spinal muscular atrophy, distal, autosomal recessive, 6

Spinal muscular atrophy, distal, autosomal recessive, 6 (also known as DSMA6) is a condition that primarily affects the peripheral nerves and muscles, leading to characteristic distal muscle weakness and other motor abnormalities. It results from pathogenic variants in the REEP1 gene, which plays a role in maintaining normal nerve cell structure and function. The condition is inherited in an autosomal recessive manner, meaning that affected individuals have mutations in both copies of the REEP1 gene. Prevalence information is not well established, and detailed birth prevalence data is not available.

The clinical presentation of DSMA6 is defined by a constellation of neuromuscular features that are consistently observed. Individuals present with peripheral axonal neuropathy, distal muscle weakness, hypotonia, and skeletal muscle atrophy, along with distinctive findings such as arthrogryposis-like hand anomalies, wrist drop, and foot dorsiflexor weakness. Respiratory challenges are evident through diaphragmatic paralysis, paradoxical respiration, and recurrent acute respiratory tract infections, while musculoskeletal abnormalities include plantar flexion contracture, talipes equinovarus, and high palate. In addition, affected children exhibit global developmental delay, and after a period of apparently typical early development, they experience a phase of developmental regression marked by loss of previously acquired skills. Not all individuals experience all features, and severity varies considerably.

DSMA6 is caused by pathogenic variants in the REEP1 gene, which is essential for proper cellular structure and nerve function. In this autosomal recessive condition, both copies of the REEP1 gene must be mutated for the disease to manifest. This means that each parent carries one altered copy of the gene, and when both pass the variant to their child, the full clinical syndrome develops. Families are encouraged to seek genetic counseling to understand the implications for future pregnancies, as the recurrence risk in autosomal recessive disorders is based on both parents being carriers.

Management of DSMA6 incorporates targeted therapies that have received FDA approval, including SPINRAZA (nusinersen), EVRYSDI (risdiplam), and the FDA-approved gene therapy Zolgensma (onasemnogene abeparvovec-xioi). As these treatments have specific eligibility criteria, a multidisciplinary care approach is central to providing individualized care. Long-term management involves regular surveillance by a dedicated care team to monitor respiratory function, muscle strength, mobility, and developmental progress. Patients should discuss treatment options with their healthcare professionals to determine which interventions may be most beneficial, and genetic counseling is recommended to help families understand the implications of the diagnosis.

DSMA6 is a lifelong condition characterized by a complex course that may include an early phase of developmental regression, followed by a period of relative stabilization and variable long-term outcomes. With current standards of care and the availability of newer therapeutic options, many individuals experience improved quality of life and have outcomes that can differ significantly between patients. Outcomes described in medical literature continue to evolve as standards of care improve, and it is important to recognize that severity and symptoms vary widely between individuals. Families often find it helpful to connect with specialists familiar with this condition, and genetic counseling can offer additional guidance regarding long-term management and family planning.