Combined D-2- And L-2-Hydroxyglutaric Aciduria

A number sign (#) is used with this entry because combined D-2- and L-2-hydroxyglutaric aciduria is caused by homozygous or compound heterozygous mutation in the SLC25A1 gene (190315) on chromosome 22q11.

Biallelic mutation in the SLC25A1 gene can also cause congenital myasthenic syndrome-23 (CMS23; 618197), a less severe disorder.

Description

Combined D-2- and L-2-hydroxyglutaric aciduria (D-2-HG and L-2-HG) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (summary by Muntau et al., 2000).

See also isolated L-2-hydroxyglutaric aciduria (236792) and isolated D-2-hydroxyglutaric aciduria (see 600721).

Clinical Features

Muntau et al. (2000) reported 3 patients, including 2 sibs, with severe neonatal encephalopathy associated with combined D-2- and L-2-hydroxyglutaric aciduria. The first patient presented in the neonatal period with hypotonia, irritability, uncontrollable seizures, poor eye contact, and poor feeding. He developed macrocephaly, hepatomegaly, and respiratory insufficiency requiring tracheostomy. Dysmorphic features included dolichocephaly, mild craniofacial dysmorphism, and clinodactyly of the fifth fingers. Brain imaging at age 3 months showed mild enlargement of lateral ventricles, several small germinal layer cysts over the head of the caudate nucleus, and delayed gyration and myelination. He had essentially no psychomotor development, and died at age 3.5 years. Laboratory studies showed increased urinary levels of D-2-HG, L-2-HG, and 2-oxoglutaric acid. The patient's younger sister was found to have mildly increased D-2-HG during prenatal testing; L-2-HG was normal. After birth, the girl showed a severe, rapidly deteriorating neonatal onset encephalopathy with intractable seizures, hypotonia, recurrent inspiratory stridor, and dyspnea, resulting in death at age 2.5 months. Extensive laboratory studies in this patient also showed increased 2-oxoglutaric acid and variably increased D-2-HG and L-2-HG in urine, plasma, and cerebrospinal fluid. Muntau et al. (2000) hypothesized that the variable levels of these organic acids in this patient reflected repeated testing at different ages. The third child showed a similar course, with neonatal encephalopathy, respiratory insufficiency, seizures, hypotonia, choreoathetotic and dystonic movements, microcephaly, cortical visual failure, and severe developmental delay. Brain MRI showed enlargement of lateral ventricles, delayed gyration, opercularization, and myelination, cysts over the caudate nucleus, and cerebellar hypoplasia. This patient died at the age of 8 months. Organic acid studies showed combined elevation of D-2-HG, L-2-HG, and 2-oxoglutaric acid. An older brother had died of unknown causes on the first day of life.

Nota et al. (2013) described a total of 12 patients from unrelated families of Arabic, European, or Latin American descent with combined D-2- and L-2-hydroxyglutaric aciduria. Eight of the patients were female, 4 were male. Eight of the patients had died at ages ranging from 1 month to 5 years 1 month. The oldest living patient was a 9-year-old female. All had developmental delay, hypotonia, and seizures. None of the patients had developed cancer. Patients had low to normal citrate and isocitrate with increases in D-2- and L-2-hydroxyglutaric acid. Malate and fumarate were elevated. Succinate was normal to twice the upper limit of normal. Alpha-ketoglutarate varied from one-fourth normal to 10 times normal range. SLC25A1 activity was 6.1 to 57% of control activity in the 7 patients in whom it was measured.

Edvardson et al. (2013) reported an 18-month-old girl, the third child of nonconsanguineous Ashkenazi Jewish parents, who was born at term of average size and at day 10 was admitted for poor sucking and apathy. She had marked hypotonia with erratic breathing and prolonged apnea, for which gastrostomy and tracheostomy were inserted. She made no developmental progress and developed generalized epilepsy by the age of 5 months which responded well to clonazepam. She had no spontaneous voluntary movements and eye contact was minimal. Ophthalmologic evaluation showed hypoplastic optic nerves. Weight and height were at the 3rd centile. Head circumference, initially on the 3rd centile, was -3 SD, consistent with acquired microcephaly. Urinary organic acids showed a large peak of 2-hydroxyglutaric acid and Krebs cycle intermediates. Brain MRI at 3 weeks showed complete agenesis of the corpus callosum but was otherwise normal. Chaouch et al. (2014) found that the patient with D2L2AD reported by Edvardson et al. (2013) had markedly increased jitter and blocking on EMG, consistent with myasthenic syndrome. Her symptoms did not fluctuate and did not improve with 3,4-DAP and ephedrine. Chaouch et al. (2014) noted that patients with D2L2AD have more significant neurologic deficits than patients with CMS23, and that CMS may not be detected.

Inheritance

The transmission pattern of combined D-2-HG and L-2-HG in the families reported by Muntau et al. (2000) was consistent with autosomal recessive inheritance.

Molecular Genetics

Nota et al. (2013) identified missense, nonsense, and frameshift mutations in homozygosity and compound heterozygosity in 12 patients with combined D-2- and L-2-hydroxyglutaric aciduria (e.g., 190315.0001, 190315.0002).

In a patient with combined D-2- and L-2-hydroxyglutaric aciduria, Edvardson et al. (2013) identified compound heterozygous missense mutations (190315.0003, 190315.0004) in the SLC25A1 gene.