Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin.
We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.
Vilarinho
L
L
Clinical Biology Unit, Medical Genetics Institute, Porto, Portugal. laura.vilarinho@igm.min-saude.pt
Cardoso
M L
ML
Gaspar
P
P
Barbot
C
C
Azevedo
L
L
Diogo
L
L
Santos
M
M
Carrilho
I
I
Fineza
I
I
Kok
F
F
Chorão
R
R
Alegria
P
P
Martins
E
E
Teixeira
J
J
Cabral Fernandes
H
H
Verhoeven
N M
NM
Salomons
G S
GS
Santorelli
F M
FM
Cabral
P
P
Amorim
A
A
Jakobs
C
C
D000293:Adolescent; D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D005192:Family Health; D005260:Female; D005977:Glutarates / Q000652:urine*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D011174:Portugal; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D005977:Glutarates; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase