Severe cortical malformation and acquired cataract – An unusual presentation of DYNC1H1 mutation in twins

Abstract

Objective: Cytoplasmatic dynein, a microtubules-associated protein, is crucial for proper neuronal migrations and differentiation. Dominant mutations in the heavy chain1 of the protein (DYNC1H1) are associated with various neurodevelopmental and neurodegenerative diseases such as spinal muscular atrophy with lower extremity dominance (SMA-LED), hereditary motor and sensory neuropathy (HMSN), intellectual disability with neuronal migrations defects and cortical malformations such as posterior predominant pachygyria, lissencephaly and corpus callosum anomalies. We present twin girls with severe congenital cerebral malformations, refractory epilepsy and acquired cataracts due to a de novo mutation in DYNC1H1 identified in girl 1. Methods: Description of twin girls with severe cortical malformation and acquired cataract and family based gene sequencing analysis to identify de novo mutation in DYNC1H1 in girl 1. Results: After prenatal sonographic detection of corpus callosum anomalies in both twins in an otherwise uneventful pregnancy, postnatal cMRI in girl 1 showed partial agenesis of corpus callosum, bilateral polymicrogyria and asymmetric ventricles; in girl 2 subtotal agenesis of corpus callosum, hypoplastic cerebellum and multiple cortical dysplasias. Both girls developed severe intellectual disability, intractable epilepsy since the age of 4 (girl 1) resp. 6 month (girl 2), spastic (1) resp. ataxic (2) cerebral palsy and microcephaly. Cataracts occurred in both girls at the age of 12 months. A gene panel analysis identified a de novo mutation in the DYNC1H1-Gen (c.11015C>T/p.Ser3672Leu) in girl 1 considered pathogenic. Conclusion: Our findings broaden the clinical spectrum and expand the phenotypes associated with DYNC1H1-mutations and suggest a role of dynein in human ocular development. The observation confirms the role of DYNC1H1 in central and peripheral neuronal function and could have implications on molecular diagnostics in complex cortical malformations by adding DYNC1H1 to related genes in microtubule-dependent motor protein pathways.