Spinal Muscular Atrophy

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The Spinal Muscular Atrophies (SMA) are a group of autosomal recessive disorders which lead to progressive loss of brainstem and spinal lower motor neurones, resulting in progressive motor weakness and ultimately death.


Werdnig and Hoffman independently described the SMAs in the 1890s.


Contents

Subtype Classification

Subtype classification is largely based on the clinical severity and age at which features present:

  • Type I - Severe SMA or Werdnig-Hoffmann disease
  • Type II - Intermediate SMA
  • Type III - Mild SMA or Kugelberg-Welander Disease
  • Type IV - Adult onset SMA


It is well recognised that there is a wide range of disease severity and that there is a spectrum from less severe to more severe even within each subtype. Classification is further compounded since severity of disease and age at onset do not always correlate. As such, prognosis may also be widely variable within each sub-classification.


To avoid giving misleading prognosis, is has been recommended that "Werdnig-Hoffman disease" is used for severe infantile forms of SMA and "Kugelberg-Welander disease" for the later-onset, mild ambulant form. Intermediate cases could then be grouped according to severity.


Incidence

The SMAs are the second commonest autosomal recessive inherited conditions (after cystic fibrosis).

  • Incidence ~ 10 per 100 000 live births approximately.
  • Carrier frequency is uncertain
    • UK: low frequency (1 per 60-80)
    • Germany / Italy: intermediate (1 per 50)
  • Males more commonly affected, particularly with Types I and II (early onset).


Distribtution of subtypes:

  • SMA type I ~ 25%
  • SMA type II ~ 50%
  • SMA type III ~ 25%
  • SMA type IV


Age at onset

  • SMA type I: (Werdnig Hoffman): birth to 6 months (death usually before 2 years).
  • SMA type II : 6 and 18 months (survival beyond 4 years)
  • SMA type III (Kugelberg-Welander): after 18 months (benign course)
  • SMA type IV (adult onset): Mean onset ~ mid 30s.


Aetiology and Genetics

SMA involves progressive loss of lower motor neurones from the spinal cord and certain brainstem motor nuclei (Cranial Nerves V, VII, IX, XII).

  • Mutations have been found in 'Survival Motor Neurone' gene (SMN) in chromosome 5q11-13. The SMN protein is part of a complex involved in the assembly of small ribonuclearproteins, which in tern play an important role in early messenger RNA (mRNA) processing. Mutations produce loss of protein function.
  • Inheritance is autosomal recessive.
  • It is not yet known why this affects lower motor neurones selectively.

Two other genes have been implicated in some cases of SMA:

  • NAIP gene, Neuronal apoptosis inhibitory protein (AIP).
  • BFT2p44 gene: Mutations in this gene have been found in 15% of patients with SMA.


Clinical Features and Diagnosis

In general, features are of progressive muscle weakness secondary to progressive loss of motor neurones.


Weakness is characteristically symmetrical and affects proximal muscles more than distal muslces and legs more than arms.


SMA type I - see Werdnig-Hoffmann disease for details.

  • The most severe form. Onset soon after birth.
  • Reduced foetal movements ~1/3. May cause arthrogryposis.
  • Hypotonia. 2/3 floppy at birth.
  • Bulbar dysfunction: poor suck/swallow.
  • Respiratory failure results in death.


SMA type II - the commonest form

  • Developmental motor delay. Difficulty sitting/standing
  • Postural tremor of fingers / muscle fasciculations
  • Pseudohypertrophy of gastrocnemius.
  • Musculoskeletal deformities
  • Lifespan: 2-30 years.


SMA type III - mild form

  • Slowly progressive weakness, often proximal
  • Mild motor delay / impairment.
  • Late bulbar dysfunction


SMA type IV - relatively benign.


Many SMA variants have been described. Indeed, other gene defects have been implicated.


Investigations

  • Creatinine Kinase (CK): normal (SMA 1) or slightly elevated (SMA II - IV)
  • Genetic testing (pre or post-natal): chromosome 5q


Tests to differentiate SMA from other neurological or myopathic conditions:

  • Electrophysiology
    • Reduced compound motor action potentials (severity dependent)
    • Fibrillation potentials (early disease)
    • Spontaneously firing motor action unit potentials at 5-15Hz are thought to be unique to SMA I and II.
    • Sensory nerve conduction normal
  • Muscle biopsy
    • Histology: atrophy with compensatory hypertrophy, 'type grouping' (groups of large and small fibres).
    • Chronic forms may resemble muscular dystrophies
  • CSF: normal


Differential Diagnoses

  • Marfan or Prader-Willi syndrome
  • Metabolic disorders (including the organic acidurias and mitochondrial diseases)
  • Acid maltase deficiency (type II glycogenosis)
  • Type II (Pompe) glycogen storage disease
  • Infantile Gaucher disease
  • GM1 gangliosidosis
  • Hurler syndrome
  • Adrenoleukodystrophy
  • Down syndrome
  • Botulism
  • Congenital hypomyelination neuropathy
  • Congenital polyneuritis
  • Neonatal and congenital myasthenia gravis
  • Peripheral neuritis
  • Poliomyelitis
  • Spinal cord transection


Treatment

Treatment is largely supportive. Typical complications include:

  • Respiratory failure
  • Scoliosis
  • Contractures

Genetic counselling should be offered.


Prognosis

Mechanism of death commonly involves respiratory complications, particulary due to infections.

  • High death rates are associated with early onset disease.
  • Prognosis is widely variable with types II - IV.


By sub-type:

  • SMA type I ~ 95% mortality by 18 months age.
  • SMA type II ~ Survival at age 10 = 98%, age 20 = 77%
  • SMA type III ~ Life expectancy close to the normal population. Worse prognosis if onset before 3 years age.
  • SMA type IV


References


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