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Hyperammonemia is a medical emergency, and the cause must be identified quickly in order to treat appropriately. Malnutrition is a known risk factor for hyperammonemia; however, there are limited reliable lab indicators used to identify malnutrition. Early identification of the etiology of hyperammonemia is crucial to optimizing care, specifically reintroduction of appropriate amounts of protein into the diet. Herein, we discuss three patients with complex medical histories and clinical signs of malnutrition who presented with hyperammonemia. In all three patients, both hypoaminoacidemia and pyroglutamic aciduria were observed. Specifically, all patients had low tyrosine, tryptophan, methionine, and branched-chain amino acids. Recognizing this biochemical pattern could result in more rapid initiation of supplementing protein, a primary tenet of treatment in malnutrition-related hyperammonemia. We highlight the unique features of malnutrition-related hyperammonemia, propose mechanisms to explain the pattern, and suggest a framework for managing these cases.

GM1 gangliosidosis is a lysosomal storage disease (LSD) caused by β-galactosidase deficiency, characterized by the accumulation of gangliosides in various tissues. Among different GM1 forms (infantile form, late-infantile and juvenile form, and late-onset form), the infantile form is the most severe: despite an early clinical onset with rapid neurodegeneration, coarse face, abdominal visceromegaly and skeletal abnormalities, the diagnosis is usually delayed, given the lack of recognized early disease-specific markers. We report the case of a newborn presenting with mild edema of hands and feet, mild transient hypoalbuminemia and isolated hyperphosphatasemia at three weeks of life. The first cardiological evaluation showed mild mitral regurgitation. Despite the absence of neurological symptoms, organomegaly, or a coarse face, the turgid consistency of the limbs, together with mitral regurgitation and persistent hyperphosphatasemia, led to multiorgan investigations with discovery of bilateral cherry-red spots and a beak-shaped lumbar vertebra. The cardiological follow-up revealed a dysplastic mitral valve. In the suspicion of a lysosomal disease, biochemical investigations were planned. An altered profile of urinary oligosaccharides, along with low β-galactosidase activity in leukocytes, led to the diagnosis of infantile GM1 gangliosidosis at 3 months of age. The GLB1 gene analysis confirmed the diagnosis. Genetic testing for GLB1 should be considered in cases of persistent hyperphosphatemia, especially if it is associated with any other clinical indicator of GM1, such as limb edema.

The objective of this study is to evaluate whether early enzyme replacement therapy (ERT) initiation is associated with a lower incidence of echocardiogram abnormalities and cardiac conduction abnormalities compared to later ERT initiation. We identified a cohort of patients treated with ERT for infantile onset Pompe disease (IOPD) and evaluated their cardiac outcomes by comparing clinically collected longitudinal functional echocardiogram and electrocardiogram (EKG) data. Longitudinal mixed-effects analysis was used to compare cardiac outcomes among the cohort based on timing of ERT initiation as a continuous variable (months of age) and accounted for repeated measures in an individual patient. Time-to-event analysis and Cox regression were performed to evaluate the time to achievement of normal left ventricular mass index (LVMI) based on ERT initiation as a dichotomous variable (≤ 1 month versus > 1 month of age). Early treatment was associated with significant improvements in cardiac remodeling as demonstrated by multiple cardiac parameters with better outcomes based on earlier treatment such as interventricular septum thickness in diastole and systole, left ventricular posterior wall thickness in diastole and systole, and biventricular hypertrophy. The early-treated cohort (those started on ERT ≤ 1 month of age) achieved a normal LVMI faster compared to late-treated patients. Early treatment with ERT in patients with IOPD leads to improved cardiac chamber dimension parameters. Treatment initiation ≤ 1 month of age can shorten the time to achieve a normal LVMI. Our findings were limited by the nature of the data collection, which was retrospective and clinically driven; the results presented in this study, however, support the clinical importance of early therapeutic intervention in IOPD. Early initiation with ERT in patients with IOPD can shorten the time to achieve a normal LVMI and can improve cardiac chamber dimension parameters.

Persistent chylomicronemia is associated with severe hypertriglyceridemia (sHTG) and plasma triglycerides (TG) levels sustainably > 10 mmol/L (880 mg/dL) despite lipid lowering therapies. The main risk of persistent chylomicronemia is acute pancreatitis (AP). During the second and third trimester of pregnancy, TG levels significantly increase, which represents a serious risk of AP in women with preexisting chylomicronemia. New emerging therapies such as plozasiran, a GalNAc-conjugated small interfering RNA (siRNA) against ApoC3, are developed to manage persistent chylomicronemia, but no data are currently available on their safety and efficacy during pregnancy. We report herein the case of a woman with persistent chylomicronemia randomized in the PALISADE study to receive plozasiran 25 mg quarterly, who had an unplanned pregnancy during the clinical trial. The 34-year-old patient received one dose of plozasiran 8 weeks before conception and the experimental treatment was ceased afterwards. The pregnancy went well, TG levels did not rise above 10 mmol/L (880 mg/dL) during the whole pregnancy, even during the last two trimesters where TG levels usually increase two- to four-fold from baseline and she did not experience any AP episode. She delivered a healthy baby at 39 weeks. This case suggests that plozasiran might be safe for the mother and the fetus and could prevent incremental pregnancy-driven TG elevation and occurrence of AP in women with sHTG. This is consistent with the long duration of action and hepatic half-life of plozasiran in clinical studies where TG levels remained sustainably lower than baseline > 9 months after the last injection.

Carbonic anhydrase VA (CAVA) deficiency (OMIM 114761) is an ultra-rare inborn error of metabolism with fewer than 20 cases described. Affected infants present in the first days of life with hyperammonaemia, lactic acidosis, ketonaemia and encephalopathy. Prenatal genetic testing can facilitate the diagnosis of subsequent affected pregnancies and permit proactive clinical management to prevent metabolic decompensation. Here we describe the clinical course of two sibling infants antenatally diagnosed with CAVA deficiency who were monitored and managed in the newborn period without decompensation. The proband, their older brother, had presented on day four of life with marked lactic acidosis, hyperammonaemia and encephalopathy requiring haemofiltration due to CAVA deficiency. His brothers were each born in a tertiary neonatal setting. They were managed with regular 3-4 hourly breastfeeds with supplementary expressed breast milk and formula top-ups to ensure optimal nutrition. In addition, they received carglumic acid (100 mg/kg daily) for 5 days. Regular biochemical monitoring was undertaken with measurement of acid-base status and ammonia levels. In contrast to their older brother, these male siblings had unremarkable neonatal periods with no significant clinical or biochemical concerns, demonstrating that in a neonate known to be affected with CAVA deficiency, early intervention can be instituted to minimise the risk of metabolic decompensation in the neonatal period.

Pyridox(am)ine-5'-phosphate oxidase (PNPO) deficiency is characterized by early-onset epileptic encephalopathy refractory to standard antiseizure medications. It is caused by variants in the PNPO gene, resulting in deficient PNPO enzyme activity, which normally converts pyridoxine-5'-phosphate and pyridoxamine-5'-phosphate (two vitamers of vitamin B6) into the active cofactor, pyridoxal-5'-phosphate (PLP). Treatment relies on PLP or pyridoxine in some cases. Long-term outcomes remain suboptimal. We describe two cases of unrelated children treated with vitamin B6 (pyridoxine) in utero: one with a confirmed prenatal PNPO diagnosis and one at risk due to family history but ultimately unaffected. In utero pyridoxine, combined with early postnatal PLP treatment, allowed excellent seizure control and normal neurodevelopment in the long term. Notably, our first patient, treated from birth, is now 10 years old, representing the oldest reported PNPO-deficient individual treated from birth. Case 2 highlights the safety of prenatal B6 supplementation even in unaffected fetuses. These observations support prenatal pyridoxine supplementation as a safe and potentially beneficial strategy in at-risk PNPO pregnancies.

Riboflavin (RF, vitamin B2) is an essential vitamin of which the co-factors are critical to numerous cellular processes. RF is used as a treatment for inherited metabolic diseases (IMDs), although its effectiveness in many disorders has not been established. We aim to summarize all available data on the efficacy and safety of RF in the management of IMDs. A systematic literature search was conducted for articles reporting the effectiveness of RF in IMDs. RF therapy was considered "effective" in an IMD if more than 75% of patients showed a positive response, "uncertain" in case of a positive response in fewer than 75% of patients, and "not effective" if patients deteriorated or died following RF therapy. RF therapy was reported in 381 articles addressing 33 separate IMDs. A positive effect was established in MADD type 3 (n=536, 93.1% responsive), RTD 2,3 (n = 94, 90.4% responsive), ACAD 9 (n = 29, 75.9% responsive), and FAD transporter deficiency (n = 5, 100% responsive). The effect was uncertain in complex I and II deficiency, ethylmalonic encephalopathy, FAD synthase deficiency, glutaric aciduria type 1, L2 hydroxyglutaric aciduria, and MADD type 2. RF was not effective in MADD type 1. Adverse effects were infrequent and mild. RF therapy in MADD type 3, RTD 2 and 3, ACAD9, and FAD transporter deficiency is safe and effective. Access to RF for these patients is crucial. For a substantial group of IMDs, the effect of RF remains uncertain. In these conditions, a trial of RF therapy with clearly defined outcome criteria might be considered.

Hypophosphatasia (HPP) is an inherited metabolic disease caused by deficient tissue-nonspecific alkaline phosphatase (ALP) activity and characterized by skeletal and nonskeletal symptoms, including muscle weakness and fatigue. We hypothesized that mitochondrial respiration is impaired in muscle in HPP, independent of skeletal manifestations, and that the second-generation ALP enzyme replacement therapy (ERT) efzimfotase alfa improves respiration. Akp2GW-/- mice were used for this purpose. Body weight, bone mineralization, and survival were validated in Akp2GW-/- mice versus Akp2-/- mice, an established model of HPP. No significant differences were found, validating the Akp2GW-/- model. Respiratory outcomes were measured in skeletal muscle fiber bundles in age- and sex-matched Akp2GW-/- and Akp2GW+/+ (wild-type) mice; bone mineralization was assessed. Mean maximal respiration and mitochondrial spare respiratory capacity (SRC) in vehicle-treated Akp2GW-/- mice were 37% and 30% of values from wild-type mice, respectively, independent of skeletal manifestations. Efzimfotase alfa treatment significantly improved maximal respiration in tissue from Akp2GW-/- mice by 147% versus vehicle (p = 0.0059) and improved SRC by 262% versus vehicle (p = 0.0008). Mean maximal respiration and SRC in tissue from efzimfotase alfa-treated Akp2GW-/- mice were 92% and 107%, respectively, of tissue from wild-type mice. Cellular ultrastructure of muscle biopsies from people with HPP showed atypical mitochondrial morphology, including branching cristae and dispersed matrix. In a mouse model of HPP, we show that the altered mitochondrial respiration in skeletal muscle is improved by ERT and that HPP is characterized by altered muscle mitochondrial morphology in humans. Together, these data suggest ERT could improve muscular symptoms in HPP.

Cell trafficking disorders(CTDs) are rare, heterogeneous inherited conditions marked by impaired intracellular transport mechanisms such as vesicular trafficking, cytoskeletal dynamics, and organelle interactions. Although clinical awareness is increasing, CTDs are often underdiagnosed due to phenotypic overlap with mitochondrial, lysosomal, and glycosylation disorders. We retrospectively analyzed 14 pediatric patients with molecularly confirmed CTDs at a single center. Clinical, biochemical, imaging, and genetic findings were reviewed to explore genotype-phenotype relationships and shared clinical features. The cohort included 8 females and 6 males, with a median diagnostic age of 29 months (range: 1-86 months). Common initial symptoms were developmental delay, hypotonia, seizures, and hepatosplenomegaly. MRI abnormalities were noted in 7 patients. Elevated serum lactate and dicarboxylic aciduria were observed in 9 and 6 patients, respectively. Creatine kinase was raised in several cases, prominently in one with TANGO2 deficiency. Elevated AST (n = 12) and ALT (n = 5) indicated mild hepatic involvement. Immunological abnormalities included immunoglobulin deficiency (n = 3) and protein C/S deficiency (n = 4). Recurrently mutated genes were AP4M1 and NPC1 (n = 2 each); others included BSCL2, PACS1, RAB3GAP1, STXBP1, TANGO2, HERC1, KIF1A, ATP1A3, VPS13B, and NLGN3. Two novel variants were identified: AP4M1 c.929 + 1G>T and NPC1 c.145A>T. This case series highlights the clinical and biochemical convergence of genetically diverse CTDs, emphasizing the role of trafficking defects in neurodevelopmental and systemic dysfunction. Expanding diagnostic panels to include trafficking-related genes and adopting a mechanism-based classification may improve early recognition and tailored management of these complex disorders.

MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.

Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by pathogenic variants in GBE1, resulting in deficient glycogen branching enzyme (GBE) activity and formation of abnormal glycogen ("polyglucosan"). GSD IV manifests across a spectrum of clinical dimensions-including hepatic, neurologic, muscular, and cardiac involvement-which vary in severity. The early-onset forms, historically referred to as Andersen disease, present at different stages ranging from in utero to adolescence. The adult-onset form, referred to as adult polyglucosan body disease (APBD), typically presents in middle to late adulthood. To date, no epidemiological study of GSD IV has been performed. Understanding the global prevalence of GSD IV is critical to increase disease awareness, improve diagnostic rates, inform therapeutic development, and engage pharmaceutical companies. In collaboration with the Rare Genomes Project at the Broad Institute of MIT and Harvard and the APBD Research Foundation, this study curated variants in GBE1 and calculated prevalence across nine genetic ancestry groups. The estimated global carrier frequency of GSD IV is 1 in 243 individuals, and the global genetic prevalence is 1 in 235 784 individuals. Based on the 2024 world population, the estimated number of affected individuals with GSD IV is approximately 34 800. These estimates highlight a significant underdiagnosis of GSD IV and underscore the urgent need for increased awareness of this metabolic disorder. This model of collaboration between researchers, patient advocacy organizations, and genetic data sharing programs provides a framework for estimating the prevalence of other rare diseases in the global population.

Diagnostic delay is common in mitochondrial disease, and its drivers remain unclear despite advances in molecular diagnostics. We retrospectively analyzed 61 individuals with molecularly confirmed mitochondrial disease at the Mount Sinai Mitochondrial Disease Clinic, diagnosed after 2016. Diagnostic delay was partitioned into intervals from symptom onset to clinical suspicion, and from suspicion to molecular diagnosis. Demographic, phenotypic, and genetic data were abstracted from health records, and Human Phenotype Ontology terms were compared before and after diagnosis using ClinPhen. Most delays occurred between symptom onset and clinical suspicion (mean 8.17&#x2009;years) rather than after suspicion (mean 1.28&#x2009;years), yielding a mean total delay of 8.22&#x2009;years (median 3.0). Delay decreased sharply by year of birth (r&#x2009;=&#x2009;-0.99, p&#x2009;<&#x2009;49.92&#x2009;&#xd7;&#x2009;10-39) and symptom onset (r&#x2009;=&#x2009;-0.96, p&#x2009;<&#x2009;8.14&#x2009;&#xd7;&#x2009;10-27), but showed no meaningful trend with year of diagnosis. Canonical features such as seizures, hypotonia, and stroke were frequently documented years before suspicion, underscoring missed opportunities. Diagnostic delay may reflect missed recognition rather than testing limitations. Systematic capture of early phenotypes and AI/NLP-based mining of electronic health records could proactively flag patients for reflexive sequencing, shortening diagnostic delay.

Glycogen storage disease 1b (GSD1b) typically presents in early infancy with poor fasting tolerance, hepatomegaly, and neutropenia. We report two siblings who were diagnosed with GSD1b in adulthood. Both had a normal fasting tolerance throughout childhood and, as adults, were able to fast for at least 16&#x2009;h without developing hypoglycaemia. The older sibling developed nodular cirrhosis during adolescence. The younger sibling exhibited a more pronounced metabolic phenotype, including hyperuricaemia leading to recurrent gout and nephrolithiasis. He experienced occasional episodes of mild neutropenia that were corrected with empagliflozin treatment. To our knowledge, these represent the first reported patients with GSD1b presenting in adulthood with non-hypoglycaemic complications of the disease and without overt neutropenia or neutrophil dysfunction.

COASY protein associated neurodegeneration is a rare, progressive autosomal recessive neuroferritinopathy due to pathogenic mutations in the COASY gene, coding for the mitochondrial located coenzyme A synthase. Clinical manifestations include seizures, progressive spasticity, dystonia, neuropathy, cognitive decline and neuropsychiatric abnormalities. Both foetal and childhood onset phenotypes are described. We report three patients with COASY protein associated neurodegeneration who were identified on newborn screening with a dried bloodspot acylcarnitine pattern consistent with carnitine palmitoyltransferase 1a deficiency, that is, an elevated ratio of free carnitine (C0) to the sum of palmitoylcarnitine (C16) and octanoylcarnitine (C18):[C0/(C16+C18)]. Two siblings, who died in infancy, displayed neurological features from birth, with magnetic resonance imaging of the brain displaying immature cortical sulcation, parenchymal atrophy and pontocerebellar hypoplasia. The third patient presented with global developmental delay, pyramidal signs and seizures with brain magnetic resonance imaging at age 15&#x2009;months demonstrating a thin corpus callosum, symmetric diffusion restriction throughout the basal ganglia and evidence of deposition in the globus pallidus. This report demonstrates that phenotypes of COASY protein associated neurodegeneration should be included in the differential diagnosis of dried blood spot acylcarnitine pattern suggestive of carnitine palmitoyltransferase 1a deficiency and may represent new potential for early diagnosis.

Pyridox(am)ine 5' Phosphate Oxidase deficiency (PNPO) presents with refractory epilepsy responsive to treatment with pyridoxal 5' phosphate (PLP) or pyridoxine. A 15-year-old boy with PNPO deficiency and cirrhosis underwent orthotopic liver transplantation for hepatocellular carcinoma without extra-hepatic disease. Pre-transplant, the boy was cognitively normal with well controlled epilepsy on PLP 50&#x2009;mg/kg/day. Continuous EEG monitoring was used pre-operatively and post-operatively to identify encephalopathy resulting from PLP deficiency. B6 vitamers (pyridoxine [PN], pyridoxamine [PM], pyridoxal [PL] and phosphorylated forms [PNP, PMP, PLP]) were assayed at times of encephalopathy (symptoms and/or EEG) and for pharmacokinetics. Doses of PLP were titrated to prevent encephalopathy and limit side effects. The intraoperative/immediate postoperative periods were managed with intravenous PLP at a dose which could be reduced to 7.8&#x2009;mg/kg/day before encephalopathy recurred. Post-transplant, transition to oral PLP (100&#x2009;mg/kg/day) led to fulminant hepatic impairment, which improved when IV dosing resumed. Subsequent transition to full oral PLP dosing took 9&#x2009;months with a final dose of 24&#x2009;mg/kg/day oral PLP. PLP showed dose dependent hepatotoxicity with associated rises in alpha-fetoprotein levels. Gradual PLP dose changes and frequent oral dosing minimised encephalopathy episodes and hepato-toxicity. Six years post-transplant, liver biopsy showed moderate portal fibrosis (Ishak fibrosis stage 2/6, LAFSc score 3/9). Encephalopathy/seizures were associated with lower plasma PL concentrations (40 times above physiological levels); but high plasma PLP concentrations did not prevent encephalopathy. Despite liver transplantation, requirements for supraphysiologic doses of PLP continued, suggesting impaired neuronal PLP salvage is the major factor determining PLP requirements in PNPO deficiency.

Primary mitochondrial diseases frequently affect the central nervous system, yet the extent, distribution and progression of white matter hyperintensities (WMHs) remain insufficiently characterised, particularly in terms of quantitative volumetrics and longitudinal progression. Although WMHs are typically attributed to cerebral small-vessel disease, mitochondrial disorders may cause white matter injury through distinct vascular and metabolic mechanisms. We conducted a retrospective single-centre study at Turku University Hospital including 36 patients with mitochondrial disease, each with at least one brain MRI (73 images). Longitudinal data were available for 15 patients. Three-dimensional T1-weighted and FLAIR images (1.5/3&#x2009;T) were analysed with the FDA-cleared cNeuro tool to obtain intracranial volume-normalised WMH and lesion volumes and an automated global Fazekas score. At baseline (median age 49&#x2009;years), WMHs were present in all supratentorial regions. Over time, WMH volumes increased significantly in periventricular, deep and juxtacortical regions, while lesion progression was predominantly periventricular. Fazekas scores remained generally low and stable. In follow-up imaging, women and patients carrying the m.3243A>G variant showed a greater burden of WMHs and lesions, compared with men and those with other mitochondrial diagnoses. WMH load did not differ according to history of stroke-like episodes. Mitochondrial disease is associated with early and progressive WMH accumulation, particularly in individuals with the m.3243A>G variant, and the pattern exceeds what would be expected from conventional vascular risk factors alone. These findings support a disease-specific mechanism of white matter vulnerability and highlight the importance of quantitative MRI for monitoring progression in mitochondrial disease.

Propionic acidemia is an inborn error of metabolism involving an enzymatic defect of propionyl-CoA carboxylase that results in the build-up of toxic metabolites which can induce metabolic decompensation. Secondary mitochondrial dysfunction in propionic acidemia has been commonly recognized; however, its clinical presentation and management are not well represented in literature. Here, we present a case of profound hyperglycemia and lactic acidosis without hyperammonemia in a propionic acidemia patient, where medical management incorporated mitochondrial dysfunction via a brief reduction in glucose infusion rate. We review the literature on propionic acidemia and mitochondrial dysfunction in an effort to provide a tangible clinical case where considerations of mitochondrial dysfunction were made to guide further decision making in taking care of this patient population.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in ALDH5A1, encoding the mitochondrial enzyme SSADH. This enzyme catalyses the conversion of succinic semialdehyde to succinic acid in the &#x3b3;-aminobutyric acid (GABA) degradation pathway. SSADH deficiency leads to the accumulation of neurotoxic metabolites, including &#x3b3;-hydroxybutyrate (GHB), and presents with developmental delay, hypotonia, ataxia, seizures, behavioral disturbances, and intellectual disability. We report a 10-month-old Caucasian male with global developmental delay, central hypotonia, and delayed motor milestones. He presented acutely with left-sided hemiplegia following irritability and vomiting. Brain MRI showed bilateral (right&#x2009;>&#x2009;left) T2 hyperintensities and diffusion restriction in the globus pallidus. Urine organic acid analysis via gas chromatography-mass spectrometry revealed markedly elevated 4-hydroxybutyric acid and 4,5-dihydroxyhexanoic lactone, pathognomonic for SSADH deficiency. Molecular testing identified compound heterozygous ALDH5A1 variants: c.278G>T p.(Cys93Phe) and c.612G>A p.(Trp204*), both previously reported as pathogenic. Parental segregation confirmed trans configuration. Three weeks postillness, he developed focal seizures, which have remained well controlled on levetiracetam. His seizure onset in infancy is notably earlier than the typical early childhood onset (~9&#x2009;years) reported in SSADH deficiency. This case expands the phenotypic spectrum of SSADH deficiency to include metabolic stroke as a presenting feature in infancy and highlights the importance of early recognition and molecular confirmation to guide management and emerging therapeutic strategies.

Hereditary tyrosinemia type I (HT-1) is a rare metabolic disorder treated by NTBC, requiring careful therapeutic and nutritional monitoring. While follow-up traditionally relies on urinary succinylacetone, plasma NTBC and plasma amino acids, dried blood spot (DBS) methods have introduced alternative monitoring options. However, the optimal biochemical monitoring remains debated. This study evaluated the clinical utility of NTBC measurements compared with established biomarkers in HT-1. In this retrospective single-centre study, we analysed biological data from 12 HT-1 patients treated with NTBC over 6&#x2009;years. We analysed correlations between NTBC, succinylacetone, &#x3b4;-aminolevulinic acid (&#x3b4;-ALA) and alpha-fetoprotein concentrations, and compared tyrosine and phenylalanine levels in DBS and plasma. Succinylacetone suppression in both urine and blood was achieved across a broad range of NTBC concentrations, suggesting that blood succinylacetone is a more reliable marker of metabolic control than NTBC levels. Elevated urinary &#x3b4;-ALA levels were observed in some samples despite unquantifiable succinylacetone, indicating that succinylacetone may not fully reflect neurological risk. NTBC concentrations showed limited correlation with alpha-fetoprotein, reinforcing the continued need for imaging in hepatocellular carcinoma surveillance. DBS measurement of tyrosine and phenylalanine displayed variable biases relative to plasma, particularly for tyrosine, highlighting the challenges of using DBS for nutritional monitoring. While NTBC remains central in the treatment of HT-1 patients, its blood concentrations offer limited added value for long-term monitoring. Focusing on succinylacetone measurement, along with &#x3b4;-ALA and alpha-fetoprotein to evaluate neurological and hepatic risks, is recommended. Plasma remains the preferred matrix for amino acids monitoring. Larger multi-centre studies are needed to confirm these findings.