Molecular Genetics And Metabolism[JOURNAL]
Sun
200 papers
Elevated cerebrospinal fluid 2-Hydroxybutyric acid in two siblings with aspartate-glutamate carrier 1 deficiency.
Urquiza N, Partikian A, Bluml S … +5 more , Saitsu H, Matsumoto N, Griffith LW, McGowan R, Yano S
Mol Genet Metab · 2026 Jan · PMID 41475179 · Publisher ↗
The mitochondrial aspartate-glutamate carrier 1 (AGC1 or aralar) is a key component of the malate-aspartate shuttle (MAS), which transfers NADH-derived reducing equivalents from the cytosol into mitochondria to support o...
The mitochondrial aspartate-glutamate carrier 1 (AGC1 or aralar) is a key component of the malate-aspartate shuttle (MAS), which transfers NADH-derived reducing equivalents from the cytosol into mitochondria to support oxidative phosphorylation. Disruption of MAS leads to cytosolic NADH accumulation, NAD depletion, and a reduced NAD/NADH ratio, impairing redox-sensitive enzymes. AGC1 is primarily expressed in the central nervous system. AGC1 deficiency is a rare autosomal recessive disorder characterized by seizures, intellectual disability, and hypomyelination. The disorder impairs mitochondrial export of aspartate, thereby reducing neuronal synthesis of N-acetylaspartate (NAA), which is essential for myelination by oligodendrocytes. Consequently, hypomyelination is noted on MRI, and NAA appears decreased on MR spectroscopy (MRS). CASE STUDY: Two Hispanic male siblings (now 21y and 17y) with a homozygous SLC25A12 mutation (p.Gly398Val) presented with seizures, intellectual disability, hypotonic-ataxic cerebral palsy, and characteristic MRI/MRS findings. Their diagnosis was confirmed by whole exome sequencing when they were 9 and 4 years old, respectively. MRI showed cerebral atrophy and cortical dysplasia. MRS showed diffuse reduction in NAA and a consistent but unknown signal at 3.62 ppm. Aspartate supplementation did not result in any clinical or imaging improvement. Subsequently, both were treated with a modified Atkins/ketogenic diet with MCT oil in addition to antiseizure medications for eight years, with inconsistent dietary adherence. The elder brother has remained stable with some developmental progress, while the younger brother recently experienced mild regression following a period of developmental stability. Follow-up imaging showed no significant change. CSF organic acid analysis revealed elevated 2OH-butyrate, lactate, pyruvate, and acetoacetate, with low levels of glycolate, glyoxylate, and 5-oxoproline. Both brothers exhibited a marked preference for high-protein foods and an aversion to sweets from early childhood, mirroring dietary patterns commonly observed in citrin deficiency. DISCUSSION: We describe the two oldest known individuals with AGC1 deficiency. Their neuroimaging results remained largely stable over eight years of ketogenic therapy. The elder sibling showed modest progress, while the younger regressed in some motor milestones at age 16. Although blood and urine metabolomics were non-diagnostic, CSF organic acids revealed patterns suggestive of impaired redox balance, supporting mitochondrial dysfunction as a key feature of AGC1 deficiency.
The acylcarnitine profile in patients with PKAN may mimic CPT1 deficiency.
Yılmaz-Gümüş E, Genç E, Kılavuz S … +6 more , Öztürk G, Erdin S, Ömercikoğlu-Özden H, Türkdoğan D, Günal D, Öztürk-Hişmi B
Mol Genet Metab · 2026 Jan · PMID 41475178 · Publisher ↗
BACKGROUND: Coenzyme A (CoA), synthesized from pantothenate, is an essential cofactor required for numerous pivotal enzymatic reactions. Abnormal acylcarnitine profiles similar to those observed in carnitine palmitoyltra...
BACKGROUND: Coenzyme A (CoA), synthesized from pantothenate, is an essential cofactor required for numerous pivotal enzymatic reactions. Abnormal acylcarnitine profiles similar to those observed in carnitine palmitoyltransferase 1 (CPT1) deficiency have been reported in patients with coenzyme A synthetase (COASY)-related diseases and phosphopantothenoylcysteine synthetase (PPCS) deficiency. To the best our knowledge, a CPT1-like acylcarnitine profile has not yet been reported in patients with pantothenate kinase-associated neurodegeneration (PKAN). We aimed to evaluate whether the acylcarnitine profile could serve as a diagnostic clue for PKAN. METHODS: All patients diagnosed with PKAN and followed at our center were included in the study. Clinical, biochemical, and genetic data were retrospectively extracted from medical records. RESULTS: The study cohort comprised five patients from five unrelated families. Three patients presented with classic PKAN, while two had atypical PKAN. CPT1-like acylcarnitine profiles were detected in patients with classic PKAN. Two patients exhibited elevated C0 and C0/(C16+C18) ratios; in one case, these values returned to normal during follow-up. In the third patient, only the C0/(C16 + C18) ratio was elevated, while C0 remained within the normal range. Different genetic variants were detected in our patients. CONCLUSION: Elevated C0 and/or elevated C0/(C16 + C18) ratio may serve as a diagnostic clue for PKAN, similar to other inherited disorders of CoA biosynthesis.
Dietetic guidance for nutritional management of people with phenylketonuria receiving sepiapterin.
MacDonald A, Ahring K, Bledsoe A … +11 more , Fujimoto H, Giorda S, Kogelmann C, Kopesky J, Nagy L, O'Neill S, Pinto A, Poloni S, Roberts P, van Wegberg AMJ, Hollander S
Mol Genet Metab · 2026 Jan · PMID 41442848 · Publisher ↗
BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism. If untreated, elevated blood phenylalanine (Phe) levels lead to neurological and behavioral impairments. Phe levels can b...
BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism. If untreated, elevated blood phenylalanine (Phe) levels lead to neurological and behavioral impairments. Phe levels can be managed through a lifelong Phe-restricted diet; however, this can be challenging to maintain. Sepiapterin is an adjunct therapy for PKU that has shown efficacy in reducing blood Phe levels in both tetrahydrobiopterin (BH)-responsive and BH-non-responsive people with PKU in clinical trials. Practical guidance is needed for dietitians and other healthcare professionals supporting the dietary management of people with PKU who are initiating or receiving sepiapterin. METHODS: A group of international dietitians participated in a questionnaire, virtual meeting, and series of online sessions to develop globally applicable consensus recommendations to support individuals with PKU who are initiating or receiving sepiapterin treatment. RESULTS: The expert consensus group has issued 32 recommendations on using sepiapterin in PKU, covering the following topics: preparation, administration, response evaluation, dietary liberalization, protein substitute adjustment, healthy food choices, illness management, and if necessary, treatment cessation. These statements provide a framework to standardize care, clarify therapeutic effectiveness, guide natural protein escalation, reduce low-Phe protein substitutes, and maintain nutritional adequacy. By integrating pharmacological and dietary approaches, the guidance promotes equitable access, supports informed resource allocation, and reinforces the importance of patient-friendly education and ongoing monitoring. CONCLUSIONS: This guidance is intended to inform clinical practice and foster consistency in the use of sepiapterin for individuals with PKU. The recommendations should evolve as new scientific evidence and growing clinical experience continue to shape best practice.
Neurological and psychiatric issues in 187 adults with early-treated PKU: The ECOPHEN study.
Giret C, Charrière S, Feillet F … +20 more , Fouilhoux A, Astudillo L, Lavigne C, Arnoux JB, Odent S, Gay C, Schiff M, Mazodier K, Kuster A, Rigalleau V, Thauvin C, Leguy-Seguin V, Lêvesque H, Sacaze E, Besson G, Thoreau B, Le Gouge A, Gissot V, Douillard C, Maillot F
Mol Genet Metab · 2026 Jan · PMID 41421263 · Publisher ↗
INTRODUCTION: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene leading to phenylalanine hydroxylase deficiency. This results in the accumulation of phenylalanine (Phe) in blood...
INTRODUCTION: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene leading to phenylalanine hydroxylase deficiency. This results in the accumulation of phenylalanine (Phe) in blood and brain, causing neurological and psychiatric impairments if untreated. Newborn screening (NBS) introduced in the 1960s enables early PKU diagnosis, allowing prompt dietary or sapropterin treatment. The long-term outcomes in adults with early-treated PKU, however, may include subtle neurocognitive deficits alongside somatic neurological and psychiatric complications, which remain incompletely characterized. PATIENTS AND METHODS: The ECOPHEN study was a French 5-year multicenter prospective cohort assessing neuropsychiatric disorders in adults with early-treated PKU. RESULTS: Here are presented the data at inclusion. The study recruited 187 patients who were classified by PKU severity-classic, mild, or mild persistent hyperphenylalaninemia-and diet adherence status. Neurological history revealed symptoms in 11.2 % of patients, exclusively in classic PKU, including tremor, migraines, and balance disorders, without significant differences between diet groups. Neurological examination abnormalities predominantly included abnormal deep tendon reflexes in classic PKU patients. Psychiatric issues affected 25.7 % of patients across severity groups, mainly depressive episodes and anxiety, with no clear influence of diet adherence. DISCUSSION/CONCLUSION: The present study highlights neurological complications persisting despite early treatment, particularly in classic PKU. Diet adherence and current plasma Phe levels did not correlate significantly with neurological or psychiatric outcomes, possibly due to suboptimal metabolic control. Limitations included the cross-sectional design, absence of control group, and retrospective data collection. Overall, adults with early-treated PKU show a generally favorable outcome but remain at risk for neuropsychiatric manifestations, supporting the need for lifelong follow-up including neurologic and psychiatric evaluation.
Complementary and alternative medicines and cannabis use among individuals with erythropoietic protoporphyria.
Draisin E, Rome CP, Hedstrom K … +3 more , Overbey J, Balwani M, Naik H
Mol Genet Metab · 2026 Jan · PMID 41401659 · Full text
INTRODUCTION: Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) are rare, inherited disorders that present with severe cutaneous phototoxicity. Pain from phototoxic reactions does not respond to analg...
INTRODUCTION: Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) are rare, inherited disorders that present with severe cutaneous phototoxicity. Pain from phototoxic reactions does not respond to analgesics, and there is a need to identify therapies to address EPP-pain. Anecdotal reports from individuals with EPP indicate that cannabis may alleviate symptoms during phototoxic reactions. These reports warrant further systematic investigation. Therefore, this study aimed to explore how patients with EPP utilize cannabis and complementary and alternative medicines (CAM). MATERIALS & METHODS: A cross-sectional survey assessing the use of CAMs and cannabis in individuals with EPP and XLP was conducted. The survey included demographics, EPP/XLP symptoms, CAM use (the International CAM Questionnaire and Daily Session (I-CAM-Q)), and cannabis use (the Frequency, Age of Onset and Quantity of Cannabis Use Inventory (DFAQ-CU)). RESULTS: A total of 149 participants completed the survey. More than half of participants (62.9 %, 78/124) reported having used cannabis, either currently or in the past. Among the cannabis users, 12.9 % (9/70) reported using it only for EPP symptoms, 34.2 % (24/70) only recreationally, and 47.4 % (37/70) for both reasons. Individuals reported that cannabis mitigated anxieties around symptoms, though it was not perceived to directly reduce EPP-pain. Participants with more severe symptoms reported higher cannabis use. Few participants reported seeing a CAM provider for symptoms related to EPP, with most seeing providers to improve general well-being or for other reasons not related to EPP. Additionally, 76.0 % (89/117) of participants used self-help practices, though generally not for their EPP symptoms. DISCUSSION: Overall, findings from this study suggest that cannabis may be impactful on secondary effects of EPP symptoms. Also, that individuals with EPP primarily used other CAMs to improve general well-being rather than as treatment for EPP-related symptoms or pain. Given the limited treatment options for EPP-pain and the findings here, additional research is needed to determine the effectiveness of cannabis on EPP symptoms.
Navigating molecular therapies: The emerging role of mRNA in treating inherited metabolic diseases.
Castro-Alpízar JA, Lenderink MJ, Nieuwenhuis EES … +2 more , Kooijmans SAA, Fuchs SA
Mol Genet Metab · 2026 Jan · PMID 41391248 · Publisher ↗
Inherited metabolic diseases (IMDs) are a diverse group of rare genetic disorders caused by enzymatic deficiencies that disrupt essential biochemical pathways. Current treatments remain largely supportive and fail to add...
Inherited metabolic diseases (IMDs) are a diverse group of rare genetic disorders caused by enzymatic deficiencies that disrupt essential biochemical pathways. Current treatments remain largely supportive and fail to address the molecular root cause. Messenger RNA (mRNA)-based therapeutics, delivered by lipid nanoparticles (LNPs), have recently emerged as a powerful treatment strategy: mRNA enables transient and programmable protein expression, while LNPs provide an effective, non-viral vehicle with natural liver tropism. Initial phase I/II clinical trials and n = 1 cases in liver-dominant IMDs have shown encouraging results. Yet, given the rarity of each IMD and the small patient numbers in individual trials, definitive insights into efficacy and safety require integrating evidence across multiple disorders. In this review, we synthesize the emerging clinical trial evidence of mRNA-LNP therapies across IMDs, highlighting both enzyme replacement and genome editing strategies. We discuss the clinical promise and modularity of these approaches, alongside remaining challenges related to durability, immunogenicity, and extrahepatic delivery. The recent and anticipated evolving developments position mRNA-LNP therapeutics at the forefront of precision medicine, offering a flexible therapeutic platform with applications ranging from bridge therapy to long-term stabilization or potential one-time disease-modifying interventions, transforming the prospect of IMD management.
An update on clinical practice for Duarte galactosemia.
Fridovich-Keil JL, Singh RH
Mol Genet Metab · 2026 Jan · PMID 41380659 · Publisher ↗
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Underrecognized need for early detection of inborn errors of metabolism in China: A population-based study of 14.31 million residents (2012-2023).
Li MJ, Zhao MM, Li Q … +6 more , Kim H, Feng RQ, Guo MN, Zheng JP, Liu C, Yang JK
Mol Genet Metab · 2026 Jan · PMID 41371076 · Publisher ↗
Inborn errors of metabolism (IEMs) are a major subgroup of rare diseases, comprising over 1000 genetic disorders that disrupt essential biochemical pathways. Globally, they cause an estimated 23,500 childhood deaths annu...
Inborn errors of metabolism (IEMs) are a major subgroup of rare diseases, comprising over 1000 genetic disorders that disrupt essential biochemical pathways. Globally, they cause an estimated 23,500 childhood deaths annually. Despite diagnostic advances indicating a cumulative incidence of ∼1 in 800 births, population-based data from China remain scarce. We conducted a population-based study of 14.31 million permanent residents in the Great Beijing Area (2012-2023) using the municipal disease registry. Rare diseases were identified using ICD-10 codes mapped to the 2018 and 2023 National Rare Disease Catalog, from which 13 classified as IEMs were included in this study. Age-standardized incidence rates (ASIRs) were calculated, and disease patterns were compared with international newborn screening (NBS) data. Of 12,371 rare disease diagnoses, 314 (2.5 %) were IEMs. The ASIR was 0.180 per 100,000 person-years (95 % CI: 0.031-0.565) in 2012 and remained stable at 0.159 (95 % CI: 0.023-0.532) in 2023. Early-onset cases (<1 year) comprised 41.7 %. The mean diagnostic age was 11.0 years, with a median of 1.0 year. Methylmalonic acidemia without homocystinuria (40.8 %), phenylketonuria (29.9 %), and Fabry disease (6.7 %) were most common; males accounted for 60.5 % of cases. Although the prevalence of certain IEMs was broadly consistent with global data, the markedly low ASIR suggests substantial underdiagnosis of IEMs in China. This first large-scale, population-based study of IEMs in China reveals underestimation of true disease burden. Expanding and standardizing NBS coverage, broadening genetic testing, implementing mandatory screening, and integrating long-term care into health systems are urgent policy priorities.
A proposed nosology of inherited disorders of the extracellular matrix (ECM): Insights from the IEMbase and dyadic classification.
Giunta C, Marcionelli G, Ferreira CR … +2 more , Blau N, Rohrbach M
Mol Genet Metab · 2026 Jan · PMID 41349292 · Publisher ↗
We have identified 252 inherited disorders of the extracellular matrix (ECM) caused by 154 different gene defects and have proposed a classification system in 8 categories based on their mode of action: 1. Disorders of E...
We have identified 252 inherited disorders of the extracellular matrix (ECM) caused by 154 different gene defects and have proposed a classification system in 8 categories based on their mode of action: 1. Disorders of ECM glycoproteins, 2. Disorders of ECM proteoglycans, 3. Disorders of proteins in TGF-beta signaling pathway, 4. Disorders of fibrillar collagens, 5. Disorders of fibrillar collagen processing and maturation, 6. Disorders of non-fibrillar collagens, 7. Other disorders of connective tissue with bone fragility and 8. Other disorders of connective tissue. Additionally, using information from IEMbase, we have described the clinical involvement of 18 organs and systems, as well as essential laboratory investigations for each type of ECM disorder. Skeletal, ocular, neurological and dysmorphic manifestations were the most prevalent, occurring in 18 %, 12 %, 10 %, and 10 % of ECM disorders, respectively. This was followed by cardiovascular, dermatological, ear-related, muscular, digestive, endocrine, and hematological symptoms (3-7 %). Among the skeletal symptoms, those affecting joints, spine, upper limbs, lower limbs and mineralization were the most common with rates of 25.8 %, 18.0 %, 14.3 %, 14.1 % and 11.5 %, respectively. 27.4 % of the disorders display a single phenotype, with skeletal issues being the most common at 17.8 % and ocular abnormalities 12.2 %. Conversely, 72.6 % of disorders have multiple phenotypes, with LTBP4-related Cutis laxa (10 phenotypes) and SMAD4- related Myhre Syndrome (gain of function) at the end of the spectrum with up to 11 phenotypes. The information provided in this study, including our proposed dyadic classification system for ECM disorders, may be useful for healthcare providers caring for individuals with conditions associated with ECM problems.
Genotype-phenotype correlations of GFAP variants in type I Alexander disease subtypes.
Bachetti T, Vaia Y, Grossi A … +14 more , Rosamilia F, Bertini E, Nicita F, Bellitto D, Eichler F, Bernard G, Nagy A, Zerem A, Heidari M, Tavasoli AR, Moroni I, Ceccherini I, Tonduti D, AxD Type I Study Group
Mol Genet Metab · 2026 Jan · PMID 41349291 · Publisher ↗
INTRODUCTION: Alexander disease (AxD) is a rare and progressive leukodystrophy caused by variants in the Glial Fibrillary Acidic Protein (GFAP) gene. AxD presents as Type I and Type II, based on clinical and neuroradiolo...
INTRODUCTION: Alexander disease (AxD) is a rare and progressive leukodystrophy caused by variants in the Glial Fibrillary Acidic Protein (GFAP) gene. AxD presents as Type I and Type II, based on clinical and neuroradiological features. However, Type I patients variable disease progression has led to sub-classify them into subtypes Ia-Ib-Ic-Id. Our study investigated genotype-phenotype correlations in Type I AxD across these subtypes. METHODS: A cohort of 74 genetically confirmed Type I AxD patients was analysed, with variants classified according to the clinical subtypes Ia, Ib, Ic, and Id. Genotypic-phenotypic correlations were explored both across all subtype groups and in stratified analyses based on patients' ability to achieve independent ambulation versus those who never acquired this milestone. To investigate the functional consequences of a representative variant, in vitro assays were performed. Selected mutant GFAP protein was expressed and their ability to assemble into intermediate filament networks was assessed. RESULTS: The study revealed a progressive decrease in GFAP allelic heterogeneity across disease subtypes from Ia to Id. Additionally, GFAP pathogenic variants in exon 1 were more frequent in milder forms, whereas mutations in exon 4 were predominantly observed in severe phenotypes. In addition, changes at p.R239 and p.R79 residues showed an opposite trend, with variants affecting p.R239 never detected in Id subtype, while variants affecting p.R79 never detected in Ia. Specific aminoacidic changes at the p.R79 residue were able to stratify patients based on ability to acquire independent ambulation or not. Furthermore, the distribution of Combined Annotation Dependent Depletion (CADD) scores showed an inverse correlation with the acquisition of autonomous ambulation. CONCLUSIONS: These results suggest that specific GFAP variants could be potential predictors for disease progression in Type I AxD, supporting patients' subclassification and underscoring the importance of considering both genetic and clinical factors in AxD management, particularly as therapeutic interventions are being developed.
Focused ultrasound delivery of enzyme replacement therapy to the brain of Gaa-/- Pompe disease mice.
Nowlin P, Zhang Y, Chrisholm A … +7 more , Zhang H, Dai J, Owusu-Yaw BS, Young SP, Bali D, Upadhyay J, Todd N
Mol Genet Metab · 2026 Jan · PMID 41349290 · Publisher ↗
Clinically used enzyme replacements therapies (ERTs) have been successful in mitigating peripheral tissue pathology in patients with infantile onset (IOPD) and late onset (LOPD) Pompe disease (PD). However, none of the a...
Clinically used enzyme replacements therapies (ERTs) have been successful in mitigating peripheral tissue pathology in patients with infantile onset (IOPD) and late onset (LOPD) Pompe disease (PD). However, none of the approved therapies are known to cross the blood brain barrier (BBB) and patients with PD have progressive central nervous system (CNS)-associated impairments due to lysosomal glycogen accumulation in the CNS. Here we investigate the use of focused ultrasound (FUS) to temporarily open the BBB as a treatment strategy for achieving delivery of intravenously administered recombinant human acid alpha glucosidase enzyme (rhGAA) into targeted regions of the mouse brain. We investigated GAA delivery and glycogen accumulation in 5-month-old Gaa-/- knockout mice following administration of two clinically available rhGAA ERTS (alglucosidase alfa and avalglucosidase alfa) at different dosages with and without FUS-BBB opening over four biweekly treatment sessions. BBB opening was targeted specifically to the striatum and cortex bilaterally in the FUS groups. Diphenhydramine was administered intraperitoneally 10 min before ERT to avoid anaphylactic response. Mice were sacrificed 24 h after the last treatment session. One hemisphere was used for histological analysis based on periodic acid Schiff (PAS) and H&E stained sections. The other hemisphere was used for biochemical assays to measure GAA enzyme activity and glycogen content. Contrast MRI showed consistent BBB opening over all mice treated with FUS with no significant differences in extent of BBB opening between hemispheres or treatment session. We observed significant reductions in the level of PAS staining for FUS + ERT treated mice compared to No FUS + ERT treated mice, indicative of successful ERT delivery across the BBB resulting in glycogen clearance. Biochemical analysis supported these results, showing an increase in GAA enzyme activity and reduction in glycogen content for FUS + ERT treated mice compared to No FUS + ERT groups. Future work will determine if this promising treatment paradigm can rescue disease phenotypes that are downstream of glycogen accumulation and work towards clinical translation.
Lysinuric protein intolerance: Allogeneic peripheral blood stem cell transplantation for an inborn error of metabolism and immunity.
Zubarovskaya N, Mayr JA, Aigner E … +4 more , Strebinger G, Kalkan-Uçar S, Lawitschka A, Wortmann SB
Mol Genet Metab · 2026 Jan · PMID 41337869 · Publisher ↗
Lysinuric protein intolerance (LPI) is not only an inborn metabolic disease with gastrointestinal, hepatic, renal and lung involvement but also an inborn error of immunity potentially leading to life-threatening autoimmu...
Lysinuric protein intolerance (LPI) is not only an inborn metabolic disease with gastrointestinal, hepatic, renal and lung involvement but also an inborn error of immunity potentially leading to life-threatening autoimmune disorders (e.g. systemic lupus erythematosus (SLE), hemophagocytic lymphohistiocystosis (HLH)). Recently, one case of allogeneic hematopoietic stem cell transplantation (allo-HSCT) reversing SLE and HLH in a LPI patient was reported. We present 21 years of follow-up in a second LPI patient having undergone allogeneic peripheral blood stem cell transplantation (allo-PBSCT) for HLH.
Vascular complications and imaging-based cardiovascular risk assessment in Mucopolysaccharidoses: A systematic review.
McCarron EP, Burgess V, Rogers SK … +5 more , Woolfson P, Jenkins P, Jones SA, Wang R, Stepien KM
Mol Genet Metab · 2026 Feb · PMID 41320576 · Publisher ↗
BACKGROUND: Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterised by glycosaminoglycan (GAG) accumulation, leading to progressive multisystem disease. Cardiovascular complications, including arterial...
BACKGROUND: Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterised by glycosaminoglycan (GAG) accumulation, leading to progressive multisystem disease. Cardiovascular complications, including arterial wall stiffness, and valvular dysfunction, are major causes of morbidity and mortality. Conventional cardiovascular risk tools are unreliable in MPS, and the role of vascular imaging remains underdefined. AIM: This systematic review evaluated vascular complications in paediatric and adult MPS patients, focusing on carotid intimal-media thickness (CIMT) and functional vascular parameters (e.g. carotid cross-sectional compliance (cCSC), carotid incremental elastic modulus (cIEM), carotid cross-sectional distensibility (cCSD)), to assess their utility for cardiovascular risk stratification. METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane Library was conducted (inception-July 2025). Eligible studies reported vascular outcomes in MPS types I, II, III, IV, VI, or VII using imaging or functional measures. Risk of bias was assessed using ROBINS-I for observational studies and RoB 2.0 for the single randomised trial. RESULTS: Eight studies comprising 224 patients were included. CIMT was consistently increased across subtypes, with adult values frequently observed in childhood, indicating accelerated vascular pathology. Patients demonstrated reduced arterial compliance, increased arterial stiffness, and a high prevalence of mitral and aortic valvular disease. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplantation (HSCT) showed partial attenuation of vascular pathology. CONCLUSION: CIMT and vascular stiffness are sensitive markers of subclinical vasculopathy in MPS where conventional cardiovascular risk tools may remain unreliable. Standardised vascular imaging and biomarker development are needed to improve risk stratification and long-term outcomes (particularly in adults).
Predicting subtypes of glycogen storage disease type IV: Challenges of hepatic subtypes and genotype-phenotype correlation.
Taylor A, Yacob D, Fung B … +8 more , Mangray S, Boué DR, Flanigan KM, Koch RL, Kishnani PS, Bali D, Weymann A, Mori M
Mol Genet Metab · 2025 Dec · PMID 41308240 · Publisher ↗
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disease caused by the deficiency of the glycogen branching enzyme encoded by GBE1. GSD IV can present with variable age of onset and severity of dis...
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disease caused by the deficiency of the glycogen branching enzyme encoded by GBE1. GSD IV can present with variable age of onset and severity of disease processes involving liver, central and peripheral nerves, muscles, and heart. Adult Polyglucosan Body Disease (APBD) is now increasingly recognized as a continuum of the GSDIV spectrum. If the clinical disease presentation includes progressive liver failure, treatment may require liver transplant to prevent morbidity and mortality. The variable presentation of GSD IV, including the hepatic phenotypes, creates diagnostic and treatment challenges. Here we describe a girl presenting with hypotonia and hepatomegaly at age 4 years; genetic analysis revealed compound heterozygosity in GBE1: c.1621A>G p.(Asn541Asp) and c.1655C>T p.(Pro552Leu). Based on her presentation and genotypes, her phenotypic prognosis was not immediately clear. She was monitored closely for liver disease progression including, synthetic dysfunction, cholestasis, or cirrhosis, but her liver function proved stable over time. Recent analysis suggested that liver disease progression is a spectrum and some develop a progressive/severe hepatic form and others stabilize with an attenuated hepatic form. Previous reviews of GSD IV genotype-phenotype correlations have not adequately addressed the prediction of hepatic phenotype based on GBE1 genotypes. We performed an updated comprehensive literature search and genotype-phenotype analysis, while updating the GBE1 genotypes according to the HGVS nomenclature. Our detailed and comprehensive review of GSDIV adds to the previously published literature available on GSD IV genotypes (Li et al. 2010, Iijima 2018, Souza et al. 2021).
Experimental insights into MMACHC variants using a novel minigene system.
Dong Y, Xu X, Li W … +6 more , Wang L, Wu B, Wang P, Li D, Shu J, Cai C
Mol Genet Metab · 2025 Dec · PMID 41275642 · Publisher ↗
BACKGROUND: Methylmalonic aciduria and homocystinuria, cblC type, the most prevalent disorder of cobalamin (cbl) metabolism, results from genetic variants in the MMACHC gene. Although public databases document numerous s...
BACKGROUND: Methylmalonic aciduria and homocystinuria, cblC type, the most prevalent disorder of cobalamin (cbl) metabolism, results from genetic variants in the MMACHC gene. Although public databases document numerous splice variants of this gene, experimental evidence confirms pathogenicity for only a limited proportion. METHODS: We constructed a plasmid system encompassing the complete coding sequence of the MMACHC gene, enabling direct validation of protein expression following the evaluation of MMACHC splice variant effects. Using a minigene assay, we evaluated the impact of selected variants on the splicing and quantified their protein expression levels. RESULTS: 26 variants, including a subset of missense variants that are usually underestimated but can also lead to aberrant splicing, were predicted by splicing prediction tools. Experimental testing proved that 14 candidate variants disrupted normal splicing of the MMACHC gene and induced diverse splicing events that encompass exon skipping, partial exon skipping, intron retention, and cryptic splicing. However, 10 variants had no effect on pre-mRNA splicing but significantly lowered the protein expression levels. CONCLUSION: Our study elucidates the potential pathogenic mechanisms of some MMACHC variants and validates the utility of a novel plasmid system for the effective assessment of MMACHC variant pathogenicity. The application of this laboratory method for the analysis of patient-identified variants has the potential to be very valuable for the diagnosis of cblC disease at an early stage.
Survival, growth, and safety findings in patients with rapidly progressive, infantile-onset LAL-D: Results from the international LAL-D registry.
Vijay S, Evans J, Lacaille F … +2 more , Abel F, Heras JL
Mol Genet Metab · 2025 Dec · PMID 41270440 · Publisher ↗
In symptomatic infants, lysosomal acid lipase deficiency (LAL-D; historically Wolman disease) is characterized by a rapidly progressive disease course of hepatosplenomegaly and liver disease. This course includes liver f...
In symptomatic infants, lysosomal acid lipase deficiency (LAL-D; historically Wolman disease) is characterized by a rapidly progressive disease course of hepatosplenomegaly and liver disease. This course includes liver failure, malabsorption and growth failure, and systemic inflammation, such as hemophagocytic lymphohistiocytosis, typically leading to death by 6 months of age if untreated. Sebelipase alfa (KANUMA®; Alexion, AstraZeneca Rare Disease, Boston, MA) is a recombinant human LAL (a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme) approved for the treatment of LAL-D in infants with rapidly progressive disease as well as in children and adults with LAL-D. Previous studies showed that enzyme replacement therapy (ERT) with sebelipase alfa led to survival with improved growth and development, hematologic parameters, and liver parameters and was well tolerated. We report long-term outcomes in 29 patients with rapidly progressive LAL-D who were symptomatic in infancy using patient data from the International LAL-D Registry, an ongoing observational, multicenter, international registry (NCT01633489) that collects data on patients with LAL-D. Among these 29 patients treated with sebelipase alfa, 41 % were male, and 28 % had participated in clinical trials with sebelipase alfa. Median age (Q1, Q3) was 2.3 months (1.8, 3.1) at the start of ERT. Patients received a starting ERT dose of ≤1 mg/kg or ≥3 mg/kg per week. In patients who had participated in clinical trials of sebelipase alfa, the starting dose was driven by the clinical trial protocol and was between 0.2 and 1.0 mg/kg per week. Overall, 27 of 29 (93 %) patients survived during the median observation time (Q1, Q3) of 6.2 years (3.5, 8.4). At baseline, 11 patients had abnormally low weight-for-age z scores (<-2); for 5 of these patients, weight stabilized after 6 to 12 months of treatment (z scores between -2 and 2). Adverse events occurred in 23 (79 %) patients. Eleven (38 %) patients experienced adverse events potentially related to sebelipase alfa, which were generally not severe and most resolved. Four patients among 7 tested developed antidrug antibodies, and 3 had positive results for neutralizing antidrug antibodies. These results confirmed the dramatic survival and metabolic benefit associated with sebelipase alfa ERT in patients with symptomatic, rapidly progressive LAL-D.
Potential benefits of l-serine in children with GRIN2B loss-of-function variants: Randomized n-of-1 trials.
den Hollander B, Rothuizen-Lindenschot M, Le HL … +11 more , Ramautar JR, Müller AR, Geertjens L, Vaz FM, van Eeghen AM, Cornel MC, Jacobs BAW, Bruining H, van de Ven PM, Brands MM, van Karnebeek CD
Mol Genet Metab · 2025 Dec · PMID 41265180 · Publisher ↗
BACKGROUND: GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in GRIN2B, leading to impaired N-methyl d-aspartate receptor (NMDAR) function. l-serine, a precursor to...
BACKGROUND: GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in GRIN2B, leading to impaired N-methyl d-aspartate receptor (NMDAR) function. l-serine, a precursor to d-serine that modulates NMDAR activity, has shown therapeutic potential for GRIN2B loss-of-function (LoF) variants. METHODS: The efficacy of oral l-serine supplementation in 4 children with GRIN2B LoF variants were evaluated in the first double-blind, randomized, placebo-controlled, one-year n-of-1 trials. The trial consisted of 2 cycles of 6 months. RESULTS: The Perceive, Recall, Plan, and Perform Assessment (PRPP-A) showed a significant improvement in Performance Mastery at 1.5 months (p = 0.0373), while 11 of 14 other PRPP-A measures showed mean differences that were numerically in the same direction toward a positive l-serine effect (not significant). Secondary outcomes varied across patients, for those with statistical group analysis, no significant difference were observed. Individual improvements were noted in information processing/adaptive function (n = 3/4), quality of life (n = 3/4), sleep (n = 1/2), irritability (n = 2/4), and language (n = 1/3), based on objective assessments and anecdotal parent reports. CONCLUSION: These pioneering n-of-1 trials provide insights into l-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified. Future trials should focus on refining patient selection, the use of multiple baseline designs, establishing a core outcome set and pooling treatment data to better understand patient-specific responses.
Evaluation and follow-up of newborns screening positive for mucopolysaccharidosis II: Results from an international modified Delphi consensus.
Burton BK, Ellinwood NM, Hoffman KK … +1 more , Muenzer J
Mol Genet Metab · 2025 Dec · PMID 41265179 · Publisher ↗
Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S, EC 3.1.6.13), due to pathological varia...
Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulfatase (I2S, EC 3.1.6.13), due to pathological variants of the I2S gene (IDS). Clinically, MPS II is a chronic progressive multisystem developmental and degenerative disorder, typically associated with manifestations in early childhood. Intravenous enzyme replacement therapy has been available since 2006, with improved outcomes seen with early initiation of therapy. Newborn screening for MPS II in a public health setting has been ongoing in Taiwan since 2015 and in some states of the USA since 2017. These developments prompted a successful nomination of MPS II to be included as a core screening condition on the US Federal Recommended Uniform Screening Panel (RUSP), which was approved by the US Secretary of Health and Human Services on August 2, 2022. With the promise of expanded public health screening for MPS II, there was a perceived need for a set of consensus recommendations on MPS II newborn screening, the clinical confirmation of screened positive cases, and their clinical management. To this end an international expert panel of 21 members from 8 countries was convened to conduct a modified Delphi consensus on the evaluation and follow-up of newborns who screened positive for MPS II, the results of which are presented.
Utility of 24(S)-hydroxycholesterol as a proximal biomarker to monitor long-term intrathecal adrabetadex therapy in individuals with Niemann-Pick disease, type C1.
Porter FD, Alexander DM, Albert OK … +6 more , Robbins KP, Labor DA, Borruso AJ, Farhat NY, Jiang X, Berry-Kravis E
Mol Genet Metab · 2025 Dec · PMID 41260183 · Full text
Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol. Individuals with NPC1 manifest progressive neurodegeneration. Identification and characteriz...
Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by endolysosomal storage of unesterified cholesterol. Individuals with NPC1 manifest progressive neurodegeneration. Identification and characterization of proximal biomarkers is essential for developing therapeutic interventions. Increased levels of 24(S)-hydroxycholesterol (24(S)OHC) after intrathecal administration of adrabetadex reflect correction of the biochemical defect in neurons. In this study, we show that 24(S)OHC remains a robust proximal biomarker in individuals treated with IT adrabetadex for over four years.
Measuring dietary intake among participants with a urea cycle disorder using standard diet records or a novel food photography app.
Sim E, Gregor A, MacLeod E … +6 more , Moore R, Ravelli MN, Schoeller DA, Harding CO, Jacobs P, Gillingham MB
Mol Genet Metab · 2025 Dec · PMID 41242089 · Full text
Nutrition management of urea cycle disorders (UCDs) focuses on limiting dietary protein and providing adequate energy to ensure appropriate growth and prevent catabolism. Dietary protein intakes are recommended to patien...
Nutrition management of urea cycle disorders (UCDs) focuses on limiting dietary protein and providing adequate energy to ensure appropriate growth and prevent catabolism. Dietary protein intakes are recommended to patients; however, assessment of actual protein intake is challenging as standard assessment methods are recognized to be inaccurate, time-consuming, and cumbersome. A new dietary collection method utilizes a smartphone camera; participants take photos of meals and snacks for remote analysis by a registered dietitian. This food photography method using the mFood app was compared to traditional 3-day diet records in individuals with UCDs and reported energy intake for both were validated against an objective gold-standard measurement of total energy expenditure (TEE) by doubly labeled water. In weight-stable adults, energy intake is approximately equal to TEE. Eight individuals ≥16 years old participated in a randomized crossover design study. In this cohort, protein intake was 13 % and 15 % of energy for 3-day diet records and mFood, respectively. There was no statistical difference in gram intake of the macronutrients between the two methods. Compared to TEE, participants reported 16 % lower total energy intake by 3-day diet records and 22 % lower energy intake by mFood, demonstrating limited benefit to using mFood. We highlight the importance of utilizing consistent nutrient analysis methods to compare dietary assessments within a population. mFood, although not superior to traditional dietary collection methods, was preferred by the majority of participants and offers a novel method for collecting nutrition information in individuals with UCD who frequently find this task cumbersome.
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