A novel protein truncating mutation in L2HGDH causes L-2-hydroxyglutaric aciduria in a consanguineous Pakistani family.
Metab Brain Dis
; 37(1): 243-252, 2022 01.
Article
en En
| MEDLINE
| ID: mdl-34719772
ABSTRACT
BACKGROUND:
L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly.METHODS:
In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools.RESULTS:
Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Oxidorreductasas de Alcohol
Tipo de estudio:
Etiology_studies
Límite:
Humans
/
Male
País/Región como asunto:
Asia
Idioma:
En
Revista:
Metab Brain Dis
Asunto de la revista:
CEREBRO
/
METABOLISMO
Año:
2022
Tipo del documento:
Article
País de afiliación:
Pakistán