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CLCN2-Related Leukoencephalopathy

, MD, PhD, , PhD, , MD, and , PhD.

Author Information

Initial Posting: .

Estimated reading time: 14 minutes

Summary

Clinical characteristics.

CLCN2-related leukoencephalopathy (CC2L) 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), learning disabilities in some (ranging from mild to severe cognitive impairment), and headaches in some (usually intermittent, severe, and diffuse). Affected individuals remain ambulatory and do not require support for walking, and none has become blind. To date CC2L has been reported or identified in 16 individuals from 15 families. It is not yet known if the findings occurring in single individuals (i.e., vertigo, tinnitus, and progressive hearing loss; psychiatric symptoms; and paroxysmal kinesigenic dyskinesia) are part of the phenotypic spectrum or unrelated findings.

Diagnosis/testing.

The diagnosis of CC2L 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, ophthalmologic examination, and audiologic assessment

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in older and younger sibs of a proband to identify those who would benefit from early diagnosis and routine surveillance for motor, cognitive, vision, and hearing impairment.

Genetic counseling.

CC2L is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible when the CLCN2 pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

CLCN2-related leukoencephalopathy (CC2L) should be suspected in individuals with certain nonspecific neurologic findings, decreased visual acuity, and characteristic abnormalities on brain MRI [Depienne et al 2013, Di Bella et al 2014, Hanagasi et al 2015].

Neurologic

  • Mild ataxia
  • Learning disabilities
  • Headache

Visual

  • Decreased vision caused by chorioretinopathy or optic atrophy

Brain MRI

Major criteria. Abnormally low signal on T1-weighted images and abnormally high signal on T2-weighted images (Figure 1) in the:

Figure 1. . MRI of an individual age 50 years with CC2L.

Figure 1.

MRI of an individual age 50 years with CC2L. Note the T2-weighted signal abnormalities (a-d) in the middle cerebellar peduncles (blue arrow in a), cerebral peduncles (green arrow in b), and posterior limb of the internal capsule (red arrow in d). All (more...)

  • Posterior limbs of the internal capsules
  • Midbrain cerebral peduncles
  • Middle cerebellar peduncles

Supportive criteria

  • Abnormally low signal on T1-weighted images and abnormally high signal on T2-weighted images in the:
    • 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.
    * Mild T2-weighted hyperintensity of the white matter and mild T1-weighted hypointensity, isointensity, or hyperintensity relative to gray matter [Schiffmann & van der Knaap 2009]
  • Diffusion restriction (assessed by apparent diffusion coefficient values [Depienne et al 2013]) in part or all of the structures mentioned under major and supportive criteria
    Note: More recently an affected individual had no diffusion restriction [Di Bella et al 2014].

Other

  • Male infertility caused by oligospermia/azoospermia

Establishing the Diagnosis

The diagnosis of CC2L is established in a proband by identification of biallelic pathogenic variants in CLCN2 (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of CLCN2 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes CLCN2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of chloride channel-2 related leukoencephalopathy.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Chloride Channel-2 Related Leukoencephalopathy

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
CLCN2Sequence analysis 3All CLCN2 pathogenic variants reported to date
Gene-targeted deletion/duplication analysis 4Unknown 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Since its discovery in 2013, CLCN2-related leukoencephalopathy (CC2L) has been reported in eight individuals [Depienne et al 2013, Di Bella et al 2014, Hanagasi et al 2015] and diagnosed in eight additional individuals from seven families [Author, personal observation]. Consequently, the phenotypic spectrum may only be partially known and statements about relative frequency of features are of limited value.

The phenotypic spectrum of CC2L ranges from childhood onset with mild ataxia, learning disabilities, and headaches to adult onset with mild ataxia and decreased vision. Infertility has been observed in two adult males [Di Bella et al 2014; Author, personal observation]. To date, single individuals with vertigo, tinnitus, and progressive hearing loss [Depienne et al 2013]; psychiatric symptoms [Depienne et al 2013]; and paroxysmal kinesigenic dyskinesia [Hanagasi et al 2015] have been reported. Thus, it is not yet clear if these findings are part 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 CC2L is age 65 years. No disease-related deaths have been reported to date.

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 have mild learning problems from early on, but most have normal intellect. One affected individual had severe cognitive impairment and psychosis.

Headache. Some affected individuals complain of intermittent severe diffuse headaches [Author, personal observation].

Eyes. Some affected individuals have a retinopathy or optic atrophy leading to mild visual impairment. Some affected individuals have visual field defects at formal testing, indicating subclinical retinopathy. None has become blind.

Male infertility. One male with azoospermia (but no neurologic dysfunction) was found to have CC2L during a work-up for infertility [Di Bella et al 2014]. One male with a history of infertility was diagnosed with CC2L when he was investigated for severe headaches [Author, personal observation].

Routine laboratory tests, including CSF analysis, are normal.

Genotype-Phenotype Correlations

Individuals with two null alleles and individuals with two missense pathogenic variants have been reported with onset in either childhood or adulthood without evidence of any genotype-phenotype correlations, although it should be noted that to date the number of affected individuals reported and known to the authors is small.

Prevalence

The prevalence of CC2L is unknown. The small number of known affected individuals suggests that the disease is exceedingly rare. Numerous individuals with CC2L, however, may also remain 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.

Differential Diagnosis

Because the clinical findings of CLCN2-related leukoencephalopathy (CC2L) are nonspecific, it is not possible to establish the diagnosis on a clinical basis alone or to develop a differential diagnosis.

In contrast, the differential diagnosis of the MRI findings of bilateral symmetric signal abnormalities of the middle cerebellar peduncles and variable signal abnormalities in the brain stem and cerebellar and cerebral white matter include the following:

  • Adult autosomal dominant leukoencephalopathy related to LMNB1 duplications is characterized by executive dysfunction, memory decline, personality changes, motor impairments, and seizures. Mean age of onset is in the fourth decade. Affected individuals eventually become bedridden with spasticity and rigidity. Brain MRI is characterized by cerebral white matter abnormalities with frontal preponderance.
  • Fragile X-associated tremor/ataxia syndrome, which occurs in adult males (and some females) who have an FMR1 premutation, is characterized by late-adult onset progressive cerebellar ataxia and intention tremor. Brain MRI shares with CC2L the typical middle cerebellar peduncle signal abnormalities, but lacks both the signal abnormalities in the cerebral peduncles and posterior limbs of the internal capsules and the diffusion restriction typical of CC2L.
  • Wilson disease is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these, in individuals ranging from age three years to older than 50 years. Kayser-Fleischer rings resulting from copper deposition in Descemet’s membrane of the cornea are frequently present. Abnormalities of brain MRI are highly variable and may involve the brain stem, but with a configuration different from that of CC2L.
  • Adult-onset Alexander disease mainly affects the lower brain stem, which is clinically evident as bulbar dysfunction. The hallmark brain MRI abnormality is atrophy of the medulla oblongata. Brain stem signal abnormalities with a predilection for the medulla may also be present.
  • Adrenomyeloneuropathy manifests most commonly in the late twenties with progressive paraparesis, sphincter disturbances, sexual dysfunction, and often impaired adrenocortical function. All features are progressive over decades. The primary MRI finding is spinal cord atrophy. Corticopontine and corticospinal projection fibers are frequently involved.
  • Cerebrotendinous xanthomatosis is characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction with dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures. The most important and earliest MRI abnormalities are signal abnormalities in the dentate nucleus and cerebellar hemispheric white matter. Additionally, signal abnormalities are often present in the corticospinal tracts and medial lemniscus in the brain stem, and slight signal changes are often seen in the periventricular cerebral white matter.
  • Leukoencephalopathy with brain stem and spinal cord abnormalities and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. MRI invariably shows spinal cord signal abnormalities over its entire length. Brain stem signal abnormalities are more variable and rarely involve the middle cerebellar peduncles and cerebral peduncles.

All disorders mentioned can be differentiated by the MRI findings mentioned and the diagnosis can be confirmed by appropriate biochemical and/or genetic testing.

See also Leukodystrophy Overview, which should cover all or most of the differential diagnosis information for this disorder.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CLCN2-related leukoencephalopathy (CC2L), the following evaluations are recommended:

  • Neurologic examination
  • Brain MRI if not performed at the time of diagnostic work up
  • Physical therapy/occupational therapy assessment, if significant neurologic problems are present
  • Ophthalmologic examination with attention to visual acuity and visual fields
  • Audiologic examination
  • For adult males: evaluation of testicular function
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Supportive therapy includes the following as needed:

  • Physical therapy and rehabilitation to improve motor function
  • Special education
  • Treatment of headache
  • Guidance for visual impairment
  • For males with infertility: consultation with a male infertility specialist

Surveillance

Annual evaluations including:

  • Neurologic examination
  • Ophthalmologic examination
  • Audiologic assessment

MRI follow up can be performed once every few years, in the event that the neurologic manifestations change.

Evaluation of Relatives at Risk

Using the CLCN2 pathogenic variants identified in the proband, it is appropriate to evaluate the older and younger sibs of a proband in order to identify 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.

Pregnancy Management

No pregnancy complications have been identified in affected women to date [Author, personal observation].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CLCN2-related leukoencephalopathy (CC2L) 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., carriers of one CLCN2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has 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. Offspring will inherit a CLCN2 pathogenic variant from a parent with CC2L.

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 (Heterozygote) 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, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the CLCN2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CC2L are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for CLCN2-Related Leukoencephalopathy have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CLCN2-Related Leukoencephalopathy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
CLCN23q27​.1Chloride channel protein 2CLCN2 databaseCLCN2CLCN2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CLCN2-Related Leukoencephalopathy (View All in OMIM)

600570CHLORIDE CHANNEL 2; CLCN2
615651LEUKOENCEPHALOPATHY WITH ATAXIA; LKPAT

Gene structure. CLCN2 comprises 15,467 base pairs. The longest transcript variant, NM_004366.5, has 24 exons. The gene has been reported to encode ten transcript variants, four of which are protein-coding. For details on gene and transcripts, see Table A, Gene.

Pathogenic variants. To date 18 pathogenic variants have been identified in 15 probands.

Six variants are located in exon 14 and two in exon 11; the remaining are distributed throughout the gene.

With the small number of known affected individuals to date, no information is available on prevalence in specific ethnic groups.

Table 2.

CLCN2 Variants Known to the Authors

Variant
Classification
DNA Nucleotide ChangePredicted Protein ChangeReference
Sequences
Uncertain
significance 1
c.130G>A 2p.Gly44ArgNM_004366​.5
NP_004357​.3
c.143C>G 3p.Pro48Arg 4
c.203G>A 3p.Arg68His 4
c.218G>A 2p.Arg73His
c.246C>G 2p.Phe82Leu
c.221-14_221-4del11 5
c.596G>C 3p.Gly199Ala 4
c.704G>A 6p.Arg235Gln 4
c.1730G>A 6p.Arg577Gln 4
c.1856–3C>T 7p.0? 8
c.1930C>T 6p.Arg644Cys
c.1937G>A 3p.Arg646Gln 4
c.2003C>G 2p.Thr668Ser
c.2063G>A 2, 7, 9p.Arg688Gly
c. 2144G>Ap.Gly715Glu
c.2154G>C 7, 9p.Glu718Asp
c.2173C>T 3p.Arg725Trp 4
c.2240G>A 3p.Arg747His 4
c.2273G>A 2p.Ser758Asn
c.2279C>T 2p.Ala760Val
Possibly
pathogenic
c.597dup 5p.Met200AspfsTer32
Pathogenicc.64-1107_639del 10p.Met22LeufsTer5
c.292G>C 11p.Gly98Arg 11
c.430_435del 10p.Leu144_Ile145del
c.828dupG 10p.Arg277AlafsTer23
c.925C>T 11p.Arg309Ter 11
c.1015G>C 11p.Val339Leu 11
c.1113delinsACTGCTCAT 12p.Ser375CysfsTer6
c.1143delT 10p.Gly382AlafsTer34
c.1304delT 11p.Leu435ArgfsTer7 11
c.1397G>A 11p.Gly466Glu 11
c.1412G>A 11p.Arg471His 11
c.1422_1423delTG 11p.Glu475LysfsTer79 11
c.1499C>T 10p.Ala500Val
c.1507G>A 13p.Gly503Arg
c.1709G>A 2, 10p.Trp570Ter
c.1795G>A 11p.Asp599Asn 11
c.1957A>T 11p.Arg653Ter 11
c.2386C>T 11p.Gln796Ter 11

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variants reported here were identified in the heterozygous state in patients with epilepsy and/or control individuals.

2.
3.
4.

These variants were shown to have a functional impact on CLC-2 function but the pathogenicity of these variants for CC2L in the homozygous state remains unproven.

5.
6.
7.
8.

Effect on protein unknown

9.
10.
11.

Author, unpublished data

12.
13.

Normal gene product. The start of the open reading frame in exon 1 is utilized in all four transcript variants. The longest protein-coding transcript NM_004366.5 expresses a protein encompassing 898 amino acids. This protein has 12 transmembrane domains and two intracellular CBS domains, and constitutes a voltage-gated chloride channel present at the plasma membrane.

Abnormal gene product. All pathogenic variants identified to date have been shown or suggested to result in either complete or partial loss of function of the protein chloride channel-2 by different mechanisms [Depienne at al 2013]. Overexpression studies have shown that the proteins with the variant p.Leu144_Ile145del, p.Ala500Val, or p.Trp570Ter are retained in the endoplasmic reticulum and are not transported to the plasma membrane. Pathogenic variants introducing a premature termination codon probably lead to mRNA degradation by nonsense-mediated decay [Depienne et al 2013]. Not all variants have, however, been tested [Di Bella et al 2014; Table 2, footnote 11].

Mouse model. Clcn2-mutant and knockout mice have been studied since 2001 [Bösl et al 2001, Blanz et al 2007, Edwards et al 2010]. The phenotype is dominated by visual impairment due to retinopathy and male infertility due to testicular degeneration resulting in azoospermia. A leukoencephalopathy characterized by intramyelinic edema was observed when investigating the brain, but was not clinically apparent [Blanz et al 2007, Edwards et al 2010]. The mutated mice had no other disease signs and had a normal life span [Bösl et al 2001, Blanz et al 2007, Edwards et al 2010].

References

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Chapter Notes

Revision History

  • 5 November 2015 (me) Review posted live
  • 22 April 2015 (mvdk) Original submission
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