HPD and Hawkinsinuria

The enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD) has been implicated in the pathogenesis of hawkinsinuria, a rare metabolic disorder. Multiple independent studies have consistently identified heterozygous missense mutations in HPD associated with this disorder. The literature reports several unrelated probands in which dominant mutations in HPD correlate with hallmark symptoms, emphasizing a clear genotype‐phenotype relationship. These investigations have employed both case reports and multi‐patient studies to validate the association. The integration of genetic screening with biochemical assays has strengthened the clinical relevance of HPD mutations in the context of hawkinsinuria. Furthermore, the findings support that even subtle alterations in enzyme function can lead to significant metabolic derangements.

Clinically, hawkinsinuria is characterized by features such as failure to thrive and conjugated hyperbilirubinemia. The autosomal dominant inheritance pattern differentiates it from other metabolic disorders linked to HPD, notably tyrosinemia type III, which follows a recessive mode. Detailed patient evaluations have consistently demonstrated that heterozygous mutations in HPD result in the persistent excretion of hawkinsin—a sulfur amino acid derivative—in urine. The clinical presentations across the reported cases underline a disease mechanism that is both unique and reproducible. This distinct pattern aids clinicians in differentiating hawkinsinuria from overlapping metabolic conditions. In summary, the clinical phenotype coincides well with the genetic findings and reinforces the diagnostic utility of HPD screening.

Genetic evidence from multiple studies has identified recurrent mutations in HPD, including the missense variant c.634G>A (p.Val212Met). In one study, two unrelated Greek neonates diagnosed with hawkinsinuria harbored this pathogenic allele, while other reports describe heterozygous variants such as the A33T change detected in patients with the syndrome. Collectively, the case series account for at least 5 unrelated probands (PMID:11073718) and are further supported by additional independent findings (PMID:30984715, PMID:31342835). This robust accumulation of genetic data contributes to a strong conclusion regarding the causative role of HPD mutations in hawkinsinuria. The consistency in variant detection across diverse populations underscores the significance of this gene–disease association. Such extensive genetic evidence is critical for establishing accurate diagnostic criteria.

Functional studies further corroborate the genetic findings by demonstrating that HPD mutations disrupt normal enzyme activity. In vitro assays and structural modeling experiments have revealed that these missense variants, including those affecting metal-binding residues, lead to decreased catalytic efficiency or altered substrate processing. For example, product analysis and inhibition studies have provided mechanistic insights consistent with the metabolic phenotype observed in patients (PMID:20677779). Additionally, detailed biochemical assessments have shown that the mutations can modify the enzyme’s conformational dynamics, thereby impacting its function (PMID:26936969). These experimental results not only validate the pathogenicity of the variants but also offer a rationale for potential therapeutic interventions. The convergence of genetic and functional data establishes a cogent narrative supporting HPD’s role in hawkinsinuria.

While HPD mutations are also implicated in tyrosinemia type III via a recessive mechanism, the evidence for hawkinsinuria is distinct. In hawkinsinuria, the dominant inheritance pattern and unique biochemical profile argue for an alternative mechanistic model. Some reports have noted overlapping phenotypes; however, careful clinical and genetic evaluations have delineated clear boundaries between the two disorders. This distinction is essential for accurate patient diagnosis and management. The relative paucity of conflicting genetic data reinforces the specificity of HPD mutations in the etiology of hawkinsinuria. Clinicians are, therefore, advised to consider the context of inheritance and functional impact when interpreting HPD variants.

In conclusion, the integration of robust genetic evidence, functional assays, and meticulously documented clinical findings supports a strong association between HPD mutations and hawkinsinuria. The convergence of data from at least 5 unrelated probands, along with consistent in vitro mechanistic insights, substantiates the gene–disease relationship. This evidence not only informs diagnostic decision‑making but also underpins the development of tailored therapeutic strategies. A key take‑home message is that recurrent heterozygous mutations in HPD are clinically actionable markers for diagnosing hawkinsinuria, thereby enhancing patient care and guiding future research.

References

• Molecular genetics and metabolism • 2000 • Mutations in the 4‑hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria PMID:11073718
• Frontiers in pediatrics • 2019 • Hawkinsinuria With Direct Hyperbilirubinemia in Egyptian‑Lebanese Boy PMID:30984715
• The Journal of international medical research • 2020 • Hawkinsinuria clinical practice guidelines: a Mexican case report and literature review PMID:31342835
• Journal of pediatric endocrinology & metabolism : JPEM • 2016 • Hawkinsinuria in two unrelated Greek newborns: identification of a novel variant, biochemical findings and treatment PMID:26226126
• Biochemistry • 2010 • Product analysis and inhibition studies of a causative Asn to Ser variant of 4‑hydroxyphenylpyruvate dioxygenase suggest a simple route to the treatment of Hawkinsinuria PMID:20677779
• The Biochemical journal • 2016 • The different catalytic roles of the metal‑binding ligands in human 4‑hydroxyphenylpyruvate dioxygenase PMID:26936969

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