The Attenuated Phenotype of CNTNAP1-Related Neuropathy Mimics Spastic-Dystonic Cerebral Palsy

CNTNAP1 encodes a contactin-associated protein 1, which is essential for formation and organization of myelinated nerve fibers. Biallelic pathogenic variants in CNTNAP1 cause a severe congenital hypomyelinating neuropathy, characterized by hypotonia, arthrogryposis, respiratory failure, and early lethality. We describe two brothers, seven and 13 years old, with spastic tetraparesis and limb dystonia, in whom we identified compound heterozygous variants in CNTNAP1. Comprehensive neurophysiological evaluation revealed an unusual, asymmetric pattern of hypomyelination that spared lower limb nerves. Moreover, brain neuroimaging showed only mild terminal zone hypomyelination. This report extends the phenotypic spectrum of CNTNAP1 encephalopathy to primarily upper motor neuron disease with the predominant spastic features. In addition, it provides further evidence for the association of CNTNAP1 with dystonia. Importantly, CNTNAP1 mutations should be suspected in individuals with unexplained hypotonia and pyramidal syndrome even in the absence of apparent hypomyelination on brain imaging and normal conduction velocities in routinely examined nerves.