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Eur J Med Genet. 2018 Dec 17. pii: S1769-7212(18)30416-6. doi: 10.1016/j.ejmg.2018.12.010. [Epub ahead of print]

CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia.

Author information

1
Department of Medicine (Neurology), University of Alberta, Edmonton, Canada. Electronic address: Aakash.shetty@uhnresearch.ca.
2
Department of Human Genetics, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Montreal Neurological Institute, McGill University, Montreal, Canada.
3
Department of Medicine (Neurology), University of Alberta, Edmonton, Canada.
4
Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Montreal Neurological Institute, McGill University, Montreal, Canada.
5
Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
6
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
7
Department of Medicine (Neurology), University of Alberta, Edmonton, Canada; Departments of Medical Genetics and Pediatrics, University of Alberta, Edmonton, Canada.

Abstract

AIMS AND OBJECTIVE:

To characterize the phenotype of CAPN1 (SPG76) mutations in patients diagnosed with hereditary spastic paraplegia (HSP).

BACKGROUND:

The CAPN1 gene, located on chromosome 11q13.1, is a protein-coding gene involved in neuronal plasticity, migration, microtubular regulation and cerebellar development. Several families with CAPN1 mutations have recently been reported to present with autosomal recessive (AR) HSP and/or ataxia.

METHOD:

Patients with HSP were identified through neurological and genetic clinics with detailed phenotyping. Whole exome sequencing revealed novel pathogenic CAPN1 mutations in four patients from 3 families.

RESULTS:

Affected families were of Turkish, Japanese, and Punjabi descent and all were consanguineous. Onset of spastic paraplegia in the four patients was between 20 and 37 years. Two also had mild ataxia. Three different novel, homozygous mutations in CAPN1 were found: c.2118+1G > T, c.397C > T, c.843+1G > C. The patient with the earliest onset also manifested profound muscle weakness, likely related to a second homozygous mutation in DYSF (dysferlinopathy).

CONCLUSIONS:

The phenotype of AR CAPN1 mutations appears to be spastic paraplegia with or without ataxia; onset is most commonly in adulthood. Eye movement abnormalities, skeletal defects, peripheral neuropathy and amyotrophy can sometimes be seen. Occasionally, patients can present with ataxia, illustrating the genotypic and phenotypic overlap between HSP and spastic ataxia. With the advent of exome sequencing, mutations in more than one gene can be identified, which may contribute to the phenotypic variation, even within a family.

KEYWORDS:

Ataxia; CAPN1 mutation; Hereditary spastic paraparesis(HSP)

PMID:
30572172
DOI:
10.1016/j.ejmg.2018.12.010

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