For SMA types III and IV, a limb-girdle muscular dystrophy is the main differential diagnosis.

X-linked spinobulbar muscular atrophy (Kennedy disease)

The main differential diagnosis for X-linked SBMA is ALS. This diagnosis can usually be made on the basis of the history and physical examination.

Postpolio syndrome

PPS is a diagnosis of exclusion. Thus, a careful medical history and clinical examination are necessary to exclude all other conditions that may cause similar symptoms, which include ALS, multiple sclerosis, collagen vascular diseases, depression, hypothyroidism, myasthenia gravis, inclusion body myopathy, and infectious myopathy.

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