RESUMO
Distal arthrogryposis (DA) is a feature in genetically and clinically heterogeneous groups of disorders. Mostly myopathic and neurogenic defects have been described, but many patients remain without genetic diagnosis. We are elaborating on the clinical presentation of neonatal cases with DA who carry novel mutations in the nonselective sodium leak channel (NALCN). Two patients reported herein were remarkable for central hypertonicity in addition to DA. By trio-whole exome sequencing, two undescribed de novo mutations in NALCN were revealed. Both mutations (p.F317C and p.V595F) are located on pore-forming segments of NALCN. Dominant NALCN mutations in the pore-forming segments have been identified in similar patients, whereas recessive mutations outside the pore-forming segments result in different phenotypes. Our findings with central hypertonia broaden the phenotypic spectrum of de novo mutations in the pore-forming segments of NALCN. Recent findings of successful acetazolamide treatment in patients with channelopathies might point to potential therapies based on the ion channel similarities and the location of the mutation.
