Spinal Muscular Atrophy (SMA) is a congenital motor neuron degenerative disorder typically resulting from loss of the SMN1 gene on chromosome 5q13.1 While homozygous loss of SMN1 has been reported to account for anywhere from 95%2 to approximately 50%3 of cases with SMA, there are patients with lower motor neuron presentations resembling SMA who are found to have disease-causing mutations in genes other than SMN1, leading to a growing list of pathogenic gene variants associated with “non-5q”4 or SMN1-negative congenital SMAs.5,6 but with expanded use of gene sequencing, more pathogenic mutations are sure to be found, and clinicians should not that the standard gene panels currently in use may not capture every potential genetic cause.3
Atypical forms of SMA and SMA-like diseases with adult onset (SMA type 4) are discussed below.
- The prototypical adult onset SMA is spinal and bulbar muscular atrophy, also known known as Kennedy disease.5 Patients with spinal and bulbar muscular atrophy experience progressive bulbar and limb weakness beginning in the fifth decade of life.7 Spinal and bulbar muscular atrophy is an X-linked disorder associated with > 36 CAG expansions within the first exon of the androgen receptor located on Xq12.5 The involvement of sensory neurons and endocrine function differentiate Kennedy disease from SMA type 4.5
- Hexosaminidase A and B deficiencies, causing adult-onset lysosomal storage disease due to variants in HEXA and HEXB genes, are autosomal recessive diseases that can present as late onset SMA-like diseases with proximal weakness of the lower extremities.5,8 Severe psychiatric manifestations and seizures occur in these disorders8 and differentiate the lysosomal storage diseases from SMA4.
- Approximately10% of amyotrophic lateral sclerosis (ALS) is congenital, associated with variants in the copper/zinc superoxide dismutase gene-1 (SOD-1), the TAR DNA-binding protein 43 (TDP-43), or the fused in sarcoma/translation in liposarcoma (FUS/TLS), senataxin (SETX), vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) genes, among a growing list of over 20 known genetic causes.5,9,10 11ALS due to congenital causes will present with a variably progressive weakness that is the result of mixed upper and lower motor neuron loss that is often associated with a fronto-temporal dementia,9 features that make it quite distinct from type 4 SMA.
- SMA followed by cardiac involvement is a form of Emery-Dreifuss muscular dystrophy, an adult onset SMA caused by variants in the LMNA gene that codes for laminin A and C proteins. Inherited in an autosomal dominant pattern, patients with variants in LMNA will experience slowly progressive muscle weakness and muscle atrophy beginning in the humero-peroneal groups with eventual extension to the scapular groups and the pelvic girdle.12 The cardiomyopathy of Emery-Dreifuss muscular dystrophy, which includes potentially fatal conduction disturbances,12 is not a feature of type 4 SMA.13
- Hereditary motor and sensory neuropathy (HMSN-P) is a slowly progressive neuromuscular disease attributed to autosomal dominant inherited variants in the TRK-fused gene (TFG).5 Patients begin with muscle cramps and weakness in their twenties and progress to have respiratory insufficiency and swallowing difficulties with death 4-5 decades after onset.14 The involvement of respiratory and bulbar muscles does not occur in type 4 SMA.13
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