CLCN2 ‐Related Leukoencephalopathy in Two Unrelated Patients Due to Novel Variants

CLCN2‐related leukoencephalopathy (CC2L) also known as Leukoencephalopathy with ataxia (LKPAT), is a rare autosomal‐recessive leukoencephalopathy often presenting with mild and nonspecific neurological symptoms and has characteristic patterns of white matter oedema observed in magnetic resonance imaging (MRI) of the brain. ¹ , ² , ³ To the best of our knowledge, only around 30 cases of CC2L ¹ have been reported to date.

Case‐1, an 18‐year‐old woman, born of consanguineous parentage with otherwise normal developmental and family history (Fig. 1A), presented with an 11‐month history of episodic mild–moderate headache with dizziness without nausea, vomiting, photophobia or phonophobia lasting 1–2 h occurring around once a week and occasional non radiating low backache. The patient attributed these symptoms to a trivial trauma she sustained 2‐months prior to the onset. On probing, the patient and her mother reported subtle non‐disabling walking difficulty which again was attributed to the trauma. The patient was referred to us in view of abnormal magnetic resonance imaging (MRI) that was done for headache and backache.

FIG. 1.

Pedigree and Sanger sequencing chromatogram. (A) Pedigree of the Case‐1. (B) Pedigree of Case‐2. (C) Sanger sequencing chromatogram of the case‐1 and the parents showing variant CLCN2:c.1542_1543del (red arrow) in homozygous state in the patient and heterozygous carrier state (green arrow) in parents. (D) Sanger sequencing chromatogram of the case‐2 and the father showing variant CLCN2:c.1137C > A (orange arrow) in homozygous state in the patient and heterozygous carrier state (blue arrow) in the father parents. wt, wild‐type.

On examination (Video 1), she had normal cognition, vision, hearing, speech and eye movements. The patient had mild lower limb spasticity with normal power, sensation, deep tendon reflexes and plantar response. Mild incoordination was noted in all four limbs with spastic ataxic gait and impaired tandem (The International Cooperative Ataxia Rating Scale [ICARS] score‐15). The rest of her neurological and other system examination was normal.

Video 1.

Case‐1: Mild finger‐nose and knee–heel‐shin incoordination with intentional tremor and mildly impaired tandem gait (International Cooperative Ataxia Rating Scale score—15). The video was taken after written informed consent for online publication and dissemination.

Routine blood investigations, ammonia, lactate, vitamin B12, homocysteine levels and thyroid function test were normal, and screening for abnormal metabolite in serum and urine was negative. MRI brain showed bilateral symmetrical T2‐FLAIR hyperintensities in centrum semi‐ovale including U fibers, posterior limb of internal capsule, splenium of corpus callosum, cerebral peduncles, decussation of superior cerebellar peduncles, central tegmental tract, corticospinal tract and middle cerebellar peduncles and diffusion restriction in posterior limb of internal capsule as described in Fig. 2A–H. In addition, bilateral optic nerve was thick and hyperintense. Nerve conduction study was normal whereas the latency of visual, brainstem auditory and somatosensory evoked potentials were prolonged. Exome sequencing revealed a novel homozygous 2‐bp deletion in the CLCN2 gene (CLCN2:c.1542_1543delAG;p.Ser516HisfsTer38;NM_004366.6) resulting in a frameshift and premature truncation of the protein. This variant was classified as pathogenic (PVS₁PM₂PP₃) according to American College of Medical Genetics (ACMG) guidelines. Sanger sequencing revealed a heterozygous carrier state in the parents (Fig. 1B). A diagnosis of CC2L was made and the family members were counseled regarding the prognosis of the disease and managed symptomatically.

FIG. 2.

T2‐FLAIR (A–E, I–N), T2 (F), DWI (G, O) and ADC (H, P) sequences of Magnetic Resonance Imaging (MRI) Brain of Case‐1 (A–H) and Case‐2 (I–P). MRI brain showing bilateral symmetrical T2‐FLAIR hyperintensity involving centrum semi‐ovale including U fibers (A, I), posterior limb of internal capsule (long black arrow B, J), splenium of corpus callosum (short black arrow, B, J), cerebral peduncles (black arrowhead, C, K), decussation of superior cerebellar peduncles (C, K), central tegmental tract (long white arrow, D, L), corticospinal tract (short white arrow, D, L; red arrow, F, N) and middle cerebellar peduncles (white arrowhead, D, E, L, M) and diffusion restriction in posterior limb of internal capsule (red arrowhead, G, H, O, P).

Case‐2, a 32‐year‐old man, born of consanguineous parentage and a normal developmental and family history (Fig. 1C), presented with a 3‐year history of episodic mild to moderate headache with nausea, photophobia or phonophobia lasting 1–2 h, 2–3 episodes per month. The patient was referred to us in view of an abnormal MRI. On examination, except for the mild spasticity, minimal incoordination in bilateral lower limbs, and mild ataxic gait with impaired tandem (ICARS‐7), the rest of the examination, including cognition, vision and fundus, were normal.

The blood investigations were normal, whereas the MRI brain showed findings similar to Case‐1 (Fig. 2I–P). Exome sequencing revealed a novel homozygous missense variant in the CLCN2 gene (chr3:c.1137C > A;p.Phe379Leu;NM_004366.6). Sanger sequencing revealed carrier status in the father (Fig. 1D). Even in the presence of the supportive clinical presentation with classical MRI findings, the variant could only be classified as a variant of uncertain significance according to the ACMG guidelines (PM₂PP_3,4). The patient underwent genetic counseling, symptomatic therapy for headaches, and physiotherapy for mild ataxia.

Pathogenic mutations in CLCN2 have been reported in patients with CC2L. CLCN2 encodes chloride channel‐2 (ClC‐2), a plasma membrane chloride channel expressed ubiquitously in the human body, including the brain. ⁴ Although the molecular mechanism of ClC‐2 is still elusive, it is thought to regulate the homeostasis of ions and water in the brain. ¹ CC2L is characterized by mild and often non‐specific neurological findings such as headache and mild spastic‐ataxia, as seen in both of our cases, and in addition, can have a cognitive, psychiatric, visual, and auditory impairment (Table S1). Even though headache has been reported in CC2L, it can be an unrelated coincidental finding. In contrast to previous reports of male infertility due to azoospermia, there was no infertility in Case‐2. To date, no affected males with offspring have been reported. ²

Often, abnormal MRI is found when evaluated for the nonspecific neurological findings such as headache or non‐neurological findings. The MRI pattern is characteristic and can clinch the diagnosis. Confluent, non‐enhancing T2/FLAIR hyperintense with corresponding T1 hypointense with or without diffusion restricting lesions commonly noted in posterior limb of internal capsule, cerebral peduncle, middle cerebellar peduncle and additionally may also involve pontine pyramidal tracts, central tegmental tracts, superior cerebellar peduncles and its decussation, cerebellar white matter, callosum, and cerebral white matter. ¹ , ² , ³ The MRI changes precedes the neurological symptoms as there are reports of subclinical CC2L with incidental MRI abnormality detected when evaluated for non‐neurological symptoms such as infertility and optic atrophy. ⁵ , ⁶

Even though the MRI findings are often extensive, the clinical syndrome tend to be mild, remain stable or progress extremely slowly with prolonged survival. ² , ⁷ So far, all reported cases have remained ambulatory and no disease‐related deaths have been reported. ¹ , ² Management is often supportive and symptomatic with regular surveillance for the development of various neurological manifestation. Genetic counseling is important to make informed decisions regarding the available options to avoid perpetuation of this disorder in the family.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

V.V.H.: 1A, 1B, 1C, 3A.

P.P.: 1B, 1C, 3B.

J.S.: 1B, IC, 3B.

N.K.: 1B, IC, 3B.

P.K.P.: 1A, 1C, 3B.

R.Y.: 1A, 3B.

B.M.: 1A, 1C, 3B.

M.N.: 1A, 1C, 3B.

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was obtained for this work. Patients’ informed consent was obtained for video recording, dissemintaion and publication. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This work was supported by a research grant provided by Science and Engineering Research Board (SERB), Department of Science & Technology, Government of India (EMR/2017/004853).

Financial Disclosures for the Previous 12 Months: There are no financial disclosures to report.

Supporting information

TABLE S1. Clinical details of the CCL2 cases reported so far