Neurogenic arthrogryposis, hypotonia, dysmorphic features plus malformation of cortical development further expands the ARL6IP1 loss-of-function phenotype

Abstract

Biallelic variants in ARL6IP1 are associated with a rare, complicated form of progressive hereditary spastic paraplegia. Among the few cases reported thus far, two distinct phenotypic clusters with upper and lower motor neuron pathology and varying severities have emerged. Here, we describe a proband who presented with decreased fetal movements, intrauterine growth retardation, arthrogryposis multiplex congenita (AMC), dysmorphic features, weakness and hypotonia. Course was complicated by extubation failure and feeding problems at age 3 months. Muscle biopsy demonstrated neurogenic changes. Magnetic resonance imaging revealed thin corpus callosum and simplified gyri most notable at the insula with incomplete opercularization. The proband developed tongue fasciculations at 5 months, and passed away at 15 months of age. A homozygous deletion of exon 1–3 of ARL6IP1 was identified through exome sequencing. ARL6IP1-related phenotypes now include in utero involvement, neurogenic AMC, dysmorphic features, microcephaly and malformations of cortical development, in the absence of spastic paraplegia.