In other species: dog

Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 236792 (trait) , 609584 (gene)

Links to MONDO diseases:

• MONDO:0009370: L-2-hydroxyglutaric aciduria

Mendelian trait/disorder: yes

Mode of inheritance: Probably autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Species-specific name: L-2-hydroxyglutaric aciduria (L-2-HGA)

Molecular basis: Christen et al. (2021) "sequenced the genome of the affected [domestic longhair] cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. " Christen et al. (2023) report a second likely causal variant in a domestic shorthair cat: "An XM_023255678.2:c.397C>T nonsense variant in the L2HGDH gene encoding L-2-hydroxyglutarate dehydrogenase was identified using whole genome sequencing."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Christen et al. (2021): "A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. ... The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. ... The [domestic longhair] cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months." Christen et al. (2023) report a case of a 9-month old male domestic shorthair cat "evaluated for increasing frequency of generalized tonic-clonic seizures. ... The cat was reported to have had episodes of circling between the seizures. Upon examination, the cat had bilateral inconsistent menace response but otherwise normal physical and neurological examinations. ... Magnetic resonance imaging (MRI) of the brain identified multifocal, small, rounded intra-axial lesions within the subcortical white matter containing fluid with similar characteristics as cerebrospinal fluid. Evaluation of urine organic acids showed increased excretion of 2-hydroxyglutaric acid. ... Levetiracetam treatment was initiated [for the domestic shorthair cat] ... , but the cat died after a seizure 10 days later."

Breeds: Domestic Longhair, Domestic Shorthair.
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: