Kugelberg Welander Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is caused by successive motor unit degeneration. Muscle atrophy, caused by a progressive loss of the anterior horn cells in the spinal cord, is universal. The motor nuclei in the lower brainstem, usually those of cranial nerves V-XII (V, VII, IX, XII), also may be involved. Various stages of degeneration can be observed histologically at these sites. As the nerve cells decrease in number, replacement gliosis, pyknosis, and secondary Wallerian degeneration in the roots and peripheral nerves are observed. These processes generally begin at the caudal end of the cord and typically are symmetrical. The lower limbs usually are affected sooner and more profoundly than are the upper limbs. This degeneration most often affects the proximal musculature before it impacts the distal. Note that, unlike in amyotrophic lateral sclerosis (ALS), no corticospinal tract involvement is seen in SMA.

A study by Querin et al involving adult patients with SMA type III or IV found that spinal cord gray matter had considerably atrophied between C2 and C6, while, possibly owing to an adaptive mechanism, the gray matter had grown denser in the motor and extramotor cortical regions.[8]

Frequency

United States

Spinal muscular atrophy (SMA) has an estimated incidence of 1 case per 15,000 live births. The genetic carrier prevalence is 1:80.

International

SMA has an estimated incidence of 1 case per 15,000-20,000 live births worldwide.

Mortality/Morbidity

SMA types III and IV, unlike types I and II, are consistent with survival well into adulthood.[9] Significant morbidity occurs from progressive weakness, and patients may frequently fall or may have difficulty with stairs. Most patients use wheelchair mobility by their fourth decade of life. Scoliosis and joint contractures are also extremely common. Morbidity associated with these conditions often can be minimized with spinal surgery, as well as with aggressive physical therapy. Respiratory failure in SMA types III and IV is not as common as in types I and II. Respiratory complaints usually can be managed medically, and mechanical ventilation seldom is necessary.[10, 11, 12, 13]

Cardiovascular pathologies have frequently been found in cases of SMA. A literature review by Wijngaarde et al reported that among these heart-related comorbidities, cardiac rhythm disorders most often accompanied milder forms of SMA, while structural cardiac disorders (primarily septal defects and cardiac outflow tract abnormalities) were most commonly associated with more severe SMA.[14]

A study by Souza et al of 20 individuals with SMA type IV determined limb-girdle muscle weakness to be the most frequent clinical symptom, being found in 75% of the patients. Fasciculations and absence of tendon reflexes made up the most frequent neurologic findings, occurring in 45% and 90% of patients, respectively. The investigators also found that disease duration correlated with functional scale scores, including those on the Hammersmith Functional Motor Scale Expanded, the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised, the Revised Upper Limb Module, and the Spinal Muscular Atrophy Functional Rating Scale. Such correlation was also reported for the 6-minute walk test and the Timed Up and Go test.[15]

Race

Spinal muscular atrophy (SMA) affects all races equally.

Sex

Spinal muscular atrophy affects males and females at the same rate; however, disease progression is more severe in males.

Age

The age of onset for spinal muscular atrophy is discussed above in the Background section.

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• Patients with spinal muscular atrophy types III and IV usually present with an insidious onset of weakness, often following a brief period of illness, such as with influenza. The illness may have required a short period of bed rest.

• Patients most often report symptoms associated with weakness of the hip extensor and hip abductor muscles and describe difficulty climbing stairs or getting up from a seated position on the floor.

• Some patients also may report a mild tremor and occasional, painful muscle cramps.

• Difficulty walking or running also is reported by the patient.

• Parents of younger patients may report delayed developmental milestones or decreased athletic abilities in their children.

• A family history of such disorders also may be elicited.

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• Proximal muscle weakness is seen in spinal muscular atrophy, with the pelvic girdle being more affected than the shoulder girdle.[5]

• Patients have decreased muscle tone.

• Patients have diminished deep tendon reflexes. Ankle reflexes, however, may be preserved until very late in the disease's progress.

• Fasciculations may be present in the tongue or shoulder girdle muscles (especially after manual muscle testing).

• Minipolymyoclonus, a fine, irregular tremor of the outstretched fingers, may be seen. This is the result of denervation followed by reinnervation and the asynchronous firing of restructured and enlarged motor units.

• Calf pseudohypertrophy has occasionally been noted, but muscle wasting of affected musculature is more prominent.

• Patients may have a positive Gowers sign and a waddling gait.

• Approximately one third of patients have facial and masseter muscle weakness.

• Sensory examination findings are normal.

The exact etiology of spinal muscular atrophy (SMA) is unknown. SMA is an inherited disorder that almost always occurs in an autosomal recessive pattern. A few cases of autosomal dominant and X-linked recessive patterns have been reported.

All forms of SMA have been linked to a gene deletion on the long arm of chromosome 5, at band 5q13. The 2 genes associated with SMA are SMN1 (survival motor neuron 1) and SMN2, which are adjacent to each other on band 5q. SMN1 is believed to be the primary disease-causing gene.[16] SMN2 differs from it by 1 C-T transition in exon 7, leading to alternate splicing and a nonfunctional protein for 70-90% of the protein produced.[17] An attenuated disease severity and a milder phenotype appears to be correlated with the presence of 3 or more copies of SMN2.

Several mechanisms have been proposed for the relationship between the SMN genes and the natural history of SMA. The SMN1 protein has been associated with the assembly of spliceosomal ribonucleoproteins, which are critical to messenger RNA processing. The SMN1 protein has also been associated with the NAIP (neuronal apoptosis inhibitory protein) gene, a gene that helps to regulate programmed cell death. Some authors have hypothesized that a deletion of the SMN gene may be related to disturbances in the metabolism of 3',5'-adenosine monophosphate. Whether or not these disturbances contribute to neuronal degeneration in SMA remains to be seen.

A study by Sedghi et al indicated that deletions in exons 4 and 5 of NAIP are related to symptom severity in SMA.[18]

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• Molecular genetic testing[19, 20] - Routine diagnostic testing for spinal muscular atrophy (SMA) involves targeted mutation analysis to detect deletion of exons 7 and 8 of SMN1. Approximately 95-98% of individuals with a clinical diagnosis of SMA lack exon 7 in both copies of SMN1 (ie, they are homozygous for the deletion). Approximately 2-5% of individuals with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1. Routine genetic testing detects only patients with the homozygous deletion. However, additional testing is available that includes SMN1 sequence analysis for the detection of point mutations in the SMN1 gene. Genetic testing has also been developed that uses the quantitative polymerase chain reaction to determine the SMN2 gene copy number; however, such testing is not yet widely available. The SMN2 gene copy number is variable, rangingfrom0-5.

• Other testing - Serum creatine kinase levels may be elevated but usually not to the extent that they are elevated in persons with muscular dystrophy. Serum aldolase levels also are commonly elevated in persons with types III and IV SMA.

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• Ultrasonographic imaging of the muscles has been used to assess for neurogenic atrophy in spinal muscular atrophy (SMA), but it is fairly nonspecific. Ultrasonography has lost favor as a diagnostic tool for SMA. Neuroimaging of patients with SMA reveals no brain abnormalities.

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• Muscle biopsy reveals evidence of neurogenic atrophy and chronic reinnervation in spinal muscular atrophy (SMA). Skeletal muscle changes include atrophy with a combination of narrow fibers and large, hypertrophic fibers. These fibers are separated by abundant fat and fibrous tissues. Increase in the sarcolemmal nuclei with preservation of striations is observed. The phrenic (C3-C5) and sacral (S2-S4) sphincter motor neurons are spared. Typical findings consistent with neurogenic atrophy also are seen on biopsy and are discussed above in the Pathophysiology section.

• Electromyography (EMG) and nerve conduction studies (NCS) can be very useful for the physician in the diagnosis of SMA. Diffuse abnormalities on EMG are seen in the extremities and bulbar musculature. The findings are consistent with axonal degeneration. Fibrillation potentials, positive sharp waves, and complex, repetitive discharges are common. Large motor unit potentials are typical, but small amplitudes also have been seen. Upon recruitment, polyphasic motor unit potentials, decreased recruitment, fast firing, and synchronization of motor units are seen. A marked increase in jitter on electromyograms often is seen and helps to differentiate SMA types III and IV from ALS. Motor nerve conduction velocities are normal or slightly decreased. Motor unit action potentials (MUAPs) progressively decrease in amplitude. Sensory nerve action potentials (SNAPs) are normal.

Physical Therapy

Spinal muscular atrophy (SMA) has no known cure; thus, most care for the patient with SMA is focused on symptomatic control and preventative rehabilitation.[6] Maintaining the patient's joint mobility is very important because the goal is to decrease the incidence of contractures. Plantar flexion contractures are the most common.

Ankle-foot orthotics worn at night may help to provide prolonged, passive stretching to prevent worsening of ankle plantar flexion contractures.

Stretching and strength training in patients under the care of an experienced physical therapist are very important components of the preventative rehabilitation approach. For school-age patients, a physical therapist can provide consultation regarding appropriate or adaptive physical education activities. Aquatic therapy is an excellent way to maintain mobility, strength, and flexibility.

A study by Madsen et al indicated that cycle training improves maximal oxygen uptake (VO2max) in patients with Kugelberg Welander SMA, but at the cost of significant fatigue. In the study, six patients with Kugelberg Welander SMA and nine healthy controls underwent 12 weeks of cycle ergometer training; this consisted of 42 thirty-minute sessions, with patients exercising at 65-70% of their VO2max. The investigators found that the patients’ VO2max improved during their training by 27%, with no occurrence of muscle damage. However, fatigue led one patient to drop out of the study and two others to require training modifications, with three patients experiencing an increased need for sleep. According to the investigators, the results suggested that alternative training methods should be sought to improve exercise capacity in patients with Kugelberg Welander SMA.[21]

Because of the progressive weakness associated with SMA, patients may require the full-time use of a wheelchair. For these patients, there are multiple assistive devices available that enable them to maintain a level of independence. Patients are encouraged to use manual wheelchairs rather than electric ones, when possible, to maintain cardiovascular fitness and upper body strength.

Occupational Therapy

The occupational therapist plays an essential role in addressing the individual needs of patients with spinal muscular atrophy. Occupational therapy is useful for teaching the patient ways to increase his/her independence in activities of daily living (ADL). Fine motor skills may be affected by fatigue. Affected school-age patients may benefit from an occupational therapy consultation that addresses keyboarding and other ways to avoid fatigue from upper extremity activities in the classroom.

Patients may eventually require the use of a wheelchair on a full-time basis. In addition, multiple assistive devices are available that enable patients to maintain a higher level of independence.

Speech Therapy

Patients with spinal muscular atrophy may require consultation with a speech therapist if dysphagia is present or diet modification is needed.

Orthopedic

A few studies have shown that scoliosis is a major problem in half of the patients with spinal muscular atrophy (SMA) type III. However, scoliosis occurs less frequently in patients with SMA type III than it does in persons with type II, and it is not as severe. Routine radiography should be performed, and the patient may require a thoracolumbar sacral orthosis (TLSO) or may need surgery. Spinal orthoses have been shown to assist in containing the spinal deformity until instrumentation and fusion can be performed, if necessary.[22]

Hip subluxation is also common. One author reports 50% of patients with SMA type III have hip subluxation or dislocation, with rare improvement in function from surgical reduction.

Respiratory

Pulmonary disease is the major cause of morbidity and mortality in patients with SMA types I and II and in a small portion of persons with SMA type III.[10, 11, 12] The presence of expiratory muscle weakness that is greater than inspiratory muscle weakness, with relative sparing of the diaphragm, leads to impaired cough, hypoventilation during sleep, chest wall underdevelopment, and the potential for recurrent infections.

A study by Trucco et al indicated that respiratory decline differs between patients with type II and nonambulant type III SMA. In those with type II, forced vital capacity percent predicted (FVC%P) fell by 4.2% per year between ages 5 and 13 years, while in patients with nonambulant type III, the decline was 6.3% annually between ages 8 and 13 years. In both types of SMA, the reduction slowed after age 13 years, to 1.0% per year in type II and to 0.9% per year in nonambulant type III.[23]

Another author, however, found that in SMA type III, pulmonary function was preserved until age 13 years, and that by age 17 years, pulmonary function had decreased to 79%.

Pulmonary function tests can be performed, with forced vital capacity (FVC) as the best predictor of respiratory reserve; these tests should be done on a regular basis. Treatments may include noninvasive ventilation, including intermittent positive pressure ventilation, bilevel positive airway pressure ventilation, and negative pressure ventilation. Infections should be treated aggressively with antibiotics, mucolytics and bronchodilators, oxygen, chest PT and postural drainage, and a cough-assist machine.

Sleep disorders

Questions regarding sleep hygiene and fatigue should be addressed. Patients with SMA type III frequently report fatigue.[24] One case report described a 46-year-old man with SMA type III whose increasing daytime fatigue caused by nocturnal snoring and apnea resolved with nighttime use of continuous positive airway pressure with a nasal mask.[25] Another case report documented the coexistence of sleep-disordered breathing and dilated cardiomyopathy in a 53-year-old patient with SMA type III.[26] Similarly, symptoms were virtually eliminated with nighttime use of continuous positive airway pressure via nasal mask. Sleep studies can be used to screen for nocturnal hypoventilation.

Other

Other complications include the following:

• Contractures - Usually mild as long as patients remain ambulatory
• Dysphagia

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• If scoliosis develops in a patient with spinal muscular atrophy, spinal instrumentation and fusion may be necessary.[7] Some upper extremity function can be lost after fusion.

• Tendon lengthenings may be needed to improve joint position.

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• Genetic counseling for spinal muscular atrophy (SMA) - Parents, patients, and extended family members may benefit from genetic counseling. Carrier detection relies on determining the number of exon 7 – containing SMN1 gene copies present in an individual. SMA carrier testing, a polymerase chain reaction – based dosage assay, is available on a limited clinical basis. For a number of reasons, test results can be difficult to interpret and should be provided in the context of formal genetic counseling.

• Vocational rehabilitation counseling - This type of counseling may be beneficial to facilitate the transition from secondary school to postsecondary education or for vocational planning.

Numerous treatment trials for spinal muscular atrophy (SMA) have been described or are currently underway.[27]  Based on the role that mutations or deletions in SMN1 play in the development of SMA, treatments have been developed that are directed at the gene’s expression. In 2016, nusinersen became the first such agent to obtain approval from the US Food and Drug Administration (FDA). It is given intrathecally, with four loading doses administered, as well as a maintenance dose every 4 months.[28, 29] The best outcomes have been found when the drug is provided at a very young age. In 2019, onasemnogene abeparvovec-xioi became the next agent to receive FDA approval, albeit only for children under age 2 years.[30] Considering its age limitation, the drug, administered as a one-time intravenous (IV) injection, may not be relevant to the treatment of many patients with Kugelberg Welander SMA, since they are typically diagnosed at an older age. Risdiplam received FDA approval in 2020; it is a daily oral medication that can be given to SMA patients aged 2 months or older.[31]

Medications being studied for upregulation of SMN2 protein production or for increase of exon 7 inclusion include phenylbutyrate, valproic acid, suberoylanilide hydroxamic acid, and hydroxyurea. The neuroprotective medications being investigated, including gabapentin and riluzole, are thought to provide protection from oxidative stress. Albuterol has been studied for its trophic/anabolic effects. Exercise therapy in rats has shown modest improvement in survival and modest decrease in motor neuron loss. Treatment with stem cells is also an area undergoing further study.

A single study from the Russian literature in 1980 suggested that lithium may have a role in slowing the disease progression, but this has not been corroborated. Further studies are needed to investigate this.[32]

A study using thyrotropin-releasing hormone as a treatment for SMA types II and III in children showed promising results. More studies are warranted to further investigate this possible treatment.[33]

Merlini and colleagues performed a multicenter, randomized, controlled trial of gabapentin versus no treatment in 120 patients with SMA type II or III for 12 months.[34] A significant improvement in lower extremity, maximum, voluntary isometric contraction was seen.

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• Patients with spinal muscular atrophy (SMA) should have frequent follow-up care for symptomatic control of their disease. Respiratory function, nutritional state, orthopedic status, and equipment needs should be assessed at each visit. Pain control, preventative medicine, surgical intervention, and physical therapy are all essential parts of the patient's long-term care. The multidisciplinary approach, which includes family members, social workers, therapists, and physicians, is important to assist the patient in maintaining a high quality of life.

See the list below:

• Scoliosis

• Plantar flexion contractures

• Dysphagia

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• Patients with spinal muscular atrophy experience a progressive loss of motor function that usually affects the legs before it does the arms, and the proximal muscles before the distal ones.

• Patients who have never climbed stairs without a rail lose walking ability by their midteens. Patients who develop normal walking skills prior to the onset of muscle weakness can maintain this ability until the third or fourth decade.

• Life expectancy for individuals with SMA type III has been shown to be similar to that of the general population.[9]

• See Mortality/Morbidity.