SNOMEDCT: 768663003; ORPHA: 363540;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q27.1 | Leukoencephalopathy with ataxia | 615651 | Autosomal recessive | 3 | CLCN2 | 600570 |
A number sign (#) is used with this entry because of evidence that leukoencephalopathy with ataxia (LKPAT) is caused by homozygous or compound heterozygous mutation in the CLCN2 gene (600570) on chromosome 3q27.
Leukoencephalopathy with ataxia is an autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggest myelin microvacuolation restricted to certain brain regions. Clinical features include ataxia and unstable gait; more variable abnormalities may include visual field defects, headaches, and learning disabilities (summary by Depienne et al., 2013).
Depienne et al. (2013) reported 6 unrelated patients with a characteristic pattern of leukoencephalopathy on brain MRI, including 3 with adult onset and 3 with childhood onset of the disorder. Clinical features overlapped, but were variable. The adult patients had mild cerebellar ataxia with a variable combination of chorioretinopathy, visual field defects, optic neuropathy, and headaches. One patient had a schizophrenia-like disorder. The children had mild cerebellar ataxia and a variable combination of mild spasticity, visual field defects, learning disabilities, and headaches. None of the patients had seizures.
Neuroradiologic Features
Brain MRI of all 6 patients with leukoencephalopathy and ataxia reported by Depienne et al. (2013) showed prominent signal abnormalities in the middle cerebellar peduncles, midbrain cerebral peduncles, pyramidal tracts in the pons, and posterior limbs of the internal capsule. There were additional abnormalities in specific brainstem tracts and the cerebellar white matter. ADC values were decreased in all patients, indicating small water spaces within tissue microstructure. The pediatric patients also had diffuse mild signal abnormalities of the white matter, which were hyperintense compared to gray matter on T2- and T1-weighted images. These changes suggested myelin microvacuolation rather than hypomyelination. Depienne et al. (2013) noted that the clinical features of these patients were nonspecific and did not allow a diagnosis, whereas the MRI findings were specific enough to allow a diagnosis.
The transmission pattern of leukoencephalopathy with ataxia in the families reported by Depienne et al. (2013) was consistent with autosomal recessive inheritance.
In 6 unrelated patients with LKPAT, Depienne et al. (2013) identified homozygous or compound heterozygous mutations in the CLCN2 gene (see, e.g., 600570.0006-600570.0009). The first mutations were found by whole-exome sequencing. CLCN2, which is involved in brain ion and water homeostasis, was detected in astrocytes and all components of the panglial syncytium. CLCN2 was also enriched in astrocytic endfeet at the perivascular basal lamina, in the glia limitans, and in ependymal cells. All mutations were shown to cause a loss of protein function. The clinical findings were similar to those observed in Clcn2-deficient mice (see ANIMAL MODEL).
Bosl et al. (2001) found that Clcn2-null mice developed severe degeneration of the retina and the testes, which led to selective male infertility. Seminiferous tubules did not develop lumina, and germ cells failed to complete meiosis. In the retina, photoreceptors lacked normal outer segments and degenerated between days P10 and P30. The current across the retinal pigment epithelium was severely reduced at P36. Thus, Clcn2 disruption resulted in the death of 2 cell types that depend on supporting cells that form the blood-testes and blood-retina barriers.
Blanz et al. (2007) found that Clcn2-null mice were blind and developed progressive widespread spongiform vacuolation of white matter in the brain and spinal cord. Fluid-filled spaces appeared between myelin sheaths of the central but not the peripheral nervous system. However, neuronal morphology appeared normal, and neurologic deficits were mild, mainly including decreased conduction velocity in neurons of the central auditory pathway. The phenotype resembled a leukodystrophy; however, no CLCN2 mutations were found in 150 human leukodystrophy patients. Heterozygous loss of Clcn2 had no detectable functional or morphologic consequences. Neither heterozygous nor homozygous Clcn2 knockout mice had lowered seizure thresholds. Blanz et al. (2007) postulated a role for CLCN2 in glial function and ionic homeostasis in the central nervous system.
Blanz, J., Schweizer, M., Auberson, M., Maier, H., Muenscher, A., Hubner, C. A., Jentsch, T. J. Leukoencephalopathy upon disruption of the chloride channel Clc-2. J. Neurosci. 27: 6581-6589, 2007. [PubMed: 17567819] [Full Text: https://doi.org/10.1523/JNEUROSCI.0338-07.2007]
Bosl, M. R., Stein, V., Hubner, C., Zdebik, A. A., Jordt, S.-E., Mukhopadhyay, A. K., Davidoff, M. S., Holstein, A.-F., Jentsch, T. J. Male germ cells and photoreceptors, both dependent on close cell-cell interactions, degenerate upon ClC-2 Cl(-) channel disruption. EMBO J. 20: 1289-1299, 2001. [PubMed: 11250895] [Full Text: https://doi.org/10.1093/emboj/20.6.1289]
Depienne, C., Bugiani, M., Dupuits, C., Galanaud, D., Touitou, V., Postma, N., van Berkel, C., Polder, E., Tollard, E., Darios, F., Brice, A., de Die-Smulders, C. E., and 12 others. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 12: 659-668, 2013. [PubMed: 23707145] [Full Text: https://doi.org/10.1016/S1474-4422(13)70053-X]