Phenotypic characterization of hypomyelination and congenital cataract

Phenotypic Characterization of Hypomyelination and Congenital Cataract Roberta Biancheri, MD, PhD,1 Federico Zara, PhD,1 Claudio Bruno, MD,1 Andrea Rossi, MD,2 Laura Bordo, BSc,1 Elisabetta Gazzerro, MD,1 Federica Sotgia, PhD,1,3 Marina Pedemonte, MD,1 Sara Scapolan, MD,1 Massimo Bado, MD,1 Graziella Uziel, MD,4 Marianna Bugiani, MD,4 Laura Doria Lamba, MD,5 Valeria Costa, MD,6 Angelo Schenone, MD,7 Annemieke J. M. Rozemuller, MD,8 Paolo Tortori-Donati, MD,2 Michael P. Lisanti, MD,1,3 Marjo S. van der Knaap, MD, PhD,9 and Carlo Minetti, MD1 Objective: To define the clinical and laboratory findings in a novel autosomal recessive white matter disorder called hypomyelination and congenital cataract, recently found to be caused by a deficiency of a membrane protein, hyccin, encoded by the DRCTNNB1A gene located on chromosome 7p21.3-p15.3. Methods: We performed neurological examination, neurophysiological, neuroimaging, and neuropathological studies on sural nerve biopsy in 10 hypomyelination and congenital cataract patients from 5 unrelated families. Results: The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation. Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times. Neuroimaging studies demonstrated a diffuse supratentorial hypomyelination, with in some patients, additional areas of more prominent signal change in the frontal region. Sural nerve biopsy showed a slightto- severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin. Interpretation: Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous system. Ann Neurol 2007;62:121–127