Unexpected phenotypic heterogeneity in two female siblings with SMA



Poster Number: Virtual


Alexandria Melendez-Zaidi, MD, PhD, Texas Children's Hospital / Baylor College of Medicine, Farida Abid, MD, Texas Children's Hospital / Baylor College of Medicine

Background: Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder that is typically caused by absence of survival motor neuron 1 (SMN1). Canonical teaching is that the degree of disability in SMA is inversely proportional to the number of copies of the SMN1 homolog, survival motor neuron 2 (SMN2) such that more severe phenotypes (SMA type 1) have 1 copy of SMN2 while patients with 4 or more copies of SMN2 may have a “normal” phenotype. In recent years, other modifiers of disease have been reported such as copy number of the neuronal apoptosis inhibitor protein (NAIP) gene or expression levels of Plastin 3 (Yinhong et al.; Oprea et al.). Here, we present two cases of SMA in two siblings that exemplify the need for further modifier investigation.
Objectives: To discuss a rare case of SMA type II in a patient with 3 copies of SMN2 and her biological sibling with a mild phenotype and fewer copies of SMN2 (SMA type III, 2 copies of SMN2).
Results: Patient number 1 is a 28-year-old female diagnosed with SMA at 18 months of age. She became symptomatic at 7 months of age and failed to achieve early motor milestones. She has used a wheelchair since the age of 2. She has never required ventilatory support though had recurrent pneumonia as a child and neuromuscular scoliosis requiring surgical repair. She had repeated genetic testing at 24 years of age prior to use of Spinraza.
Patient number 2 is the 20-year-old full sibling of patient 1; she was diagnosed with SMA at 3 years of age. Unlike her sibling, she hit gross motor developmental milestones appropriately and continues to be ambulatory with mild toe walking and fatigue with long distances.
Conclusions: Though SMN2 copy number undoubtedly contributes to disease severity, these sibling cases demonstrate the importance of determining other genetic modifiers, particularly as more therapeutic options become available, often dependent on genotype.