An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study.
L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2-hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT-PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty-five novel mutations as well as 35 reported mutations and 14 nondisease-related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype-genotype relationship.
Steenweg
Marjan E
ME
Department of Child Neurology and VU University Medical Center, De Boelelaan 1117, Amsterdam, The Netherlands.
Jakobs
Cornelis
C
Errami
Abdellatif
A
van Dooren
Silvy J M
SJ
Adeva Bartolomé
Maria T
MT
Aerssens
Peter
P
Augoustides-Savvapoulou
Persephone
P
Baric
Ivo
I
Baumann
Matthias
M
Bonafé
Luisa
L
Chabrol
Brigitte
B
Clarke
Joe T R
JT
Clayton
Peter
P
Coker
Mahmut
M
Cooper
Sarah
S
Falik-Zaccai
Tzipora
T
Gorman
Mark
M
Hahn
Andreas
A
Hasanoglu
Alev
A
King
Mary D
MD
de Klerk
Hans B C
HB
Korman
Stanley H
SH
Lee
Céline
C
Meldgaard Lund
Allan
A
Mejaski-Bosnjak
Vlatka
V
Pascual-Castroviejo
Ignacio
I
Raadhyaksha
Aparna
A
Rootwelt
Terje
T
Roubertie
Agathe
A
Ruiz-Falco
Maria L
ML
Scalais
Emmanuel
E
Schimmel
Ulf
U
Seijo-Martinez
Manuel
M
Suri
Mohnish
M
Sykut-Cegielska
Jolanta
J
Trefz
Friedrich K
FK
Uziel
Graziella
G
Valayannopoulos
Vassili
V
Vianey-Saban
Christine
C
Vlaho
Stefan
S
Vodopiutz
Julia
J
Wajner
Moacir
M
Walter
John
J
Walter-Derbort
Claudia
C
Yapici
Zuhal
Z
Zafeiriou
Dimitrios I
DI
Spreeuwenberg
Marieke D
MD
Celli
Jacopo
J
den Dunnen
Johan T
JT
van der Knaap
Marjo S
MS
Salomons
Gajja S
GS
D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D020739:Brain Diseases, Metabolic, Inborn / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D006801:Humans; D009154:Mutation / Q000235:genetics*
D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase