Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants

Abstract

Background Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic NALCN pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic variants lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD). In our work, we aimed to expand the heterozygous NALCN-related clinical spectrum, presenting two affected individuals and a literature review.

Methods We describe two new unrelated subjects harboring monoallelic NALCN pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous NALCN patients.

Results The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (p.Phe1141Leu) heterozygous missense variants were disclosed in two subjects manifesting a similar phenotype characterized by congenital ataxia with progressive cerebellar atrophy, camptodactyly, and hypertrichosis of the arms (CAPCACH). Other NALCN subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype.

Conclusion We expand the heterozygous NALCN-related clinical spectrum from the more severe CLIFFAHDD to the milder CAPCACH phenotype. These conditions should be considered in the differential diagnosis of syndromic congenital ataxias, and the presence of camptodactyly and/or hypertrichosis may represent peculiar diagnostic clues.

Keywords

ataxia - cerebellum - sodium - WES - arthrogryposis - hypertrichosis

Ethical Approval

Submission of the manuscript has been approved by our institution (approval number RAP-2024-0004).

Patients' Consent

The patient's parents have signed the written informed consent for genetic analyses and participation in study research.

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Publication History

Received: 07 August 2024

Accepted: 21 January 2025

Article published online:
06 February 2025

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