Spinal Muscular Atrophy Clinical Presentation

Updated: Jan 04, 2017
  • Author: ; Chief Editor: Amy Kao, MD  more...
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Presentation

History

The diagnosis of spinal muscular atrophies includes the following a detailed clinical history. Obtaining a complete family history facilitates genetic counseling.

Patients with spinal muscular atrophy present with weakness and muscle wasting in the limbs, respiratory, and bulbar or brainstem muscles. They have no evidence of cerebral or other CNS dysfunction. Patients with spinal muscular atrophy often have above-average intelligence quotients (IQs) and demonstrate high degrees of intelligence.

The clinical manifestations of each particular form of spinal muscular atrophy are discussed: [15, 2, 16, 17, 18]

SMA type I - Acute infantile or Werdnig-Hoffman disease

Patients present before 6 months of age, with 95% of patients having signs and symptoms by 3 months. They have severe, progressive muscle weakness and flaccid or reduced muscle tone (hypotonia). Bulbar dysfunction includes poor suck ability, reduced swallowing, and respiratory failure. Patients have no involvement of the extraocular muscles, and facial weakness is often minimal or absent. They have no evidence of cerebral involvement, and infants appear alert.

Reports of impaired fetal movements are observed in 30% of cases, and 60% of infants with SMA type I are floppy babies at birth. Prolonged cyanosis may be noted at delivery. In some instances, the disease can cause fulminant weakness in the first few days of life. Such severe weakness and early bulbar dysfunction are associated with short life expectancy, with a mean survival of 5.9 months. In 95% of cases, infants die from complications of the disease by 18 months.

SMA type II - Chronic infantile form

This is the most common form of spinal muscular atrophy, and some experts believe that SMA type II may overlap types I and III.

Most children present between the ages of 6 and 18 months.

The most common manifestation that parents and physicians note is developmental motor delay. Infants with SMA type II often have difficulties with sitting independently or failure to stand by 1 year of age.

An unusual feature of the disease is a postural tremor affecting the fingers. This is thought to be related to fasciculations in the skeletal muscles.

Pseudohypertrophy of the gastrocnemius muscle, musculoskeletal deformities, and respiratory failure can occur.

The lifespan of patients with SMA type II varies from 2 years to the third decade of life. Respiratory infections account for most deaths.

SMA type III - Chronic juvenile or Kugelberg-Welander syndrome

This is a mild form of autosomal recessive spinal muscular atrophy that appears after age 18 months.

SMA type III is characterized by slowly progressive proximal weakness. Most children with SMA III can stand and walk but have trouble with motor skills, such as going up and down stairs.

Bulbar dysfunction occurs late in the disease.

Patients may show evidence of pseudohypertrophy, as in patients with SMA type II.

The disease progresses slowly, and the overall course is mild. Many patients have normal life expectancies.

SMA type IV - Adult-onset form

Onset is typically in the mid 30s.

In many ways, the disease mimics the symptoms of type III.

Overall, the course of the disease is benign, and patients have a normal life expectancy.

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Physical

Patients with disease of the lower motor neurons present with flaccid weakness, hypotonia, decreased or absent deep tendon reflexes, fasciculations, and muscle atrophy.

SMA type I - Acute infantile or Werdnig-Hoffman disease

Diffuse muscle weakness and hypotonia can be demonstrated with a variety of bedside maneuvers, including the traction response, vertical suspension, and horizontal suspension tests.

In general, infants with SMA type I cannot hold their heads up when pulled to the sitting position, and they will slip through the examiner's hands when held vertically. They lay limp in the physician's hand when held under the abdomen and facing down.

Weakness is greater in proximal than distal muscles and may mimic muscle disease (myopathy).

Findings on sensory examination are normal. Deep tendon reflexes are absent, as are long-tract signs and sphincteral abnormalities.

Arthrogryposis, or deformities of the limbs and joints at birth, can be observed and results from in utero hypotonia. Skeletal deformities (scoliosis) may be present.

In the infant or newborn, fasciculations are often restricted to the tongue, but tongue fasciculations can be difficult to distinguish from normal random movements unless atrophy is also present.

SMA type II - Chronic infantile form

Infants cannot get to a sitting position on their own, though they may stay upright if placed in that position.

As with SMA type I, SMA type II cause notable, symmetric proximal weakness, hypotonia, and fasciculations.

Findings on sensory examination are normal, and long-tract signs are absent. When the patient's hands are held out, a characteristic fine postural tremor may be observed.

SMA type III - Chronic juvenile or Kugelberg-Welander syndrome

Children can ambulate, but they have proximal muscle weakness and various degrees of muscle hypotonia and wasting.

The lower extremities are often more severely affected than the upper extremities.

SMA type IV - Adult-onset form

Patients are similar to those with SMA type III in presentation and clinical findings, though the overall degree of motor weakness is less severe in type IV than in type III.

Spinal muscular atrophy variants:

See the list below:

  • SMA type 0 (prenatal onset SMA or arthrogryposis multiplex congenita): This has been described in infants born with hypotonia, respiratory distress, and multiple arthrogryposis. Complete deletion of SMN and NAIP genes has been noted. [19]

  • Juvenile bulbar palsy, or bulbar hereditary motor neuronopathy (HMN) types I and II: Bulbar HMN I (Vialletto-van Laere syndrome) is an autosomal recessive syndrome that begins in the second decade of life. It is characterized by facial weakness, dysphagia and dysarthria followed by facial weakness and compromised respiratory function. The distinguishing feature of this syndrome is the development of bilateral sensorineural hearing loss.

  • Bulbar HMN II (Fazio-Londe disease): This is characterized by progressive bulbar paralysis in the first decade of life. Patients present with stridor, dysarthria, and dysphagia. Cranial-nerve involvement leads to facial diplegia, ptosis, and ophthalmoplegia. Generalized weakness of the lower motor neurons and rare corticospinal-tract signs are sometimes observed. Median survival for patients with bulbar HMN II is 18 months. [20]

  • Distal spinal muscular atrophy (spinal CMT or HMN type II): This may clinically mimic Charcot-Marie-Tooth (CMT) disease, otherwise known as hereditary motor and sensory neuropathy (HMSN) types 1 and 2: CMT is characterized by peroneal muscular atrophy, weakness, and wasting in the legs. High foot arches (pes cavus) are often present. Deep tendon reflexes are reduced or absent. Distal large fiber sensory loss is found on examination, although patients do not usually present with complaints of subjective sensory loss. Compared with CMT, patients with distal spinal muscular atrophy do not have sensory loss and the electrodiagnostic examination shows sparing of sensory nerves. [4]

  • X-lined recessive bulbospinal muscular atrophy (Kennedy disease): [21] Patients present with bulbar weakness, gynecomastia, and lower motor neuron weakness beginning at age 20-40 years. Muscles cramps often precede weakness, and facial and perioral fasciculations are seen in more than 90% of patients. Increased rates of type 2 diabetes, infertility, and hand tremor are associated with Kennedy disease. This condition results from a triple repeat mutation (cytosine-adenine-guanine [CAG]) in exon 1 of the androgen receptor gene on the X chromosome. Because of the X-linked nature of Kennedy disease, daughters of affected patients are obligated carriers; therefore, genetic counseling is indicated.

  • Scapuloperoneal spinal muscular atrophy: Type 1 (AD form) appears at age 14-26, with weakness, distal leg atrophy, and absent tendon reflexes and sparing of intrinsic foot muscles. Facial, bulbar, and pectoral muscles are rarely affected. Progression is slow, with survival into the seventh or eight decade of life.

  • Type 2 (AR form): Patients present between birth and age 5 years, with weakness and atrophy of the lower extremities and pectoral girdle. The course is variable, and patients can survive to the fourth decade. [22]

  • X-linked form scapuloperoneal spinal muscular atrophy: This has been described with an onset before age 10 years. Patients present with weakness of the pectoral girdle and arms with contractures. Cardiac conduction defects and cardiomyopathy are noted. The syndrome is slowly progressive but stabilizes by age 20 years, and patients survive to the sixth decade.

  • Davidenkow syndrome: This is a form of scapuloperoneal SMA characterized by weakness of the pectoral girdle and distal leg muscles, pes equinovarus, and distal sensory loss and fasciculations. Autosomal dominant (age of onset, 15-30 y) and autosomal recessive (age of onset, < 15 y) forms have been described. The clinical course is slow in the autosomal dominant form, whereas the course of the autosomal recessive form is unknown.

  • Fascioscapulohumeral (FSH) SMA: Most reports of this disorder are from Japan. It is an autosomal dominant or sporadic disorder characterized by limb-girdle and facial weakness occurring before age 20 years. The phenotype of FSH SMA is similar to that of FSH dystrophy (FSHD), another unrelated muscular dystrophy. However, FSH SMA does not have the chromosome 4 gene deletion seen in FSHD. Progression is slow, and the overall prognosis is good.

  • Scapulohumeral spinal muscular atrophy: Described initially in a Dutch family, this autosomal dominant disorder is characterized by the onset of scapulohumeral weakness and atrophy between the fourth and sixth decades of life. Progression is rapid, with death from respiratory failure occurring within 3 years.

  • Oculopharyngeal spinal muscular atrophy: This disorder is seen mainly in people of French-Canadian descent and is characterized by bulbar and cranial-nerve weakness followed by myopathic weakness of the limbs. The pattern of inheritance is autosomal dominant with variable penetrance. The onset is usually in the fourth to fifth decades of life, and the disease is slowly progressive.

  • Ryukyuan spinal muscular atrophy: This is an autosomal recessive disorder described in men who live in the Japanese community on Ryukyu Islands. The onset is before age 5 years, and the disease is characterized by weakness and atrophy of the lower extremities, skeletal abnormalities (eg, scoliosis), and foot deformities (eg, pes cavus). Deep tendon reflexes are diminished or absent. The course of disease is unknown. [23]

  • Spinal muscular atrophy with pontocerebellar hypoplasia (PCH1): This heterogeneous autosomal recessive disorder is characterized by generalized muscle weakness, global developmental delay, and early death. One study found that 30-40% of patients with milder disease course had protein EXOSC3 mutations. [24]

  • Other: Other variants have been described, including multiple long-bone fractures at birth, diaphragmatic paralysis with early respiratory failure, congenital heart defects, arthrogryposis, segmental amyotrophy, vocal-cord paralysis (distal HMN type VII), and disease of the anterior horn cell with agenesis of the corpus callosum (SMA with respiratory distress). [25, 26, 27] SMA with respiratory distress presents with rapid decline over 2 years, followed by a plateau, and is linked with mutation in the IGHMBP2 gene. [28] An autosomal dominant late-onset lower motor neuronopathy was discovered in 2 Finnish families with linkage to a mutation on band 22q11.2-q13.2. [29] A rare form of autosomal dominant proximal SMA has been identified with a possible linkage to an SETX gene mutation. [30]

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Causes

In 1995, the SMN gene, responsible for SMA types I-III, was mapped to the long arm of chromosome 5. (See Pathophysiology.)

Two copies of the SMN gene have been identified on the 5q arm: a telomeric SMN gene (SMNt, or SMN1) and a centromeric SMN gene (SMNc, or SMN2). These 2 genes are nearly identical except for base-pair changes in exons 7 and 8. About 95% of all cases of SMA involve a homozygous deletion of the SMN1 gene. [31]

Expression of SMN1 produces the full-length SMN protein. In contrast, expression of SMN2 produces a truncated version of the SMN protein that is missing the 16 amino acids from the carboxy terminus. This truncated protein results from a base-pair switch in exon 7 of the SMN2 gene. This switch leads to alternative splicing of SMN2 mRNA, with removal of the exon 7 sequence. About 70-80% of the gene product is in the form of this truncated protein. Only about 10-25% of the protein produced is the full-length functioning form. [31]

Deletions or mutations in the SMN1 gene substantially decrease expression of the SMN protein. Expression of SMN2 alone does not appear to produce sufficient amounts of SMN protein to permit normal mRNA processing in the lower motor neurons. A correlation between SMN2 copy number and disease phenotype has been proposed, with increased copy associated with milder disease. [32] Additionally, low SMN protein levels are associated with more severe disease forms. [33] Inefficient or abnormal mRNA processing appears to have a toxic effect on the lower motor neurons and results in cellular degeneration. [34]

SMN protein is part of a multimeric protein complex that plays a critical role in the assembly of snRNPs. These snRNPs are essential for early pre-mRNA splicing. The hypothesis is that impaired or reduced formation of snRNPs impairs mRNA splicing, with a toxic effect on normal cellular function. Why this mutation results in such selective degeneration of lower motor neurons is unclear, though the SMN protein is expressed in many types of neurons and organ systems. [35]

Neuronal apoptosis inhibitory protein (AIP), NAIP, gene was also identified in 1995. Homozygous deletions of this gene are found in 45% of patients with SMA type I and in 18% of patients with SMA types II or III. This gene belongs to a class of highly conserved AIPs that help to regulate programmed cell death. Deletion of this gene appears to be associated with severe phenotypes of SMA. [36]

Mutations in BFT2p44 have been found in 15% of patients with SMA. [37]

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