Clinical Guidance

SMN1. No correlation exists between the type of SMN1 pathogenic variants and the severity of disease: the homozygous exon 7 deletion is observed with approximately the same frequency in all phenotypes. SMN2. Small amounts (up to one quarter) of full-length transcripts generated by SMN2 produce functional protein and result in the milder SMA phenotypes. The number of copies (dosage) of SMN2 (arranged in tandem on the same allele on both chromosomes) ranges from zero to five . The presence of two copies of SMN2 is approximately 80% predictive of the SMA I phenotype, whereas the presence of four or more copies of SMN2 is approximately 88% predictive of achieving the ability to ambulate with supportive care only (SMA III/IV) . Modifying factors that are not fully understood are likely to contribute to the variability in clinical severity, as can be demonstrated with individuals who have three copies of SMN2. Data from are summarized in . Table 3. Spinal Muscular Atrophy: SMN2 Copy Number and Clinical Phenotype SMN2 CopyNumber | SMA Clinical Phenotype1

Source: GeneReviews — "Spinal Muscular Atrophy"

Diagnostic Criteria

A consensus document on the diagnosis of children with spinal muscular atrophy (SMA) was initially developed by and was updated by .

Suggestive Findings

Scenario 1. Abnormal newborn screening (NBS) result

• NBS for spinal muscular atrophy (SMA) is primarily based on real-time PCR that detects the common SMN1 deletion and may also detect SMN2 copy number on dried blood spots .

• Follow-up molecular genetic testing confirmation of a positive NBS result is recommended . SMN2 copy number should also be obtained on confirmatory testing.

Source: GeneReviews — "Spinal Muscular Atrophy"

Differential Diagnosis

Table 5. Disorders to Consider in the Differential Diagnosis of Spinal Muscular Atrophy

Management Guidelines

Detailed recommendations on management of care in individuals with spinal muscular atrophy (SMA) have been published; see (full text) and (full text). Furthermore, treatment algorithms for infants diagnosed through newborn screen have been published (full text). Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with SMA, the affected individual should be referred to a multidisciplinary clinic. Regardless of SMA subtype, clinical care should be based on an individual's current functional status. Issues to consider are listed in . Table 6. Spinal Muscular Atrophy: Evaluations to Consider Following Initial Diagnosis

Clinical Guidance

Prolonged fasting should be avoided, particularly in the acutely ill infant with SMA .

Source: GeneReviews — "Spinal Muscular Atrophy"

Therapies Under Investigation

A number of different therapeutic approaches are in development, including further studies on the approved therapeutics discussed above. See the SMA Drug Pipeline maintained by Cure SMA for a list of therapies in preclinical and clinical development phases. SMN2-targeted therapeutic approaches. Therapeutic approaches in this category aim to alter SMN2 splicing to increase the proportion of transcripts containing exon 7 and thus increase full-length survival motor neuron (SMN) protein. Antisense oligonucleotides are single-stranded RNA molecules specifically designed to target complementary sequences in the SMN2 transcript, leading to inclusion of exon 7. Nusinersen and risdiplam work through this mechanism. SMN-independent approaches.

Source: GeneReviews — "Spinal Muscular Atrophy"

Surveillance Guidelines

Where available, targeted therapy should be initiated as soon as possible for eligible individuals. A treatment algorithm for the evaluation of presymptomatic infants has been published . Presymptomatic individuals with five copies of SMN2 should be carefully monitored for the development of symptoms to determine appropriate timing to initiate targeted and/or supportive therapies. For those who are receiving a targeted therapy, review of prescribing information and the package insert is suggested, as recommendations for ongoing surveillance are changing rapidly for each targeted therapy. Both potential side effects and new phenotypes associated with targeted treatments continue to emerge. Individuals with SMA are evaluated at least every six months; weaker children are evaluated more frequently. Multidisciplinary surveillance at each visit includes assessments of nutritional state, respiratory function, motor function, and orthopedic status (spine, hips, and joint range of motion) to help determine appropriate interventions.

Source: GeneReviews — "Spinal Muscular Atrophy"