HAL – Histidinemia

Histidinemia is an autosomal recessive metabolic disorder characterized by elevated histidine levels in body fluids and reduced urocanic acid in blood and skin, detected primarily through neonatal screening programs. Despite early reports of intellectual disability and speech impairment, most patients identified by screening exhibit normal intelligence. The causative gene, HAL (histidine ammonia-lyase), encodes the enzyme responsible for the first step of histidine catabolism.

Genetic analyses of 50 unrelated histidinemic individuals revealed four missense mutations in HAL, including c.776C>T (p.Pro259Leu) (PMID:15806399). Two exonic and two intronic polymorphisms were also identified, but only the missense changes correlated with enzyme deficiency. One family study demonstrated compound heterozygous inheritance of R322P and P259L, confirming autosomal recessive transmission (PMID:15806399).

Functional studies in a murine model carrying the orthologous R322Q mutation showed reduced histidase protein stability and enzymatic activity when expressed in COS cells, mirroring the human phenotype (PMID:8486363). These data support a loss-of-function mechanism due to protein instability.

No studies have disputed the HAL–histidinemia relationship, and experimental evidence from both human and mouse systems is concordant. Together, the identification of pathogenic missense variants in multiple probands, segregation in families, and functional validation in a model organism provide robust support for the gene-disease link.

Key Take-home: Biallelic missense variants in HAL cause autosomal recessive histidinemia via enzyme instability, enabling definitive molecular diagnosis through targeted sequencing.

References

• Human genetics | 2005 | Molecular characterization of histidinemia: identification of four missense mutations in the histidase gene. PMID:15806399
• Genomics | 1993 | Identification of the mutation in murine histidinemia (his) and genetic mapping of the murine histidase locus (Hal) on chromosome 10. PMID:8486363

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