INTRODUCTION:In intoxication-type inherited metabolic disorders (IMDs), strict protein restriction is vital; noncompliance may lead to coma or death. Meat and eggs are prohibited lifelong. This study developed personalized low-protein (LP) alternatives and chewable amino acid supplements to improve dietary adherence, palatability, and overall quality of life. METHODS:LP meat, egg, and amino acid-based candy prototypes were produced using a three-dimensional (3D) food printer. Proximate composition, color, texture, and pH measurements were performed. Sensory evaluation was conducted with 15 patients. RESULTS:Fifteen patients with IMDs participated in sensory testing of 3D-printed LP foods. Visual and overall acceptability scores were high, with 93.3% expressing willingness to include products in their diets. Isoleucine and valine soft candies (SCs) and LP meat analogs received the highest ratings for texture and appearance. Arginine SC scored lower in taste and texture, aligning with instrumental softness data. Open-ended feedback emphasized emotional and dietary impact. Texture profile analysis and proximate composition confirmed feasibility of protein restriction with preserved palatability. CONCLUSION:3D food printing provides visually and texturally acceptable LP options for patients with IMDs, enhancing dietary adherence and social participation. This pioneering study is the first to develop LP meat and egg analogs, offering significant contributions to the field.

Biotinidase deficiency is an autosomal recessive disorder that disrupts biotin recycling and multiple carboxylase-dependent pathways. Early and continuous biotin therapy prevents major clinical manifestations, but its long-term biochemical effects remain unclear. This study applied untargeted metabolomic and lipidomic profiling in 54 pediatric patients with genetically confirmed BD receiving regular biotin supplementation and 30 age- and sex-matched controls. Multivariate analyses and pathway enrichment revealed distinct biochemical signatures involving amino acid, energy, and lipid metabolism. Reduced levels of serine, glycine, threonine, and tricarboxylic acid cycle intermediates suggested modified mitochondrial flux, while octopine, exhibiting an approximately 11-fold increase, was the metabolite best able to discriminate between the groups. Lipidomic profiling indicated elevations in sphingolipids, phosphatidylcholines, long-chain fatty acids, and acylcarnitines, consistent with systemic lipid remodeling. These coordinated alterations imply metabolic adaptations to sustained biotin exposure rather than ongoing pathology. Octopine and selected lipid species may represent biochemical indicators of this adaptive state. Overall, the findings highlight that clinically stable children with Biotinidase deficiency exhibit unique metabolic and lipidomic patterns reflecting long-term compensatory mechanisms, underscoring the value of combined omics approaches for understanding disease-specific homeostasis and informing personalized follow-up strategies.

BackgroundOccupational pesticide (OcP) exposure and pathogenic GBA1 variants are established risk factors for Parkinson's disease (PD). However, whether they interact to influence disease onset or severity remains uncertain.ObjectiveTo determine the prevalence of OcP exposure and other lifestyle risks in relation to GBA1 status and their interactions on age of onset (AOO) and clinical scores in a well-characterized PD cohort.MethodsWe analyzed 505 people with PD (PwP) enrolled in the Ankara Parkinson's Disease Registry (ANPAR). GBA1 variants were identified using next-generation sequencing; benign or uncertain variants were excluded. Structured, face-to-face interviews collected data on history of OcP exposure, history of head trauma, smoking, coffee and tea consumption habits. PwP with and without GBA1 variants were compared using unadjusted and adjusted tests. General linear models assessed gene-environment interactions on AOO, non-motor, and motor scores.ResultsFifty-two PwP (10.3%) carried pathogenic GBA1 variants. OcP exposure was more common in carriers than non-carriers (36% vs. 22%; adjusted OR 1.98, 95%CI: 1.07-3.67, p = 0.031). No other risk factor differed between groups. Smoking independently delayed AOO, but there were no significant GBA1 × risk/lifestyle factor interactions for AOO or for motor/non-motor scores. Head trauma, coffee, tea, and OcP exposure showed neither main nor interaction effects on severity indices.ConclusionOcP exposure is reported more often by individuals carrying pathogenic GBA1 variants, supporting a gene-environment "dual-hit" model. However, OcPs did not modify AOO or disease severity once PD was manifest.

The syndrome known as KIDAR (keratitis, ichthyosis, deafness, autosomal recessive) is extremely rare. It is caused by biallelic mutations in AP1B1, encoding adaptor-related protein complex, beta-1 subunit. AP1 complex takes part in the formation of vesicles and the selection of cargo proteins in the trans-golgi network. It also contributes to vesicular transport of ATP7A and ATP7B. Accordingly, KIDAR has been defined as both an adaptinopathy and a copper metabolism disorder. Eleven cases have been reported to date. We report two new KIDAR cases with novel splice site variants—c.1796+1 G > T and c.1796+1 G > C—in AP1B1 (NM_001127.4) gene. Functional analysis of the first variant revealed that this mutation disrupts the normal splicing process, resulting in the creation of a cryptic donor site 150 base pairs downstream of the canonical donor site which introduces a premature stop codon into the transcript. We also present a review of previously reported KIDAR cases and genetic disorders involving altering copper metabolism and highlight our patients’ new clinical features, which may broaden the recognized phenotype. A detailed study of these cases may contribute to the ongoing genetic and clinical characterization of KIDAR syndrome.

Methylmalonic acidemia (MMA) is a rare inherited metabolic disorder caused by defective conversion of methylmalonyl-CoA to succinyl-CoA. Emerging evidence suggests that both dietary protein composition and intestinal microbiota influence metabolic stability and clinical outcomes. This study aimed to evaluate the effects of stepwise dietary modification and short-term metronidazole therapy on systemic and gut-derived metabolic profiles in MMA. In this prospective, longitudinal, single-center study, eight genetically confirmed MMA patients underwent four sequential phases: baseline mixed-protein diet (50% intact protein/50% medical formula), protein restriction, intact protein enrichment (80% intact protein/20% medical formula), and adjunctive metronidazole therapy (20 mg/kg/day, 10 days/month for 3 months). Plasma amino acids, urinary metabolites, stool microbiota (16S rRNA long-read sequencing), and untargeted/tandem metabolomic profiles were analyzed at each phase. Transition to an intact protein-enriched diet significantly reduced plasma leucine levels (p = 0.008) without affecting isoleucine or valine. Urinary methylmalonic acid, 3-hydroxypropionate, lactate, and pyruvate decreased, indicating improved propionyl-CoA clearance. Microbiota diversity progressively declined, accompanied by reductions in butyrate-producing genera (Novisyntrophococcus, Lacrimispora, Hespellia). Metronidazole further lowered urinary methylmalonic acid and 3-hydroxypropionate (p = 0.017 and p = 0.028), with parallel decreases in fecal 3-indolelactic acid and phytosphingosine, suggesting suppression of gut-derived propionate and tryptophan metabolism. Despite antibiotic-induced dysbiosis with expansion of Trabulsiella (Proteobacteria), systemic propiogenic burden decreased. A phased dietary regimen emphasizing intact protein, combined with intermittent metronidazole therapy, favorably modulated biochemical and microbial parameters in MMA. These findings support microbiome-informed dietary strategies and selective gut-targeted interventions to optimize metabolic control in organic acidemias.

Progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is a rare neurodegenerative disorder caused by pathogenic variants in NAXE gene. Movement disorders are among the clinical features of PEBEL1; however, no case presenting with paroxysmal exercise-induced dyskinesia (PED) has been reported. We reported the case of a 14-year-old girl who presented with PED episodes. Six months after the onset of episodes, she developed encephalopathy and focal status epilepticus. Exome sequencing analysis identified a homozygous pathogenic variant in NAXE gene, and she was diagnosed with PEBEL1. She was started on mitochondrial cocktail and multiple antiseizure medications; however, no response was observed. With the ketogenic diet (KD), seizure control was achieved and improvement in cognitive functions was observed. PED is a clinical feature not previously reported in PEBEL1 cases, and our case expands the phenotypic spectrum of this disorder. Additionally, our case highlights that KD may be a treatment option in PEBEL1.

BACKGROUND:Inherited metabolic diseases (IMDs) are genetic disorders characterized by metabolic defects leading to toxic accumulation or deficiencies in essential molecules. Cardiovascular complications, including cardiomyopathy (CM), valve dysfunction (VD), and arrhythmias, significantly contribute to morbidity and mortality in IMD patients, necessitating comprehensive cardiac evaluation. This study investigates the relationship between IMDs and cardiovascular involvement in pediatric patients to inform clinical management. METHODS:A retrospective analysis was conducted on 1215 pediatric IMD patients (2012-2021). Cardiovascular involvement was assessed through clinical records, echocardiography, and laboratory findings. Patients with congenital heart defects were excluded. RESULTS:Among 85 IMD patients with cardiovascular involvement, the median age was 85 months, with a 20-month follow-up. CM was present in 57.6%, most commonly hypertrophic CM. VD was identified in 40%, and vasculopathy in 4.7%. Rhythm abnormalities occurred in 8.2%, with two cases of clinically significant arrhythmias. Energy metabolism disorders were most associated with CM (71.8%), while VD was predominant in lipoprotein metabolism disorders (66.7%). Cardiac involvement was most frequently detected in infancy (45.9%). Disease progression occurred in 60% of intoxication-type and 41% of energy metabolism disorders. The mortality rate was 21.2%, higher in CM patients (22.4%) than in those with VD (17.6%). CONCLUSION:Cardiovascular complications impose a substantial burden on pediatric IMD patients. Early detection and a multidisciplinary approach are crucial for improving outcomes. Comprehensive cardiac assessment and tailored interventions can mitigate risks, highlighting the need for further multicenter studies to refine management strategies.

BACKGROUND:Primary mitochondrial diseases (PMDs) comprise a genetically and clinically heterogeneous group of disorders for which evidence-based therapeutic options remain limited. Despite advances in molecular diagnosis and the identification of gene-specific therapeutic targets for selected conditions, vitamin and cofactor supplementation continues to be frequently prescribed. We aimed to evaluate prescribing patterns, dosing practices and the balance between PMDs with established genotype-directed metabolic therapy and PMDs managed with empirical supplementation in a genetically confirmed PMD cohort. MATERIALS AND METHODS:We retrospectively reviewed 62 patients with genetically confirmed PMDs followed at a tertiary pediatric metabolism center between 2015 and 2025. Demographic, genetic and treatment-related data were collected, including vitamin and cofactor use and dosing regimens. Patients were categorized as PMDs with genotype-directed therapies and PMDs managed with empirical supplementation. RESULTS:Sixty-two patients were included (43.5% female; mean age 10.7 years). Oxidative phosphorylation (OXPHOS) complex defects were the most common genetic category (35.5%). Overall, 71% of patients received at least one vitamin or cofactor supplement. Coenzyme Q10 (62.9%), carnitine (53.2%), riboflavin (48.4%), biotin (37.1%) and thiamine (35.5%) were the most frequently prescribed agents. Thirteen patients (21%) had PMDs with established targeted therapies and received genotype-directed treatment. Among the remaining 49 patients, who lacked a defined genotype-directed therapeutic option and were therefore classified as being managed with empirical supplementation, 63.2% (31/49) received at least one vitamin or cofactor supplement. CONCLUSION:Despite advances in molecular diagnosis, empirical vitamin and cofactor supplementation remains frequently used in patients with PMDs who lack established gene- or pathway-specific therapeutic options. These findings underscore the persistent gap between molecular diagnosis and evidence-based therapy and support the need for prospective multicenter studies to guide standardized treatment approaches in PMDs.

Genetic factors contributing to hearing loss (HL) are heterogeneous, and effective medical treatments remain limited. We identified 3 distinct missense variants in CPD, encoding carboxypeptidase D, in 5 individuals with congenital deafness from 3 unrelated families, affecting the catalytically active CP domain 2 of this protein. Subsequent analysis of a larger cohort from the 100,000 Genomes Project revealed an enrichment of rare protein-altering CPD variants in individuals with HL. We show that CPD localizes to sensory epithelium and nerve cells in the mouse cochlea, and the enzymatic activity of CPD, crucial for nitric oxide (NO) production through arginine processing, is impaired in affected individuals. The levels of arginine, NO, and cGMP in patient-derived fibroblasts are also decreased, leading to endoplasmic reticulum stress-mediated responses being triggered in the cells. Silencing of Cpd in organotypic mouse cochlea cultures leads to increased apoptosis. Finally, Drosophila models of CPD deficiency display defective Johnston's organ, impaired auditory transduction, and sensory and movement abnormalities. Notably, these phenotypes are partially rescued by supplementation with arginine or sildenafil, a cGMP enhancer. Our findings establish CPD mutations as a cause of congenital HL, highlighting that the NO signaling pathway offers a promising therapeutic avenue.

Mitochondrial disorders are multiorgan disorders resulting in significant morbidity and mortality. We aimed to characterize death-associated factors in an international cohort of deceased individuals with mitochondrial disorders. This cross-sectional multicenter observational study used data provided by 26 mitochondrial disease centers from 8 countries from January 2022 to March 2023. Individuals with genetically confirmed mitochondrial disorders were included, along with patients with clinically or genetically diagnosed Leigh syndrome. Collected data included demographic and genetic diagnosis variables, clinical phenotype, involvement of organs and systems, conditions leading to death, and supportive care. We defined pediatric and adult groups based on age at death before or after 18 years, respectively. We used Kruskal-Wallis with post hoc Dunn test with Bonferroni correction and Fisher exact test for comparisons, Spearman rank test for correlations, and multiple linear regression for multivariable analysis. Data from 330 deceased individuals with mitochondrial disorders (191 [57.9%] pediatric) were analyzed. The shortest survival times were observed in hepatocerebral syndrome (median 0.3, interquartile range [IQR] 0.2-0.6 years) and mitochondrial cardiomyopathy (median 0.3, IQR 0.2-5.2 years) and the longest in chronic progressive external ophthalmoplegia plus (median 26.5, IQR 22.8-40.2 years) and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (median 21.0, IQR 13.8-28.5 years). Respiratory failure and pulmonary infections were the most common conditions associated with death (52/330, 15.7% and 46/330, 13.9%, respectively). Noninvasive ventilation was required more often in children (57/191, 29.8%) than adults (12/139, 8.6%, p < 0.001), as was nasogastric or gastric tube (131/191, 68.6% in children and 39/139, 28.1% in adults, p < 0.001). On multivariate analysis, individuals with movement disorders and nuclear gene involvement had increased odds of any respiratory support use (OR 2.42 (95% CI 1.17-5.22) and OR 2.39 (95% CI 1.16-5.07), respectively). This international collaboration highlights the importance of respiratory care and infection management and provides a reference for prognostication across different mitochondrial disorders.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a rare metabolic condition that results in impaired fatty acid utilization, leading to metabolic crises, hospitalization, and reduced quality of life. Despite dietary management, many patients experience ongoing complications. Triheptanoin, a seven-carbon triglyceride, has emerged as a therapeutic alternative by providing an energy source and supporting metabolic stability. This study aims to evaluate the clinical outcomes of LC-FAOD patients receiving triheptanoin therapy in Türkiye. A retrospective nationwide study was conducted to analyze 14 patients with LC-FAOD who received oral triheptanoin as part of a compassionate use program in Türkiye. The study collected data on emergency department visits, hospitalizations, metabolic decompensation episodes, creatine kinase (CK) levels, hypoglycemia, and cardiac function. Additionally, patient-reported outcomes were assessed through surveys. The findings of the study demonstrated that triheptanoin treatment led to a significant reduction in the number of emergency service applications and hospitalizations per month ( p < 0.01). A notable decrease in the frequency of myalgia attacks was observed, while the decline in rhabdomyolysis episodes did not reach statistical significance. Furthermore, creatine kinase levels during metabolic crises exhibited a substantial decrease following triheptanoin therapy ( p < 0.0001).Among patients with cardiomyopathy, cardiac function showed improvement in four out of seven patients. Survey data indicated an improvement in appetite, physical performance, and overall quality of life. Conclusion : Triheptanoin treatment has been demonstrated to be associated with significant clinical improvements in patients diagnosed with LC-FAOD, including a reduction in the frequency of emergency department visits, hospitalizations, and metabolic crises. These findings provide support for the utilization of triheptanoin as a therapeutic approach that holds promise in the management of LC-FAOD. What is Known: • Long-chain fatty acid oxidation disorders (LC-FAOD) are associated with significant morbidity due to metabolic crises, despite conventional dietary treatment including medium-chain triglycerides (MCT). What is New: • This nationwide study demonstrates that triheptanoin therapy significantly reduces emergency visits, hospitalizations, and creatine kinase levels during crises, and improves patient-reported outcomes, including physical activity and quality of life, in LC-FAOD patients in Türkiye.

BACKGROUND:The GBA1 gene has been established as a notable risk factor in Parkinson's disease (PD). While some population-specific variants were reported, many regions of the world remain underexplored. This study investigates the prevalence, types, and clinical associations of GBA1 variants in a large cohort of patients with PD (PwP) from Turkey. METHODS:A total of 716 individuals, including 513 PwP and 203 healthy controls (HC), were evaluated. Genetic analysis of GBA1 variants was performed using nextgeneration sequencing. Additionally, whole exome sequencing (WES) was conducted on participants with detected GBA1 variants. Clinical data, including motor, non-motor, and quality of life assessments, were collected. Enzyme and substrate levels were measured from dry blood spot samples. RESULTS:GBA1 variants were found in 13.2% of PD patients, significantly higher than in HC (6.4%), corresponding to an average 2.2-fold higher prevalence. The most frequent variants were p.T369M, p.L444P, and p.N370S. Additionally, 15 variants not previously reported in PD were detected. Patients with pathogenic variants had an earlier age of onset including a higher levodopa-equivalent daily dose and motor complications. Enzyme and substrate levels did not differ significantly between the groups. In one patient, WES data showed a CTSB variant which was reported to modify the effects of GBA1. CONCLUSION:This is the largest study revealing prevalence of GBA1 variants among PwP in Turkey, with significant clinical implications. The findings enrich the literature by expanding the previously unknown landscape of GBA1 variants in this region.

Glycogen storage disease type 1 (GSD1), which is categorized into GSD1a and GSD1b, is caused by disease-causing genetic variants in G6PC or SLC37A4 genes, respectively. The aim of this study was to present clinical characteristics, novel phenotypic and molecular features as well as long-term complications of the largest cohort of patients in Turkey and one of the largest cohorts in the world. The demographic, clinical, and molecular data of GSD1a or 1b patients who were followed up between 2000 and 2024 were collected retrospectively from patients’ medical records. A total of 39 GSD1a patients were enrolled, and four different variants in the G6PC gene, c.247C > T (p.R83C), c.809G > T (p.G270V), c.562G > C (p.G188R), c.480G > A (p.W160*) were revealed. The most common variant among Turkish GSD1a patients was the c.247C > T (p.R83C) variant with an allele frequency of about 90

Objectives: This study aimed to identify clinical, laboratory, and radiological features that could serve as red flags for diagnosing inherited metabolic disorders (IMDs) with hepatic involvement in childhood. Methods: We retrospectively reviewed the medical records of 1,237 children from a pediatric metabolism department, with suspected or diagnosed IMDs. Patients with hepatic involvement were divided into two groups: Group 1 (diagnosed with IMDs) and Group 2 (undiagnosed). Demographic, clinical, laboratory, and radiological data were compared between the groups. Results: Hepatic involvement was observed in 415 patients (33.5 %), with 206 (49.2 %) diagnosed with IMDs. Group 1 had higher rates of consanguineous marriage and affected siblings. Complex molecule disorders (20.4 %), mitochondrial (16.0 %), and lipid metabolism disorders (16.0 %) were the most common IMDs. Dysmorphic findings were more frequent in Group 1 (28.2 vs. 16.3 %, p=0.004), while diarrhea was less common (4.4 vs. 12.0 %, p=0.005). Ammonia and lactate levels were higher in Group 1 (p<0.001 and p=0.032, respectively). Hepatomegaly was more frequent in Group 1 (53.3 vs. 22.6 %, p<0.001). Pathological abdominal ultrasonography was the only significant multivariate predictor (OR: 89.377, p=0.026). Overall survival was 87.7 %, with no difference between groups. Conclusions: Consanguineous marriage, affected siblings, dysmorphic findings, absence of diarrhea, and pathological abdominal USG are key predictors of IMDs in hepatic involvement cases.

The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.