Manifestation of recessive combined D‐2‐, L‐2‐hydroxyglutaric aciduria in combination with 22q11.2 deletion syndrome

Abstract

22q11.2 deletion syndrome is one of the most common human microdeletion syndromes. The clinical phenotype of 22q11.2 deletion syndrome is variable, ranging from mild to life-threatening symptoms, depending mainly on the extent of the deleted region. Brain malformations described in association with 22q11.2 deletion syndrome include polymicrogyria, cerebellar hypoplasia, megacisterna magna, and agenesis of the corpus callosum (ACC), although these are rare. We report here for the first time a patient who manifested combined D-2- and L-2-hydroxyglutaric aciduria as a result of a hemizygous mutation in SLC25A1 in combination with 22q11.2 deletion. The girl was diagnosed to have ACC shortly after birth and a deletion of 22q11.2 was identified by genetic analysis. Although the patient showed cardiac anomalies, which is one of the typical symptoms of 22q11.2 deletion syndrome, her rather severe phenotype and atypical face prompted us to search for additional pathogenic mutations. Three genes present in the deleted 22q11.2 region, SLC25A1, TUBA8, and SNAP29, which have been reported to be associated with brain malformation, were analyzed for the presence of pathogenic mutations. A frameshift mutation, c.18_24dup (p.Ala9Profs*82), was identified in the first exon of the remaining SLC25A1 allele, resulting in the complete loss of normal SLC25A1 function in the patient's cells. Our results support the notion that the existence of another genetic abnormality involving the retained allele on 22q11.2 should be considered when atypical or rare phenotypes are observed.

The Mitochondrial Citrate Carrier (SLC25A1) Sustains Redox Homeostasis and Mitochondrial Metabolism Supporting Radioresistance of Cancer Cells With Tolerance to Cycling Severe Hypoxia

“…Thereby, pharmacologic inhibition of SLC25A1 with BTA reproduces another metabolic effect of genetic inhibition of SLC25A1 where somatic loss of SLC25A1 induced a broad dysregulation of mitochondrial metabolism with accumulation of L- and D-enantiomers of 2-HG in NCI-H460 cells ( 44 ). Moreover, deletion of the SLC25A1 gene in humans causes the neurometabolic disorder D- and L-2-hydroxyglutaric aciduria, which is also characterized by increased accumulation of 2-HG ( 60 , 61 ). These observations make it highly likely that elevated D-2-HG levels observed in response to BTA treatment are a direct and acute consequence of SLC25A1 inhibition.…”

In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?

“…Corpus callosum agenesis, optic nerve hypoplasia, and facial dysmorphism accompany these core clinical signs [354, 355]. SLC25A1 hemizygous mutation in combination with 22q11.2 deletion has been reported in an individual with severe brain, heart, and face phenotypes along with combined D-2- and L-2-hydroxyglutaric aciduria [356].…”

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

“…Since 2013 until now, 24 mutations in SLC25A1 have been found in 27 patients suffering from combined D-2-and L-2-hydroxyglutaric aciduria [39][40][41][42][43][44][45] (Table 1 and Table S1). SLC25A1 deficiency patients exhibit lower levels of citrate and isocitrate in the urine as compared to controls.…”

“…Moreover, two mutations (p.Asp69Tyr and p.Arg247Gln) causing SLC25A1 deficiency are associated with congenital myasthenic syndromes and mild intellectual disability [41]. In addition, few patients manifested combined D-2-and L-2-hydroxyglutaric aciduria and diGeorge syndrome caused by a SLC25A1 mutation on one allele and a microdeletion of 22q11.2, which contains SLC25A1 and two other genes, on the homologous chromosome [45].…”