高チロシン血症２型

INTRODUCTION: Congenital bile acid synthesis defects are rare autosomal recessive disorders that typically present in early infancy with cholestasis, progressive liver dysfunction, and, in severe cases, acute liver failure. These conditions may mimic other metabolic diseases detected in newborn screening, complicating early diagnosis. The AKR1D1 gene encodes Δ4-3-oxosteroid 5β-reductase, a key enzyme in primary bile acid synthesis, and pathogenic variants cause bile acid synthesis defect type 2 (OMIM #235555). CASE DESCRIPTION: We report a 3-month-old male infant with severe neonatal cholestasis and a history of elevated tyrosine levels in newborn screening. Pregnancy was high risk and unmonitored, with birth outside a hospital. Parental consanguinity was first-degree. Early metabolic evaluation showed transient normalization of tyrosine levels, but subsequent analyses revealed recurrent hyper-tyrosinemia. Urinary organic acids showed increased 4-hydroxyphenyl metabolites, with absent succinylacetone, excluding tyrosinemia type I. Progressive cholestasis developed, accompanied by coagulopathy, hyperbilirubinemia, hyperammonemia, and markedly elevated alpha-fetoprotein. Imaging revealed no structural liver abnormalities. Clinical exome sequencing identified a novel homozygous start-loss variant in AKR1D1, likely abolishing functional enzyme production. Metabolic studies confirmed increased urinary excretion of 3-oxocholenoic acids consistent with abnormal bile acid synthesis and supporting a diagnosis of bile acid synthesis defect type 2. Oral cholic acid therapy led to stabilization and improvement in clinical and biochemical parameters. DISCUSSION/CONCLUSION: This case illustrates the diagnostic complexity of neonatal cholestasis, particularly when initial metabolic findings suggest alternative etiologies. It highlights the importance of newborn screening as a tool for broader diagnostic suspicion and the critical role of early molecular diagnosis and multidisciplinary care. Timely recognition and targeted therapy can improve outcomes, prevent liver transplantation, and enable accurate genetic counseling, especially in consanguineous families.

Hereditary tyrosinemia type 1 (HT1) is a life-threatening metabolic disorder caused by the toxic accumulation of tyrosine and its metabolites. While treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) combined with a strict dietary regimen has improved outcomes, it imposes a significant lifelong burden and is associated with debilitating side effects and incomplete protection. Here, we developed an engineered probiotic with an optimized design, e-EcN-HT, and demonstrated its comprehensive efficacy and safety in HT1 across multiple animal models, including fumarylacetoacetate hydrolase (FAH)-/- mice, FAH-/- rabbits, and Bama minipigs. Our findings indicate that e-EcN-HT not only mitigates multifaceted acute manifestations of FAH-/- mice, including neonatal death and acute liver injury, but also improves chronic liver lesions when combined with NTBC. The therapeutic effect translated successfully to the FAH-/- rabbit model. Moreover, e-EcN-HT administration led to rapid metabolism of orally administered 13C-tyrosine, confirming robust and active tyrosine consumption in pigs. Comprehensive safety assessments across murine and porcine models showed that e-EcN-HT was well tolerated, with no significant adverse effects, systemic dissemination, or detrimental disruption to the resident gut microbiota. Collectively, our multi-species preclinical data underscore the potential of engineered bacteria as a viable therapeutic strategy for HT1 and possibly other metabolic disorders.

4-Hydroxylphenylpyruvate dioxygenase (HPPD) is a crucial enzyme in the tyrosine catabolic pathway, catalyzing the conversion of 4-hydroxylphenylpyruvate (HPP) to homogentisate (HG). Missense substitutions in HPPD are associated with type III tyrosinemia and hawkinsinuria. This study investigated disease-related variants in terms of their roles in HPPD structure stability and function. Our whole-cell assay showed a loss of soluble protein expression for G154S, Y160C, and I267F variants, suggesting that the three locations at the domain interface can be critical for proper protein folding. The A33T, A268V, and I335M variants exhibited low soluble protein expression and reduced bioactivity, indicating the three locations at their specific structural motifs affect protein folding but can be less effective. The biochemical analysis found that the N241S variant underwent an uncoupled reaction, forming an oxepinone intermediate that reacts with cysteine and forms the hawkinsin adduct. The A33T and V212M variants, which produced no intermediate product, exhibited similar substrate binding affinity as WT enzymes, but they had decreased structural stability and HG production (aligned with bioassay findings). The reduced structural stability and HG production, and the loss of substrate binding with HPPD-Co(II) complex for the A268V variant suggested that its location is related to the stable conformation of the metal binding motif. The reduced substrate binding affinity and catalytic efficiency for V340L variant suggested the effect at the active site entrance. This study showed the molecular underpinnings of how disease-related substitutions at specific structural locations affect the structural stability and function of HPPD.

Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-μM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1.

OBJECTIVES: Tyrosinemia type III is an extremely rare autosomal recessive disorder of tyrosine metabolism caused by mutations in the HPD gene, which encodes 4-hydroxyphenylpyruvate dioxygenase (HPPD). Wolff-Parkinson-White (WPW) syndrome is a congenital cardiac conduction disorder characterized by the presence of an accessory atrioventricular pathway. While each condition is rare in isolation, their coexistence has not been previously reported. CASE PRESENTATION: We present a unique case of a 6-year-old boy with known WPW syndrome who was admitted with ketotic hypoglycemia after prolonged fasting and omission of propranolol doses. Metabolic work-up revealed persistently elevated plasma tyrosine levels. Genetic testing confirmed tyrosinemia type III due to a novel homozygous HPD variant [c.559A>G (p.Asn187Asp)]. The persistence of the WPW pattern despite decreased plasma tyrosine levels suggests that there is no direct causal relationship. He was also diagnosed with attention-deficit/hyperactivity disorder, specific learning disorder, and borderline intellectual functioning. CONCLUSIONS: This case highlights the importance of metabolic evaluation in pediatric patients presenting with unexplained hypoglycemia, particularly in the presence of pre-existing cardiac disorders.