Clinical characteristics: CLCN2-related leukoencephalopathy is characterized by nonspecific neurologic findings, mild visual impairment from chorioretinopathy or optic atrophy, male infertility, and characteristic findings on brain MRI. Neurologic findings include mild ataxia (action tremor and gait instability following initially normal motor development; occasionally, mild spasticity), cognitive impairment in some (typically mild, rarely severe), psychiatric symptoms in some (depression and schizophrenia-like symptoms), headaches in some (usually intermittent, severe, and diffuse) and auditory symptoms in some (hearing loss, tinnitus, vertigo). Affected individuals remain ambulatory, do not require support for walking, and rarely become blind. To date CLCN2-related leukoencephalopathy has been reported or identified in 31 individuals from 30 families. It is not yet known if the findings occurring in a few individuals (i.e., epilepsy and paroxysmal kinesigenic dyskinesia) are part of the phenotypic spectrum or unrelated findings.
Diagnosis/testing: The diagnosis of CLCN2-related leukoencephalopathy is established in a proband by identification of biallelic pathogenic variants in CLCN2 on molecular genetic testing.
Management: Treatment of manifestations: Supportive care including physical therapy and rehabilitation to improve motor function, special education as needed, treatment of headache, guidance for visual impairment.
Surveillance: Annual: neurologic examination. Every 2-3 years: ophthalmologic examination and audiologic assessment.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of older and younger sibs of a proband in order to identify as early as possible those who would benefit from early diagnosis and routine surveillance for motor, cognitive, vision, and hearing impairment.
Genetic counseling: CLCN2-related leukoencephalopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CLCN2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CLCN2 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing for CLCN2-related leukoencephalopathy are possible.
Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.