D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity?
D-2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D-2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid gamma-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes.
van der Knaap
M S
MS
Department of Child Neurology, Free University Hospital, Amsterdam, The Netherlands.
Jakobs
C
C
Hoffmann
G F
GF
Nyhan
W L
WL
Renier
W O
WO
Smeitink
J A
JA
Catsman-Berrevoets
C E
CE
Hjalmarson
O
O
Vallance
H
H
Sugita
K
K
Bowe
C M
CM
Herrin
J T
JT
Craigen
W J
WJ
Buist
N R
NR
Brookfield
D S
DS
Chalmers
R A
RA
D015415:Biomarkers; D002552:Cerebral Ventricles / Q000473:pathology; D002675:Child, Preschool; D002819:Chorea / Q000000981:diagnostic imaging / Q000473:pathology / Q000652:urine*; D003560:Cysts; D004805:Ependyma / Q000473:pathology; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000473:pathology / Q000652:urine*; D005192:Family Health; D005260:Female; D005977:Glutarates / Q000652:urine*; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009123:Muscle Hypotonia / Q000000981:diagnostic imaging / Q000473:pathology / Q000652:urine; D010641:Phenotype; D014057:Tomography, X-Ray Computed; D015354:Vision, Low / Q000000981:diagnostic imaging / Q000473:pathology / Q000652:urine; D005680:gamma-Aminobutyric Acid / Q000134:cerebrospinal fluid
D015415:Biomarkers; D005977:Glutarates; C019417:alpha-hydroxyglutarate; D005680:gamma-Aminobutyric Acid