ORGANUM
Spinal muscular atrophy (SMA) is an inherited autosomal recessive disease with varying phenotypes that is characterised by progressive muscle weakness, reduced tone with associated destruction of alpha motor units. It is a disease of the lower motor neuron. There are four main subtypes defined by the age of onset and severity. It may begin in intrauterine life or any time thereafter.
Progressive degeneration of anterior horn cells is the key manifestation of SMA. In 95% of cases, SMA results from a homozygous deletion of SMN1 on chromosome 5q13; although, this cannot explain the significant clinical heterogeneity in phenotype. There are two versions of the SMN gene:
Telomeric version (SMN1)
Centromeric version (SMN2)
Individuals vary in the number of copies of SMN2 they posses. SMN1 transcription produces a functionally complete mRNA, that can then be encoded to create the SMN protein. SMN2 transcription results in functionally complete mRNA 10% to 15% of the time, resulting in far fewer SMN protein being encoded than SMN1. SMN2 is identical to SMN1 except for a single C-T substitution in exon 7. The substitution promotes splicing 80% to 85% of the time during transcription and the resultant removal of exon 7. This truncated mRNA causes similarly truncated non-functional proteins. Patients with SMA are lacking SMN1 and therefore are dependent on residual SMN2 production of functional SMN protein for alpha motor neuron function and subsequent survival. There is, therefore, a positive correlation seen between the number of copies of SMN2 and phenotype severity with SMA type 1 typically having 1 to 2 copies of SMN2 and SMA type 4 having 3 to 5 SMN2 copies.
There is not a perfect correlation as there are anomalies in phenotypic variation in SMN2, leading to varying amounts of functional SMN protein production in different individuals. Therefore a low number of SMN2 copies with a milder clinical phenotype have been described.
SMA incidence has been estimated at 1 in 6000 to 11000, with a carrier frequency in the of mutations in SMN1 of 2% to 3%
The earlier in life the process starts, the more severe the progression. Infants with SMA type 1 present in early infancy with severe hypotonia, generalised weakness and facial involvement. Infants have normal cognitive, social and language skills and sensations.
Fasciculations (quivering of the lateral aspect of the tongue) are best identified by inspecting the mouth when the child is asleep. Deep tendon reflexes are absent. With progression, breathing becomes rapid, shallow and predominantly. In an extremely weak child, respiratory compromise leads to atelectasis, pulmonary infection, and deaths. Most infants with SMA type 1 die within the first 2 years. Children with SMA type 2 may survive to adulthood. Children with SMA type 3 can appear normal, with slower progression of weakness and a normal life expectancy.
Type 0 (Type 1a, congenital SMA)
Presents in the neonatal period with hypotonia, early respiratory failure, severe weakness, and typically decreased fetal movements with associated arthrogryposis (multiple joint stiffness) . Death usually occurs at birth or within the first month of life; this is a rare phenotype.
Type 1 (Werdnig-Hoffman disease, 'non-sitters', severe SMA)
This presents in the first six months of life with limited head control, hypotonia and areflexia. Type I is defined as non-sitters with a frog-like posture when supine. The weakness of intercostal muscles and preserved diaphragmatic function leads to a paradoxical breathing pattern and a bell-shaped chest. Swallowing difficulties are a typical features with tongue fasciculations and associated complications such as failure to thrive and aspiration. Other cranial nerves are not normally affected initially, but facial nerve weakness typically develops later in the course. Notably, cognition is not affected, and patients are often described as alert and bright when diagnosed. Without ventilatory support, most succumb to the disease before two years of age. Type I is sometimes devidied further into Ia (Type 0), IB : Onset < 3 months, Ic : Onset 3-6 months.
Type 2 (Dubowitz disease)
If SMA is suspected following a history and exam, genetic testing is usually sufficient to confirm a diagnosis of SMA. PCR can help to detect homozygous exon 7 deletion in the SMN1 gene. Other diagnostic tests are:
Creatinine kinase - May be normal or mildly elevated
Nerve conduction studies - Sensory nerves demonstrate normal action potentials, motor nerves may show diminished motor action potentials
Needle electromyography (EMG) - SMA type I: Denervation changes with reinnervation. SMA II+III: Neurogenic patterns (action potentials with prolonged duration, increased amplitude and diminished recruitment)