全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
D-2-HYDROXYGLUTARIC ACIDURIA 1; D2HGA1

D-2-HYDROXYGLUTARIC ACIDURIA 1; D2HGA1

Alternative titles; symbolsD2HGA▼ DescriptionD-2-hydroxyglutaric aciduria is a neurometabolic disorder first described by Chalmers et al. (1980). Clinical sympto...

Alternative titles; symbols

  • D2HGA

▼ Description
D-2-hydroxyglutaric aciduria is a neurometabolic disorder first described by Chalmers et al. (1980). Clinical symptoms include developmental delay, epilepsy, hypotonia, and dysmorphic features. Mild and severe phenotypes were characterized (van der Knaap et al., 1999). The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, often, cardiomyopathy. The mild phenotype has a more variable clinical presentation.

Genetic Heterogeneity of D-2-Hydroxyglutaric Aciduria

D-2-hydroxyglutaric aciduria-2 (D2HGA2; 613657) is caused by heterozygous mutation in the mitochondrial isocitrate dehydrogenase-2 gene (IDH2; 147650) on chromosome 15q26.

▼ Clinical Features
Nyhan et al. (1995) described 3 female patients, including 2 sibs, who were found to have excess accumulation of D-2-hydroxyglutaric acid in the urine. The phenotype was quite variable, even among the sibs, but included mental retardation, macrocephaly with cerebral atrophy, hypotonia, seizures, and involuntary movements. One of the patients developed severe intermittent vomiting and was given a pyloromyotomy. The electroencephalogram demonstrated hypsarrhythmia. There was an increased concentration of protein in cerebrospinal fluid, an unusual finding in inborn errors of metabolism. Increased CSF protein has also been observed in mitochondrial disorders, peroxisomal disorders, and Krabbe disease (245200).

Van der Knaap et al. (1999) reported clinical, biochemical, and neuroimaging data on 8 previously undescribed patients with D-2-hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. The most frequent findings, regardless of the clinical phenotype, were epilepsy, hypotonia, and psychomotor retardation. Additional findings, mainly occurring in the severe phenotype, were episodic vomiting, cardiomyopathy, inspiratory stridor, and apneas. The most consistent MRI finding was enlargement of the lateral ventricles, occipital more than frontal. In both the severe and mild forms, MRI showed subependymal cysts and signs of delayed cerebral maturation.

Amiel et al. (1999) reported 2 unrelated cases with D-2-hydroxyglutaric aciduria presenting with epileptic encephalopathy. Both patients had minor facial anomalies, including a 'coarse' facial appearance, broad nasal bridge, and large protruding ears. The authors noted that minor facial anomalies had been observed in some reported cases of this condition. They suggested that D-2-hydroxyglutaric aciduria should be considered in patients with minor facial anomalies and epileptic encephalopathy of unknown origin.

Wajner et al. (2002) reported an infant with intermittent urinary excretion of D-2-hydroxyglutaric (D-2-OHG) acid who died at the age of 10 months from cardiogenic shock due to cardiomyopathy. High urinary concentrations of D-2-OHG acid and succinic acid, as well as increased levels of lactic acid, were detected on 3 different occasions, whereas a normal urinary profile of organic acids was found on 1 occasion. The clinical findings in this patient consisted of generalized hypotonia, irritability, developmental delay, generalized tonic seizures, lethargy, cardiomyopathy, and respiratory distress. Cerebral MRI revealed bilateral lesions in the substantia nigra, the periaqueductal area, the medial part of the thalamus, the hypothalamus, the caudate nucleus, putamen, and globus pallidus. This pattern is suggestive of a mitochondrial disorder. However, respiratory chain enzyme activities were normal in fibroblasts. Exogenous supplementation of D-2-OHG acid strongly inhibited cytochrome-c oxidase activity in fibroblasts from the patient and from normal controls in vitro. Wajner et al. (2002) concluded that their patient had an unusual form of D-2-hydroxyglutaric aciduria and that the increase of lactic acid and some citric acid cycle intermediates encountered in some patients with D-2-hydroxyglutaric aciduria may be due to a functional defect of the respiratory chain directly caused by the accumulation of the D-2-OHG acid.

Clarke et al. (2003) reported a girl with an intermediate form of D-2-hydroxyglutaric aciduria. In the neonatal period, she showed respiratory insufficiency, increased sleepiness, and poor feeding. Physical features included turricephaly, brachycephaly, broad, flat face with coarse features, including a short upturned nose, broad nasal tip, thick alae nasi, small nostrils, and a prominent jaw. Her ears were low set, cupped, and simple in structure, and the earlobes were anteverted. At 3 months of age, she developed grand mal and complex partial seizures. EEG showed abundant epileptiform activity, and brain imaging showed mild enlargement of the ventricles. Urinary D-2-hydroxyglutarate was markedly increased. At age 31 months, she showed significant global developmental delay, cortical visual impairment, microcephaly, and mild hypotonia. Clarke et al. (2003) noted that the physical features were similar to those of the patients reported by Amiel et al. (1999).

Struys et al. (2005) reported 3 individuals from 2 unrelated consanguineous Palestinian families with mild forms of D-2-hydroxyglutaric aciduria. In 1 family, 2 sibs were asymptomatic and showed normal development at ages 10 and 3 years, respectively. In the second family, the child developed absence seizures with myoclonic jerks at age 8 years, showed difficulty in reading, hyperactivity, and behavioral problems, but had normal gross and fine motor development. IQ was assessed as 75.

Misra et al. (2005) reported 4.5-year-old monozygotic twin sisters, born of nonconsanguineous African American parents, with D-2-hydroxyglutaric aciduria confirmed by genetic analysis (609186.0005; 609186.0006). The girls had markedly different phenotypes. The more severely affected girl had multiple congenital anomalies, hypotonia, severe developmental delay, epileptic encephalopathy, ventriculomegaly, and cortical atrophy with periventricular leukomalacia. In contrast, her sister had a normal neurocognitive and neuroradiologic phenotype without congenital abnormalities. Both girls had similar dysmorphic facies, with dolichocephaly, malar flattening, and broad nasal root, and both had similar biochemical profiles. The discordant phenotype indicated that epigenetic differences or environmental factors must have influenced the phenotypic response to the biochemical defect, rather than allelic heterogeneity.

D-2-hydroxyglutaric aciduria has been described in association with spondyloenchondromatosis (614875), a rare skeletal dysplasia that presents with multiple enchondromata in the metaphyses of the long bones associated with dysplastic vertebral bodies (Honey et al., 2003; Talkhani et al., 2000; Bayar et al., 2005).

▼ Diagnosis
Prenatal Diagnosis

Clarke et al. (2003) reported successful prenatal diagnosis of D-2-hydroxyglutaric aciduria in 2 subsequent pregnancies of a couple with an affected child. Amniotic fluid samples taken at 15.5 and 16 weeks' gestation, respectively, indicated markedly elevated levels of D-2-hydroxyglutaric acid.

▼ Molecular Genetics
In 2 unrelated patients with D-2-hydroxyglutaric aciduria, Struys et al. (2005) identified mutations in the D2HGDH gene. One patient was homozygous for a missense mutation (609186.0001); the other patient, originally described by Gibson et al. (1993), was compound heterozygous for a missense mutation (609186.0002) and a splice site mutation (609186.0003) that resulted in a null allele.

In 3 individuals from 2 unrelated Palestinian families with mild forms of D-2-hydroxyglutaric aciduria, Struys et al. (2005) identified homozygous mutations in the D2HGDH gene (609186.0004 and 609186.0005). The findings confirmed that both the mild and severe forms of the disorder are caused by mutations in the D2HGDH gene.

Kranendijk et al. (2010) identified presumed pathogenic mutations in the D2HGDH gene in 24 (48%) of 50 patients with increased levels of D-2-hydroxyglutaric acid in urine, plasma, and/or cerebrospinal fluid. Reduced enzyme activity was confirmed in patients with D2HGDH mutations, whereas those without mutations had normal enzyme activity. In addition, those with mutations had significantly lower D-2-hydroxyglutaric acid concentrations in body fluids compared to those without mutations. Overall, the results suggested that at least 1 additional genetic locus is associated with hyperexcretion of D-2-hydroxyglutaric acid.

To study the functional effects of missense mutations in the D2HGDH gene in patients with increased urinary excretion of D-2-hydroxyglutarate, Pop et al. (2019) used site-directed mutagenesis to introduce 21 reportedly pathogenic and 10 novel potentially pathogenic mutations into HEK293 cells. Eighteen of the D2HGDH mutations (e.g., I147S, 609186.0002) resulted in almost complete loss of D2HGH enzyme activity (less than 6%) compared to wildtype; the other 13 mutations showed residual D2HGDH activity ranging from 17 to 94%, necessitating more in-depth analysis of the mutations to assess potential pathogenicity. Pop et al. (2019) concluded that functional characterization of D2HGDH mutations may be beneficial for understanding pathogenicity of individual mutations.

▼ Animal Model
Nyhan et al. (1995) found increased excretion of D-2-hydroxyglutaric acid in the urine of an 11-year-old female Irish setter/Labrador crossbred dog with a 2-year history of lethargy, progressive muscle weakness, and panting. The dog's muscle biopsy demonstrated triglyceride droplets characteristic of a lipid storage myopathy, as well as scattered atrophic angular fibers. D-2-hydroxyglutaric acid is an intermediate in the metabolism of gamma-aminobutyric acid (GABA), glutamate, and 5-aminolevulinic acid. Levels of GABA were elevated in the cerebrospinal fluid of 2 of the patients with D-2-hydroxyglutaric aciduria.

Tags: 2q37.3