CLCN2-related leukoencephalopathy with novel compound heterozygous variants followed with magnetic resonance imaging over 17 years: a case report.
CLCN2-related leukoencephalopathy
Case report
Chloride channel 2
Dizziness
Headache
Journal
BMC neurology
ISSN: 1471-2377
Titre abrégé: BMC Neurol
Pays: England
ID NLM: 100968555
Informations de publication
Date de publication:
23 Oct 2024
23 Oct 2024
Historique:
received:
31
05
2024
accepted:
14
10
2024
medline:
24
10
2024
pubmed:
24
10
2024
entrez:
24
10
2024
Statut:
epublish
Résumé
CLCN2-related leukoencephalopathy (CC2L) is a rare autosomal recessive disorder caused by biallelic variants of CLCN2, which encodes chloride channel 2. Although CC2L is associated with distinct radiological features, it presents with a wide range of clinical features. A 34-year-old woman presented to our hospital with a sudden onset of vertigo with headache. The patient reported intermittent headaches and tingling in both arms since the age of 31 years. On the first visit, the patient was alert and neurologically intact, except for slight hyperreflexia of the limbs without laterality. Head magnetic resonance imaging (MRI) showed high-intensity signals on axial T2-weighted fluid-attenuated inversion recovery and diffusion-weighted images bilaterally in the posterior limbs of the internal capsules, cerebral peduncles, superior and middle cerebellar peduncles, decussation of superior cerebellar peduncles, and central tegmental tract. All the patient's symptoms were resolved or eased following supportive care. The patient stopped attending our hospital at the age of 46 years. At 51 years of age, the patient revisited our hospital because of the recurrence of vertigo, headache, and nausea. She did not present with any abnormalities by neurological examination. Head MRI showed widespread high-intensity signals similar to those 17 years ago. Genetic testing revealed compound heterozygous variants in CLCN2 (NM_004366.6): a novel variant c.1828 C > T, p.(Arg 610*) from her father and c.61dup, p.(Leu21Profs*27) from her mother. The patient was finally diagnosed with CC2L. She received supportive treatment, which made her symptoms manageable. This is a detailed report of a patient with adult-onset CC2L who was successfully diagnosed and followed up with head MRI. This report provides new insights into CC2L and highlights its persistent, distinct, and stable characteristics observed in head MRI over one decade and the difficulty in forming a diagnosis without MRI when patients have minimal and common symptoms, such as in the present case.
Sections du résumé
BACKGROUND
BACKGROUND
CLCN2-related leukoencephalopathy (CC2L) is a rare autosomal recessive disorder caused by biallelic variants of CLCN2, which encodes chloride channel 2. Although CC2L is associated with distinct radiological features, it presents with a wide range of clinical features.
CASE PRESENTATION
METHODS
A 34-year-old woman presented to our hospital with a sudden onset of vertigo with headache. The patient reported intermittent headaches and tingling in both arms since the age of 31 years. On the first visit, the patient was alert and neurologically intact, except for slight hyperreflexia of the limbs without laterality. Head magnetic resonance imaging (MRI) showed high-intensity signals on axial T2-weighted fluid-attenuated inversion recovery and diffusion-weighted images bilaterally in the posterior limbs of the internal capsules, cerebral peduncles, superior and middle cerebellar peduncles, decussation of superior cerebellar peduncles, and central tegmental tract. All the patient's symptoms were resolved or eased following supportive care. The patient stopped attending our hospital at the age of 46 years. At 51 years of age, the patient revisited our hospital because of the recurrence of vertigo, headache, and nausea. She did not present with any abnormalities by neurological examination. Head MRI showed widespread high-intensity signals similar to those 17 years ago. Genetic testing revealed compound heterozygous variants in CLCN2 (NM_004366.6): a novel variant c.1828 C > T, p.(Arg 610*) from her father and c.61dup, p.(Leu21Profs*27) from her mother. The patient was finally diagnosed with CC2L. She received supportive treatment, which made her symptoms manageable.
CONCLUSIONS
CONCLUSIONS
This is a detailed report of a patient with adult-onset CC2L who was successfully diagnosed and followed up with head MRI. This report provides new insights into CC2L and highlights its persistent, distinct, and stable characteristics observed in head MRI over one decade and the difficulty in forming a diagnosis without MRI when patients have minimal and common symptoms, such as in the present case.
Identifiants
pubmed: 39443882
doi: 10.1186/s12883-024-03919-2
pii: 10.1186/s12883-024-03919-2
doi:
Substances chimiques
CLC-2 Chloride Channels
0
Chloride Channels
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
412Subventions
Organisme : Japan Society for the Promotion of Science
ID : 23K27566
Organisme : Japan Agency for Medical Research and Development
ID : JP23ek01099674
Organisme : Japan Agency for Medical Research and Development
ID : JP21wm0425019
Organisme : Ministry of Health, Labour and Welfare
ID : JPMH23FC1010
Organisme : Ministry of Health, Labour and Welfare
ID : JPMH21FC1015
Organisme : National Center of Neurology and Psychiatry
ID : 6-8
Informations de copyright
© 2024. The Author(s).
Références
Hoshi M, Koshimizu E, Miyatake S, Matsumoto N, Imamura A. A novel homozygous mutation of CLCN2 in a patient with characteristic brain MRI images - a first case of CLCN2-related leukoencephalopathy in Japan. Brain Dev. 2019;41(1):101–5.
doi: 10.1016/j.braindev.2018.07.011
pubmed: 30077506
Min R, Depienne C, Sedel F, Abbink TEM, van der Knaap MS. CLCN2-Related Leukoencephalopathy. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al. editors. GeneReviews(
Nóbrega PR, RBdP A, Souza KS, de Souza JLB, PL GSBL, da Silva DJ, et al. Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia. Brain Commun. 2024;6(1):fcad273.
doi: 10.1093/braincomms/fcad273
pubmed: 38173802
Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013;12(7):659–68.
doi: 10.1016/S1474-4422(13)70053-X
pubmed: 23707145
Cid LP, Montrose-Rafizadeh C, Smith DI, Guggino WB, Cutting GR. Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues. Hum Mol Genet. 1995;4(3):407–13.
doi: 10.1093/hmg/4.3.407
pubmed: 7795595
Wang H, Xu M, Kong Q, Sun P, Yan F, Tian W, et al. Research and progress on ClC–2 (review). Mol Med Rep. 2017;16(1):11–22.
doi: 10.3892/mmr.2017.6600
pubmed: 28534947
pmcid: 5482133
Chen S, Francioli LC, Goodrich JK, Collins RL, Kanai M, Wang Q, et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024;625(7993):92–100.
doi: 10.1038/s41586-023-06045-0
pubmed: 38057664
Tadaka S, Kawashima J, Hishinuma E, Saito S, Okamura Y, Otsuki A, et al. jMorp: Japanese multi-omics reference panel update report 2023. Nucleic Acids Res. 2024;52(D1):D622–32.
doi: 10.1093/nar/gkad978
pubmed: 37930845
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.
doi: 10.1038/gim.2015.30
pubmed: 25741868
pmcid: 4544753
Di Bella D, Pareyson D, Savoiardo M, Farina L, Ciano C, Caldarazzo S, et al. Subclinical leukodystrophy and infertility in a man with a novel homozygous CLCN2 mutation. Neurology. 2014;83(13):1217–8.
doi: 10.1212/WNL.0000000000000812
pubmed: 25128180
Zeydan B, Uygunoglu U, Altintas A, Saip S, Siva A, Abbink TEM, et al. Identification of 3 novel patients with CLCN2-Related Leukoencephalopathy due to CLCN2 mutations. Eur Neurol. 2017;78(3–4):125–7.
doi: 10.1159/000478089
pubmed: 28746943
Ozaki A, Sasaki M, Hiraide T, Sumitomo N, Takeshita E, Shimizu-Motohashi Y, et al. A case of CLCN2-related leukoencephalopathy with bright tree appearance during aseptic meningitis. Brain Dev. 2020;42(6):462–7.
doi: 10.1016/j.braindev.2020.02.008
pubmed: 32173090
Xu P, Chen Z, Ma J, Shan Y, Wang Y, Xie B, et al. Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. Hum Genet. 2023;142(4):577–93.
doi: 10.1007/s00439-023-02531-7
pubmed: 36964785
Guo Z, Lu T, Peng L, Cheng H, Peng F, Li J, et al. CLCN2-related leukoencephalopathy: a case report and review of the literature. BMC Neurol. 2019;19(1):156.
doi: 10.1186/s12883-019-1390-7
pubmed: 31291907
pmcid: 6617604