title: GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course.
abstract: Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2.
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Medical Genetics, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy. Electronic address: ilariapezzini@yahoo.it.
authors.forename: I
authors.initials: I
authors.lastname: Pezzini
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Medical Genetics, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Geroldi
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Medical Genetics, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Capponi
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Medical Genetics, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gulli
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Clinical Neurology, University of Genoa, Largo P. Daneo 3, 16132, Genoa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Schenone
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Clinical Neurology, University of Genoa, Largo P. Daneo 3, 16132, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Grandis
authors.affiliation: Department of Child Neuropsychiatry Unit, G. Gaslini Institute, Largo G. Gaslini 5, 16147, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Doria-Lamba
authors.affiliation: Neurology and Neurophysiopathology Unit, S. Croce e Carle Hospital, Via M. Coppino 26, 12100 Confreria-Cuneo, Italy.
authors.forename: C
authors.initials: C
authors.lastname: La Piana
authors.affiliation: Department of Child Neuropsychiatry, C. Arrigo Hospital, Alessandria, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cremonte
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Pisciotta
authors.affiliation: Neurology Division, "Salvatore Maugeri" Foundation, Institute of Telese Terme, BN, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Nolano
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Manganelli
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, University Federico II of Naples, Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Santoro
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Medical Genetics, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Mandich
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infantile Sciences (DINOGMI), Medical Genetics, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Bellone
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017776:Autonomic Pathways / Q000473:pathology / Q000503:physiopathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D010641:Phenotype; D055815:Young Adult
chemical_list: C118663:GDAP protein; D009419:Nerve Tissue Proteins
keywords: Axonal CMT; Charcot–Marie–Tooth disease; Dominant inheritance; GDAP1