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Brain. 2015 Jun;138(Pt 6):1477-83. doi: 10.1093/brain/awv074. Epub 2015 Mar 28.

Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation.

Author information

1
1 Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
2
2 Dr John T Macdonald Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
3
3 Laboratoire de génétique médicale, CHU-Ste-Justine, Montreal, Quebec, H3T 1C5, Canada.
4
4 Department of Biochemistry, McGill University, Montreal, Quebec, H3G 0B1, Canada.
5
5 Cliniques des maladies neuromusculaires, CSSS-Jonquière, Quebec, G7H 7K9, Canada.
6
6 Department of Neurology and Neurosurgery, Jewish General Hospital, McGill University, Montreal, Quebec, H3T 1E2, Canada.
7
1 Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada 5 Cliniques des maladies neuromusculaires, CSSS-Jonquière, Quebec, G7H 7K9, Canada Bernard.Brais@mcgill.ca.

Abstract

Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes.

KEYWORDS:

ataxia; axonal neuropathy; lysosomal disorder; whole-exome sequencing

PMID:
25818867
PMCID:
PMC4542621
DOI:
10.1093/brain/awv074
[Indexed for MEDLINE]
Free PMC Article

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