Spinal muscular atrophy (types I–III/IV)

5q-SMA is clinically classified into subtypes by age of onset and the maximum motor function attained, and this classification guides prognosis and management. SMA type 0 represents the most severe, congenital form, which begins in utero and leads to severe muscle weakness, hypotonia, joint stiffness (arthrogryposis multiplex congenita), atrial septal defects and severe respiratory failure in newborns. Infants have severe respiratory compromise/failure and, with supportive care only, rarely survive past age six months. Life expectancy is very limited; infants rarely survive past six months. SMA type I (Werdnig-Hoffmann) manifests before the age of six months with marked weakness and motor regression; affected children never achieve independent sitting, and it accounts for around 60% of all cases. Death usually occurs within the first few years of life. SMA type II(intermediate type) manifests between the ages of six and 18 months; affected individuals attain independent sitting but never walk independently. SMA type III (Kugelberg-Welander) typically manifests after the age of 18 months, with proximal weakness causing frequent falls while ambulation is preserved. Life expectancy is generally not significantly reduced. SMA type IV (adult SMA) is the least common form of SMA and affects fewer than 5% of all cases. It presents in the second or third decade with mild proximal weakness. Respiratory complications are a major source of morbidity in types I and II, and scoliosis, hip dislocation, and joint contractures are frequent across the subtypes.

The estimated incidence is around 1 in 10,000 live births in Europe, with a population prevalence of approximately 1 to 2 per 100,000 persons. Carrier frequencies vary by ancestry, reported at around 1 in 45 in White populations and around 1 in 100 in populations of sub-Saharan African descent.

5q-SMA is caused by biallelic germline pathogenic variants in SMN1 (5q13.2), which encodes the survival motor neuron (SMN) protein required for snRNP biogenesis and motor-neuron survival. SMN1 and its paralog gene SMN2 reside in a highly complex genomic region on chromosome 5q12.2-q13.3 that is frequently subject to unequal crossing over and gene conversion, resulting in variable copy numbers (CNVs) of SMN1 and SMN2. These genes are nearly identical in sequence- each comprise nine exons and differ only in eight nucleotides. A single nucleotide difference alters splicing so that SMN2 yields predominantly truncated, unstable protein and only small amounts of full-length SMN, which is why SMN2 cannot fully compensate for SMN1 loss. More than 95% of affected individuals carry a homozygous deletion of SMN1 exon 7, either as a result of homozygous deletions or gene conversion of SMN1 sequence into SMN2 sequences. The rest of the patients are compound heterozygous for such a deletion along with a pathogenic variant. Because each SMN2 copy contributes a little full-length protein, a higher SMN2 copy number is strongly correlated with a milder phenotype in individuals with an SMN1 deletion.

5q SMA is inherited in an autosomal recessive manner. Each pregnancy of two carrier parents carries a 25% risk for an affected child, a 50% chance of a carrier child, and a 25% chance of inheriting neither pathogenic variant. The clinical severity is further modified by SMN2 copy number. Carrier testing is based on SMN1 copy-number determination. Most people have one copy of SMN1 on each chromosome ([1+1] SMN1 genotype); however, about 5%-8% of the population (silent carriers) have two copies of SMN1 on a single chromosome and a deletion on the other chromosome, known as a [2+0] SMN1 genotype. Thus, normal two-copy result reduces but does not exclude carrier status, leaving a residual carrier risk. Preimplantation and prenatal molecular testing are possible once the familial pathogenic variant has been identified in the family.

SMA is established in a patient with clinical suspicion (history of motor difficulties or regression, proximal muscle weakness, reduced/absent deep tendon reflexes, evidence of motor unit disease) and/or biallelic pathogenic variants in SMN1 detected by molecular genetic testing. Electromyography may demonstrate evidence of motor-unit disease and support clinical suspicion. As SMN2 copy number often modifies the phenotype, it is also determined alongside the SMN1 testing for prognostic correlation

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant, clarifying the genetic aetiology and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual, with the SMN2 copy number informing prognostic assessment.
• A known familial variant supports predictive and carrier testing of at-risk relatives, so they can clarify their personal risk and access counselling where indicated.

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