OBJECTIVE: To describe the phenotype, genotype, neuroimaging features, and outcome of PLPBP-related vitamin B-dependent epilepsies. We present a systematic review, along with a multicenter case series of patients with PL...OBJECTIVE: To describe the phenotype, genotype, neuroimaging features, and outcome of PLPBP-related vitamin B-dependent epilepsies. We present a systematic review, along with a multicenter case series of patients with PLPBP deficiency. METHODS: We collected individual data on clinical, radiological, genetic, and outcomes for a multicenter case series (n = 8) and all previously published cases (n = 46). We conducted a thematic analysis to identify consistent features across all cases and applied a clinical score system specifically developed to assess the impact of PLPBP-related vitamin B-dependent epilepsy on neurodevelopmental and seizure outcome in each case. RESULTS: We identified 14 eligible studies involving 46 patients. Including our additional cases, the total number of individuals with PLPBP variants increased to 54. The most common type of variant was missense variants (48%), with the variant c.370-373del being the most frequently reported (18.5%). Based on our clinical severity scoring system, which evaluates the degree of neurodevelopmental impairment and seizure control, more than two thirds of patients were classified as having moderate to severe disease. All individuals in the reviewed studies presented with early neonatal seizures, with the majority occurring within the first 24 h of life (55.5%) or the first week of life (76%). Common clinical features observed included antenatal anomalies, prematurity, fetal distress, and microcephaly. Analysis of brain MRI studies identified anomalies in 65% of cases, including white matter abnormalities (54%), periventricular or temporal cysts (27%), anomalies of the corpus callosum (15.4%), and global brain underdevelopment with broad gyri and shallow sulci (44%). Genotype-phenotype analysis revealed an association of missense variants and compound heterozygous variants with an attenuated phenotype, while biallelic truncating variants and homozygous variants were linked to severe phenotypes and/or early mortality. CONCLUSIONS: This systematic review and multicenter case series of a large cohort of individuals with PLPBP deficiency delineates the clinical, radiological, and genetic spectrum of PLPBP-related vitamin B-related epilepsies, an autosomal-recessive disease. It also highlights the best treatment approaches and potential predictors for disease severity and survival.
Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT...Mitochondrial diseases are genetic disorders caused either by nuclear or mitochondrial DNA (mtDNA) alterations and characterized by high genetic and phenotypic variability. The common mtDNA m.3243 A > G variant in the MT-TL1 gene leads to clinical manifestations ranging from the classical MELAS (myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome to milder phenotypes such as MIDD (maternally inherited diabetes and deafness) or a spectrum of clinical features of intermediate severity defined as MELAS-Spectrum. The heterogeneous disease course makes the identification of biomarkers for monitoring disease progression challenging, particularly if we consider the occurrence of stroke-like episodes (SLEs), which remain unpredictable events. Here, we assessed two biomarkers, neurofilament light chain (NF-L) and circulating cell free-mtDNA (ccf-mtDNA), in a cross-sectional study in MELAS patients, including both patients in the interictal period and during SLEs, and MELAS-Spectrum patients. Both biomarkers were significantly elevated in MELAS patients during SLEs, compared to the other patients. In addition, we found significant correlation between NF-L and m.3243 A > G blood heteroplasmy in MELAS patients, as well as between NF-L and clinical severity in the whole patients cohort. Despite the limitations derived from the small sample size and the cross-sectional sample collection, our study confirms the value of NF-L and ccf-mtDNA as biomarkers efficiently hallmarking SLEs, highlighting their potential use to monitor the progression of MELAS.
Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to dev...Primary mitochondrial diseases (PMD) are a growing number of disorders caused by mitochondrial dysfunction. There is not yet a consensus on the precise definition of PMD. Therefore, this study presents an approach to developing a nosology for standardized, systematic classification of PMD, harmonized with ICIMD and IEMbase. A total of 452 PMD causative genes were included. The classification includes 18 categories: 1) Disorders of amino acid metabolism; 2) Disorders of peptide and amine metabolism; 3) Disorders of carbohydrate metabolism; 4) Disorders of fatty acid and ketone body metabolism; 5) Disorders of energy substrate metabolism; 6) Mitochondrial DNA-related disorders; 7) Nuclear-encoded disorders of oxidative phosphorylation; 8) Disorders of mitochondrial cofactor biosynthesis; 9) Disorders of mitochondrial DNA maintenance and replication; 10) Disorders of mitochondrial gene expression; 11) Other disorders of mitochondrial function; 12) Disorders of metabolite repair/proofreading; 13) Disorders of lipid metabolism; 14) Disorders of nucleobase, nucleotide and nucleic acid metabolism; 15) Disorders of tetrapyrrole metabolism; 16) Disorders of organelle biogenesis, dynamics and interaction; 17) Disorders of vitamin and cofactor metabolism and 18) Neurotransmitter disorders. We also describe the clinical involvement of 22 organs and systems and laboratory features. The most prevalent symptoms (per gene) were neurological (21.1%), ocular (10.3%), muscular (9.0%), gastrointestinal (8.3%), and cardiovascular (7.9%).
Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive oph...Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1-2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.
GTP cyclohydrolase I deficiency is a rare inherited disorder of biogenic amine metabolism due to pathogenic GCH1 variants, manifesting as DOPA-responsive dystonia or severe encephalopathy. Pathogenic variants in the NEXM...GTP cyclohydrolase I deficiency is a rare inherited disorder of biogenic amine metabolism due to pathogenic GCH1 variants, manifesting as DOPA-responsive dystonia or severe encephalopathy. Pathogenic variants in the NEXMIF gene cause X-linked intellectual disability and epilepsy. Here, using trio-WES approach, we identified a rare, previously uncharacterized GCH1 p.Arg170Gly variant and a novel NEXMIF p.Asp155GlnfsTer2 variant in a female patient. This study aimed to confirm the pathogenicity of these variants and elucidate their underlying molecular pathomechanisms by molecular in vitro studies. First, we confirmed that the NEXMIF variant introduces a premature stop codon at the cDNA level, implying loss of NEXMIF protein function. To explore the functional consequences of the GCH1 variant, we expressed and purified wild-type (WT) and p.Arg170Gly homodecameric GCH1, as well as a mixed population of heterodecameric GCH1 proteins, and performed biochemical characterization. Kinetic studies revealed that the catalytic efficiency of the mutant homo- and heterodecameric GCH1 was reduced by 37- and 9-fold, respectively, compared to the WT enzyme, confirming a significant loss of activity. Furthermore, the presence of mutant GCH1 monomers negatively affected catalytic cooperativity in the decameric enzyme. Circular dichroism indicated that p.Arg170Gly slightly impacts the structure of the protein, as shown by reduced α-helical content in the mutant homodecamer. In summary, we provide the first functional evidence that the GCH1 p.Arg170Gly variant is pathogenic mainly due to reduced enzyme activity, and that its combination with a novel NEXMIF loss-of-function variant manifests as a complex neurological phenotype arising from two distinct disorders.
Raman R, Horst B, Shahrokh Z
… +8 more, Hatambeygi N, Zare M, Leszczyniecka M, Harris JS, Banks WA, Hansen KM, Erickson MA, Ekins S
Mol Genet Metab
· 2026 Mar · PMID 41576655
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CLN1 Batten disease is caused by mutations in the CLN1 gene which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1). Disease progression is marked by intellectual and motor deterioration, seizures, v...CLN1 Batten disease is caused by mutations in the CLN1 gene which codes for the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1). Disease progression is marked by intellectual and motor deterioration, seizures, vision loss, and early mortality. There are no approved treatments for this severe pediatric condition. We describe the development and characterization of recombinant human PPT1 (rhPPT1) suitable for use as a clinical enzyme replacement therapy in CLN1 Batten patients. rhPPT1 displays similar mannose-6-phosphate receptor (M6PR)-dependent uptake kinetics in neuronal cell lines from human, rat and non-human primate but not in mouse cells. rhPPT1 crosses the blood-brain-barrier (BBB) in adult mice which is uncommon for unmodified lysosomal enzymes, and is independent of the M6PR and sialic acid receptors even though analytical characterization of rhPPT1 shows complex M6P and sialic acid containing glycans. Our findings suggest for the first time that intravenous dosing of rhPPT1 may be complementary to other dosing strategies in CLN1 patients and may expand its use for other applications.
Glycosylation is one of the most important posttranslational modifications. When the glycosylation machinery is affected, this leads to a congenital disorder of glycosylation (CDG). CDG are a class of rare multisystemic...Glycosylation is one of the most important posttranslational modifications. When the glycosylation machinery is affected, this leads to a congenital disorder of glycosylation (CDG). CDG are a class of rare multisystemic diseases that often affect the endoplasmic reticulum (ER). Although vascular complications have been reported in CDG, the contribution of endothelial dysfunction to these phenotypes remains incompletely understood. Here, we evaluated the effect of glycosylation deficiency on endothelial dysfunction by generating two endothelial cell models using pharmacological inhibitors: tunicamycin (a well-known glycosylation inhibitor at the level of DPAGT1), and 2-deoxy-2-fluoro-D-mannose (FMan). This is a novel inhibitor that inhibits mannose and related sugar-phosphate metabolism. These cell models were subjected to transcriptomics, proteomics, and tracer metabolomics to pinpoint the pathways that are most affected across these different levels. Both transcriptomics and proteomics revealed ER stress as the top upregulated feature. This was functionally characterized by decreased cell growth, induced apoptosis, decreased cell migration, and induced an immune response. The barrier function of the cells was not affected. Here, we demonstrate that N-glycosylation deficiency triggers an ER stress response, contributing to endothelial dysfunction, and investigated ER stress mitigation as a potential therapeutic strategy for CDG.
Rodrigues A, Sweigert E, Robinson D
… +15 more, Kregel M, Williamson J, Koehler A, Schreckengast S, Forry C, Loeven K, Puffenberger E, McVey A, Hendrickson C, Patel A, Thomas A, Thomas S, Brigatti KW, Strauss K, Meier GL
Surplus calories are used to prevent protein catabolism in patients with maple syrup urine disease (MSUD) but can also lead to obesity and its related complications. At present, there are no evidence-based guidelines to...Surplus calories are used to prevent protein catabolism in patients with maple syrup urine disease (MSUD) but can also lead to obesity and its related complications. At present, there are no evidence-based guidelines to inform weight loss strategies for patients with inborn errors of metabolism. Obese MSUD patients often resist weight loss due to the fear of metabolic decompensation, and their dietary options are limited by dependence on medical foods with fixed nutritional composition. We examined the anthropometric and biochemical effects of metformin in nine adults with severe (classic) MSUD who were instructed to reduce their calorie intake from medical food by 10%. Eight participants (67% female) completed the 52-week study; one withdrew following elective liver transplantation. Baseline median age, body mass index (BMI), and glycosylated hemoglobin (HgbA1C) were 33.8 years (IQR 25.3-41.6), 38.3 kg/m (IQR 31.6-42.2), and 5.3% (IQR 5.0-5.6), respectively. We titrated the daily metformin dose to a median of 2000 mg (IQR 1000-2000) by week 25, at which time seven (88%) participants successfully reduced total calories from medical food by 10%. Metformin was generally well tolerated. Diarrhea was the most common treatment-related complication, affecting 56% of participants, and limited dose escalation in two (22%) of them. No participant achieved the primary outcome of a > 10% BMI change. However, metformin therapy allowed for modest and significant reductions in weight (-2.8%, p = 0.023), BMI (-2.8 kg/m2, p = 0.016), and calories from medical food without altering plasma leucine concentrations or the proportion of dietary protein from intact sources. Serum triglycerides, high-density lipoprotein, and HgbA1C did not change over the study period. Based on these clinical observations, we conclude that classic MSUD patients can safely use metformin to aid weight loss without triggering metabolic instability, and may therefore tolerate more aggressive weight loss strategies.
The Hunter Outcome Survey (HOS) collected global, real-world data on the natural history of mucopolysaccharidosis II and its treatment with intravenous idursulfase. For eligible patients, home therapy offers a convenient...The Hunter Outcome Survey (HOS) collected global, real-world data on the natural history of mucopolysaccharidosis II and its treatment with intravenous idursulfase. For eligible patients, home therapy offers a convenient alternative to in-clinic therapy. Using data in HOS as of January 2023, we provide an updated assessment of the safety/tolerability profile of home therapy with idursulfase. The analysis population comprised 333 patients who had received at least one home infusion and 708 patients who had never received home therapy. Median (10th percentile [P10], 90th percentile [P90]) age at home therapy start was 8.9 (2.9, 21.1) years. Median (P10, P90) ages at latest visit were 15.5 (7.7, 29.3) years in the home therapy group and 13.9 (5.2, 29.0) years in the no home therapy group. Patients received a median (P10, P90) of 6.0 (0.8, 12.0) years of home infusions after 1.8 (0.3, 8.7) years of in-clinic therapy, and these timings varied by geographic region. The infusion-related reaction (IRR) rate was 0.11/patient-year during home therapy, 0.13/patient-year for the in-clinic period for the same patients (first 6 months excluded), and 0.05/patient-year for patients who never received home therapy (first 6 months excluded). More than 60% of IRRs were categorized as mild. The adverse event (AE) rate was lower during home therapy (0.59 AEs/patient-year) than during the in-clinic period for the same patients (0.86 AEs/patient-year). Among patients who never received home therapy, the rate was 0.60 AEs/patient-year. Deaths occurred at a rate of 2.17 deaths/100 patient-years of home therapy and 3.60 deaths/100 patient-years among patients never treated with home therapy. No deaths were deemed related to treatment. The rate of missed infusions was 0.52/year during the home therapy period compared with 1.42/year during the in-clinic period for the same patients and 0.57/year for patients who never received home therapy. Our data indicate a similar safety/tolerability profile for intravenous idursulfase administered at home and in clinic in patients with mucopolysaccharidosis II.
Starosta RT, He M, Gracie S
… +10 more, Kierstein J, Thiel C, Himmelreich N, Liu Y, Zhang W, Edmondson AC, Meeks N, Larson A, Van Hove JLK, Kochhar A
Mol Genet Metab
· 2026 Mar · PMID 41529427
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Fucosylation disorders are rare types of congenital disorders of glycosylation (CDG), the most common being SLC35C1-CDG, which is classically described as a leukocyte adhesion deficiency (hence the previous name of "leuk...Fucosylation disorders are rare types of congenital disorders of glycosylation (CDG), the most common being SLC35C1-CDG, which is classically described as a leukocyte adhesion deficiency (hence the previous name of "leukocyte adhesion deficiency type II") with dysmorphic features, short stature, and moderate-to-severe developmental and intellectual disabilities. In more recent years, several cases have been described of individuals with bi-allelic SLC35C1 variants and biochemical proof of hypofucosylation who had short stature, dysmorphic features, and intellectual disability, but no hematological abnormalities. In this article, we report a patient with growth faltering, neuroirritability, nystagmus, developmental delays, microcephaly, dysmorphic features, and hypogammaglobulinemia G. Biochemical investigations including serum N-glycan profiling, fucosylation-focused whole serum glycoprotein profiling, and serum lectin blots, all of which showed significant global hypofucosylation. Exome sequencing revealed a single likely pathogenic variant, SLC35C1 (NM_018389.4):c.503_505delTCT, p.(Phe168del), which was inherited from an unaffected mother. Whole genome sequencing with manual review of raw data did not reveal any second pathogenic variants; SLC35C1 mRNA sequencing was negative for changes in the second allele or allelic imbalance. The patient was started on L-fucose supplementation, with subsequent improvements in weight and head circumference, normalization of IgG levels, and remarkable developmental catch-up. Biochemically, there was an increase in abundance of previously decreased fucosylated glycan species in serum, especially FucGlcNAcMan (a glycan that is known to be enriched in neutrophils). In summary, we present here further evidence for the role of L-fucose supplementation in treating hypofucosylation disorders and suggest that IgG and fucosylated glycan species may be useful as biomarkers in this scenario, although further research is needed to validate them as such. It is likely that the early introduction of L-fucose in this patient may have led to the excellent developmental outcomes observed.
Clinical care and management of inborn errors of metabolism (IEM) are lifelong, complex, and resource-intensive for the healthcare team, patient, and families. A cohort of individuals with IEM who in addition have gender...Clinical care and management of inborn errors of metabolism (IEM) are lifelong, complex, and resource-intensive for the healthcare team, patient, and families. A cohort of individuals with IEM who in addition have gender incongruence (GI) presents a unique challenge of patient care in current practices. Here, we discuss four patients with different IEM (phenylketonuria (PKU), 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD), ornithine transcarbamylase (OTC) deficiency that presented with GI either in their adolescence or adulthood. We review their IEM management and evolving expression of GI as we highlight the influence of various clinical and psychosocial stressors, including social acceptance and self-esteem. Significant research on the comorbidity between IEM and GI has not yet received attention in the literature. Here we aim to explore this underrepresented topic to encourage expansion of knowledge and how to navigate the complex management and support to individuals with IEM experiencing GI.
Agrawal N, Bianconi S, Jaeger R
… +6 more, Farhat NY, Alexander DM, Sinaii N, Hadigan C, Berry-Kravis E, Porter FD
Mol Genet Metab
· 2026 Mar · PMID 41529425
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PURPOSE: Niemann-Pick Disease, Type C1 (NPC1) is a neurodegenerative lysosomal disease in which the first manifestation is often cholestatic liver disease at birth. The neurodegenerative symptoms typically manifest later...PURPOSE: Niemann-Pick Disease, Type C1 (NPC1) is a neurodegenerative lysosomal disease in which the first manifestation is often cholestatic liver disease at birth. The neurodegenerative symptoms typically manifest later. The aim of this study was to see if the presence and severity of liver disease at birth predicted whether a participant would develop liver disease later and if there was any correlation with the age of onset of neurological symptoms. METHODS: Liver disease was characterized in 93 individuals with NPC1 using FibroScan, abdominal ultrasound, and plasma liver function tests at baseline and longitudinally over up to a four-year period. This information was correlated with the presence or absence of liver disease noted at birth. RESULTS: Higher liver stiffness measurement scores, suggesting increased risk for liver fibrosis, were associated with a history of significant liver disease in infancy (p = 0.001). A history of absent or mild/moderate liver disease at birth had no correlation with differences in liver stiffness measurements The presence of any degree of liver disease at birth corresponded to earlier onset of neurological symptoms compared to having no liver disease at birth (p = 0.002). Those with no history of neonatal liver disease had an average age of 10.3 years at time of neurological symptoms, compared to 5.9 years for those with mild/moderate disease and 3.6 years for those with severe disease (p = 0.002). CONCLUSIONS: The presence of liver disease at birth can provide prognostic information on when individuals with NPC1 may manifest neurologic symptoms. In addition, individuals who had severe liver disease at birth are at higher risk for developing clinically significant liver disease after the neonatal period. Given multiple reports of hepatocellular carcinoma in individuals with NPC1, those with a history of severe liver disease should be closely monitored.
INTRODUCTION: Fabry disease (FD), also known as Anderson-Fabry disease, is a heterogeneous, multisystem lysosomal storage disorder with an X-linked inheritance pattern. Its estimated prevalence in the general population...INTRODUCTION: Fabry disease (FD), also known as Anderson-Fabry disease, is a heterogeneous, multisystem lysosomal storage disorder with an X-linked inheritance pattern. Its estimated prevalence in the general population ranges from approximately 1 in 40,000 to 1 in 100,000 individuals. FD results from partial or complete deficiency of the lysosomal enzyme alpha-galactosidase A (α-Gal A), caused by pathogenic variants in the GLA gene. This enzymatic deficiency leads to progressive lysosomal accumulation of glycosphingolipids, resulting in multisystem involvement with a broad clinical spectrum. Clinical manifestations may appear as early as childhood. OBJECTIVE: To develop evidence-based recommendations for the diagnosis, treatment, and follow-up of pediatric patients with FD. MATERIALS AND METHODS: A literature search was conducted in Medline and Embase for studies published between January 2021 and May 2025. Additional information was obtained from development group websites, consensus documents, technology evaluations, Google Scholar, clinical experts, and reference lists. The quality of evidence was assessed according to the type of source. A modified Delphi consensus process was carried out with external experts, and an 80 % agreement threshold was established to define the final recommendations. RESULTS: The evidence search identified 47 publications. Consensus was reached on 57 recommendations regarding diagnosis, treatment, and surveillance. These recommendations were validated by external clinical experts from Colombia, Argentina, Spain, Mexico, and the USA. CONCLUSIONS: The recommendations presented in this document are based on the most up-to-date evidence available at the time of the search and the judgment of clinical experts. They are expected to support daily clinical practice for the diagnosis, treatment, and follow-up of pediatric patients with FD.
Many inborn errors of metabolism (IEM) fulfil clinically relevant criteria and therefore are considered metabolic diseases. Typically, these conditions are due to impaired biosynthesis or breakdown of substances within s...Many inborn errors of metabolism (IEM) fulfil clinically relevant criteria and therefore are considered metabolic diseases. Typically, these conditions are due to impaired biosynthesis or breakdown of substances within specific pathways. However, there is also a growing number of metabolic conditions that are understood to represent merely biochemical phenotypes but are not linked to typical clinical findings and do not require treatment. The distinction between disease and non-disease is often not straightforward, but may have several nuances as well as overlaps, and may even be impossible to definitely classify as in many instances there is a continuum from non-disease to disease rather than categories. This article aims for deeper insights into the characteristics of conditions under discussion in this regard.
Mutations in the Ndufs4 gene encoding the accessory subunit of complex I (CI) of the mitochondrial oxidative phosphorylation (OXPHOS) system, are the most common causes of Leigh Syndrome (LS). LS is a severe infantile ne...Mutations in the Ndufs4 gene encoding the accessory subunit of complex I (CI) of the mitochondrial oxidative phosphorylation (OXPHOS) system, are the most common causes of Leigh Syndrome (LS). LS is a severe infantile neurodegenerative disorder characterised by various clinical phenotypes ranging from ataxia, cardiomyopathy, swallowing difficulties, visual problems, psychomotor regression to fatal respiratory failure. The mechanistic processes contributing to the onset and progression of these clinical manifestations remain poorly understood. This study investigates tissue-specific proteomic changes in a mouse model of LS using quantitative proteomics as a hypothesis-generating technique. Six distinct tissues, namely three brain regions (brainstem, cerebellum, olfactory bulb), heart, kidney, and liver, were collected from the LS mouse model (Ndufs4 KO mice) and compared to wild type (WT) controls using SWATH-MS analysis as a data acquisition method. Functional enrichment analysis revealed distinct tissue-specific cellular responses which include a shift toward amino acid metabolism in the heart, increased mitochondrial translation in the kidney, and alterations in phase II detoxification pathways in the liver. Our results unravel candidate mechanisms for tissue-specific vulnerability and highlight the regulation of PTEN gene transcription as potential driver of neurodegeneration. These findings provide data-driven hypotheses for tissue-specific vulnerability in LS, highlighting potential mechanisms and therapeutic targets. This study established a foundation for future hypothesis-driven research into the tissue-specific pathophysiology of mitochondrial disease.
BACKGROUND: Metabolic myopathies (MM) are a diverse group of genetic disorders that impair cellular energy metabolism, resulting in exercise intolerance and fatigue. Previous studies have reported benefits of physiothera...BACKGROUND: Metabolic myopathies (MM) are a diverse group of genetic disorders that impair cellular energy metabolism, resulting in exercise intolerance and fatigue. Previous studies have reported benefits of physiotherapy in patients with MM, however, objective assessments of their efficacy remain limited. The C glucose breath test (C-GBT) is a non-invasive measure of glucose metabolism through the detection of CO expelled from the tricarboxylic acid cycle. This study utilizes the in vivoC-GBT assessment pre- and post-therapeutic intervention to evaluate the impact of a supervised 12 wk. at-home resistance training program on patients with MM. OBJECTIVES: The first experiment was to assess the repeatability of the in vivoC-GBT through triplicate study days in healthy controls. The second experiment was to assess C-glucose metabolism in participants with MM pre- and post-therapeutic intervention. DESIGN: Six healthy adult controls (3 F: 3 M) aged 22-29 y, and three adolescent participants (1 F: 2 M) aged 10-18 y with diagnosed MM were recruited. Participants completed up to three study days pre- and post-intervention, consuming a 1.5 mg/kg body weight dose of [U-C] d-glucose, and 1.5 g/kg body weight Trutol® glucose beverage. Breath samples collected during the 4 h study day were analyzed for C enrichment with isotope ratio mass spectrometry, and used to calculate rate of glucose oxidation (mg/kg/min). Measured C enrichment was used to calculate the rate of glucose oxidation (mg/kg/min) and interpreted with Area Under the Curve analysis, and determination of maximum rate (C). RESULTS: Repeatability of the C-GBT was confirmed in healthy participants, with average coefficients of variation (CV) being 8.9 % in males and 8.6 % in females at C. Among MM participants, exercise intervention increased glucose oxidation 23.5 % in subject MM-01 (F, 14 y), and 9 % in MM-02 (M, 16 y); but decreased -11.7 % in MM-04 (M, 17 y). All subjects showed a marginal increase in lean body mass (2-4 %). CONCLUSIONS: The non-invasive 4 h C-GBT protocol shows potential as a feasible tool for clinicians to monitor glucose utilization due to its low patient burden and good repeatability. Future work should validate the repeatability of the assay in a larger patient population to confirm its translational potential to guide the management of MM patients.
Sun B, Yi H, Han SO
… +5 more, Li S, Eisner W, Brooks ED, Bacon R, Koeberl DD
Mol Genet Metab
· 2026 Mar · PMID 41485391
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Systemically administered gene therapy is under development for the treatment of Pompe disease, an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. We evaluated recombinant AAV9 vec...Systemically administered gene therapy is under development for the treatment of Pompe disease, an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) deficiency. We evaluated recombinant AAV9 vectors expressing GAA driven by the minimal G6PC promoter (AAV9-G6PC.GAA) and by a hybrid CRM4-G6PC promoter (AAV9-MyoG6PC.GAA) and intravenously administered the vectors (1 × 10 vg/kg) to adult Gaa knockout (Gaa-KO) mice that were analyzed 3 or 12 weeks later. In the 3-week experiment, both AAV vector treatments led to significant increase in GAA activity in the liver, heart, quadriceps, gastrocnemius, and diaphragm. The AAV9-MyoG6PC.GAA treated mice had significantly higher GAA activities in the heart and limb muscles than the AAV9-G6PC.GAA treated mice. Both AAV9-G6PC.GAA and AAV9-MyoG6PC.GAA vectors significantly cleared glycogen accumulation in the heart, quadriceps, gastrocnemius, and diaphragm. AAV9-G6PC.GAA-treated mice had slightly decreased glycogen content in the brain, in comparison with untreated mice. AAV9-MyoG6PC.GAA was further evaluated in a 12-week study. GAA activities were significantly increased in the liver, heart, and skeletal muscles of AAV9-MyoG6PC.GAA-treated mice. Glycogen contents were significantly decreased by the AAV9-MyoG6PC.GAA treatment in the heart and skeletal muscle of male mice, accompanied by the improvement of muscle functions in the grip strength test. However, female mice had an attenuated response with lower GAA activity and higher glycogen content in comparison with males, which correlated with lower plasma GAA activity. Anti-GAA antibody responses were not detected in any AAV-treated mice. In summary, adding a muscle enhancer to the G6PC minimal promoter that drives high-level GAA expression in liver increased efficacy in the heart and skeletal muscle without provoking antibody responses in Gaa-KO mice.
BACKGROUND: The use of omics technologies in the field of neurometabolic disorders (NMD) continues to grow each year. Genomics is most widely used, but metabolomics is a powerful, complementary tool emerging in this fiel...BACKGROUND: The use of omics technologies in the field of neurometabolic disorders (NMD) continues to grow each year. Genomics is most widely used, but metabolomics is a powerful, complementary tool emerging in this field. With this review, we aim to assess the usefulness of untargeted metabolomics in the identification of new biomarkers in pediatric NMD for understanding the pathophysiology and for diagnostics and therapeutic strategies. METHODS: We conducted a review of the literature of untargeted metabolomics used for the study of NMD with principal manifestations in pediatric age, analyzing a total of 168 published works. Of those, only 47 fulfilled eligibility criteria and were reviewed as full text. The following variables and outcomes were assessed: type of study, disease, sample material, number of patients involved, choice of controls, methods used for untargeted metabolomics, principal metabolic findings, and pathophysiological/clinical implications. RESULTS: Small molecule disorders were the predominant group, accounting for 47 % of the NMD studies. Almost all the studies (93 %) were based on MS-technology, confirming its technical versatility and superior performance for metabolomic investigations. The most impactful and frequent findings were the detection of new biomarkers (55 %) and recognition of new pathophysiological mechanisms in known diseases (62 %). CONCLUSIONS: Untargeted metabolomics is an unbiased and powerful tool in the field of NMD. Further technical improvements, larger databases and reduced analytical costs, combined with worldwide collaboration and standardization regarding preanalytical and analytical aspects, is expected to make this a cost-effective supplement to targeted analyses in the field of NMD. Are we finally entering the metabolomics era?
Levstek T, Breznik N, Balant Marin K
… +9 more, Podkrajšek T, Vujkovac B, Nowak A, Oliveira JP, Dostálová G, Linhart A, Šafaříková M, Altarescu G, Trebušak Podkrajšek K
Fabry disease is a rare, X-linked lysosomal storage disorder that often leads to progressive kidney dysfunction. Despite carrying the same pathogenic GLA variant, patients exhibit considerable variability in the onset an...Fabry disease is a rare, X-linked lysosomal storage disorder that often leads to progressive kidney dysfunction. Despite carrying the same pathogenic GLA variant, patients exhibit considerable variability in the onset and progression of Fabry nephropathy, suggesting the involvement of additional genetic modifiers. This study aimed to investigate the possible role of genetic polymorphisms in non-coding regions. A total of 284 patients with Fabry disease were included in the study and divided into two groups based on the progression of the kidney disease. Ten selected single nucleotide polymorphisms located in non-coding regions of podocyte-related genes were analyzed using quantitative PCR with TaqMan probes. The analysis revealed significant associations between specific genotypes and an increased risk of rapid progression of Fabry nephropathy. In particular, the rs9992101 and rs17319721 polymorphisms in the SHROOM3 gene were significantly associated with higher odds of accelerated kidney function decline. However, neither of these polymorphisms nor the polygenic risk scores were associated with conventional biomarkers of kidney disease. Our results suggest that non-coding genetic variants in podocyte-related genes may contribute to the phenotypic variability observed in Fabry nephropathy. The integration of such genetic biomarkers into clinical practice could improve early risk stratification, support more individualized patient monitoring, and facilitate therapeutic decision-making.