5q Spinal Muscular Atrophy

Introduction

5q spinal muscular atrophy (SMA), commonly known as SMA, is a group of hereditary neuromuscular diseases characterised by the degeneration of motor neurons in the spinal cord and brainstem. This leads to progressive muscle weakness and wasting, resulting in significant disability. SMA is the leading neuromuscular cause of infant death. Based on the data in 2024, the birth prevalence of SMA in Hong Kong is 7 per 100,000 births, which is higher than the rates reported in Japan and Taiwan.

Causes

5q-SMA is caused by mutations in both copies of the survival motor neuron 1 (SMN1) gene, located on chromosome 5q13.2. The majority of patients (95-98%) have a homozygous deletion of either exon 7 or both exon 7 and 8 of the SMN1 gene. Only 2-5% of patients have compound heterozygous mutations, with a deletion of exon 7 in one copy of SMN1 and a point / small mutation on the other copy of SMN1. This alteration in the gene leads to a reduction in SMN protein in motor neurons, causing motor neuron death and preventing muscles from receiving proper signals from the brain, which results in progressive weakness and muscle wasting.

Mode of Inheritance

5q-SMA is an autosomal recessive disease. Heterozygous carriers do not develop symptoms, but couples who are both carriers have a 25% risk of having a child inheriting both copies of defective SMN1 gene, who will then develop the disease.

It is important to note that there is a second gene, SMN2, which can also produce SMN protein. However, due to a slight variation in its structure, it typically produces less functional SMN protein. Individuals with SMA often have multiple copies of the SMN2 gene, and the number of copies can affect the severity of the disease. More SMN2 copies typically result in milder forms of SMA because they can partially compensate for the loss of SMN1 function.

Signs and Symptoms

There are three types of paediatric-onset SMA: SMA types I, II, and III.

SMA type I, the most severe form of SMA, accounts for 60% of total SMA cases and is the leading cause of infant mortality, with most children dying before the age of two without respiratory support. Affected babies are generally normal at birth, but develop symptoms including muscle weakness, weak cry, breathing difficulties and feeding problems within the first six months of life. They never achieve independent sitting, and their generalized weakness progresses rapidly. The median age of death is eight months.

Children with SMA type II, which accounts for 25-30% of total SMA cases, have intermediate severity. They can sit alone but cannot stand or walk unaided. Some eventually lose their ability to sit and develop feeding difficulties and severe respiratory problems.

Children with SMA type III can walk unaided, but around 50% will eventually lose their ambulation, usually during adolescence.

Musculoskeletal complications, including hip subluxation, hip dislocation, and kyphoscoliosis are more common in children with SMA especially type I and II.

Children with SMA are also at increased risk of bone fragility due to the impact of progressive muscle weakness on bone strength. The increased risk of long bone fracture could lead to fracture-induced loss of ambulation, and the more common vertebral fractures frequently results in back pain.

Diagnosis

Diagnostic evaluation begins with comprehensive history taking followed by a physical examination and further diagnostic investigations, which can include genetic test to look for deletions or mutations of the SMN1 gene.

• A standardized genetic diagnostic method can detect a homozygous SMN1 exon 7 deletion or SMN1 exon 7 & 8 deletion.
• Compound heterozygous mutations, including an SMN1 exon 7 deletion (allele 1) and an SMN1 intragenic small mutation (allele 2), can be detected by a combination of genetic diagnostic approaches.

Management

Management of SMA patients includes standard of care provided by a multidisciplinary team, and medical treatment to maintain or improve motor performance and quality of life. The care team typically comprises of a paediatric neurologist specialising in neuromuscular diseases, an endocrinologist, an orthopaedic surgeon, a respiratory specialist, other specialists, along with rehabilitation teams including physiotherapists, occupational therapists, speech therapists, orthotists and dietitians.

Ongoing assessments of mobility, hand function, swallowing, breathing, contractures, hip status, spinal curve progression, bone health, and weight gain enable the multidisciplinary team to tailor treatment plans for the child as the disease progresses.

Medical treatments

• Disease-modifying treatments: Currently three SMA treatments are available in Hong Kong. The first drug, Nusinersen, is an antisense oligonucleotide given regularly via the intrathecal route. The second treatment is a small molecule called Risdiplam, given daily orally. Both treatments can be given to all age groups with SMA. The third treatment is the gene replacement therapy Onasemnogene abeparvovec-xioi, administered intravenously as a one-off treatment, and is only approved for children less than two years of age. All three treatments can increase the functional SMN protein. These novel therapies have been shown to significantly improve the clinical outcomes of patients with SMA, especially in young patients when the treatment is started at an early age.
• Treatment for bone health: Regular supplements of Vitamin D and calcium are recommended to ensure good bone health. For those confirmed to have osteoporosis, regular treatment with bisphosphonate will be initiated.

Rehabilitation therapies

• Physiotherapy: This includes regular range of motion and stretching exercises to prevent contractures. Gentle exercises, often a combination of hydrotherapy and recreational-based activities, can help prevent muscle atrophy due to disuse.
• Orthosis: The use of braces can keep the muscles and tendon stretched, slowing the progression of contractures. Spinal brace can slow down the progression of scoliosis.
• Mobility aids: Canes, walkers, and wheelchairs can assist in maintaining mobility and independence. Stander can support passive standing.
• Nutrition counselling: It plays a crucial role in the care for SMA. It is designed to ensure that each child’s nutritional intake is adequate for their growth and overall good health. Diet modification with thickening could prevent easy choking. Adequate dietary fibres and fluid intake can prevent constipation. Avoiding high fat diet could reduce reflux issue.

Breathing assistance

Some children may benefit from the use of a ventilator to assist breathing during sleep at night and even during the day.

Surgery

Surgery may be needed to correct contractures or severe spinal curvature, or for progressive hip subluxation, especially for those who are walkers or assisted walkers.

Follow-up Care

Comprehensive care model in HKCH

SMA newborn screening and SMA treatment programme are both centralised at the HKCH. The programme is catered to:

• All newly diagnosed SMA babies identified by newborn screening.
• All symptomatic SMA children who are eligible and approved for SMA treatment.

Our neurology team collaborates closely with the neonatal team and other members of the multidisciplinary team, striving to initiate SMA treatment as early as possible, ideally before four to six weeks of age.

A combined Neurology (SMA)–Endocrine (bone health)–Orthopaedic clinic has been established for all children with SMA. Regular respiratory, motor and nutritional evaluations by the multidisciplinary team are conducted at least annually. It works closely with the parent hospital team to provide personalised and coordinated care for each individual patient.

SMA is a motor neuron disease characterised by progressive deterioration with multi-system involvements. The deterioration can be effectively managed with a good standard of care and early initiation of disease-modifying treatments. The earliest initiation of disease-modifying treatment at the pre-symptomatic or early symptomatic stage for those infants diagnosed by newborn screening has the best clinical outcomes. The HKCH is also committed to provide personalised treatment through multidisciplinary team monitoring and timely intervention tailored to individual child’s needs. We strive to combine clinical care and research, aiming to advance the care and improve outcomes for individuals with SMA.

References

Ip HNH, Yu MKL, Wong WHS, Liu A, Kwan KYH, Chan SHS. Treatment of Symptomatic Spinal Muscular Atrophy with Nusinersen: A Prospective Longitudinal Study on Scoliosis Progression. J Neuromuscul Dis. 2024;11(2):349-359. doi: 10.3233/JND-230077.

Acknowledgement

Principal author: Dr Sophelia Chan on behalf of Neurology Team, HKCH

Initial posting: Nov 2025

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