Spinal muscular atrophy is a group of hereditary neuromuscular disorders characterized by progressive degeneration of the motor neurons in the spinal cord and lower brainstem. When there is disruption in the signals between motor neurons and the skeletal muscles, the muscles become weakened and atrophic. The affected patients will have progressive difficulty in the control of movement, eating and breathing.
The most common form of SMA, the 5q-SMA, is caused by defects in both copies of the survival motor neuron 1 (SMN1 gene) located on chromosome 5q 13.2. Majority of the patients (95 to 98%) have homozygous deletion of exon 7 or both exon 7 and 8 of the SMN1 gene. Only 2-5% of the patients have compound heterozygous mutations with deletion of exon 7 in one copy of SMN1 and a point/small mutation on the other copy of SMN1.
There are other rare forms of SMA which are not caused by SMN1 gene mutation such as SMA with respiratory distress, distal SMA etc. These forms vary considerably in severity and are broadly called non 5q-SMA. Unless specified, the word “SMA” in the content below refers to 5q-SMA only.
(The original graphic is converted into the following text version for your easy access to the information.)
Normal SMN1 gene: SMN1 gene consists of normal exon and can produce mRNA with complete sequencing. Normal SMN protein can thus be produced to maintain the health and normal function of motor neurons.
SMN1 gene of SMA patient: In individuals with spinal muscular atrophy, a deletion or mutation is found in exon 7 of the SMN1 gene. The mRNA produced from the affected gene lacks exon 7 sequence. As a result, there is insufficient SMN protein production and their health and function of motor neurons would be affected.
The SMN1 gene produces the survival motor neuron (SMN) protein that maintains the normal function and health of the motor neurons. The inadequate level of SMN protein in children with SMA leads to progressive loss of motor neurons in the spinal cord, causing gradual weakness and wasting of the skeletal muscles. The weakness is often more severe in the trunk and proximal leg and arm muscles than in the muscles of the hands and feet.
There is a broad spectrum of severity in SMA caused by defects in the SMN1 gene, from onset at birth with breathing difficulties to mild muscle weakness in adulthood. The most common forms of SMA can be classified into SMA type 1, type 2, type 3 and the less common form is SMA type 4. The classification of the types is based on the age of symptom onset and the highest motor milestone achieved.
SMA type 1, also called Werdnig-Hoffmann disease or infantile onset SMA, is evident before 6 months of age. It is the most common and a very severe form of SMA. Without any treatment, the affected children never sit or stand, and most of them die before the age of 2 due to respiratory failure.
SMA type 2, the intermediate form, usually has symptom onset between 6 and 18 months of age. The affected children can sit without support but are unable to stand or walk unaided. Life expectancy is often reduced but most individuals live into young adulthood.
SMA type 3, also called Kugelberg-Welander disease, has symptom onset after 18 months of age. The affected children can walk independently. Life expectancy is not affected.
SMA type 4, or called adult onset SMA, has normal life expectancy.
There are 4 types of SMA:
SMA is inherited in an autosomal recessive manner, i.e., the affected individual has two mutated SMN1 gene, usually inheriting one from each parent. Those who carry only one mutated SMN1 gene are carrier of the disease without having any symptoms. In autosomal disease, more than one person in the same family (e.g. sibling) can be affected.
(The original graphic is converted into the following text version for your easy access to the information.)
If both parents are SMA carriers, for each pregnancy (no matter it is a baby boy or girl), there is a 1 in 4 chance that the child has 2 copies of normal gene (who is not affected), a 1 in 2 chance that the child has one normal and one faulty gene who is a carrier just like the parents, and a 1 in 4 chance that the child has two copies of faulty gene who is at risk for SMA.
Genetic test is available to look for deletions or mutations of the SMN1 gene.
For homozygous type of mutation, including SMN1 exon 7 deletion and SMN1 exon 7 & 8 deletion, it can be detected by MLPA. The mutation detection rate is 95-98%.
For compound heterozygous mutation, including SMN1 exon 7 deletion (allele 1) and SMN1 intragenic mutation (allele 2) which refers to small intragenic deletions or insertions as well as nonsense, missense and splice site mutations, it can be detected by MLPA together with targeted sequencing. The mutation detection rate is 2-5%.
Symptoms
Signs
Standard of care management for SMA includes multi-specialty care. Physiotherapy, occupational therapy and rehabilitation help to maintain muscle strength, prevent contractures and improve range of motion. Rehab equipment such as brace, orthosis, walking aids and wheelchair help to improve functional independence. Proper nutrition and caloric intake are essential to maintain health, growth and strength. Those with feeding difficulty requires gastrostomy feeding. Non-invasive ventilation use can improve breathing. Those with spinal curve progression require spinal brace support and even scoliosis surgery. Currently there are disease-modifying treatments available for SMA patients in Hong Kong. The benefit is best documented in those affected infants and children when the treatments were started at young age. Patients with SMA type 1 now live longer and can reach higher motor milestones like sitting, standing and even walking with the early start of treatment. The disease modifying treatments also improve the motor outcome for patients with SMA type 2 and 3. The best motor outcomes are observed in babies identified by newborn screening with treatments started at the pre-symptomatic age.
For further enquiries on the treatment options, please consult your attending doctor.
Enquiries
Department of Clinical Genetics, HKCH
Office Tel: 5741 3186
Acknowledgement: Pamphlet content is written by the Neurology Team of the Hong Kong Children's Hospital
June 2024
Hong Kong Children's Hospital
Department of Paediatrics & Adolescent Medicine, HKU