Spinal muscular atrophy (SMA)

The non-5q spinal muscular atrophies and distal hereditary motor neuropathies form a clinically and genetically heterogeneous group defined by lower motor neuron dysfunction. Affected individuals present with progressive muscle weakness and wasting, frequently distal and length-dependent, although proximal patterns also occur. Age of onset ranges from congenital or infantile disease to adult onset, depending on the causative gene. Recognised non-5q leading forms include spinal muscular atrophy with respiratory distress type 1 (SMARD1, IGHMBP2), which presents with infantile respiratory distress; SMA with lower extremity predominance (SMA-LED, BICD2); X-linked SMA/SMAX (ATP7A, UBA1); SMA with progressive myoclonic epilepsy (SMA-PME, ASAH1); and the pontocerebellar hypoplasia forms (EXOSC3, EXOSC8, VRK1). Some forms are confined to the peripheral nervous system and skeletal muscle, whereas others also involve the central nervous system. This breadth is exemplified by the DYNC1H1-related spectrum, which extends from a neuromuscular-only phenotype to combined central and peripheral nervous system involvement.

Non-5q spinal muscular atrophy (non-5q SMA) accounts for roughly 5% of all spinal muscular atrophy cases. Due to insufficient data, no reliable statement on prevalence can currently be made. The individual non-5q disorders are rare to ultra-rare; for contrast, the separate 5q form of spinal muscular atrophy has an estimated incidence of 1/3,900 to 1/16,000 live births in Europe.

This panel includes 22 genes. Germline pathogenic variants in these genes disrupt the development, maintenance or function of motor neurons and their distal axons, though the specific molecular consequence is gene-dependent. The clinically most recognised genes include DYNC1H1, IGHMBP2, TRPV4, BICD2, and GARS, among others. A characteristic feature of this group of disorders is phenotypic overlap: pathogenic variants in one gene can produce presentations variously labelled distal hereditary motor neuropathy, distal spinal muscular atrophy or motor . They may overlap with other nosological entities such as dHMN, CMT type 2, , hereditary spastic paraplegia (HSP), or even mitochondrial disease and myopathy.

Mode of inheritance and subsequent recurrence risk depends on the identified gene and cannot be generalized across the panel. For the most frequently mutated genes, it is autosomal dominant (DYNC1H1, TRPV4, BICD2 and GARS) and autosomal recessive (IGHMBP2). Where a familial pathogenic variant has been identified, prenatal molecular testing is technically possible.

Diagnosis rests primarily on molecular genetic testing. Because many disorders in this group produce overlapping clinical pictures, the specific diagnosis is established by molecular testing rather than by phenotype alone. Clinical examination, electrophysiology and family history define the motor-predominant phenotype but cannot pinpoint the causative gene.

Main differential diagnoses include:

• 5q spinal muscular atrophy: proximal weakness, areflexia and tongue fasciculations; caused by biallelic variants and covered by a separate panel; SMN1
• : peripheral neuropathy with distal weakness and sensory loss; MFN2, PMP22 and others
• SORD deficiency: axonal motor neuropathy with elevated serum sorbitol; SORD
• SPTLC1-related hereditary sensory neuropathy: axonal neuropathy with cataracts and hearing loss; SPTLC1

Genetic testing serves several purposes:

• Establishing the diagnosis: a molecular genetic diagnosis confirms the clinical suspicion and provides a precise, gene-level explanation for the presentation.
• Clinical management: identification of the germline pathogenic variant supports condition-specific management decisions made by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant is known, at-risk relatives can be offered predictive testing to clarify their variant status.

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