Case #1: Male, born full-term. Croatian and Ukrainian heritage. First steps at 16 months. At 6 years old had frequent falls and unable to jump, run or skip. Initial exam at 6 years showed distal upper and lower extremity weakness, intact sensation, trace reflexes. Over time, noted progressive weakness and tongue fasciculations. EMG at 9 years showed neurogenic changes at motor nerves. SMA testing showed SMN1 1 copy with A111G point-mutation, SMN2 3 copies. Father is SMA carrier and A111G mutation is de-novo. Initiated Nusinersen at 11 years old.
Case #2: Female, born full-term, twin A. Ukrainian. Hypotonic and weak within 1st month. SMA carrier. Progressive weakness requiring O2 support and NG-Tube feeding. At 5 months old identified additional point mutation on SMN1, 2 copies of SMN2. Received Zolgensma at 7.5 months and is on Risdiplam.
Case #3: Female, born full-term. Armenian heritage. Maternal half-aunt with possible muscular dystrophy. Hypotonic since birth and delayed motor milestones. Normal neuroimaging and CK at 5 months. SMN testing showed SMN1 1 copy, SMN2 2 copies. WES trio did not identify clinically-significant variants. EMG at 5 months showed chronic & active axonal polyneuropathy. Additional point mutation on SMN1; c.549del (p.Lys184Serf*29). Received Zolgensma at 6 months and is on Risdiplam.
Discussion: Since the development of FDA-approved therapies for Spinal Muscular Atrophy (SMA) and its subsequent addition to the RUSP and newborn screening in all 50 states, it is possible to misconstrue SMA as an easily-detected and treatable disorder. However these cases demonstrate how variable and difficult this can be for the 5% estimated to be due to other mutations. Maintaining our clinical acumen and pursuing in-depth genetic testing can be necessary. Further studies may identify populations with higher rates of compound heterozygosity. Advocating for insurance coverage of genetic testing is in our patient’s best interest.