Spinal Muscular Atrophy and Disease-Modifying Treatments

SMA is an autosomal recessive disorder resulting from loss of function of both alleles of the SMN1 gene at 5q13. About 95 per cent of patients have a homozygous exon 7 deletion and the remainder are compound heterozygous for a deletion and a point mutation. Carrier frequency is between 1 in 40 and 1 in 60 in most populations.

SMN2 copy number

SMN2 lies adjacent to SMN1 and only a small proportion of its transcripts produce full-length protein. As copy number increases, more functional SMN protein is produced and the phenotype is milder. One copy is associated with the most severe prenatal-neonatal form, two copies with type 1, three copies with type 2 and sometimes type 3, and four or more copies with type 3 and sometimes type 4. The relationship is statistical rather than individually predictive, but it remains the main criterion used in presymptomatic treatment decisions.

Clinical types

• Type 0 (prenatal): reduced fetal movement, severe hypotonia at birth, respiratory failure, joint contractures.
• Type 1 (0-6 months): independent sitting is never achieved. Severe hypotonia, frog-leg posture, paradoxical breathing, a bell-shaped chest, weak cry, sucking and swallowing difficulty, tongue fasciculations, areflexia. Facial expression and eye movements are preserved and the infant is alert and socially engaged — this preserved alertness is a diagnostic clue.
• Type 2 (6-18 months): sitting is achieved, independent walking is not. A fine tremor of the fingers is characteristic; scoliosis and restrictive lung disease are the main problems. Intelligence is normal.
• Type 3 (after 18 months): independent walking is achieved and may be lost over time. Proximal weakness, frequent falls, difficulty climbing stairs.
• Type 4 (adult onset): mild proximal weakness.

This classification is based on the highest motor milestone achieved in the untreated natural history. In the treatment era these boundaries have blurred, but the terminology remains in use as a shared language.

Diagnosis

Where there is clinical suspicion, SMN1 deletion analysis is requested directly; electromyography, muscle biopsy and other intermediate steps are not required. The result can be available within days and SMN2 copy number should be determined at the same time. In a small proportion of cases SMN1 is normal and the picture arises from other genes such as DYNC1H1, BICD2, the distal SMA genes, or IGHMBP2 in SMARD1 with respiratory distress; genetic investigation should not stop when SMN1 is normal in a typical case.

Disease-modifying treatments

Three mechanisms are in use: SMN2 splicing modifiers, SMN1 gene replacement and muscle-directed therapy. The information below is current as of October 2026; licensing and indications change, and current product information and national reimbursement status should be verified separately.

• Nusinersen: an antisense oligonucleotide that binds SMN2 pre-mRNA and promotes inclusion of exon 7; given intrathecally. Administration can be technically difficult in patients with scoliosis or previous spinal surgery. A higher-dose regimen was approved in March 2026 on the basis of the DEVOTE study.
• Risdiplam: an orally administered small-molecule SMN2 splicing modifier taken daily. Avoiding intrathecal access is an advantage in patients with scoliosis and in advanced disease. Approved in 2020, with a tablet formulation added in 2025.
• Onasemnogene abeparvovec: single-dose gene replacement delivering SMN1 via an AAV9 vector. The intravenous form is used in small infants, with weight limits and anti-AAV9 antibody status as determining factors. An intrathecal form was approved in late 2025 and can be used in patients aged two years and above. The main safety concerns are hepatotoxicity (requiring corticosteroid prophylaxis and close transaminase monitoring), thrombocytopenia and thrombotic microangiopathy.
• Apitegromab: approved on 11 September 2026, the first muscle-directed therapy in SMA, targeting the myostatin pathway. It is used as an add-on in patients aged two years and above who are already receiving an SMN-directed therapy. The approval information draws attention to a risk of fracture.

Treatment choice depends on age, motor status, SMN2 copy number, spinal status, liver function, anti-AAV antibody status and family preference regarding route of administration.

Presymptomatic treatment

The greatest effect of treatment is obtained when it is started before symptoms appear. In an infant identified through newborn screening the decision rests on SMN2 copy number; starting treatment without delay is accepted practice in infants with one to three copies. With four or more copies, approaches differ between centres and close surveillance or early treatment are both discussed.

Framework for follow-up

• Motor function: an appropriate scale (CHOP-INTEND, HINE-2, HFMSE, RULM) every three to six months on treatment.
• Respiratory: cough effectiveness, overnight oximetry and capnography, spirometry where age permits; every six months, more often in non-sitters.
• Nutrition and swallowing: weight and growth at every visit; videofluoroscopy if there are concerns.
• Spine and hips: examination every six to twelve months, imaging as required.
• Bone health: annual vitamin D status and fracture enquiry.
• Immunisation: seasonal influenza, pneumococcal, and RSV prophylaxis where appropriate.