The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a
rate-limiting enzyme in the Krebs cycle that plays a pivotal role in
mitochondrial metabolism. OGDHL expression is restricted mainly to the
brain in humans. Here, we report nine individuals from eight unrelated
families carrying bi-allelic variants in OGDHL with a range of
neurological and neurodevelopmental phenotypes including epilepsy,
hearing loss, visual impairment, gait ataxia, microcephaly, and
hypoplastic corpus callosum. The variants include three homozygous
missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three
compound heterozygous single-nucleotide variants
(p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and
p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant
(p.Cys553Leufs∗16), and one homozygous stop-gain variant
(p.Arg440Ter). To support the pathogenicity of the variants, we
developed a novel CRISPR-Cas9-mediated tissue-specific knockout with
cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL.
Pan-neuronal knockout of dOgdh led to developmental lethality as well as
defects in Krebs cycle metabolism, which was fully rescued by
expression of wild-type dOgdh. Studies using the Drosophila system
indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe
loss-of-function alleles, leading to developmental lethality, whereas
p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are
hypomorphic alleles, causing behavioral defects. Transcript analysis
from fibroblasts obtained from the individual carrying the synonymous
variant (c.1464T>C [p.Val488Val]) in family 2 showed that the
synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal
cells with OGDHL knockout exhibited defects in mitochondrial
respiration, indicating the essential role of OGDHL in mitochondrial
metabolism in humans. Together, our data establish that the bi-allelic
variants in OGDHL are pathogenic, leading to a Mendelian
neurodevelopmental disease in humans.