Orfadin (nitisinone) / Astellas, SOBI - LARVOL DELTA

Response to comment on: Evaluating the impact of nitisinone at mosquito-lethal doses on Lutzomyia longipalpis. (PubMed, PLoS Negl Trop Dis) - No abstract available

Journal

Plasma and urinary NMR metabolic profiling of the phenylalanine-tyrosine pathway in nitisinone-treated alkaptonuria: comparison of two dosing regimens and identification of a candidate pharmacodynamic biomarker. (PubMed, Mol Genet Metab) - "These findings highlight the complementary diagnostic value of plasma and urinary NMR profiling and underscore the limitations of current dosage strategies in controlling nitisinone-induced hyper-tyrosinaemia. NMR metabolomics provides a non-invasive, simultaneous snapshot of pathway-wide metabolic changes and represents a powerful tool for personalised therapeutic monitoring in AKU."

Biomarker • Journal • PK/PD data • Metabolic Disorders

Deciphering and improving human homogentisate 1,2-dioxygenase function through knowledge gaining directed evolution: implications for alkaptonuria. (PubMed, Int J Biol Macromol) - "Current therapy with nitisinone lowers HGA levels but does not restore HGD function, motivating further investigation of HGD structure-function relationships...Tunnel and pocket analyses showed that N31S, S54D and D86H produced a more compact hexamer, whereas a P359E + Q354P double mutant reduced catalytic pocket solvent accessibility and volume, supporting the observed activity differences. Overall, these findings demonstrate that HGD activity can be modulated by substitutions outside the catalytic pocket, providing new insight into HGD function and genotype-phenotype relationships underlying AKU."

Journal • Metabolic Disorders

Comment on: Evaluating the impact of nitisinone at mosquito-lethal doses on Lutzomyia longipalpis. (PubMed, PLoS Negl Trop Dis) - No abstract available

Journal

Early Targeted Neonatal Screening and Treatment in Type I Tyrosinemia: Impact on Complication Prevention (SSIEM 2026) - "Medical treatment with nitisinone (NTBC) has transformed the prognosis, with efficacy strongly dependent on early initiation... This small series highlights the importance of early (neonatal) treatment in preventing severe complications in Tyr 1, provided adherence is maintained. It also underscores the fatal risk associated with treatment discontinuation and the potential neurocognitive complications linked to suboptimal dietary management. Effective prevention requires not only early diagnosis and treatment but also rigorous monitoring of NTBC therapy and dietary control through periodic measurement of succinylacetone, tyrosine, and phenylalanine levels."

ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Hematological Disorders • Hepatocellular Cancer • Hepatology • Liver Failure • Mental Retardation • Ophthalmology • Solid Tumor • Thrombocytopenia

Neurocognitive Manifestations in Two Patients With Tyrosinemia Type I on Long-Term Nitisinone Treatment (SSIEM 2026) - "Cognitive manifestations were not consistently reported in TT1 patients prior to the introduction of nitisinone, but have been reported by several studies thereafter. Further research should be promoted in order to establish the long-term neurocognitive outcome in this group of patients."

Clinical • Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Genetic Disorders • Immunology • FANCA

Generation of FAH and SLC7A11 knockouts to study metabolism in tyrosinemia type 1 (SSIEM 2026) - "Patients are treated with nitisinone (NTBC), which blocks tyrosine degradation upstream of FAH deficiency...In vitro FAH and SLC7A11 KO HepG2 models confirmed successful gene disruption at genomic and protein levels, providing a platform to study metabolic and redox alterations in HT1, with further functional and metabolic characterization ongoing. These models provide a platform to investigate the role of SLC7A11 in modulating disease severity in FAH deficiency, with relevance to oxidative stress-driven tissue damage and metabolic imbalance."

Hepatology • Liver Failure • Metabolic Disorders • SLC7A11

Impact of Low Phenylalanine Free Diet on Compliance and Metabolic Control in Tyrosinemia Type 1 (SSIEM 2026) - "Although nitisinone effectively suppresses the production of toxic metabolites, it subsequently elevates plasma Tyr levels... This protocol, allowing the unrestricted consumption of low-Phe vegetables and fruits, successfully increases natural protein intake and enhances dietary compliance in Tyrosinemia Type 1 patients without causing elevations in Tyr levels."

Compliance • Hepatocellular Cancer • Metabolic Disorders • Solid Tumor

Biochemical outcomes and clinical features of nitisinone therapy in alkaptonuria: experience from an adult cohort (SSIEM 2026) - "Alkaptonuria in this cohort was characterized by substantial osteoarticular burden and frequent genitourinary lithiasis. Nitisinone effectively reduced homogentisic acid levels but significantly increased tyrosine concentrations, necessitating strict dietary control, close monitoring, and tyrosine-free supplementation in all cases."

Clinical • Cardiovascular • Immunology • Metabolic Disorders • Obesity • Osteoarthritis • Osteoporosis • Otorhinolaryngology • Rare Diseases

Succinylacetone markedly disrupts hepatic bioenergetics: a potential mechanism underlying liver injury in tyrosinemia type I (SSIEM 2026) - "Furthermore, despite the clinical benefits of nitisinone (NTBC), progressive liver dys-function still occurs in many patients, highlighting the need to better elucidate the underlying pathomechanisms of liver damage in this disease...The potential protective effect of N-acetylcysteine (NAC) was also assessed... Our findings demonstrate that SA disrupts hepatic mitochondrial bioenergetics, possibly through redox-sensitive mechanisms, providing insights into the metabolic basis of liver injury in TT1. These results highlight mitochondrial dysfunction associated with oxidative stress as a key contributor to disease pathophysiology and support the exploration of antioxidant-based strategies as adjunctive therapies. Financial support: FAPERGS [#24/2551-0001239-7], Instituto Nacional de Ciência e Tecnologia Saúde Cerebral (INCT-SC) [#406020/2022-1], FIPE-HCPA, and PROPESQ-UFRGS."

Hepatology • Liver Failure • Metabolic Disorders

Comorbidities of Adult Alkaptonuria Patients Living in Hungary (SSIEM 2026) - "3 patients take central muscle relaxants (2 tolperisone, 1 tizanidine), one patient receives intraarticular steroid treatment regularly. In the described group of AKU patients, orthopedic and cardiovascular comorbidities are the most prevalent. Nitisinone might be able to reduce the burden of orthopedic manifestations."

Clinical • Cardiovascular • Coronary Artery Disease • Heart Failure • Metabolic Disorders • Musculoskeletal Diseases • Musculoskeletal Pain • Nephrology • Orthopedics • Osteoporosis • Renal Calculi

Clinical Presentation and Treatment Strategies in Pediatric Alkaptonuria: A Systematic Review (SSIEM 2026) - "Nitisinone use was rare (3/79, 3.8%)... Pediatric alkaptonuria is primarily characterized by early biochemical manifestations, particularly dark urine, while clinically significant complications emerge later. Management strategies remain heterogeneous, with limited use of disease-modifying therapies and insufficient outcome data. Standardized reporting and prospective studies are needed to define optimal early management and evaluate the long-term benefits of emerging treatments."

Clinical • Review • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Pediatrics • Renal Calculi

Plasma Proteomic Signatures in Alkaptonuria. (PubMed, Biology (Basel)) - "These findings define an AKU plasma proteomic signature dominated by complement activation and humoral immune alterations, together with extracellular matrix, erythrocyte-, and coagulation-associated changes. The persistence of most alterations across treatment groups suggests that residual systemic proteomic dysregulation remains despite nitisinone treatment."

Journal • Inflammation • Metabolic Disorders • Rare Diseases • APOA2 • CLU

A Diagnostic Dilemma: Hypophosphatemic Rickets Unmasking Tyrosinemia Type 1: A Case Report. (PubMed, Clin Case Rep) - "Due to the atypical findings, genetic testing was performed and confirmed the diagnosis of Hereditary tyrosinemia Type 1. Her survival without liver failure remains atypical for Pakistan."

Journal • Hepatology • Liver Failure

Assessing the risk of cataracts associated with medications: A pharmacovigilance analysis of the FAERS database. (PubMed, Medicine (Baltimore)) - "Mirvetuximab soravtansine, nitisinone, and belantamab mafodotin demonstrated the strongest signals. In conclusion, this large-scale signal detection analysis utilizes real-world data to provide a comprehensive list of medications potentially associated with cataracts. Future research is required to validate these statistical associations."

Adverse events • Journal • Cataract • Oncology • Ophthalmology

SMILES-based degree molecular descriptors and machine learning for QSPR modeling of anti-alkaptonuria drugs. (PubMed, Front Chem) - "Nine representative compounds, including Nitisinone, Ascorbic Acid, Ibuprofen, Naproxen, Paracetamol, Tramadol, Methotrexate, Sulfasalazine, and Glucosamine, were analysed using several molecular descriptors such as molecular weight, logP, hydrogen bond donors and acceptors, rotatable bonds, and polar surface area. This study introduces a machine learning-driven QSPR framework that integrates SMILES-derived degree-based topological indices with ensemble learning techniques for predicting physicochemical properties of anti-alkaptonuria drugs. The proposed approach demonstrates improved predictive performance on small datasets and highlights the effectiveness of combining graph-theoretic molecular descriptors with advanced machine learning methods."

Journal • Metabolic Disorders

A design-optimized engineered bacterium for enhanced efficacy and safety in treating tyrosinemia type 1: a multi-species preclinical study. (PubMed, Mol Ther) - "While treatment with nitisinone (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...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."

Journal • Preclinical • CNS Disorders • Hepatology • Liver Failure • Metabolic Disorders • Oncology • Psychiatry

Non-viral gene therapy via hydrodynamic delivery through the biliary system yields therapeutic expression in porcine models of tyrosinemia and phenylketonuria (ASGCT 2026) - "Translating this finding into a tyrosinemia pig model, FAH-/- pigs were obtained weighing between 40-50 kg, previously maintained on nitisinone since birth...These pilot studies demonstrates that non-viral hydrodynamic delivery can achieve therapeutically meaningful gene expression sufficient to modify disease biomarkers in porcine models of tyrosinemia and phenylketonuria. Future work will focus on optimizing the vector design and DNA dosing to improve therapeutic efficacy, as well as evaluating durability of expression and long-term safety in these large animal models."

Gene therapy • Preclinical • Gene Therapies • Metabolic Disorders • Phenylketonuria • Rare Diseases

Liver-directed mRNA therapy for the rare disease Alkaptonuria (ASGCT 2026) - "Current treatment involves the small molecule inhibitor nitisinone, which blocks upstream formation of HGA...B) IHC analysis of liver tissue from mice injected with 1 mg/kg mRNA-LNP show HGD protein in wild-type liver (brown) but not in untreated AKU liver. In treated AKU mice, HGD expression was detected in both hepatocytes and Kupffer cells (examples indicated)."

Metabolic Disorders • Osteoarthritis • Rare Diseases • Targeted Protein Degradation

Access to orphan drugs in adults with inherited metabolic diseases in Switzerland: a single-center retrospective cohort study. (PubMed, Orphanet J Rare Dis) - P | "In this cohort from a specialized adult metabolic clinic, most patients with an indication for OD therapy accessed treatment. However, administrative burden, fragmented reimbursement procedures, and regulatory delays may still affect timely treatment initiation in certain situations. These findings highlight the need for continued efforts to streamline regulatory and reimbursement pathways and to ensure equitable access to innovative therapies for rare diseases."

Journal • Orphan drug • Retrospective data • Metabolic Disorders • Rare Diseases

Spontaneous Achilles tendon rupture as the initial presentation of ochronosis: a case report. (PubMed, Int J Surg Case Rep) - "Ochronosis should be considered in unexplained tendon ruptures. Surgical repair and metabolic management, including nitisinone, can optimize outcomes."

Journal • Metabolic Disorders • Mood Disorders • Pain

Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I. (PubMed, J Med Chem) - "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."

Journal • Nephrology • Renal Disease

Unveiling the unexpected: refractory rickets as an uncommon presentation of tyrosinemia type I. (PubMed, BMC Pediatr) - No abstract available

Journal • Nephrology

Quantitative Succinylacetone Measurement by Gas Chromatography-Tandem Mass Spectrometry (GC-MS/MS) Facilitates Diagnosis, Monitoring, and Characterization of Tyrosinemia Type 1 and Other Hypersuccinylacetonemias. (PubMed, JIMD Rep) - "However, quantitation of SA in the nanomolar range is important for monitoring patients treated with nitisinone, for identifying attenuated or atypical forms of HT1, and for confirmation or refutation of the diagnosis of HT1 following a positive newborn screen...Using GC-MS/MS instead of GC-MS allowed a limit of quantitation of 1 nmol/L while decreasing the required specimen volumes, as well as reducing the number of sample processing steps, chromatographic run time, and instrument maintenance. This assay facilitates laboratory diagnosis and monitoring of HT1, permits identification and characterization of other hypersuccinylacetonemias including maleylacetoacetate isomerase deficiency, and is also a valuable tool for research studies using animal models and cellular models of HT1."

Journal

Expanding the HGD Variant Spectrum and Addressing Missing Heritability in a 96-Patient Cohort (ACMG 2026) - "This comprehensive analysis of 96 individuals with AKU expands the HGD variant spectrum by identifying 14 novel variants, two of which meet criteria for P, 10 for LP, and two Variants of Unknown Significance, thereby improving molecular diagnostic yield and refining HGD variant databases used in clinical testing. The recurrent intronic variant in five individuals with unresolved biallelic genotypes highlights the potential contribution of deep intronic alleles to missing heritability and underscores the value of RNA-based studies in variant reclassification. These findings are directly relevant to the design and interpretation of molecular testing for AKU, including future newborn screening strategies in the nitisinone era."

Clinical • Ankylosing Spondylitis • Cardiovascular • Immunology • Inflammatory Arthritis • Metabolic Disorders • Rheumatology • Seronegative Spondyloarthropathies • Spondylarthritis