Clinical, neuroimaging, and genetic features of L-2-hydroxyglutaric aciduria in Arab kindreds.

BACKGROUND AND OBJECTIVES: L-2-hydroxyglutaric aciduria is a neurometabolic disorder with autosomal recessive mode of inheritance in which patients exhibit elevated L-2-hydroxyglutaric acid in body fluids, central nervous system manifestations, and increased risk of brain tumor formation. Mutations in L2HGDH gene have been described in L-2-hydroxyglutaric aciduria patients of different ethnicities. The present study was conducted to perform a detailed clinical, imaging and genetic analysis. DESIGN AND SETTINGS: A cross-sectional clinical genetic study of 16 L-2-hydroxyglutaric aciduria patients from 4 Arab consanguineous families examined at the metabolic clinic of the hospital. PATIENTS AND METHODS: Genomic DNA was isolated from the blood of 12 patients and 10 unaffected family members, and the L2HGDH gene was sequenced. DNA sequences were compared to the L2HGDH reference sequence from GenBank. RESULTS: All patients exhibit characteristic clinical, biochemical, and imaging features of L-2-hydroxyglutaric aciduria, and 4 patients exhibited increased incidence of brain tumors. The sequencing of the L2HGDH gene revealed the c.1015delA, c.1319C > A, and c.169G > A mutations in these patients. These mutations encode for the p.Arg339AspfsX351, p.Ser440Tyr, and p.Gly57Arg changes in the L2HGDH protein, respectively. The c.169G > A mutation, which was shown to have a common origin in Italian and Portuguese patients, was also discovered in Arab patients. Finding of the homozygous c.159T SNP associated with the c.169G > A mutation in Arab patients points to an independent origin of this mutation in Arab population. CONCLUSION: The detailed description of clinical manifestations and L2HGDH mutation in this study is useful for diagnosis of L-2-hydroxyglutaric aciduria in Arab patients. While reoccurrence of an L2HGDH mutation in L-2-hydroxyglutaric aciduria patients of different ethnicity is extremely rare, the c.169G mutation has an independent origin in Arab patients. It is likely that this mutation may also be present in patients of other ethnicities.

A novel HAX1 gene mutation in severe congenital neutropenia (SCN) associated with neurological manifestations.

Autosomal recessive severe congenital neutropenia (SCN) results from a maturation arrest of granulopoiesis at the level of promyelocytes and apoptosis of myeloid cells. In SCN patients, mutations have been described in the HAX1 gene. Most of the SCN patients who carry nonsense mutations that are common to both transcript variants of the HAX1 gene also exhibit neurological deficits. This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. Sequencing of the HAX1 gene of this SCN patient identified a novel nonsense c.463_464insC homozygous mutation in exon 3, which is common to both transcript variants of the gene. This mutation encodes for a p.Gln155ProfsX14 change and causes premature truncation of the HAX1 protein. Neutrophils isolated from the patient exhibited spontaneous apoptosis and loss of inner mitochondrial membrane potential, which were further enhanced upon treatment with hydrogen peroxide. This study adds to the spectrum of novel HAX1 gene mutations and disease manifestations in ethnically distinct SCN patients. Our report describes the only nonsense mutation in the HAX1 gene present in SCN patients of Arab origin.