Leukoencephalopathy with Ataxia and Familial Hyperaldosteronism Type II via the CLCN2 Gene

CLCN2-related leukoencephalopathy is a rare neurological disorder with childhood or adult onset. The major symptoms include mild cerebellar ataxia, chorioretinopathy with visual field defects, optic neuropathy, mild cognitive impairment, headaches, and male oligo-/azoospermia. The minor features include epilepsy, paroxysmal kinesigenic dyskinesia, mild spasticity, and auditory abnormalities. MRI image analysis shows abnormally low signal on T1-weighted images and abnormally high signal on T2-weighted images in the posterior limbs of the internal capsules, midbrain crura cerebri, and middle cerebellar peduncles. Phenotype is variable (Depienne et al. 2013. PubMed ID: 23707145; Zeydan et al. 2017. PubMed ID: 28746943).  

CLCN2-related familial hyperaldosteronism type II results from excess production of the adrenal steroid aldosterone with early onset before 20 years old. Patients present with features such as hypertension and headache. Laboratory findings include increased serum aldosterone, increased aldosterone:renin ratio, decreased renin, and hypokalemia (Scholl et al. 2018. PubMed ID: 29403011; Fernandes-Rosa et al. 2018. PubMed ID: 29403012).

As leukoencephalopathy and hyperaldosteronism can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

CLCN2-related leukoencephalopathy with ataxia is inherited in an autosomal recessive manner, whereas CLCN2-related familial hyperaldosteronism type II is inherited in an autosomal dominant manner. Pathogenic variants in CLCN2 include missense, nonsense, splicing, small deletions and duplications, and small indels. A complex DNA arrangement has also been reported (Human Gene Mutation Database). A few de novo variants have been reported (Xie et al. 2019. PubMed ID: 31054517; Fernandes-Rosa et al. 2018. PubMed ID: 29403012).

CLCN2 encodes a voltage-gated chloride channel. Pathogenic variants with loss of function cause brain intramyelinic edema and myelin vacuolation, leading to leukoencephalopathy. Variants with gain of function result in primary aldosteronism due to increased expression of aldosterone synthase and aldosterone production in adrenocortical cells. A mouse model with loss of function Clcn2−/− displayed leukodystrophy as well as early postnatal retinal and testicular degeneration. Another mouse model with gain of function (p.Gly24Asp variant) presented primary aldosteronism (Gaitán-Peñas et al. 2017. PubMed ID: 28905383; Fernandes-Rosa et al. 2018. PubMed ID: 29403012). CLCN2 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Pathogenic variants in CLCN2 are considered a rare cause of leukoencephalopathy. To date, CLCN2-related leukoencephalopathy has been reported or identified in 16 patients from 15 families (Min et al. 2021. PubMed ID: 26539602; updated in May 20, 2021). In more than 80 patients with unsolved early-onset primary aldosteronism, 8 patients were confirmed to have a heterozygous variant in CLCN2 (Scholl et al. 2018. PubMed ID: 29403011).

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CLCN2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).