The Journal of the Arkansas Medical Society Med Journal Feb 2020_Final | Page 16

by Kapil Arya MBBS, MD 1 ; Amit Agarwal, MD 2 ; Vikki Stefans, MD 3 ; Aravindhan Veerapandiyan, MD 1 Scientific Article 1 Pediatric Neurology; Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Ark. Pediatric Pulmonology; Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Ark. 3 Physical Medicine and Rehabilitation; Arkansas Children's Hospital, University of Arkansas for Medical Sciences, Little Rock, Ark. 2 Spinal Muscular Atrophy: the Changing Landscape of Diagnosis and Management in Arkansas and Beyond Abstract S pinal muscular atrophy (SMA) is a neurodegenerative, autosomal reces- sive disorder usually due to biallelic deletions or, in rare cases, inactivating mutations of exon 7 of the SMN1 gene. Clinical classification is based on the highest motor mile- stone achieved. Intrathecal nusinersen treatment, the first disease modifying therapy approved by the U.S. Food and Drug Administration, produces improvements in motor function for patients with SMA. Also, single-dose SMN gene replacement therapy shows very promising results and awaits FDA approval. Research indicates that early treat- ment leads to the greatest benefit, emphasizing the need for newborn screening for SMA. preserved reflexes that gradually diminish over time, can typically stand and walk, and have a wide spectrum of motor functional impairment. Type IV is the mildest form of SMA. It is adult onset with very slow progression. There is also a form of later adult onset autosomal dominant disease due to mutation of a different gene that is outside the scope of this discussion. Cognition is preserved in all types. Prognosis is varied based on the clinical severity across the four types and within each type. 2 Failure to achieve motor de- velopmental milestones or, in less severely af- fected patients, a gradual loss of acquired motor milestones, is due to hypotonia plus weakness. Weakness is typically more profound in the low- er than the upper extremities, where antigravity function may be preserved. Fine motor effects and tremor, if present, are relatively mild. Introduction Spinal muscular atrophy (SMA) is an autosomal, recessive severe motor neuron disease and the leading genetic cause of infant mortality, affect- ing approximately 1 in 10,000 babies. About 1 in every 50 Americans is a genetic carrier for SMA. 1 Patients are roughly categorized into one of four types of SMA clinically, based on age of symptom onset and the highest physical mile- stone achieved. Type I SMA has symptom onset before the age of six months, and patients gener- ally do not attain the ability to sit independently. Typical clinical manifestations include neonatal hypotonia, proximal weakness, tongue fascicu- lations, and areflexia progressing to respiratory and bulbar weakness. There may be reduced fetal movement in utero. Children with type II SMA may have slightly later onset of symptoms, often between six and 18 months of age; they achieve independent sitting, but are typically un- able to walk. Children with type III SMA become symptomatic after 18 months of age, may have 164 • The Journal of the Arkansas Medical Society Genetics SMA is caused by homozygous deletion or mu- tation of survival motor neuron 1 (SMN1) gene at chromosome 5q. Genetic diagnosis is made by deletion/duplication analysis and/or gene se- quencing from blood samples. SMN1 produces survival motor neuron (SMN) protein, which is present in the cell body, axons, and dendrites of motor neurons. Absent or insufficient levels of SMN protein leads to the selective death of spinal motor neurons, possibly mediated by dys- function of small ribonuclear proteins that affect splicing of other essential genes. A second and almost identical gene, survival motor neuron 2 (SMN2), is present in most human genomes and makes low levels of SMN protein. During SMN2 splicing, a small segment of required RNA, exon 7, is excluded from the final mRNA transcript; this results in the production of mostly truncated and rapidly degraded SMN protein, with only 10- 15% functional SMN protein. Thus, the greater the number of SMN2 copies, the milder the SMA phenotype. Most children with type I SMA have only one or two SMN2 copies, most with type II have three copies, and with type III or IV there are three to four copies or more. Some infants with one copy are very severely affected and unable to breathe independently at birth. It is thought that with no copies, the condition is lethal in utero, accounting for the discrepancy between carrier rate and birth rate. SMN2 production does not directly make up for the loss of SMN protein production from SMN1, but the SMN protein production is increased proportional to the SMN2 copy number. Therefore, the number of SMN2 copies is inversely related to symptom severi- ty and clinical subtype. However, considerable variation in clinical phenotypes can occur both between patients with the same number of SMN2 copies. Research on discordant families has led to the identification of several genetic modifiers of SMA, including plastin-3 and neurocalcin del- ta. It is likely, therefore, that further genetic and other disease-modifying factors are still to be dis- covered. 1,2,3 Management Historically, the management of SMA focused on symptomatic and supportive treatment, with an emphasis on supporting ventilation. There is pro- gressive respiratory failure. Ineffective cough is a result of respiratory muscle weakness and con- tributes to repeated respiratory infections. The goal of pulmonary management is to normalize gas exchange by decreasing atelectasis; this is achieved by airway secretion mobilization and clearance, assisted coughing, and respiratory support via invasive or non-invasive ventilation. Supplemental oxygen is not the first line of treat- www.ArkMed.org