Spinal muscular atrophy (SMA)

What it is

SMA is a degenerative disease of the alpha motor neurons of the anterior horn of the spinal cord and the bulbar nuclei. SMN protein, encoded by SMN1, is needed in every cell but motor neurons are the most exquisitely dependent. The almost identical SMN2 gene produces a small amount of functional protein because of a single nucleotide difference that affects splicing — and the number of SMN2 copies determines how much full-length SMN protein the body can still produce, and therefore the severity of disease.

All three disease-modifying treatments work by increasing the amount of functional SMN protein: nusinersen and risdiplam by promoting inclusion of exon 7 in SMN2 transcripts, and onasemnogene by delivering a functional SMN1 gene under an AAV9 capsid.

How it presents

Without treatment, the clinical spectrum is wide:

• Type 0 (very rare) — symptoms in utero, neonatal severe weakness, often fatal without intervention
• Type 1 (~50%) — onset by 6 months, never sits independently. Without treatment: progressive weakness, bulbar involvement, respiratory failure, death by age 2 in most
• Type 2 — onset 6–18 months, sits but never walks independently. Progressive proximal weakness, scoliosis, contractures, restrictive lung disease
• Type 3 — onset after age 18 months, walks independently. Two sub-types: 3a (age 1.5–3) loses ambulation by adolescence/young adult; 3b (age 3–18) walks into adult life with progressive proximal weakness
• Type 4 — adult-onset, mild
• Common across types: tongue fasciculations, proximal > distal weakness, preserved cognition, areflexia, no sensory involvement

Diagnosis

Diagnosis is genetic: targeted SMN1 deletion testing detects the homozygous SMN1 exon 7 deletion in 95% of cases, with SMN2 copy number as a key prognostic add-on. The 5% who have one SMN1 deletion and one point mutation need full SMN1 sequencing. EMG and muscle biopsy are now almost never needed.

Newborn screening — dried blood spot SMN1 deletion testing — is now universal in much of Europe, North America and parts of Asia. Pre-symptomatic identification and treatment is the single biggest change of the last decade.

Disease-modifying treatments

Three treatments are licensed worldwide. They are roughly comparable in mechanism (raise SMN protein) but very different in route, frequency, age range and cost; choice depends on age, weight, SMN2 copy number, family preference and regulatory access.

• Nusinersen (Spinraza) — antisense oligonucleotide that modifies SMN2 splicing to produce full-length SMN protein. Given by lumbar intrathecal injection: 4 loading doses over 2 months then maintenance every 4 months for life. ENDEAR (type 1), CHERISH (type 2/3) and NURTURE (pre-symptomatic) trials all positive. Long real-world experience now from 2017
• Onasemnogene abeparvovec-xioi (Zolgensma) — one-time IV infusion of an AAV9 vector carrying a functional SMN1 cDNA. Licensed for children with SMA under 2 years of age (US) or weighing under 21 kg (EU). STR1VE-US and SPR1NT (pre-symptomatic) trials show dramatic motor gains. Adverse effects: hepatotoxicity (steroid cover for 2 months mandatory), thrombocytopenia, rare thrombotic microangiopathy
• Risdiplam (Evrysdi) — daily oral small molecule that modifies SMN2 splicing. Licensed for all SMA types from age 2 months onwards. FIREFISH (type 1), SUNFISH (type 2/3), RAINBOWFISH (pre-symptomatic), JEWELFISH (real world). Easier to deliver than nusinersen but lifelong daily dosing
• Combination therapy — increasingly used in real practice (one-time gene therapy + ongoing oral risdiplam), though formal trial evidence is limited; the 2024 RESPOND study evaluated nusinersen on top of onasemnogene in suboptimal responders
• Pre-symptomatic treatment (via newborn screening) is the situation with the best outcomes: most children treated within the first 4–6 weeks of life achieve normal motor milestones, in contrast to symptomatic-onset treatment where the goals are stabilisation and modest improvement

Supportive care

Even with disease-modifying therapy, structured multidisciplinary care remains the foundation:

• Respiratory — non-invasive ventilation (nocturnal then 24-hour if needed), cough assist, chest physiotherapy, regular pneumococcal and influenza vaccination
• Nutrition — gastrostomy in severe weakness; high-energy diet; reflux management
• Orthopaedic — scoliosis surgery (vertical expandable prosthetic titanium rib or growing rods in younger children, then definitive fusion), hip surveillance, contracture prevention
• Physiotherapy and occupational therapy — every level needs structured, ongoing motor support
• Communication — AAC devices, eye-gaze technology
• Psychological support — for the child and the family
• Multidisciplinary clinic — neurology, physio, OT, respiratory, dietitian, orthopaedic, social work, genetic counselling

Prognosis

With pre-symptomatic gene therapy or early oral / intrathecal SMN-raising treatment, most children with what would have been type 1 SMA achieve sitting, many achieve standing, and some achieve walking. Survival without invasive ventilation has moved from under 10% to over 90% at age 2. With symptomatic-onset treatment, outcomes are more modest but still dramatically better than the natural history. The question is no longer 'how long will my child live' but 'what motor milestones will they achieve and how can we optimise supportive care alongside the disease-modifying treatment'.

How an educational review can help

SMA care is changing every year — three competing treatments, evolving combination protocols, expanding newborn screening, and complex insurance and access questions. An educational review can pull together where the evidence stands today, place an individual child on the SMA care pathway, and help you prepare focused questions about the right disease-modifying treatment, timing, and combination — for your treating team.

It is an educational second opinion — not a diagnosis, treatment or prescription — and it does not replace the care of your child's own clinicians.