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Hearing impairment as an early sign of alpha‐mannosidosis in children with a mild phenotype: Report of seven new cases
Author(s) -
Lehalle Daphné,
Colombo Roberto,
O'Grady Michael,
Héron Bénédicte,
Houcinat Nada,
Kuentz Paul,
Moutton Sebastien,
Sorlin Arthur,
Theve Julien,
Delanne Julian,
Gay Sebastien,
Racine Caroline,
Garde Aurore,
Tran MauThem Frédéric,
Philippe Christophe,
Vitobello Antonio,
Nambot Sophie,
Huet Frédéric,
Duffourd Yannis,
Feillet François,
ThauvinRobinet Christel,
Marlin Sandrine,
Faivre Laurence
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61273
Subject(s) - sign (mathematics) , audiology , alpha (finance) , phenotype , medicine , pediatrics , psychology , developmental psychology , biology , genetics , mathematics , gene , mathematical analysis , construct validity , psychometrics
Alpha‐mannosidosis (AM) is a very rare (prevalence: 1/5 births) autosomal recessive lysosomal storage disorder. It is characterized by multi‐systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha‐mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha‐mannosidase in leucocytes and screening for abnormal urinary excretion of mannose‐rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDE R ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3–23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two‐sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.