Phenotypic continuum in IGHMBP2-related disorders: a portfolio of cases from typical to Guillain-Barré syndrome-like...

IGHMBP2-related disorders comprise a clinical spectrum from spinal muscular atrophy with respiratory distress type 1 (SMARD1) to Charcot-Marie-Tooth disease type 2S, with increasingly recognized atypical and overlapping phenotypes. We report four pediatric cases from three unrelated families with biallelic pathogenic variants in IGHMBP2. Case 1, a premature infant represents SMARD1. Case 2 had infantile-onset neuropathy without respiratory symptoms. Case 3 and 4, two siblings, presented with a Guillain-Barré syndrome-like phenotype, cauda equina enhancement on spinal neuroimaging, elevated cerebrospinal fluid protein, and electromyography revealing acute motor and sensory axonal neuropathy. Despite an initial response to intravenous immunoglobulin, previous symptoms in Case 3 led to consideration of an immune-mediated neuropathy superimposed on a genetic background. Genetic analysis identified a homozygous nonsense variant in Cases 1 and 2, and novel compound heterozygous missense variants in Case 3 and 4. Thus, the list of overlapping genetic and acquired neuropathies now also includes IGHMBP2-related CMT2S.