LAUSR

BACKGROUND Congenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. METHODS Whole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. RESULTS A novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. CONCLUSIONS These findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.