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.

Suggestive Findings

CLCN2-related leukoencephalopathy should be suspected in individuals with the following findings and family history.

Clinical findings

• Mild ataxia
• Mild cognitive impairment
• Psychiatric symptoms
• Headache
• Decreased vision caused by chorioretinopathy or optic atrophy
• Auditory symptoms including hearing loss, tinnitus, and vertigo
• Male infertility caused by oligo-/azoospermia

Imaging findings on brain MRI

• Abnormally low signal on T₁-weighted images and abnormally high signal on T₂-weighted images (Figure 1) in the:
  • Posterior limbs of the internal capsules
  • Midbrain crura cerebri
  • Middle cerebellar peduncles
• Additional findings can include abnormally low signal on T₁-weighted images and abnormally high signal on T₂-weighted images in the following:
  • Pyramidal tracts in the pons
  • Central tegmental tracts in medulla, pons and midbrain
  • Superior cerebellar peduncles
  • Decussation of the superior cerebellar peduncles in the midbrain
  • Cerebellar white matter
  • Corpus callosum
  • Cerebral white matter, either with a signal behavior suggestive of hypomyelination or nonspecific, mild inhomogeneous signal abnormalities

Figure 1.

MRI of an individual age 50 years with CLCN2-related leukoencephalopathy. Note the T₂-weighted signal abnormalities (a-d) in the middle cerebellar peduncles (blue arrow in a), crura cerebri (green arrow in b), and posterior limb of the internal capsule (more...)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CLCN2-related leukoencephalopathy is established in a proband by identification of biallelic pathogenic variants in CLCN2 (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive MRI findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of CLCN2-related leukoencephalopathy has not been considered (individuals with absence of the typical MRI phenotype) are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The phenotypic spectrum of CLCN2-related leukoencephalopathy ranges from childhood onset with mild ataxia, learning disabilities, and headaches to adult onset with mild ataxia and decreased vision [Depienne et al 2013]. Infertility or involuntary childlessness in adulthood has been observed in four adult males [Di Bella et al 2014; Authors, personal observation]. Several individuals with psychiatric concerns (depression or psychosis) and/or auditory abnormalities including mild hearing loss, tinnitus, and vertigo have been observed. Other medical concerns occurring in a few individuals may be rare parts of the phenotype or unrelated findings. The disease course has been reported as stable to slowly progressive; considering that adults were previously normal, extremely slow progression is most likely. All individuals reported to date have remained ambulatory. The oldest known individual with CLCN2-related leukoencephalopathy is age 70 years. No disease-related deaths have been reported to date.

To date, 31 individuals have been identified with biallelic pathogenic variants in CLCN2 [Depienne et al 2013; Di Bella et al 2014; Hanagasi et al 2015; Giorgio et al 2017; Zeydan et al 2017; Guo et al 2019; Hoshi et al 2019; Ngo et al 2020; Ozaki et al 2020; Parayil Sankaran et al 2020; Authors, personal observation]. The following description of the phenotypic features associated with this condition is based on these reports and personal observations.

Motor skills. Initial motor development is normal. At presentation, most affected individuals display signs of mild cerebellar ataxia with action tremor and gait instability; some also show mild signs of spasticity. Affected individuals remain ambulatory and do not require support for walking.

Cognitive skills. Some affected individuals have mild learning problems from early on, but most initially have normal intellect. Mild cognitive decline has been observed in some affected individuals [Guo et al 2019; Authors, personal observation]. One affected individual had severe cognitive impairment.

Psychiatric symptoms. Depression and psychosis or schizophrenia-like symptoms have been observed in several affected individuals [Depienne et al 2013; Authors, personal observation].

Headache. Some affected individuals complain of intermittent severe diffuse headaches.

Vision. Some affected individuals have a retinopathy or optic atrophy leading to mild visual impairment; blindness has been observed in one adult. Some affected individuals have visual field defects at formal testing, indicating subclinical retinopathy. Double vision has also been observed in some.

Auditory abnormality. Individuals with progressive hearing loss [Depienne et al 2013], unilateral mild hearing loss [Zeydan et al 2017], tinnitus [Guo et al 2019] and vertigo/dizziness [Parayil Sankaran et al 2020; Authors, personal observation] have been observed.

Male infertility. One male with azoospermia (but no neurologic dysfunction) was found to have CLCN2-related leukoencephalopathy during a workup for infertility [Di Bella et al 2014]. Three adult males diagnosed with CLCN2-related leukoencephalopathy have had a history of involuntary childlessness [Authors, personal observation]. To date, no affected males with offspring have been observed.

Other. A single individual with paroxysmal kinesigenic dyskinesia [Hanagasi et al 2015] has been reported.

An infant who presented with frequent generalized tonic-clonic seizures at age three months has been reported. Seizures were effectively controlled by anti-seizure medication (phenobarbital and valproate). A boy age 13 years with the exact same homozygous pathogenic variant as the infant did not have epilepsy [Ozaki et al 2020].

Two additional individuals with biallelic pathogenic variants in CLCN2 and epilepsy were identified [Authors, personal observation]. Since epilepsy has a fairly high incidence in the general population and any brain disease in itself enhances the risk of epilepsy, it is not possible to say whether this is related to CLCN2-related leukoencephalopathy. Animal studies are also inconclusive; one study reports interictal epileptic brain activity and a lowered seizure threshold in Clcn2-null mice [Cortez et al 2010], while two other studies report no alteration of seizure threshold in Clcn2-null mice [Bösl et al 2001, Blanz et al 2007]. Therefore, the link between partial or complete loss of chloride channel-2 function and epilepsy remains unresolved.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Prevalence

The prevalence of CLCN2-related leukoencephalopathy is unknown. The small number of known affected individuals suggests that the disease is exceedingly rare. Numerous individuals with CLCN2-related leukoencephalopathy, however, may also be undiagnosed because they remain asymptomatic at an advanced age, lack a specific clinical phenotype, or have findings (e.g., headaches or infertility due to azoospermia or oligozoospermia) that do not prompt evaluation by brain MRI.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CLCN2-related leukoencephalopathy, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

CLCN2-related leukoencephalopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one CLCN2 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CLCN2 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with CLCN2-related leukoencephalopathy are obligate heterozygotes (carriers) for a pathogenic variant in CLCN2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a CLCN2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the CLCN2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the CLCN2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CLCN2-related leukoencephalopathy are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CLCN2 codes for the chloride channel-2 (ClC-2), which is expressed in the plasma membrane of almost all mammalian cells. All pathogenic variants leading to CLCN2-related leukoencephalopathy identified to date have been shown or suggested to result in either complete or partial loss of function of ClC-2 by different mechanisms [Depienne at al 2013, Gaitán-Peñas et al 2017]. Despite its ubiquitous expression, loss of ClC-2 function leads to specific pathology of the brain, eyes, and testes.

In the brain, ClC-2 is found in both neurons and glia. Clcn2-knockout mice show a leukodystrophy phenotype with extensive myelin vacuolization [Blanz et al 2007]. Vacuolization appears to depend on neuronal activity. Clcn2-knockout mice are typically blind due to retinal degeneration that results in reduced or absent activity in the optic nerve. Remarkably, this optic nerve is selectively spared from vacuolization [Blanz et al 2007], suggesting that myelin vacuolization in Clcn2-knockout mice is mainly a consequence of action potential-mediated disruption of ionic homeostasis. In neurons, ClC-2 may alter levels of excitability and modulate synaptic transmission [Földy et al 2010, Ratté & Prescott 2011]. However, using cell type-specific transgenic techniques in mice, it was recently shown that loss of ClC-2 from supportive glial cells (both astrocytes and oligodendrocytes), with intact neuronal expression, fully recapitulates the leukodystrophy phenotype [Göppner et al 2020].

In astrocytes, ClC-2 shows enhanced expression in processes around blood vessels, in the glia limitans, in the ependymal lining, and in astrocyte-astrocyte contacts [Depienne et al 2013]. Loss of ClC-2 function from glial cells is thought to lead to a disturbance in brain ion and water homeostasis. Myelin vacuolization, as seen in individuals with CLCN2-related leukoencephalopathy, is a common pathologic occurrence in diseases in which ion and water homeostasis is disturbed [Min & van der Knaap 2018].

ClC-2 interacts with the glial proteins GlialCAM and MLC1 [Sirisi et al 2017], which are associated with the leukodystrophy known as megalencephalic leukoencephalopathy with subcortical cysts. However, it should be noted that the leukodystrophy caused by pathogenic variants of CLCN2 fundamentally differs from MLC in its clinical and MRI manifestations. The exact nature of the interaction between these proteins is therefore still unclear.

Retinal and testicular degeneration have been described in Clcn2-knockout mice [Bösl et al 2001]. Using cell-type specific loss of Clcn2 in mouse models, it was shown that retinal pathology is specifically due to loss of ClC-2 in retinal pigment epithelial cells. Testicular degeneration and azoospermia are caused by loss of ClC-2 from Sertoli cells [Göppner et al 2020]. A common denominator for all affected organs therefore appears to be that ClC-2 function is crucial in "supportive" cell types (glia, retinal pigment epithelial cells, sertoli cells). The chloride channel is likely important for balancing ions and water in the extracellular milieu of the brain, retina, and testes [Göppner et al 2020].

Mechanism of disease causation. Loss of function

CLCN2-specific laboratory technical considerations. Two large multiexon deletions identified in this gene are difficult to detect using standard sequencing. An updated list of more than 25 CLCN2 pathogenic variants specifically linked to CLCN2-related leukoencephalopathy is available from the authors. See Author Notes.

Author Notes

The Amsterdam Leukodystrophy Center (ALC; Amsterdam UMC, the Netherlands) is headed by Professor Marjo van der Knaap. The purpose of the Center is to optimize diagnostics and care for patients with leukodystrophies, and to perform translational research with the aim to advance insight into disease mechanisms and develop and implement new therapies. Within the center, patient care, clinical studies, and fundamental experimental work on genetics, molecular biology, and neurophysiology are combined. Prof Van der Knaap has pioneered MRI diagnostics, and was the first to describe and genetically define many leukodystrophies. The research team of Dr Rogier Min within the ALC focuses on understanding cellular aspects of ion and water homeostasis in the brain using electrophysiologic and imaging methods.

To obtain a list of known pathogenic variants in CLCN2 associated with CLCN2-related leukoencephalopathy, please contact us (ln.cmumadretsma@paankrednav.sm).

Acknowledgments

We thank patients with CLCN2-related leukoencephalopathy and their families for their cooperation. We are grateful to their physicians for providing us with the requested clinical information and for sending us MRI scans. We thank the clinical genetics lab in Amsterdam, in particular Dr RML Vervenne, for excellent support with CLCN2 sequencing.

Revision History

• 20 May 2021 (ha) Comprehensive update posted live
• 5 November 2015 (me) Review posted live
• 22 April 2015 (mvdk) Original submission

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