Molecular Genetics And Metabolism[JOURNAL]
Sun
200 papers
Inflammation and autophagy impairment in presymptomatic pediatric patients with Fabry disease identified by newborn screening.
Gragnaniello V, Burlina AP, Cazzorla C … +5 more , Loro C, Gueraldi D, Porcù E, Salviati L, Burlina AB
Mol Genet Metab · 2026 Jun · PMID 41875760 · Publisher ↗
BACKGROUND: Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of α-galactosidase A. Although the accumulation of glycosphingolipids occurs very early, clinical manifestations are often delayed. Li...
BACKGROUND: Fabry disease (FD) is a lysosomal storage disorder caused by a deficiency of α-galactosidase A. Although the accumulation of glycosphingolipids occurs very early, clinical manifestations are often delayed. Little is known about the cellular changes that occur in the presymptomatic phase and may progressively cause damage. To this aim, we evaluated inflammatory markers, cellular stress, and autophagy in presymptomatic pediatric patients with FD identified through newborn screening. METHODS: We conducted a cross-sectional study of 12 male presymptomatic FD patients with a mean age of 3.11 years. We measured plasma cytokine levels (IL1β, TNFα, and IL6) by ELISA. In six patients we also analyzed cellular stress (p-p38) and autophagy markers (LC3, Beclin, Atg3, Atg5, Atg7, Atg12, and Atg16L) by Western blot in peripheral blood mononuclear cells. RESULTS: We observed elevated levels of IL1β and TNFα in 10/12 and 11/12 patients, respectively. P-p38 activation increased by an average of 1.31-fold (SD 1) compared to controls. Autophagy markers showed significant reductions, with LC3-II levels decreasing by an average of 53% (SD 54%). Upstream autophagy mediators (Beclin, Atg3, Atg5, Atg7, Atg12, and Atg16L) were also reduced. CONCLUSIONS: This study is the first to demonstrate the presence of inflammation and autophagy inhibition in pediatric presymptomatic FD patients. These findings provide new insights into the early pathogenesis of FD and suggest potential biomarkers for disease progression.
Efficacy of JAK1/2 inhibitors in AGS genes-related interferonopathies: A multicenter retrospective observational study with treated vs untreated comparison.
Marinella G, Vaia Y, Politano D … +28 more , Galli J, Nicita F, Popple MM, Pichiecchio A, Pasquariello R, Parazzini C, Pinelli L, Longo D, Severino M, Fazzi E, Orcesi S, Tonduti D, Battini R, AGS Study Group, Orsini A, Zunica F, Arrigoni F, Nicolosi S, Insalaco A, Cattalini M, Cordelli DM, Soliani L, Fetta A, Operto FF, Amadori E, Mancardi MM, Volpi S, Orsi SM
Mol Genet Metab · 2026 Jun · PMID 41871482 · Publisher ↗
Aicardi-Goutières syndrome (AGS) and genes-related interferonopathies are a group of multisystem disorders involving the central nervous system, caused by pathogenic variants in genes regulating nucleic acid metabolism a...
Aicardi-Goutières syndrome (AGS) and genes-related interferonopathies are a group of multisystem disorders involving the central nervous system, caused by pathogenic variants in genes regulating nucleic acid metabolism and type I interferon signaling, leading to chronic interferon overproduction. This retrospective multicenter study analyzed the efficacy and safety of Janus kinase 1/2 (JAK1/2) inhibitors in 12 patients treated with Baricitinib or Ruxolitinib, compared with 20 untreated patients. Treatment showed improvement in immunological and dermatological symptoms, while the impact on neurological manifestations was limited and heterogeneous, with greater benefits in patients with mild or intermediate phenotypes and earlier treatment initiation. Neuroroimaging analyses in untreated patients showed radiological improvements equal to or greater than those treated, raising doubts about the true impact of JAK 1/2 inhibitors on the neuroradiological course. Adverse events were rare and mild, confirming the favorable safety profile of this treatment. The results suggest that the pathogenetic complexity of AGS goes beyond the JAK-STAT pathway, highlighting the need for larger prospective studies to identify subgroups most likely to benefit from this therapeutic approach and to refine treatment strategies.
Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
van Kuilenburg ABP, Mandel H, Moady TA … +21 more , Sloma R, Fedida A, Leen R, Jansen-Meijer J, Paperna T, Sheffer VF, Dobritzsch D, Hochwald O, van der Wel NN, Grootemaat AE, Chulsky S, Rootman MS, Eran A, Yousef MA, Dinwiddie A, Manor J, Van Karnebeek CDM, Kalfon L, Hershkovitz T, Tal G, Falik Zaccai TC
Mol Genet Metab · 2026 Jun · PMID 41865506 · Publisher ↗
Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy. We...
Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy. We describe three infants from two unrelated families who presented clinically with neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure, progressing to either a persistent vegetative state or early death. One patient remains alive at the age of six years. Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range. Notably, brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects. Exome sequencing identified a homozygous, unreported missense variant in GLS (NM_014905.5:c.1174G > A; p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant (NM_014905.5:c.1031 T > C; p.Leu344Pro) in the proband from family 2. Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency. In addition, patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired mitochondrial respiratory function. The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and/or urea cycle defects.
Alglucosidase alfa demonstrates effectiveness and safety in Chinese patients with late-onset Pompe disease: A multi-center prospective study.
Li D, Jiao K, Yang H … +11 more , Ma M, Qiu W, Wang Z, Hu J, Qiu Z, Shang H, Li B, Wu W, Shen D, Zhu W, Zhao Y
Mol Genet Metab · 2026 Jun · PMID 41865505 · Publisher ↗
OBJECTIVE: Pompe disease is a rare, progressively debilitating lysosomal disorder. Enzyme replacement therapy (ERT) is an established treatment targeting the underlying enzyme deficiency. Alglucosidase alfa has shown ben...
OBJECTIVE: Pompe disease is a rare, progressively debilitating lysosomal disorder. Enzyme replacement therapy (ERT) is an established treatment targeting the underlying enzyme deficiency. Alglucosidase alfa has shown benefits in survival, ambulation, and respiratory function and was approved in China for both infantile-onset (IOPD)and late-onset Pompe disease (LOPD) in 2015.To assess the effectiveness and safety of 52-week Alglucosidase alfa treatment among Chinese patients with LOPD in a multicenter, single arm, open-label, prospective clinical study. METHODS: Forty-one eligible LOPD patients received Alglucosidase alfa infusions at 20 mg/kg every 2 weeks for 52 weeks. Primary endpoints included the six-minute walk test (6MWT), percentage of predicted forced vital capacity (FVC), and safety profile. Secondary endpoints encompassed manual muscle test (MMT), maximal inspiratory and expiratory pressure (MIP and MEP), Quick motor function test (QMFT) scores, and health-related quality of life (SF-12). RESULTS: After 52 weeks, the mean 6MWT distance significantly improved by 43.6 m (P = 0.0017). Although the mean percentage of predicted FVC improved by 2.4%, the difference was not statistically significant (P = 0.1424). MIP and MEP percentages improved, reaching maximal improvement at 38 weeks. Both MMT and QMFT scores demonstrated significant improvements, with increases of 2.5 points (P < 0.0001) and 5.6 points (P < 0.0001), respectively. PCS significantly improved by 3.8 points (P = 0.0039), while MCS improvement was not statistically significant. A total of 32 participants (78.0%) experienced 137 treatment-emergent adverse events (TEAEs). Most of these TEAEs were mild to moderate in severity and resolved without sequelae. CONCLUSIONS: Alglucosidase alfa demonstrated a positive benefit-risk profile in Chinese LOPD patients, confirming its safety and effectiveness.
Clinical-genetic features of the TBCE-related spectrum disorders: A focus on the childhood-onset neurodegenerative phenotype.
Sartorelli J, Sgobbi P, Battini R … +10 more , Schifino M, Trovato R, Compagnucci C, Lauri A, Tartaglia M, Sferra A, D'Amico A, Diodato D, Bertini E, Nicita F
Mol Genet Metab · 2026 Jun · PMID 41833177 · Publisher ↗
BACKGROUND: Tubulin-folding cofactor E (TBCE) plays a central role in tubulin heterodimer formation and disaggregation. Both TBCE biallelic and monoallelic pathogenic variants have been associated with human diseases inv...
BACKGROUND: Tubulin-folding cofactor E (TBCE) plays a central role in tubulin heterodimer formation and disaggregation. Both TBCE biallelic and monoallelic pathogenic variants have been associated with human diseases involving endocrine and/or neurologic system. This study aimed to expand current knowledge on the neurodegenerative phenotype associated with TBCE variants, and to explore possible genotype-phenotype correlations. METHODS: Subjects with a neurodegenerative syndrome caused by biallelic TBCE variants were recruited from three centers. Clinical, genetic, neuroimaging and neurophysiological data were collected retrospectively and, when available, longitudinally. A systematic literature review focusing on genotype-phenotype correlations was also performed. RESULTS: Thirteen subjects, including eight newly reported and five previously published, were enrolled. Data from 322 additional patients were available from systematic literature review, for a total of 335 TBCE mono- and biallelic patients. Sanjad-Sakati syndrome was the most frequent form (85%), while the neurodegenerative phenotype accounted for a minority (5%) of cases. TBCE-related neurodegeneration ranged from progressive spastic-ataxic tetraparesis, optic atrophy and distal motor axonal neuropathy, consistent with already named PEAMO (progressive encephalopathy with amyotrophy and optic atrophy) to milder complex spastic paraparesis. Brain imaging often revealed progressive thinning of the corpus callosum, cerebro-cerebellar atrophy, white matter abnormalities and possible iron accumulation in deep grey matter structures. Additional relevant features included scoliosis, respiratory and gastrointestinal dysfunctions. Genotype-phenotype correlation and a distinct geographic distribution were identified across phenotypes. CONCLUSION: Pathogenic biallelic TBCE variants present phenotypic heterogeneity, with at least four different phenotypes, with genotype-phenotype correlation. TBCE-related neurodegeneration is a severe multisystem disorder that requires multidisciplinary management.
TTC19-related mitochondrial complex III deficiency: Clinical and genetic characterization of 10 patients from 5 unrelated Arab families.
Alghamdi M, Alahmad A, Alaboudi M … +17 more , Alsheikh S, Alanazy MH, Albash B, Alaqeel A, Almontashiri NA, Jamjoom D, Bashiri FA, Hamad MH, Ali HH, Alwatidi M, Alharbi E, Omar S, Marafi D, Alabdulrazzaq F, Arold ST, McFarland R, W Taylor R
Mol Genet Metab · 2026 Jun · PMID 41818954 · Publisher ↗
Isolated mitochondrial complex III deficiency can result from pathogenic variants in several nuclear or mitochondrial genes, encoding structural subunits or assembly factors of the enzyme. It is a rare cause of mitochond...
Isolated mitochondrial complex III deficiency can result from pathogenic variants in several nuclear or mitochondrial genes, encoding structural subunits or assembly factors of the enzyme. It is a rare cause of mitochondrial phenotypes with clinically heterogeneous presentations. Pathogenic variants in the Tetratricopeptide Repeat Domain 19 (TTC19) gene have been identified as a cause of mitochondrial complex III deficiency, nuclear type 2 (MIM #615157). We report 10 patients from five unrelated Arab families, all presenting with variable severity of a progressive neurodegenerative disorder characterized by loss of ambulation, speech impairment, and cognitive regression. Long-term clinical follow-up, supported by serial neuroradiological imaging, demonstrated progressive disease evolution, further highlighting the degenerative nature of the condition. In this cohort, exome sequencing (ES) identified three distinct pathogenic variants in the TTC19 gene across the five unrelated families, highlighting both genetic heterogeneity and regional clustering. In a Saudi family, A novel in-frame TTC19 variant NM_017775.4:c.680_709del; p.(Glu227_Leu236del) was identified, resulting in the loss of 10 amino acids in the protein. The second variant, NM_017775.4:c.779_780del; p.(Tyr260*), is a frameshift deletion leading to truncation of the TTC19 protein. This recurrent variant was identified in three independent Syrian families (Families 2, 3, and 4). The third variant, NM_017775.4:c.153_156del; p.(Arg52Alafs*48), also a frameshift variant, was detected in a fifth family of Kuwaiti origin. These loss of function TTC19 variants are proposed to underlie the observed phenotypes, as supported by mitochondrial functional studies, and contribute to the expanding spectrum of TTC19-related disorders, with specific variants recurring in particular regional or ethnic populations.
Repurposing Gaucher disease therapy for Saposin C deficiency: Proof-of-concept with eliglustat.
Minea C, Deegan PB
Mol Genet Metab · 2026 Jun · PMID 41812503 · Full text
Saposin C (Sap C) deficiency (GDSAPC, OMIM #610539, ORPHA:309252) is an ultra-rare autosomal recessive disorder caused by mutations in the PSAP gene. Sap C functions as an essential activating cofactor of glucosylceramid...
Saposin C (Sap C) deficiency (GDSAPC, OMIM #610539, ORPHA:309252) is an ultra-rare autosomal recessive disorder caused by mutations in the PSAP gene. Sap C functions as an essential activating cofactor of glucosylceramidase (GCase) and facilitates the degradation of glucosylceramide in the lysosome. In the absence of its activator, GCase is structurally intact but its function is impaired, leading to pathological accumulation of glucosylceramide in the lysosome. Sap C deficiency resembles another rare autosomal recessive disorder, Gaucher disease (GD), in which pathogenic variants in the GBA1 gene result in GCase deficiency and accumulation of glucosylceramide within the lysosomal compartment of the mononuclear phagocyte system. Despite the overlapping clinical features of Sap C and GD, the therapeutic implication is utterly different. To date, no specific therapy is approved for Sap C deficiency. Enzyme replacement therapy (ERT), highly effective in GD is biologically implausible in Sap C deficiency, where the GCase structure is normal but lacks its essential activator for its functions. In GD, substrate reduction therapy (SRT) is an alternative to ERT by limiting the synthesis of glucosylceramide through inhibition of glucosylceramide synthase. Given that substrate accumulation is the common pathological consequence in both GD and Sap C deficiency, we hypothesized that SRT with Eliglustat, a potent glucosylceramide synthase inhibitor, could also benefit patients with Sap C deficiency. We describe the first documented therapeutic attempt using eliglustat in Sap C deficiency. A 47-year-old patient with PSAP mutations causing Sap C deficiency who presented with features similar to those seen in GD, has received Eliglustat over the course of 9 years, demonstrating an improvement in her hepatosplenomegaly, haematological parameters, biomarkers and bone density, providing proof-of-concept that Eliglustat can be of benefit when the GCase cofactor is deficient. However, no improvement was observed in the patient's seizure activity where future brain penetrant molecules may be of benefit.
Development and validation of a clinical severity score for long-chain fatty acid oxidation disorders using Real-World-Evidence from Canada.
Sultan R, Ambrose A, Bahl S … +7 more , Hung C, Horvath G, Salvarinova R, Chan A, Jain-Ghai S, Vockley J, Mercimek-Andrews S
Mol Genet Metab · 2026 Jun · PMID 41812502 · Publisher ↗
INTRODUCTION: Mitochondrial long-chain fatty acid oxidation (LC-FAO) disorders (LC-FAOD) are inherited metabolic disorders. Real-World-Data (RWD) contributes to Real-World-Evidence (RWE) for LC-FAOD, as prospective natur...
INTRODUCTION: Mitochondrial long-chain fatty acid oxidation (LC-FAO) disorders (LC-FAOD) are inherited metabolic disorders. Real-World-Data (RWD) contributes to Real-World-Evidence (RWE) for LC-FAOD, as prospective natural history studies are difficult due to their incidence of ∼1:10,000. MATERIAL AND METHODS: We generated a RWD and developed and validated a clinical severity score. RESULTS: 38 patients were included in our RWD (VLCAD n = 7; LCHAD n = 6; CACT n = 3; MAD n = 1; CPT-I n = 14; CPT-II n = 5 and CT n = 2 deficiencies). Our clinical severity score was applied to 14 patients by four independent raters (at the time of diagnosis and on treatment) and compared with an age- and sex-matched control group. Inter-rater reliability was excellent for scores at the time of diagnosis (ICC3k = 0.979 [95% CI: 0.975-0.981]) and on treatment (ICC3k = 0.942 [95% CI: 0.932-0.950]). Using k-means clustering, patients were stratified into mild (0-8), moderate (9- ≤ 14), and severe (≥15) categories. At the time of diagnosis scores were significantly higher compared with control group (p < 0.0001). DISCUSSION: Our study provides valuable new RWE with practical clinical applications for LC-FAOD including a RWD and development and validation of a clinical severity score for LC-FAOD. We think that our validated clinical severity score will help for precision therapies to improve patient outcomes in LC-FAOD. Application of our clinical severity score in more patients with LC-FAOD will allow its further validation.
Transaldolase deficiency - natural disease course towards adulthood.
Horvath VB, Tsiakas K, Brennenstuhl H … +10 more , Choukair D, Hammann N, Niesert M, Fichtner A, Prokisch H, Santer R, Wagner M, Hoffmann GF, Weis D, Lenz D
Mol Genet Metab · 2026 Jun · PMID 41806563 · Publisher ↗
Transaldolase deficiency is a rare metabolic disease caused by pathogenic variants in the TALDO1 gene. Transaldolase plays an important role in the ribose-5-phosphate production, maintaining the NADPH-dependent lipid bio...
Transaldolase deficiency is a rare metabolic disease caused by pathogenic variants in the TALDO1 gene. Transaldolase plays an important role in the ribose-5-phosphate production, maintaining the NADPH-dependent lipid biosynthesis and cellular redox homeostasis. A small number of patients, predominantly children, have been reported, with a wide range of phenotypic presentations, including liver and kidney disease, involvement of the hematopoietic and endocrine systems, as well as possible early death. We aim to provide further insight into the clinical progression of transaldolase deficiency in adolescence and adulthood. We report on three adult patients with genetically confirmed transaldolase deficiency, including two novel genetic variants in TALDO1. Although the patients have been symptomatic since newborn age, initially with hepatomegaly and cytopenias, they were only diagnosed during adolescence or adulthood. Genetic analysis was performed only at 17, 26, and 32 years, respectively, which, however, did not reveal any genetic variants that would be expected to cause a milder disease course. In adulthood, the dominant clinical features were hypergonadotropic hypogonadism, osteopenia, renal and hepatic involvement. In conclusion, when reporting three new adult cases and comparing them with 47 accessible cases from the literature, our findings suggest that, even if clinical manifestations begin in the neonatal period, the overall phenotype may remain relatively mild, with gradual progression. This means that patients presenting with otherwise unexplained progressive liver disease, kidney dysfunction, cytopenia, and hypergonadotropic hypogonadism should be tested for transaldolase deficiency. We recommend closely monitoring patients with known transaldolase deficiency regarding the above-mentioned problems.
The goal attainment scale in primary mitochondrial disease: Construct validity and lessons learned from a randomized controlled trial.
Leeuwenberg KE, IntHout J, Groothuis JT … +4 more , Cup E, Smeitink J, Mul K, Janssen MCH
Mol Genet Metab · 2026 Jun · PMID 41806562 · Publisher ↗
BACKGROUND: Primary mitochondrial diseases (PMD) are rare heterogeneous disorders caused by defective oxidative phosphorylation, with symptoms varying widely between individuals with PMD. Despite extensive research, no c...
BACKGROUND: Primary mitochondrial diseases (PMD) are rare heterogeneous disorders caused by defective oxidative phosphorylation, with symptoms varying widely between individuals with PMD. Despite extensive research, no consensus exists on outcome measures that adequately reflect function, activities, and participation for adults with mitochondrial diseases. The Goal Attainment Scale (GAS) offers a personalized, patient-centered way to capture these outcomes. However, its validity and standardized use in trials remain unclear. This study assessed GAS construct validity in a PMD trial, including comparison with the Canadian Occupational Performance Measure (COPM), and provides guidance for future application. METHODS: Data from a double-blind, randomized, placebo-controlled, exploratory Phase IIA cross-over trial on the safety and efficacy of sonlicromanol (KH176) in 18 adult m.3243 A>G patients, were retrospectively analyzed. GAS goals were categorized using the World Health Organization International Classification of Functioning, Disability and Health. Additional outcome measures with overlapping content were selected to evaluate GAS validity. Implementation quality was evaluated using 17 GAS appraisal criteria. RESULTS: Most goals addressed fatigue or lack of energy (85%, 22/26). GAS showed weak to moderate negative correlations with the Checklist Individual Strength (CC = -0.40) and Beck Depression Inventory-II scores (CC = -0.37), indicating higher GAS scores were associated with reductions in fatigue and depressive symptoms. Moderate correlations were observed between GAS and COPM scores (CC = 0.50-0.55). No significant correlations were found with the 6-min walk test, 36-item Short Form Health Survey or Newcastle Mitochondrial Disease Scale for Adults. Only 6 out of 17 (35%) implementation criteria were fully met. CONCLUSIONS: GAS demonstrated some construct validity in relation to fatigue and depressive symptoms, showed limited overlap with conventional outcome measures and suffered from suboptimal implementation. Although exploratory, these findings suggest GAS may capture patient-relevant change in individuals with PMD. To realize its potential, standardized methodology and further validation are essential for its use as a robust outcome measure in future PMD trials.
Design of a Pediatric Low Motor Function Item Battery in leukodystrophies.
Gavazzi F, Woidill S, Sevagamoorthy A … +13 more , Jawad AF, D'Aiello R, Bradford J, Lerner M, Hong P, White A, Tashnim Z, Cusack SV, Glanzman AM, Harrington A, Waldman AT, Vanderver A, Adang LA
Mol Genet Metab · 2026 Apr · PMID 41785524 · Publisher ↗
Leukodystrophies are rare genetic disorders that disrupt myelin formation in the central nervous system, leading to a broad range of neuromotor impairment. Standard assessment tools, including the Gross Motor Function Me...
Leukodystrophies are rare genetic disorders that disrupt myelin formation in the central nervous system, leading to a broad range of neuromotor impairment. Standard assessment tools, including the Gross Motor Function Measure-88 (GMFM-88), were designed to favor higher-level skills, like sitting and walking, with more limited sensitivity for earlier developmental skills. In populations where advanced gross motor skills can be profoundly limited, there is a critical need for sensitive clinical outcome assessments capable of detecting motor changes across the gross motor spectrum. This study describes the development and preliminary evaluation of the Pediatric Low Motor Function Item Battery (P-LoMo), designed to extend sensitivity into the lowest ranges of ability. Items were selected from validated assessments, including the Test of Infant Motor Performance, the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, the Bayley Scales of Infant and Toddler Development-4th Edition, the Mullen Scales of Early Learning, and the Early Clinical Assessment of Balance, through expert consensus. The P-LoMo and the GMFM-88 were administered to 168 leukodystrophy patients. Median GMFM-88 performance was 17.5%, with a skew to low performance (52% of scores within the bottom 20%). The P-LoMo median score was 71 out of 84 potential points. There was a strong correlation between assessments (Spearman's R = 0.94, p < 0.0001) across the total cohort as well as among individuals in the lowest register of performance on the GMFM-88 (Spearman's R = 0.90, p < 0.0001). The P-LoMo has the potential to improve our capacity to capture the full range of neurologic function for children with leukodystrophies and severe motor impairment. It provides a sensitive, feasible, and caregiver-aligned clinical outcome assessment. This tool has the potential to improve trial readiness, functional quantification, and evaluation of emerging therapies in pediatric populations with low motor function.
Management of pegvaliase-related skin concerns: best practice recommendations using a modified Delphi approach.
Ameijeiras AH, Vucko E, Harding CO … +7 more , Lah M, Muntau AC, Rovelli V, Thomas JA, Rose S, Lindstrom K, Sacharow S
Mol Genet Metab · 2026 Apr · PMID 41762598 · Publisher ↗
INTRODUCTION: The approval of pegvaliase (PALYNZIQ®) represented a paradigm shift in the management of phenylketonuria (PKU) by enabling sustained reductions in blood phenylalanine levels and permitting an unrestricted d...
INTRODUCTION: The approval of pegvaliase (PALYNZIQ®) represented a paradigm shift in the management of phenylketonuria (PKU) by enabling sustained reductions in blood phenylalanine levels and permitting an unrestricted diet. However, as it is a bacterially derived injectable therapy, individuals receiving pegvaliase may experience skin-related adverse events (AEs). Anticipating these AEs and other pegvaliase-related skin concerns and having best-practice strategies to manage them may be crucial to achieving optimal patient outcomes. METHODS: An expert panel comprising eight clinicians from the USA and Europe convened to develop best practice recommendations for managing pegvaliase-associated skin concerns. Employing a modified Delphi process, the panel generated 39 initial statements based on their clinical insights and results of a targeted literature review. These statements were refined over two phases of anonymous voting using a 10-point scale, with consensus predefined as ≥75% of panellists rating a statement ≥7. RESULTS: The Delphi process resulted in 18 consensus statements. These were organized into three themes: patient-centric recommendations/considerations; considerations for premedications and concomitant medications; and recommendations for monitoring. Key recommendations included comprehensive patient education to overcome needle phobia and promote self-injection; training on injection technique and rotation to reduce scar tissue formation; and the proactive use of premedications and as-needed concomitant medications to mitigate skin reactions. Recommendations also emphasize the importance of regular in-person follow-up to assess injection sites and monitor for scar tissue. Mean agreement scores ranged from 8.5 to 10, reflecting robust consensus among panel members. CONCLUSIONS: These internationally relevant, evidence-based recommendations provide a structured framework for managing pegvaliase-related skin concerns. Adoption of this guidance may enhance treatment adherence, mitigate adverse events, and ultimately improve patient outcomes.
Age-dependent reference intervals for cerebrospinal fluid and urine biomarkers of mucopolysaccharidoses.
Herber CB, Xiao S, Gho DS … +11 more , Meyer AL, Tsogtbaatar B, Suh JH, Fang M, Huntwork-Rodriguez S, Model F, Ireton K, Zhu Y, Saba JD, White KL, Bhalla A
Mol Genet Metab · 2026 Apr · PMID 41740537 · Publisher ↗
Mucopolysaccharidoses (MPSs) are characterized by deficient activity of lysosomal hydrolase enzymes, leading to progressive accumulation of glycosaminoglycans. These glycosaminoglycans can be assayed in biofluids as pote...
Mucopolysaccharidoses (MPSs) are characterized by deficient activity of lysosomal hydrolase enzymes, leading to progressive accumulation of glycosaminoglycans. These glycosaminoglycans can be assayed in biofluids as potential markers of disease severity and response to disease-modifying therapies. This study sought to calculate control reference intervals in a largely pediatric population for key MPS biomarkers: heparan sulfate (HS) and dermatan sulfate (DS) in cerebrospinal fluid (CSF) and urine, and CSF monosialic gangliosides GM2 and GM3. We also explored the effect of age on biomarker levels. Biomarker levels were measured using liquid chromatography-tandem mass spectrometry in CSF and urine samples from pediatric and young adult donors and were compared with baseline CSF and urine biomarker levels from an ongoing Phase 1/2 study of children with MPS II. Age-specific reference intervals were estimated for CSF HS, DS, and GM2, and for urine HS, DS, and the sum of HS and DS, after observing that levels of these markers decreased with age. CSF GM3 levels were not found to be age dependent, therefore a single reference interval was estimated for the reference population. In patients with MPS II, levels of HS and DS, respectively, were 6- and 7-fold higher in CSF, and 13- and 30-fold higher in urine than the upper reference interval limits. Establishing age-specific reference intervals will help to optimize biomarker use in clinical studies.
A founder variant in Tunisian PMM2-CDG patients: An integrated clinical, radiological, biochemical, and genetic study.
Kraoua L, Ben Younes T, El Asmi M … +11 more , Zioudi A, Klaa H, Miladi Z, Benrhouma H, Nagi S, Alglave S, Bruneel A, Lebredonchel E, Dupré T, Vuillaumier Barrot S, Kraoua I
Mol Genet Metab · 2026 Apr · PMID 41722273 · Publisher ↗
PMM2-CDG is the most common congenital disorder of glycosylation, characterized by a broad phenotypic spectrum involving the nervous system and multiple other organ systems. The disorder is caused by biallelic variants i...
PMM2-CDG is the most common congenital disorder of glycosylation, characterized by a broad phenotypic spectrum involving the nervous system and multiple other organ systems. The disorder is caused by biallelic variants in the PMM2 gene, leading to impaired glycosylation of proteins. Our objective was to provide a detailed clinical characterization and define the mutational spectrum of PMM2-CDG in the Tunisian population. We conducted a retrospective study on patients with genetically confirmed PMM2-CDG, followed between 2005 and 2024. Ten patients from six unrelated Tunisian families were enrolled. All presented with neurological symptoms, including psychomotor delay (10/10), cerebellar ataxia (9/10) and strabismus (9/10). Brain MRI revealed cerebellar atrophy in all patients. Dysmorphic features were common including almond-shaped eyes (9/10), large mouth (6/10), and thin upper lip (6/10). Skeletal anomalies were observed in 9/10 patients. Peripheral neuropathy was confirmed in 6/7 patients. Laboratory analyses revealed elevated transaminases (6/10), hypocholesterolemia (7/10), elevated LDH (7/10), hypoalbuminemia (2/6), and IgA deficiency (3/5). Renal anomalies included hyperechogenicity (2/9) and a duplicated collecting system (1/9). Genetic analysis revealed a homozygous variant NM_000303.3(PMM2): c.395 T > C; p.(Ile132Thr) in all patients. Haplotype analysis of the PMM2 locus showed that all 6 families shared an identical allele. In conclusion, this is the first study to characterize the clinical and genetic profile of PMM2-CDG in the Tunisian population. Despite a shared genotype, patients exhibited moderate neurological phenotypes with inter- and intrafamilial variability. The recurrent homozygous c.395 T > C; p.(Ile132Thr) variant and identical haplotype confirm a founder effect in the Tunisian population.
Lessons from late-onset Pompe disease identified by Newborn screening: A systematic review.
Boueri M, Doxey J, Boggs T … +4 more , Case LE, Nading E, Young SP, Kishnani PS
Mol Genet Metab · 2026 Apr · PMID 41719911 · Publisher ↗
CONTEXT: Late-onset Pompe disease (LOPD) is a lysosomal disease characterized by progressive weakness primarily in skeletal and respiratory muscles with symptom onset ranging from infancy to adulthood. The distinguishing...
CONTEXT: Late-onset Pompe disease (LOPD) is a lysosomal disease characterized by progressive weakness primarily in skeletal and respiratory muscles with symptom onset ranging from infancy to adulthood. The distinguishing feature between infantile-onset Pompe disease (IOPD) and LOPD is the absence of cardiomyopathy in the first year of life in LOPD. Newborn screening (NBS) has facilitated earlier detection, revealing an earlier disease spectrum than previously understood. OBJECTIVE: To systematically review NBS data from countries with published long-term follow-up, specifically Taiwan and the United States, focusing on clinical manifestations, genotypes, biomarkers, treatments, and follow-up data of LOPD. DATA SOURCES: A systematic search of PubMed was conducted up to January 2026 using the terms "Pompe disease," "late-onset Pompe disease," and "newborn screening." STUDY SELECTION: Studies were included if they reported individuals diagnosed with LOPD through NBS. Exclusion criteria included non-English articles and studies limited to infantile-onset Pompe disease. DATA EXTRACTION: 18 studies were included. Data extracted included genotype, biomarkers, muscle imaging, enzyme replacement therapy (ERT) status, and outcomes. Given the descriptive nature of the included studies, no risk of bias assessment was applied. RESULTS: Results were synthesized narratively due to heterogeneity in outcome reporting. In Taiwan, the common splice site variant c.-32-13 T > G (IVS1) in GAA was not observed, whereas IVS1 homozygosity was frequent in U.S. cohorts and generally associated with milder phenotypes. Individuals who were compound heterozygous for the IVS1 variant and a second pathogenic GAA variant demonstrated more variable presentations, with some exhibiting elevated biomarkers and early motor signs. In Taiwan, 21% (8/39 cases) initiated ERT between 1.6 months and 3 years, representing the only population-level data with longer-term follow-up to date. In the United States, early post-NBS clinical experience has been reported, including a case series describing infants with LOPD who initiated ERT following identification by NBS, as well as a case series describing symptomatic infants also identified by NBS harboring the IVS1 variant in trans with a second pathogenic variant who demonstrated biochemical and motor improvement following early ERT initiation. While many NBS-identified individuals who did not meet criteria for early treatment remained clinically stable under surveillance, emerging evidence suggests that a subset of infants with early biochemical and functional abnormalities may benefit from timely initiation of ERT. LIMITATIONS: Heterogeneous follow-up, lack of unified diagnostic criteria, and limited long-term data. CONCLUSIONS: NBS has expanded our understanding of emerging phenotypes that were not previously recognized. Future efforts should prioritize long term follow-up, phenotyping, and clearer ERT initiation guidelines. No datasets were created or analyzed for this study.
From genotype to outcome: Zygosity-specific insights in 63 cases of CLPB-related mitochondrial disease.
Heath O, Del Caño-Ochoa F, Baris S … +25 more , Carrozzo R, Coman D, Distelmaier F, Ellaway C, Feichtinger RG, Finocchi A, Guerrero-Castillo S, Halligan R, Hannibal I, Kritzer A, Lichter-Konecki U, Merkevicius K, Panis B, Pitceathly RDS, Pizzamiglio C, Iwanicka-Pronicka K, Rahman S, Seltzer L, Siepermann M, Tal G, Wevers RA, Ziętkiewicz S, Ramón-Maiques S, Mayr JA, Wortmann SB
Mol Genet Metab · 2026 Apr · PMID 41719910 · Publisher ↗
BACKGROUND: CLPB-related mitochondrial disease causes congenital neutropenia, developmental delay/intellectual disability, progressive brain atrophy, movement disorders, cataracts, and 3-methylglutaconic aciduria. Both m...
BACKGROUND: CLPB-related mitochondrial disease causes congenital neutropenia, developmental delay/intellectual disability, progressive brain atrophy, movement disorders, cataracts, and 3-methylglutaconic aciduria. Both monoallelic and biallelic forms exist. This retrospective cohort study compared clinical outcomes and genotype-structure-phenotype correlations across zygosity groups. METHODS: Sixty-three individuals (41 biallelic, 22 monoallelic; 6 unpublished) with disease-causing CLPB variants were identified via literature review and a multicenter survey. In silico modeling assessed structural impact. A modified CLPB Disease Burden Index (DBI) quantified severity. RESULTS: Median age at last follow-up was 4.0 years (IQR: 0.25-12.6) in biallelic and 12.0 years (IQR: 5.3-21.0) in monoallelic cases. Death occurred in 66% of biallelic and 23% of monoallelic individuals, with earlier median age at death in biallelic cases (6 months vs 2.4 years). Biallelic cases had significantly higher DBI scores and poorer survival (4-year survival: 50% vs 82%). Stop/stop genotypes were associated with greater disease burden than missense combinations. Structural predictions-particularly variants causing nonsense-mediated decay or ankyrin domain disruption-were stronger survival predictors than zygosity or age of onset. Early-onset disease (<12 months) correlated with more severe progression. Later onset often resulted in milder phenotypes. Hematologic and neurologic features overlapped across zygosity; cataracts and dystonia were more common in biallelic cases. Milestone attainment was poor, with <50% walking or speaking, and only 10-20% doing so on time. Four monoallelic patients received hematopoietic stem cell transplants with mixed outcomes. Granulocyte colony-stimulating factor was associated with improved survival. CONCLUSIONS: This is the largest cohort study to date comparing biallelic and monoallelic CLPB deficiency. Structural variant impact-particularly ankyrin domain disruption-emerged as a key prognostic factor.
Albumin as a glycoprotein biomarker in congenital disorders of glycosylation.
Garapati K, Jain A, Joshi N … +8 more , Sachdeva GS, Nam D, Saraswat M, Pasupuleti RR, Schultz MJ, Kozicz T, Morava E, Pandey A
Mol Genet Metab · 2026 Apr · PMID 41713138 · Full text
Congenital disorders of glycosylation (CDG) are rare inherited disorders resulting from defects in cellular glycosylation machinery. Albumin has recently been shown to be N-glycosylated at two non-canonical glycosylation...
Congenital disorders of glycosylation (CDG) are rare inherited disorders resulting from defects in cellular glycosylation machinery. Albumin has recently been shown to be N-glycosylated at two non-canonical glycosylation sites. We applied multiplexed mass spectrometry-based glycoproteomics to identify site-specific N-glycosylation alterations in albumin from patients with PMM2-CDG, MPI-CDG, SRD5A3-CDG, MAN1B1-CDG and PGM1-CDG. Our findings demonstrate that the glycosylation of albumin is indeed affected in CDG and indicate a potential role for albumin-derived glycopeptides as diagnostic biomarkers.
Whole genome sequencing from dried blood spots for newborn screening of Menkes disease and 36 other actionable inherited neurometabolic disorders.
Kaler SG, Venkataraman L, Pham MT … +3 more , Kennedy BJ, Marhabaie M, Koboldt DC
Mol Genet Metab · 2026 Mar · PMID 41687279 · Publisher ↗
Tandem mass spectrometry is currently used by the Ohio Department of Health to screen newborn infants for 36 medically actionable inborn errors of metabolism. As a complementary test for infants with abnormal biochemical...
Tandem mass spectrometry is currently used by the Ohio Department of Health to screen newborn infants for 36 medically actionable inborn errors of metabolism. As a complementary test for infants with abnormal biochemical screens, whole genome sequencing (WGS) theoretically could reduce false-positive results, facilitate timely case resolution and, in some instances, indicate a more specific diagnosis than obtained initially. Menkes disease is a X-linked recessive disorder of human copper metabolism with a predicted minimum birth prevalence of 1 in 34,810 live male births. Recent progress in treatment options for Menkes heighten the importance of newborn screening (NBS) to identify this illness within the window of therapeutic opportunity, the first 4 to 6 weeks of life. We developed a DNA extraction protocol from dried blood spots that yielded high quality DNA for whole genome sequencing and studied 24 subjects with known ATP7A variants. Analysis was confined to genes (n = 55) for neurometabolic conditions currently screened for in Ohio (n = 36) plus ATP7A (Menkes disease). WGS detected all ATP7A variants including 7 missense, 5 splice site, 4 copy number variants, 4 nonsense, 3 indels, and 1 missense/splice site. WGS also detected 5 heterozygous pathogenic variants in 5 genes that encode conditions for which Ohio screens. Our results confirm the feasibility and reliability of this approach for early Menkes disease detection and to complement tandem mass spectroscopy for detection of other actionable inherited disorders.
Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.
Barca E, Jacoby N, Naini A … +6 more , Miller ML, Emmanuele V, Winfree CJ, Tadesse S, Tanji K, Hirano M
Mol Genet Metab · 2026 Mar · PMID 41679129 · Publisher ↗
Rhabdomyolysis can be due to mitochondrial myopathy, but mitochondrial DNA (mtDNA) pathogenic variants are often overlooked in standard genetic panels. We report a 41-year-old woman with recurrent rhabdomyolysis due to a...
Rhabdomyolysis can be due to mitochondrial myopathy, but mitochondrial DNA (mtDNA) pathogenic variants are often overlooked in standard genetic panels. We report a 41-year-old woman with recurrent rhabdomyolysis due to a novel MT-CO3 variant. Muscle biopsy showed cytochrome c oxidase-negative fibers that segregated with high heteroplasmic load on single-fiber. We additionally review previously reported mtDNA variants associated with rhabdomyolysis, highlighting the diagnostic relevance of mtDNA analysis and tissue-specific testing in unexplained rhabdomyolysis.
A novel patient-Centered approach to clinical trial readiness in rare diseases: Application in Aicardi-Goutières Syndrome (AGS).
Sevagamoorthy A, Gavazzi F, Tashnim Z … +27 more , Hong P, Vaia Y, Lee-Kirsch MA, Eleftheriou D, Beerepoot S, Hully M, Berry Kravis EM, Ventola P, Raspa M, Wheeler A, DeMauro SB, Glanzman AM, Townsend E, Duong T, Cusack S, Harrington AT, Pierce S, Fitzgerald M, Fazzi E, Galli J, Orcesi S, Tonduti D, Wassmer E, Cordova D, Adang LA, Butts C, Vanderver A
Mol Genet Metab · 2026 Mar · PMID 41671914 · Full text
INTRODUCTION: Aicardi-Goutières Syndrome (AGS) is a genetic type 1 interferonopathy that causes white matter abnormalities and intracranial calcifications, resulting in varying degrees of neurologic impairment and system...
INTRODUCTION: Aicardi-Goutières Syndrome (AGS) is a genetic type 1 interferonopathy that causes white matter abnormalities and intracranial calcifications, resulting in varying degrees of neurologic impairment and systemic manifestations. Novel disease-modifying therapies for AGS are forthcoming. The 2022 Food and Drug Administration guidance, "Patient-Focused Drug Development" (PFDD), emphasizes the importance of including patients' voices early in the design of clinical trials. This represents an urgent unmet need in rare disease research. In this study, we propose and pilot a new methodology to identify patient-centered Concepts of Interest (COIs) and suitable Clinical Outcome Assessments (COAs) for clinical trials. METHODS: The study was performed under the Myelin Disease Biorepository Project within the Global Leukodystrophy Initiative Clinical Trial Network. A sequential multicomponent approach, piloted in AGS, was designed to (i) identify COIs, (ii) select COAs capable of measuring the COIs through expert consensus, and (iii) assess the feasibility of COA application. Experts were identified based on relevant scientific publications and expertise in AGS (disease experts for COI) and/or their application of relevant COAs (outcome experts for COA). Expert consensus was achieved using the modified eDelphi approach for COIs, expertise-specific multi-panel focus group discussions, and pre-and post-surveys for COA selection. Consensus was defined as ≥70% agreement among the experts. This was followed by a virtual stakeholder discussion with patients and/or patient representatives to assess the feasibility of the COA application in the context of a clinical trial. RESULTS: Based on the health priorities identified by patient caregivers, the proposed approach revealed a set of fit-for-purpose COIs across the motor, adaptive behavior, and neurologic functional domains. All experts acknowledged the significance of each caregiver-identified priority but expressed differing opinions on the likelihood of observing changes in the functional domain within a 6- to 12-month timeframe. Following this, a consensus-building approach for COA selection for each identified COI resulted in a paired COI-COA panel applicable to future AGS clinical trials. Finally, the discussion on the feasibility of application of the selected COAs with the patients and/or patient representatives elicited critical information to design a patient-centered prospective COA protocol, applicable to clinical trials and natural history studies. DISCUSSION: The proposed approach marks the first step toward a patient-centered clinical trial design for rare diseases. It establishes a paired COI-COA panel, as well as informs the design of a patient-centered prospective COA protocol for upcoming AGS clinical trials and natural history studies. Additionally, the identified COA panel facilitates the creation of a multicomponent endpoint for clinical trials, which is especially crucial in phenotypically diverse disorders like AGS. This approach is widely applicable across leukodystrophies and rare diseases.
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