Spinal Muscular Atrophy: Differential Diagnosis – Adult Onset

Spinal Muscular Atrophy (SMA) that presents in adulthood, so-called type 4 SMA, has a more restricted differential diagnosis than types 0-3. Considerations for the adult with new mild weakness are as follows:


Autoimmune diseases can present with new onset weakness. Patients with Guillain-Barré syndrome1, transverse myelitis,2 multiple sclerosis,3 and myasthenia gravis4 can feature weakness as a presenting complaint. The weakness of Guillain-Barré syndrome is more distal, and weakness in multiple sclerosis may be episodic and selective. Unlike childhood forms of SMA, adult SMA will not compromise respiratory function, but myasthenia gravis typically will.4 Neuroimaging and electrodiagnostic testing are helpful in distinguishing these autoimmune diagnoses from type 4 SMA.


The most concerning diagnosis for an adult with progressive new weakness is amyotrophic lateral sclerosis (ALS), though only a small fraction of patients will demonstrate a variant in a known disease-causing gene. 6,7 Other neurodegenerative diseases such as Parkinson’s disease or Alzheimer’s disease can present with gait instability but rarely with true weakness.7 The progression in type 4 SMA is slow and should not degrade quality of life significantly; patients with rapid deterioration require consideration of more serious neurodegenerative diseases.7

A diagnosis often confused with SMA type 4 is the adulthood onset X-linked spinal bulbar muscular dystrophy (Kennedy disease), but Kennedy disease has findings consistent androgen resistance not found in SMA.8 Though it is rare, there are also case reports of childhood neurodegenerative diseases such as hexosaminidase A deficiency (Tay-Sachs disease) with symptom onsets in adulthood.9 Mitochondrial diseases can have very late onset and protean manifestations in adults.


Infection with West Nile virus10 or enteroviruses11 can cause an acute or sub-acute flaccid paralysis. Human T-cell Leukemia Virus-1 (HTLV-1) is a cause of weakness and spastic paraplegia seen in the adult population with history of an exposure in endemic environments such as the tropics.12


A deficiency in vitamin B12 can cause weakness, along with anemia and sensory disturbances not associated with type 4 SMA.12 Vitamin D deficiency is an underappreciated cause of weakness in adults, but osteoporosis or osteopenia will differentiate this diagnosis from SMA.13


Spinal cord impingement or injury from a variety of causes such as metastatic cancer15 or inflammation3 can cause weakness or paralysis that, unlike SMA, will have an identifiable correlate on neuroimaging.


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15. Rodriguez Y, Rojas M, Pacheco Y, et al. Guillain-Barre syndrome, transverse myelitis and infectious diseases. Cellular & molecular immunology. 2018.