title: Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation.
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.
authors.affiliation: 1 Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.affiliation: 1 Neurogenetics of Motion Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, H3A 2B4, Canada.
authors.forename: Marie-Josée
authors.initials: MJ
authors.lastname: Dicaire
authors.affiliation: 3 Laboratoire de génétique médicale, CHU-Ste-Justine, Montreal, Quebec, H3T 1C5, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Allard
authors.affiliation: 4 Department of Biochemistry, McGill University, Montreal, Quebec, H3G 0B1, Canada.
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
authors.affiliation: 3 Laboratoire de génétique médicale, CHU-Ste-Justine, Montreal, Quebec, H3T 1C5, Canada.
authors.forename: Diane
authors.initials: D
authors.lastname: Leblanc
authors.affiliation: 5 Cliniques des maladies neuromusculaires, CSSS-Jonquière, Quebec, G7H 7K9, Canada.
authors.forename: Nadine
authors.initials: N
authors.lastname: Leclerc
authors.affiliation: 6 Department of Neurology and Neurosurgery, Jewish General Hospital, McGill University, Montreal, Quebec, H3T 1E2, Canada.
authors.forename: Ronald
authors.initials: R
authors.lastname: Schondorf
authors.affiliation: 5 Cliniques des maladies neuromusculaires, CSSS-Jonquière, Quebec, G7H 7K9, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Mathieu
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: 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.
authors.forename: Bernard
authors.initials: B
authors.lastname: Brais
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015417:Hereditary Sensory and Motor Neuropathy / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010146:Pain / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C033079:alpha-N-acetyl-D-glucosaminidase; D000118:Acetylglucosaminidase
keywords: ataxia; axonal neuropathy; lysosomal disorder; whole-exome sequencing
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