KMO

Inheritance Pattern: AR

Disease ID:MONDO:0019975

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0019975

Submitter: ClinGen

The gene *KMO* encodes kynurenine 3-monooxygenase, an enzyme that catalyzes the conversion of L-kynurenine to 3-hydroxykynurenine (3-HK) in the kynurenine pathway, the primary pathway for tryptophan degradation in the body. A case of pellagra with colitis was first associated with a deficiency in tryptophan metabolism at the level of kynurenine 3-monooxygenase in 1990 by Clayton et al. (PMID:1833200), though enzymatic testing of KMO and genetic analysis was not preformed. Since then, no further reports have associated pellagra with KMO, though pellagra has been associated with deficiencies in other enzymes in the kynurenine pathway and chronic alcoholism can induce pellagra via inhibition of the rate limiting enzyme in the hepatic kynurenine pathway, tryptophan 2,3-dioxygenase. However, to date, no individuals have been identified with variants in *KMO* resulting in pellagra or even a deficiency in KMO enzymatic activity. Support for a potential gene-disease relationship comes from the biochemical function of KMO (PMID:32148781) including its enzymatic function in the kynurenine pathway, which when rendered inactive, shunts the tryptophan degradation pathway towards either kynurenine acid (KYNA) catalyzed by kynurenine aminotransferase (KAT) or anthranilic acid (AA) catalyzed by KYNU. Additionally, at least two knock out *KMO* (-/-) mouse models have been described (PMIDs:28187857, 24189070). One mouse model showed evidence that KO *KMO* resulted in behavioral changes including impairments in contextual memory and increased anxiety-like behavior, though in both models, mice did not show evidence of pellagra. This result was to be expected given that mice were not fed a niacin restricted diet. Biallelic variants have been identified in other enzymes (HAOO and KYNU) in the kynurenine pathway resulting in NAD deficiency along with congenital malformations (PMID: 28792876). There is considerable evidence that phenotypes resulting from enzymatic deficiencies in the kynurenine pathway can be prevented by a diet that consists of sufficient niacin, a dietary source of NAD. Finally, impaired KMO function has been implicated in the pathophysiology of schizophrenia. In summary, there is insufficient genetic evidence to support a gene-disease relationship. A classification of No Known Disease Relationship was approved by the General IEM GCEP on 05/18/2023.