title: Genetic spectrum of hereditary neuropathies with onset in the first year of life.
abstract: Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine-Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot-Marie-Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot-Marie-Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot-Marie-Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset.
authors.affiliation: Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zimoń
authors.forename: Laetitia
authors.initials: L
authors.lastname: Yperzeele
authors.forename: Kim
authors.initials: K
authors.lastname: Van Hoorenbeeck
authors.forename: Kristien
authors.initials: K
authors.lastname: Peeters
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.forename: Yesim
authors.initials: Y
authors.lastname: Parman
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.forename: Patrick
authors.initials: P
authors.lastname: Van Bogaert
authors.forename: Adolf
authors.initials: A
authors.lastname: Pou-Serradell
authors.forename: Günther
authors.initials: G
authors.lastname: Bernert
authors.forename: Argirios
authors.initials: A
authors.lastname: Dinopoulos
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Satu-Leena
authors.initials: SL
authors.lastname: Sallinen
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fabrizi
authors.forename: Fernand
authors.initials: F
authors.lastname: Pauly
authors.forename: Peter
authors.initials: P
authors.lastname: Van den Bergh
authors.forename: Birdal
authors.initials: B
authors.lastname: Bilir
authors.forename: Esra
authors.initials: E
authors.lastname: Battaloglu
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Madrid
authors.forename: Dagmara
authors.initials: D
authors.lastname: Kabzińska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kochanski
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Miller
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007223:Infant; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D055815:Young Adult