HNMT – Autosomal Recessive Intellectual Disability 51

Histamine N-methyltransferase (HNMT) catalyzes termination of histaminergic neurotransmission in the central nervous system. Loss of HNMT activity has been linked to severe neurodevelopmental phenotypes. Genetic evidence now supports a robust association between biallelic HNMT variants and Autosomal Recessive Intellectual Disability 51.

The disorder follows an autosomal recessive inheritance pattern. Initial reports described seven individuals from two consanguineous families carrying distinct homozygous missense HNMT variants, all presenting severe intellectual disability, speech delay, autistic features, aggressive behaviour and sleep disturbances (PMID:33310825). A subsequent case report detailed a homozygous truncating variant c.88C>T (p.Gln30Ter) in an unrelated male with a comparable phenotype and marked improvement upon histamine-restricted therapy (PMID:33310825).

In 2015, two additional consanguineous families were described with homozygous missense variants c.179G>A (p.Gly60Asp) and c.623T>C (p.Leu208Pro), confirming the phenotype in four more probands (PMID:26206890). Across these studies, a total of 10 affected individuals in four unrelated families exhibited segregation of variants with disease.

Functional studies demonstrate that HNMT deficiency is loss-of-function. Patient-derived mutant constructs show complete absence or severe reduction of enzymatic activity in vitro, and Hnmt knockout mice recapitulate aggressive and sleep-wake dysregulation phenotypes consistent with the human disorder (PMID:26206890).

No studies to date have reported conflicting evidence for HNMT in intellectual disability. Collectively, the genetic segregation across multiple families, the variety of biallelic truncating and missense variants, and concordant in vitro and in vivo functional data support a Strong gene–disease association.

Key Take-home: Biallelic HNMT variants cause a clinically actionable form of intellectual disability, supporting inclusion of HNMT in diagnostic gene panels and potential histamine-modulating therapies.

References

• BMJ case reports • 2020 • Adult male patient with severe intellectual disability caused by a homozygous mutation in the HNMT gene. PMID:33310825
• Human molecular genetics • 2015 • Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. PMID:26206890

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