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This summary evaluates the association between the FAH gene and tyrosinemia type I. Early case reports described a unique patient with hepatorenal tyrosinemia in Japan, where the clinical presentation included tyrosinemia, tyrosyluria, liver cirrhosis, and renal rickets (PMID:22687740). These initial observations set the stage for further investigations into the metabolic derangements of the disorder.
Subsequent multi-patient studies have documented clinical outcomes in 52 patients diagnosed with hereditary tyrosinemia type I, establishing that treatment with NTBC (nitisinone) leads to improved liver and renal function and favorable long-term prognosis (PMID:31574857). The comprehensive evaluation of these patients provided critical insights for clinical management and early diagnosis.
Genetic evidence is derived from the identification of pathogenic variants in FAH. In particular, the intronic variant c.1062+5G>A was identified and is considered relevant as it likely disrupts proper splicing. This genetic finding, found in multiple probands under autosomal recessive inheritance, complements both the biochemical and clinical data.
The mode of inheritance in tyrosinemia type I is autosomal recessive, and although detailed segregation data are limited, available reports indicate additional affected family members that support a Mendelian pattern. The robust genetic findings, including the recurrent identification of FAH variants, underpin the gene-disease relationship.
Functional studies have further reinforced the pathogenicity of FAH deficiency. Experimental assessments, including enzymatic assays and cellular models, support a loss‑of‑function mechanism that mirrors the clinical phenotype. While these studies are fewer in number compared to the genetic analyses, their results contribute moderate functional evidence.
In conclusion, the integration of case reports, multi‐patient studies, and functional data supports a strong gene‐disease association between FAH and tyrosinemia type I. This comprehensive evidence base not only aids diagnostic decision‑making but also underlines the clinical utility of early genetic screening and intervention.
Gene–Disease AssociationStrongMultiple independent pieces of evidence, including a case report (PMID:22687740) and a multicentric study in 52 patients (PMID:31574857), support a strong gene–disease association. Genetic EvidenceStrongThe discovery of the FAH intronic variant c.1062+5G>A in several probands, consistent with an autosomal recessive transmission pattern, provides robust genetic evidence. Functional EvidenceModerateFunctional studies including enzymatic and cellular assays support a loss‑of‑function mechanism, consistent with the clinical phenotype, although the experimental data are less extensive. |