HPD – Tyrosinemia Type III

This summary describes the strong association between mutations in the HPD gene (HGNC:5147) and tyrosinemia type III (MONDO:0010162). Multiple independent studies have reported that biallelic, mostly autosomal recessive, mutations in HPD lead to a loss of enzyme function in the tyrosine catabolism pathway. These findings are supported by segregation data and the identification of pathogenic variants in unrelated probands (PMID:11073718).

The disorder manifests with variable neurological and developmental symptoms, including intellectual disability, status epilepticus, and hypertyrosinemia. In several studies, affected families demonstrated co‐segregation of HPD mutations with the clinical phenotype, with reports citing up to 19 affected relatives in extended pedigrees (PMID:35707594). This autosomal recessive inheritance pattern underscores the importance of detailed family history and biochemical investigation in diagnostic evaluation.

Genetic evidence is robust with multiple case reports and multi‐patient studies identifying both missense and loss‑of‑function variants. For instance, a homozygous missense change, c.803C>T (p.Ala268Val), was identified in a patient with tyrosinemia type III, and similar variants have been reported in several independent families (PMID:11073718; PMID:10942115). The wide variant spectrum including truncating mutations supports a strong genotype–phenotype correlation.

The clinical phenotype is further supported by the observed segregation of HPD mutations in affected individuals across different ethnic groups and case series. Studies have not only described classical biochemical abnormalities such as elevated blood tyrosine and urinary tyrosine derivatives but also variable neurologic outcomes. The phenotypic heterogeneity, which ranges from mild to severe neurological deficits, emphasizes the need for precise genetic testing in suspected cases.

Functional analyses indicate that HPD mutations compromise the catalytic activity of 4-hydroxyphenylpyruvate dioxygenase. In vitro assays and structural studies have demonstrated reduced enzyme function and a loss‐of‐function mechanism that is in concordance with the metabolic perturbations seen in patients (PMID:17560158). These experimental findings provide an additional layer of evidence supporting the pathogenicity of the identified variants.

In summary, the integration of genetic and functional evidence across multiple independent studies establishes a strong gene–disease association between HPD and tyrosinemia type III. This robust dataset supports the clinical utility of including HPD in diagnostic panels for patients with unexplained hypertyrosinemia and neurological manifestations, thereby informing both prognosis and management.

References

• Molecular Genetics and Metabolism • 2000 • Mutations in the 4‑hydroxyphenylpyruvate dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria PMID:11073718
• Acta Paediatrica • 1997 • Tyrosinemia type III: diagnosis and ten‑year follow‑up PMID:9343288
• Molecular Syndromology • 2022 • Novel Cranial Imaging Findings and a Splice‑Site Variant in a Patient with Tyrosinemia Type III PMID:35707594
• Molecular Genetics and Metabolism • 2007 • Manifestation of hawkinsinuria in a patient compound heterozygous for hawkinsinuria and tyrosinemia III PMID:17560158

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