Duran et al. (1980) reported a 5-year-old boy of Moroccan (Berber) origin who was investigated for nonspecific mental and motor delay and growth deficiency. The point of interest was a solitary, large, and persistent increase of L-2-hydroxyglutaric (2OHglu) ... Duran et al. (1980) reported a 5-year-old boy of Moroccan (Berber) origin who was investigated for nonspecific mental and motor delay and growth deficiency. The point of interest was a solitary, large, and persistent increase of L-2-hydroxyglutaric (2OHglu) acid in the urine. Barth et al. (1992) reported on a total of 8 mentally retarded patients from 5 unrelated families, including 3 pairs of sibs. Four patients were male and 4 female. L-2-hydroxyglutaric acid concentration was also found to be increased in the cerebrospinal fluid and to a lesser extent in plasma. Lysine was also increased in plasma and CSF. Onset of symptoms was in childhood, and definite cerebellar dysfunction was identified in 7. In all patients, magnetic resonance imaging (MRI) revealed an identical abnormal pattern with subcortical leukoencephalopathy, cerebellar atrophy, and signal changes in the putamina and dentate nuclei. No specific biochemical function or catabolic pathway involving L-2-hydroxyglutaric acid was known in mammals, including humans. Preliminary loading and dietary studies failed to reveal the origin of the compound. One of the 2 families from Turkey had consanguineous parents and 2 affected children. Wilcken et al. (1993) reported 3 cases from Australia, and Divry et al. (1993) reported 2 other cases. Two of the patients reported by Wilcken et al. (1993) were sisters born to fourth-cousin parents. One of the patients of Divry et al. (1993) was a Tunisian boy born to consanguineous parents. Macrocephaly, cerebellar signs, and abnormalities suggesting leukodystrophy on CT or MRI were diagnostic clues, all of which suggest that urinary analysis for organic acids is indicated. Fujitake et al. (1999) described L-2-hydroxyglutaric aciduria in 2 adult Japanese sisters, both of whom were much older (aged 57 and 47 years) than previously reported patients. MRI showed typical subcortical white matter lesions in both patients and brainstem atrophy and thickness of the calvarium in the elder sister. L-2-hydroxyglutaric acid levels were increased in urine, plasma, and CSF. The parents were not related and had no neurologic symptoms; the patients' 6 sibs also lacked neurologic symptoms. The elder sister had generalized tonic-clonic seizure and was found to have psychomotor retardation in childhood. Her mental and motor impairments were slowly progressive, especially after 25 years of age; she became unable to walk at the age of 46 years. The younger sister seemed normal until the age of 3 years, when she became unable to walk for 3 months after her first seizure. She was thought to have mild psychomotor impairment at school age but was able to work as an assistant in her father's factory after graduation from elementary school. At the age of 41 years, upon admission to another hospital for surgery of an atrial septal defect, she was found to have nocturnal myoclonus. Neurologic examination disclosed mild mental retardation and cerebellar speech, horizontal nystagmus and saccadic eye movement, dystonia of the right arm, mild limb and truncal ataxia, and ataxic gait. Her deep tendon reflexes were hyperactive. Manifestations were slowly progressive over the next 6 years. Seijo-Martinez et al. (2005) reported a 15-year-old Spanish boy with L-2-hydroxyglutaric aciduria. He was wheelchair-bound and had severe mental retardation, epilepsy, bilateral optic atrophy, strabismus, hypoacusis, spastic tetraparesis, and choreodystonia of the upper limbs. He died suddenly of massive mesenteric thrombosis. Neuropathologic examination showed mild cortical neuronal loss with intense gliosis, spongiosis, and vacuolation of the neuropil. The subcortical white matter contained numerous hyperplastic astrocytes and was severely demyelinated with cystic cavities consistent with imaging results. The basal ganglia and cerebellum were less affected, with only mild neuronal loss and no cavitations; however, spongiosis was present. Cranial nerve nuclei were not affected. Seijo-Martinez et al. (2005) noted that Canavan disease (271900) should be the major consideration in differential diagnosis. Aghili et al. (2009) reported a 17-year-old boy with L2-hydroxyglutaric aciduria who developed an anaplastic ependymoma during the course of his disease. A literature review identified 7 other patients with L2-hydroxyglutaric aciduria who developed brain tumors, suggesting an increased risk of brain tumors in this patient population.
In 21 patients with L-2-hydroxyglutaric aciduria (L2HGA) from 15 Turkish families, 14 of them consanguineous, Topcu et al. (2004) found 9 mutations in the L2HGDH gene (609584). The 9 mutations comprised 3 missense mutations, 2 nonsense mutations, 2 ... In 21 patients with L-2-hydroxyglutaric aciduria (L2HGA) from 15 Turkish families, 14 of them consanguineous, Topcu et al. (2004) found 9 mutations in the L2HGDH gene (609584). The 9 mutations comprised 3 missense mutations, 2 nonsense mutations, 2 splice site mutations, and 2 deletions. The gene encodes a putative mitochondrial protein, which the authors dubbed 'duranin,' with homology to FAD-dependent oxidoreductases. In 3 consanguineous families with L-2-hydroxyglutaric aciduria, of Belgian, Tunisian, and Lebanese origin, respectively, Rzem et al. (2004) identified homozygosity for 3 different mutations in the L2HGDH gene that cosegregated with the disease in each family. Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In a family (8600276) in which 4 of 7 children had L-2-hydroxyglutaric aciduria and profound intellectual disability and were unable to walk, Najmabadi et al. (2011) identified homozygosity for a nonsense mutation in the L2HGDH gene (609584.0007) in all of those affected. The parents were distantly related.