Prepair 1000+

Gene: D2HGDH

Green List (high evidence)

Struys et al. (2005) (PMID: 15609246) describes two patients. Patient 1 with mild facial dysmorphia, with a reduced bitemporal diameter, a prominent forehead, micrognathia and psychomotor retardation in addition to tonic, tonic-clonic, and myoclonic seizures that were not responsive to antiepileptic treatment. Was homozygous for a missense mutation. Functional studies for patient 1: Overexpression studies in HEK293 cells of the mutant missense protein showed a marked reduction of D-2-hydroxyglutarate dehydrogenase activity.

Patient 2 with generalized tonic-clonic seizures, infantile spasms with hypsarrhythmia, hypotonia, a movement disorder, cortical blindness, and developmental delay. Was compound heterozygous for a missense mutation.

Misra et al. (2005) (PMID: 16081310) assessed two monozygotic twin sisters, with compound heterozygosity for 2 mutations in the D2HGDH gene, with vastly different phenotypes. One had multiple congenital anomalies, hypotonia, severe developmental delay, epileptic encephalopathy, and cortical atrophy with periventricular leukomalacia. In contrast, her sister had a normal neurocognitive and neuroradiologic phenotype without congenital abnormalities. Both had distinctive facial features: dolichocephaly, malar flattening, and broad nasal root.

Biase et al. (2024) (PMID: 38825343) reported an infant with speech delay, developmental delay, and autism spectrum; Mild developmental delays were noted around 10 months. Speech delay, attention deficit hyperactivity disorder, and behavior issues were identified at 5 years. Found to have in-trans compound heterozygous D2HGDH variants.

Functional assays: PMID: 31349060, 20020533

Antenatal features: macrocephaly, enlarged cerebral ventricles, micrognathia

Onset can be severe neonatal, though milder, later presentations also reported. No specific treatment at present.

Created: 12 Dec 2024, 11:42 p.m. | Last Modified: 12 Dec 2024, 11:42 p.m.

Panel Version: 1.761

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
D-2-hydroxyglutaric aciduria, MIM#600721

Publications

• 15609246
• 16081310
• 31349060
• 20020533
• 38825343