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

Jacopo Sartorelli; Lorena Travaglini; Giacomo Garone; Maria L. Dentici; Lorenzo Sinibaldi; Maria C. Digilio; Antonio Novelli; Emanuele Agolini; Adele D'Amico; Enrico Bertini; Francesco Nicita

doi:10.1055/a-2524-9091

Neuropediatrics, Table of Contents

Neuropediatrics 2025; 56(03): 185-193
DOI: 10.1055/a-2524-9091

Original Article

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

Jacopo Sartorelli

¹Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Lorena Travaglini

²Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Giacomo Garone

³Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy

⁴Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy

,

Maria L. Dentici

⁵Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Lorenzo Sinibaldi

⁵Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Maria C. Digilio

⁵Rare Diseases and Medical Genetics Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Antonio Novelli

²Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Emanuele Agolini

²Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Adele D'Amico

¹Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Enrico Bertini

¹Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

,

Francesco Nicita

¹Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy

› Author Affiliations

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

Full Text

References

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