Molecular Genetics And Metabolism[JOURNAL]
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200 papers
Prevalence and clinical impact of gastrointestinal symptoms in patients with cystinosis.
de Vreugd A, van Campen ML, Cornelissen EAM … +4 more , Besouw MTP, van den Heuvel LPWJ, Janssen MCH, Levtchenko EN
Mol Genet Metab · 2026 Jun · PMID 42229032 · Publisher ↗
BACKGROUND: Cystinosis is a rare autosomal recessive lysosomal storage disease caused by mutations in the CTNS gene, resulting in lysosomal cystine accumulation and multisystem complications, including most notably kidne...
BACKGROUND: Cystinosis is a rare autosomal recessive lysosomal storage disease caused by mutations in the CTNS gene, resulting in lysosomal cystine accumulation and multisystem complications, including most notably kidney failure. Gastrointestinal (GI) symptoms are common, varying from feeding difficulties to nausea and bowel problems. These issues increase the risk of malnutrition, a concern that has received limited attention in the literature. METHODS: This mixed-method study assessed the prevalence and impact of GI complaints in 28 cystinosis patients and their caregivers. Quantitave data was collected using the Gastrointestinal Symptoms Questionnaire and the Patient-Generated Subjective Global Assessment (PG-SGA). Seven in-depth interviews were conducted to explore subjective experiences. Additionally, anthropometric measurements were compared to those of healthy individuals and bioelectrical impedance analysis (BIA) was performed in 19 adult patients. RESULTS: GI symptoms were highly prevalent, with all participants reporting at least one symptom in the four weeks preceding assessment. The most commonly reported symptoms included halitosis (68%), bloating (64%), abdominal rumbling (61%), nausea (61%), abdominal pain (54%) and altered stool patterns (54%). Qualitative interviews underscored the profound impact of various GI symptoms on the quality of life. Furthermore, cystinosis patients had significantly lower body mass index (BMI) compared to healthy controls (p < 0.01) and were more frequently underweight (p < 0.01). Overall PG-SGA scores were elevated, with 42.9% needing follow-up and education (score 2-3) and 42.9% needing nutritional intervention (score > 3). BIA revealed reduced muscle mass in 79% of evaluated participants. CONCLUSION: GI symptoms are common and burdensome in cystinosis, significantly impairing quality of life and increasing the risk of malnutrition. Early recognition and targeted intervention, including dietary support, might mitigate the risk of malnutrition and enhance overall quality of life in this patient population. PG-SGA score and BIA measurements assist in recognising the individual need for follow-up and intervention.
Resources and care structures for management of urea cycle disorders in Japan and the United States: A system-level comparison.
Nakajima Y, MacLeod E, Hirano K … +2 more , Mew NA, Oishi K
Mol Genet Metab · 2026 Jul · PMID 42217313 · Publisher ↗
BACKGROUND: Urea cycle disorders (UCD) are rare, nutrition-dependent inborn errors of metabolism in which outcomes depend on pharmacological treatment and sustained access to specialized formulas, low-protein medical foo...
BACKGROUND: Urea cycle disorders (UCD) are rare, nutrition-dependent inborn errors of metabolism in which outcomes depend on pharmacological treatment and sustained access to specialized formulas, low-protein medical foods, and dietary counseling. System-level support for dietary management varies across countries, yet comparative analyses are scarce. METHODS: We conducted a structured comparative analysis of dietary management systems for UCD in Japan and the United States (US) using clinical guidelines, policy documents, industry information, and professional reports. The review examined four domains: pharmacological and nutritional resources, availability of specialized formulas and low-protein medical foods, healthcare delivery and insurance, and the role of metabolic dietitians. RESULTS: In the US, individuals with UCD generally have access to multiple nitrogen-scavenging agents, UCD-specific or functionally equivalent formulas, and diverse low-protein staple foods, with care coordinated through specialized metabolic clinics and dietitians. Coverage for medical foods and formulas varies widely, leading to substantial out-of-pocket costs and inequities. In Japan, universal health insurance, pediatric subsidy schemes, and rare disease programs provide coverage for approved pharmacological treatments and hospital-based care. However, essential amino acids (EAA)-enriched, UCD-specific formulas are unavailable, EAA preparations are prescribed off-label, low-protein foods are limited, and most dietary products are not reimbursed. CONCLUSIONS: The US model emphasizes product diversity and multidisciplinary care within a fragmented insurance framework, whereas Japan offers universal coverage and continuity of medical care but limited structural support for dietary therapy. Integrating strengths from both systems may improve nutritional management and quality of life for individuals with UCD.
A splice-altering intronic variant in two multiplex families refines autosomal recessive COG4-related congenital disorder of glycosylation.
Micale L, Sturiale L, Russo F … +14 more , Di Muro E, Nardella G, Pracella R, Lomuscio S, Morlino S, Benvenuto M, Messina A, Palmigiano A, Carella M, d'Orsi G, Palumbo P, Palumbo O, Barone R, Castori M
Mol Genet Metab · 2026 Jul · PMID 42202558 · Publisher ↗
Autosomal recessive COG4-related congenital disorder of glycosylation [COG4-CDG(ar)] is caused by biallelic deleterious variants in COG4, which encodes a component of the conserved oligomeric Golgi complex lobe A. COG4-C...
Autosomal recessive COG4-related congenital disorder of glycosylation [COG4-CDG(ar)] is caused by biallelic deleterious variants in COG4, which encodes a component of the conserved oligomeric Golgi complex lobe A. COG4-CDG(ar) has been described in six individuals to date, and its clinical manifestations and disease mechanisms remain poorly understood. Exome sequencing identified the homozygous COG4 c.1647+5G>A variant in four affected individuals from two apparently unrelated Italian families. SNP-array genotyping revealed a common ancestral haplotype extending for 3.36 cM around COG4 and supports a founder effect for the identified variant. Whole transcriptome sequencing and reverse transcriptase PCR from peripheral blood detected an aberrant COG4 transcript which features skipping of exon 12 and results in a frameshift, predicted to introduce a premature termination codon. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry profiling of serum N-glycans showed mildly deficient galactosylation and sialylation, consistent with an impaired Golgi-mediated glycosylation. As a novel finding, N-glycosylation study of serum IgG showed analogous N-glycan anomalies. These findings and literature review define COG4-CDG(ar) as a neurometabolic disorder with a progressive course leading to severe global disability, post-natal microcephaly with brain atrophy, seizures, coagulopathy, liver involvement, recurrent infections, and defective N-glycosylation of serum proteins.
Variant classification for mucopolysaccharidosis type I; ACMG/AMP specification for IDUA from the ClinGen lysosomal diseases variant curation expert panel.
Lacaria M, Goldstein JL, Aschoff C … +22 more , Brown K, Deshpande D, Chen-Deutsch X, Ellinwood M, Farman MR, Mendez R, Louis IV, Prout J, Roark K, Selvanathan A, Stafford A, Fernandez R, Ratzsch AC, Weaver M, Bali D, Donti T, Lund T, Pollard L, Vairo FPE, Wood T, Rehder C, Clarke L
Mol Genet Metab · 2026 Jul · PMID 42190545 · Full text
With the increasing use of DNA sequencing technologies in healthcare, an accurate understanding of the clinical relevance of genetic variants is vital for the appropriate integration of these results into personalized ca...
With the increasing use of DNA sequencing technologies in healthcare, an accurate understanding of the clinical relevance of genetic variants is vital for the appropriate integration of these results into personalized care. To address this need, the NIH-funded Clinical Genome Resource (ClinGen) Lysosomal Diseases Variant Curation Expert Panel (VCEP) has developed variant classification guidance for IDUA, the gene encoding alpha-L-iduronidase. Deficiency of alpha-L-iduronidase activity causes mucopolysaccharidosis type I (MPS I). IDUA variant interpretation was prioritized by the VCEP following the 2016 inclusion of MPS I in the Recommended Uniform Screening Panel (RUSP) for newborns in the USA, reflecting the critical role of IDUA sequencing in therapeutic decision-making and care of individuals identified through either newborn screening or diagnostic platforms. Furthermore, as genetic testing is increasingly used as a first line test in the diagnosis of lysosomal diseases, accurate variant classification is vital. The LD VCEP's IDUA-specific variant classification guidance is based on the American College of Medical Genetics & Genomics and Association for Molecular Pathology's (ACMG/AMP) variation classification guidelines [1], with criteria tailored specifically to IDUA and MPS I. To date, the LD VCEP has submitted classifications and supporting data for 131 IDUA variants to ClinVar and to the ClinGen Evidence Repository, where this data is publicly available. Here, we discuss the development of the ClinGen LD VCEP's IDUA-specific ACMG/AMP criteria, our results to date, challenges, and plans for future work.
Letter to the editor: Newborn screening for low blood citrulline leads to diagnosis of ornithine aminotransferase deficiency.
Summerlin M, Harding C, Starosta RT … +3 more , Sliwoski L, Viall S, Kripps K
Mol Genet Metab · 2026 Jul · PMID 42184784 · Publisher ↗
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Developmental trajectory of individuals with Pelizaeus-Merzbacher Disease (PMD).
Sevagamoorthy A, Woidill S, Sudilovsky G … +21 more , Kelley K, Vaia Y, Gavazzi F, Schmidt JL, Pizzino A, D'Aiello R, Uebergang E, Bruschi F, Mirchi A, Abe-Hatano C, Sartorelli J, Nicita F, Cunningham C, Tonduti D, Bertini E, Bernard G, Inoue K, Wolf NI, Adang LA, Shults J, Vanderver A
Mol Genet Metab · 2026 Jul · PMID 42176404 · Publisher ↗
INTRODUCTION: Pelizaeus-Merzbacher Disease (PMD) is a PLP1-related disorder for which genotype alone is insufficient to reliably determine PMD disease progression. We aim to characterize the developmental outcomes of PMD...
INTRODUCTION: Pelizaeus-Merzbacher Disease (PMD) is a PLP1-related disorder for which genotype alone is insufficient to reliably determine PMD disease progression. We aim to characterize the developmental outcomes of PMD-affected individuals and evaluate their association with early presentation features. METHODS: Molecularly confirmed PMD subjects were included. Data on baseline characteristics, developmental, and disease outcomes were abstracted from medical records and, when feasible, supplemented by caregiver interviews. Data were summarized using descriptive statistics. RESULTS: The study included 111 subjects with milestone acquisition ranging from 9.9% to 68.5% across gross motor, 41.1% to 85.6% across fine motor, and 30.0% to 66.7% across expressive communication skills. Genotype and milestone were not significantly associated. Presentation with stridor (N = 20) was associated with profound impairments (overall non-attainment ranging from 10.0% to 100%). In the absence of stridor, head control by 12 months was associated with developmental outcomes: severe outcomes (overall non-attainment ranging from 0% to 96.0%) when head control was not acquired by 12 months (N = 50), and moderate outcomes (overall non-attainment ranging from 0% to 78.0%) when head control was attained (N = 41). Median time to PMD-related complications was noted to be earlier in the profoundly impaired subtype, compared to the severe and moderate subtypes. CONCLUSIONS: PMD impairs skill acquisition, with gross motor milestones impacted more than expressive communication. Stridor and lack of head control by 12 months were associated with poor developmental outcomes and disease progression. These insights will support better characterization of disease course for newly diagnosed families, as well as future trial development.
Clinical and biochemical footprints of inherited cofactor disorders.
Di Meo I, Ferreira CR, Opladen T … +5 more , Schwarz G, Tiranti V, van Karnebeek C, van Walree E, Blau N
Mol Genet Metab · 2026 Jul · PMID 42176403 · Publisher ↗
Inherited metabolic disorders (IMDs) affecting cofactor biosynthesis, recycling, transport, or utilization cause characteristic combinations of biochemical abnormalities and multi-system clinical signs. Here, we describe...
Inherited metabolic disorders (IMDs) affecting cofactor biosynthesis, recycling, transport, or utilization cause characteristic combinations of biochemical abnormalities and multi-system clinical signs. Here, we describe footprints of 29 ICIMD-curated cofactor disorders: tetrahydrobiopterin (BH4; n = 6), molybdenum cofactor (MoCo; n = 5), vitamin B6 (pyridoxal-5'-phosphate; n = 6), niacin/nicotinamide adenine dinucleotide (NAD; n = 7), and pantothenate/coenzyme A (n = 5), by integrating disorder-specific biomarker panels with a structured symptom matrix. Across domains, heat map-based profiling highlights recurrent neurologic hot spots (seizures, movement disorders, neurodevelopmental impairment) while also revealing pathway-anchored signatures that can rapidly narrow the differential diagnosis, such as hyperphenylalaninemia with monoamine deficiency in several BH4 disorders, sulfite intoxication markers in classic MoCo deficiency, a B6-responsive neonatal epileptic encephalopathy pattern, an ocular-predominant footprint in nicotinamide mononucleotide adenylyltransferase 1 NMNAT1-related NAD disease, and cardio-metabolic failure in multiple CoA biosynthesis defects. We summarize pathomechanisms and current treatment options, emphasizing time-critical, treatable conditions (e.g., cyclic pyranopterin monophosphate (cPMP; fosdenopterin) replacement in MoCo-A; neurotransmitter and vitamin replacement strategies). This harmonized framework is intended to support early, pathway-informed testing and management in suspected cofactor-related IMDs. By aligning clinical-system patterns with biochemical 'anchors', this framework complements genomic diagnostics, guides surveillance, and prioritizes interventions in neonatal encephalopathy, childhood movement disorders, and recurrent acute metabolic crises. While newborn screening is well established for disorders of BH4 metabolism, screening for several other disorders, such as PDE-ALDH7A1 deficiency, is still in the pilot phase and available only in a few specialized centers. In contrast, genomic screening, with all its benefits and pitfalls, is emerging as a complement to classic newborn screening.
Diagnostic and therapeutic applications of the glycan biomarker H3N2b in GM1 Gangliosidosis.
Kell P, Mishra S, D'Souza P … +12 more , Tifft CJ, Dietzen DJ, Lasio LD, Carson JP, Hong X, Schiffmann R, Ledesma MD, Tayebi N, Dickson PI, Porter FD, Ory DS, Jiang X
Mol Genet Metab · 2026 Jul · PMID 42160923 · Full text
GM1 gangliosidosis is a progressive lysosomal storage disorder caused by β-galactosidase deficiency, resulting in accumulation of GM1 ganglioside and related glycoconjugates. Current diagnostic approaches rely on enzymat...
GM1 gangliosidosis is a progressive lysosomal storage disorder caused by β-galactosidase deficiency, resulting in accumulation of GM1 ganglioside and related glycoconjugates. Current diagnostic approaches rely on enzymatic and genetic testing but do not provide dynamic measures of substrate accumulation or therapeutic response. The oligosaccharide H3N2b has previously been identified as a potential biomarker of impaired β-galactosidase activity. In this study, H3N2b was quantified in plasma, urine, and cerebrospinal fluid (CSF) from patients with GM1 gangliosidosis (n = 47 plasma/urine; n = 34 CSF) and age- and sex-matched controls using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. A limited set of comparator lysosomal storage disorder samples was also analyzed to provide preliminary assessment of biomarker specificity. Longitudinal H3N2b measurements were obtained from participants receiving intravenous adeno-associated virus serotype 9 (AAV9)-mediated GLB1 gene therapy. H3N2b concentrations were significantly elevated in GM1 gangliosidosis compared with controls in plasma (cutoff 6.2 ng/mL; 100% sensitivity and specificity), urine (0.65 ng/μg creatinine; 99.3% sensitivity, 100% specificity), and CSF (5.1 ng/mL; 98.9% sensitivity, 100% specificity). H3N2b levels correlated with disease severity and were not influenced by age or sex. Among the comparator disorders analyzed, H3N2b values were generally below GM1 diagnostic cutoffs, although the comparator analysis was limited by sample availability and did not include several relevant disorders and CSF. In gene therapy recipients, plasma, urine, and CSF H3N2b concentrations decreased following treatment and closely paralleled changes in β-galactosidase activity, indicating pharmacodynamic responsiveness. These findings provide a cross-matrix clinical evaluation of H3N2b as a diagnostic and therapeutic biomarker for GM1 gangliosidosis and support its utility as a candidate biochemical biomarker to aid diagnosis and monitor treatment-associated biochemical changes.
Comprehensive analysis of hearing function in Morquio A syndrome: Implications for diagnosis and management.
Shih A, Morlet T, Klipner K … +4 more , Sahou M, Averill L, Kecskemethy H, Tomatsu S
Mol Genet Metab · 2026 Jul · PMID 42156211 · Publisher ↗
Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder characterized by systemic skeletal dysplasia and multisystem involvement. Hearing loss is frequently reported but remains insufficiently char...
Morquio A syndrome (mucopolysaccharidosis IVA) is a lysosomal storage disorder characterized by systemic skeletal dysplasia and multisystem involvement. Hearing loss is frequently reported but remains insufficiently characterized, with few studies incorporating comprehensive behavioral and electrophysiologic assessments. In this prospective study, the largest Morquio A auditory cohort to date, participants underwent detailed audiologic and imaging testing at Nemours Children's Health as part of the National Institutes of Health-sponsored natural history program. Assessments included pure-tone thresholds, speech-recognition thresholds, speech perception in quiet and noise, tympanometry, distortion-product otoacoustic emissions, auditory brainstem responses, and cortical auditory evoked potentials. Outcomes included the prevalence, type, and severity of hearing loss, as well as associations with age and clinical disease severity. Hearing loss was identified in 50.9% of 56 patients, with sensorineural loss more frequent than conductive or mixed types. Prevalence of hearing loss was significantly correlated with clinical severity (height percentile), whereas no significant correlation was observed between hearing loss severity and diagnostic age. Reduced or absent otoacoustic emissions with preserved brainstem and cortical responses indicate predominant cochlear involvement with potential secondary central contributions. Comprehensive imaging of the middle and inner ear showed no significant structural differences between patients with and without hearing loss. Hearing loss is common in Morquio A and is primarily sensorineural. The absence of associations with age or disease severity underscores the heterogeneity of auditory involvement. These findings emphasize the need for routine, comprehensive audiologic monitoring to support early detection and mitigate long-term impacts on communication and quality of life.
Progressive short stature in Pearson syndrome and the impact of organ failure.
Yoshimi A, Cario H, Timmermann K … +15 more , Kontny U, Lobitz S, Odenthal HS, Schmid I, Seitz B, Höll T, Lücke T, Borkhardt A, Strauß G, Hohnecker A, Metzler M, Karall D, Noellke P, Niemeyer CM, Grünert SC
Mol Genet Metab · 2026 Jul · PMID 42156210 · Publisher ↗
BACKGROUND: Pearson syndrome (PS) is a rare, unique primary mitochondrial disorder characterized by single large-scale mitochondrial DNA deletions, bone marrow failure, lactic acidosis, and progressive multi-organ compli...
BACKGROUND: Pearson syndrome (PS) is a rare, unique primary mitochondrial disorder characterized by single large-scale mitochondrial DNA deletions, bone marrow failure, lactic acidosis, and progressive multi-organ complications. METHODS: We retrospectively evaluated anthropometric data from 25 patients with PS. RESULTS: The median height, weight, and body mass index (BMI) standard deviation scores (SDS) at the last measurement were - 1.95 (range: -7.32 to 1.09), -1.70 (range: -12.26 to 0.11), and - 1.52 (range: -5.01 to 2.19), respectively; 50%, 40%, and 37.5% of patients, respectively, had values below -2 SDS. Longitudinal data from 18 patients showed that height and weight SDS declined progressively with age in most patients, whereas BMI SDS fluctuated without a clear age-related trend. Initiation of tube feeding improved weight and BMI SDS in some patients, while height SDS continued to decline without catch-up growth. Patients with organ failure exhibited an earlier decline in height SDS than those without organ failure. CONCLUSIONS: Patients with PS are generally short and underweight, and their short stature worsens over time. The presence of organ failure further exacerbates growth impairment.
Riboflavin-responsive hyperprolinemia type I with a PRODH p.Thr466Met variant: Clinical and fibroblast-based evidence.
Kido J, Sugawara K, Egashira I … +3 more , Yano N, Zhang C, Nakamura K
Mol Genet Metab · 2026 Jul · PMID 42150437 · Publisher ↗
Hyperprolinemia type I (HP1) is a rare autosomal recessive disorder caused by biallelic variants in PRODH, encoding the FAD-dependent enzyme proline dehydrogenase. Although persistent hyperprolinemia has been associated...
Hyperprolinemia type I (HP1) is a rare autosomal recessive disorder caused by biallelic variants in PRODH, encoding the FAD-dependent enzyme proline dehydrogenase. Although persistent hyperprolinemia has been associated with neurodevelopmental and neuropsychiatric manifestations, no established effective treatment is available. Here, we report convergent clinical and patient-derived fibroblast evidence supporting riboflavin responsiveness in HP1 due to a homozygous PRODH c.1397C>T p.(Thr466Met) variant. The patient exhibited markedly elevated plasma proline (530-625 μmol/L; reference 78-273 μmol/L), which decreased after initiation of a vitamin cocktail including riboflavin (291 and 277 μmol/L at 3 and 8 months) and decreased on riboflavin monotherapy (251 μmol/L; 12 mg/day). Urinary P5C became slightly detectable during riboflavin supplementation and was not detectable after riboflavin discontinuation. In patient-derived fibroblasts, intracellular proline was elevated compared with a control and was reduced by riboflavin therapy (40.32 to 14.85 pmol/200 μL PBS; control 21.65 pmol/200 μL PBS). PRODH mRNA showed a modest upward trend under riboflavin in fibroblasts. Although direct enzymatic activity could not be reliably assessed due to technical limitations, these multi-level findings support riboflavin as a potential cofactor-directed therapy in selected PRODH missense variants and provide a rationale for therapeutic trials with biochemical monitoring.
Assessment of patient-reported symptoms in Hermansky-Pudlak syndrome.
Zuo MXG, Zuo BLG, O'Brien KJ … +5 more , Friedman V, Appell D, Gahl WA, Merideth MA, Gochuico BR
Mol Genet Metab · 2026 Jul · PMID 42150436 · Publisher ↗
PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare multisystem disorder associated with defective biogenesis of lysosome-related organelles. Patient-reported symptoms in HPS have not been studied. METHODS: An 84-question...
PURPOSE: Hermansky-Pudlak syndrome (HPS) is a rare multisystem disorder associated with defective biogenesis of lysosome-related organelles. Patient-reported symptoms in HPS have not been studied. METHODS: An 84-question HPS symptom scale assessing symptom prevalence, severity, and frequency across multiple organ systems was developed. Eighty-five individuals with HPS or caregivers of individuals with HPS completed the questionnaire. Symptoms of participants with BLOC-2 (i.e., HPS-3, HPS-5, HPS-6) and BLOC-3 (i.e., HPS-1, HPS-4) disease and children and adults with BLOC-3 disease were compared. RESULTS: Hypopigmentation and photosensitivity affected all participants with BLOC-2 or BLOC-3 disease. Nystagmus, poor visual acuity, and easy bruising were also highly prevalent in BLOC-2 and BLOC-3 disease. Gastroesophageal reflux disease (GERD) affecting 62-69% was the most common gastrointestinal symptom. Dyspnea on exertion did not differ significantly between BLOC-3 (52%) and BLOC-2 disease (38%); wheezing affected approximately one-third. Palpitations, imbalance, headaches or migraines, and autoimmune symptoms (i.e., xerophthalmia, skin rashes, myalgia) were reported by the majority with BLOC-2 or BLOC-3 disease. GERD, xerophthalmia, and headaches or migraines were significantly more common in adults than children with BLOC-3 disease. Functional independence was reported by most adult participants with HPS. CONCLUSION: Comprehensive assessment of patient-reported symptoms showed that in addition to known manifestations of disease, GERD, cardiac, autoimmune, and neurologic symptoms are common in HPS. These results highlight the importance of patient-reported symptoms to expand the understanding of the extent and impact of their disease.
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Mol Genet Metab · 2026 May · PMID 42140708 · Publisher ↗
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Sepiapterin: From sapropterin to next-generation therapy.
Blau N
Mol Genet Metab · 2026 Jul · PMID 42119485 · Publisher ↗
Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenyl...
Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenylalanine hydroxylase (PAH), the aromatic amino acid hydroxylases, and nitric oxide synthases, whereas 7,8-dihydrobiopterin (BH2) reflects pterin redox balance and can antagonize BH4-dependent nitric oxide signaling. This review integrates historical and chemical perspectives with current biochemical and clinical understanding of BH4 homeostasis, including de novo synthesis, recycling/oxidation, and the sepiapterin salvage pathway. Sepiapterin is taken up by cells through equilibrative nucleoside transport mechanisms and is intracellularly converted through sepiapterin reductase and dihydrofolate reductase to expand BH4 pools. In healthy volunteers, oral sepiapterin produced marked systemic BH4 exposure with minimal parent-drug exposure (geometric mean Cmax 640 ng/mL for BH4 versus 1.74 ng/mL for sepiapterin after 60 mg/kg) and increased cerebrospinal fluid BH4 after 7 days of 60 mg/kg/day dosing. In phenylketonuria (PKU), the Phase 3 APHENITY trial showed a placebo-adjusted least-squares mean blood phenylalanine reduction of 395.9 μmol/L at Week 6 among sepiapterin-responsive participants, and the Phase 3 AMPLIPHY trial showed greater lowering with sepiapterin 60 mg/kg/day than with sapropterin 20 mg/kg/day (least-squares mean difference 180.4 μmol/L; 95% CI 131.4-229.5; p < 0.0001). Together, these data position sepiapterin as a next-step therapy beyond sapropterin, while underscoring the importance of biomarker studies that quantify BH4, BH2, and the BH4/BH2 ratio in plasma and cerebrospinal fluid.
Natural history of hearing loss in adults with mucopolysaccharidoses across phenotype and genotype.
McCarron EP, Stepien KM, Summerfield N … +5 more , Sharma R, Jovanovic A, Gossan N, Burkitt-Wright E, Gadepalli C
Mol Genet Metab · 2026 Jul · PMID 42107344 · Publisher ↗
BACKGROUND: Hearing loss is a recognised complication of mucopolysaccharidoses (MPS), but adult-specific data on long-term auditory outcomes remain limited. We aimed to characterise the adult natural history of hearing l...
BACKGROUND: Hearing loss is a recognised complication of mucopolysaccharidoses (MPS), but adult-specific data on long-term auditory outcomes remain limited. We aimed to characterise the adult natural history of hearing loss across MPS subtypes, including prevalence, severity, and longitudinal trajectory, and to explore associations with phenotype, genotype, and treatment exposure. METHODS: This retrospective study analysed clinical and audiological data from adults with confirmed MPS at a tertiary metabolic centre. Hearing loss was classified using standard thresholds. Cross-sectional analyses used the most recent audiogram, and longitudinal analyses compared earliest and most recent assessments. Associations with clinical and molecular variables were explored using non-parametric methods. RESULTS: Among 122 adults, 111 (90.9%) had recent audiological data. Hearing loss was present in 65.7%, predominantly sensorineural (51.4%). Severity varied significantly by subtype (p < 0.001), with greater impairment in MPS II and MPS IVA. Fifty-six patients had paired assessments over a median follow-up of 18 years. Although 14.3% showed worsening by ≥1 severity category, there was no evidence of systematic progression across the cohort. Hearing trajectories were similar irrespective of enzyme replacement therapy or haematopoietic stem cell transplantation. CONCLUSIONS: In the largest known adult cohort, hearing loss in MPS is common, subtype-specific, and predominantly sensorineural. Adults with MPS II and short-stature MPS IV are more severely affected. Hearing loss appears stable once established, suggesting a plateau in adulthood. Current therapies do not appear to modify adult auditory outcomes, underscoring the need for early intervention and lifelong audiological surveillance.
Patient experience informing outcomes and research in rare disease: Citrin deficiency as a case study.
Asami Y, Kuek LE, Chew SK … +1 more , Yu B
Mol Genet Metab · 2026 Jul · PMID 42107343 · Publisher ↗
The rapid expansion of therapies for rare diseases, including urea cycle disorders (UCDs), has intensified the need for endpoints that reflect meaningful benefit to patients. In rare inborn metabolic disorders, conventio...
The rapid expansion of therapies for rare diseases, including urea cycle disorders (UCDs), has intensified the need for endpoints that reflect meaningful benefit to patients. In rare inborn metabolic disorders, conventional clinical assessments and fragmented natural history data may not fully capture the daily disease burden. Citrin deficiency (CD) exemplifies this challenge: despite heterogeneous, age-dependent phenotypes, a "silent" or "adaptive" period is often described as largely asymptomatic based on clinical and biochemical measures. We present a patient-organization-led, patient-centered qualitative survey as a complementary approach to uncover "hidden" disease burden in a rare metabolic and urea cycle disorder. In an in-depth survey of seven adult CD patients, findings identified gaps between clinical descriptions and patient-reported disease burden. Fatigue and symptoms triggered by high carbohydrate intake emerged as key impacts on quality of life (QoL) among all surveyed patients. Other symptoms included under-recognized gastrointestinal (GI) issues, poor appetite, and psychological impacts. These findings contrasted with existing literature and questioned the concept of an asymptomatic adaptive phase. Although limited by the cohort size (n = 7), the current study illustrates how this approach can identify patient-important domains that standard clinical frameworks may under-capture. We propose that these domains should inform the development of fit-for-purpose patient-reported outcome measures (PROMs) and be integrated with relevant biochemical or molecular markers as endpoints for therapeutic studies and inform better research priorities and clinical management. More broadly, patient-organization-led qualitative surveying offers a scalable strategy to align translational efforts with outcomes that matter to patients across rare diseases.
Updates to gene-disease classifications and inheritance patterns for porphyrias.
Reeves EB, Hankey W, Clair PS … +6 more , Goldstein JL, Wilke MVMB, Feigenbaum A, Hung C, Spector E, Craigen WJ
Mol Genet Metab · 2026 Jul · PMID 42107342 · Full text
The heme synthesis pathway consists of eight enzyme-catalyzed steps, and pathogenic variants in the genes encoding these enzymes cause porphyrias. Diagnosis of certain porphyrias is often significantly delayed, due to th...
The heme synthesis pathway consists of eight enzyme-catalyzed steps, and pathogenic variants in the genes encoding these enzymes cause porphyrias. Diagnosis of certain porphyrias is often significantly delayed, due to their episodic and nonspecific symptoms that mimic more common conditions. To improve genetic diagnostics, which are increasingly used as a first-line approach, the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel identified the need to perform gene-disease curations for all genes in this pathway. During this process, we found that several genes (HMBS, UROD, CPOX, and PPOX) had multiple disease assertions, primarily differentiated by dominant versus recessive inheritance. For example, deficiency of HMBS is associated with both autosomal dominant acute intermittent porphyria (AIP) and autosomal recessive homozygous dominant AIP (HD-AIP). Yet, both conditions result from loss-of-function of the HMBS protein, and some recessive cases share identical causative variants with dominant cases. Therefore, our expert panel decided to include patients from both disease assertions (AIP and HD-AIP) as part of a single gene-disease curation rather than separating these groups of patients. This approach correctly links the variable affecting severity to allele dosage. This "lumping" process also required novel parent terms that encompass all disease subtypes and have gene-based nomenclature. Parent terms incorporating both monoallelic and biallelic subtypes were assigned a semidominant inheritance pattern, reflecting the overlapping variants and variable phenotypic severity based on residual enzyme activity. These gene-disease curations for the heme synthesis pathway pave the way for improved downstream variant curation which is a critical requirement to improve porphyria diagnostics. A key focus of this undertaking is to clarify and advance more appropriate nomenclature for these gene-disease relationships, enabling molecular laboratories to report variants in the heme synthesis pathway with greater precision.
Clinical and biochemical footprints of inherited metabolic disorders: XIX. Hypoglycemia.
Rossi A, Bocca G, Bos DK … +3 more , Ferreira CR, Blau N, Derks TGJ
Mol Genet Metab · 2026 Jul · PMID 42105432 · Publisher ↗
Hypoglycemia is one of the most common metabolic emergencies in childhood. If not promptly recognized and treated, it can cause irreversible neurological injury. In newborns, infants, and children, inherited metabolic di...
Hypoglycemia is one of the most common metabolic emergencies in childhood. If not promptly recognized and treated, it can cause irreversible neurological injury. In newborns, infants, and children, inherited metabolic diseases (IMDs) account for a large proportion of persistent or recurrent hypoglycemia, though other genetic and endocrine disorders can also be underlying causes. Timely etiological diagnosis is critical, as many causes are treatable and require specific management to prevent recurrence. We systematically reviewed and updated the list of inherited causes of hypoglycemia and identified 340 disorders, displaying characteristic clinical and biochemical "footprints" that can guide the diagnostic process. Despite the high burden and potential for targeted therapy, underdiagnosis and delayed management remain common. This article represents the nineteenth in a series aimed at creating and maintaining a comprehensive catalogue of clinical and biochemical differential diagnoses for IMDs according to system or symptom involvement.
Lysosomal storage, mitochondrial pathology, and autophagy in knockout of tripeptidyl peptidase 1 in human neuroblastoma cells in vitro.
Walus M, Kida E, Golabek AA
Mol Genet Metab · 2026 Jun · PMID 42102651 · Publisher ↗
Deficiency of tripeptidyl-peptidase 1 (TPP1; EC 3.4.14.9), a lysosomal enzyme encoded by the CLN2 gene, is associated with the lysosomal storage disorder - classic late infantile neuronal ceroid lipofuscinosis (CLN2 dise...
Deficiency of tripeptidyl-peptidase 1 (TPP1; EC 3.4.14.9), a lysosomal enzyme encoded by the CLN2 gene, is associated with the lysosomal storage disorder - classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease). The classic form of CLN2 disease leads to the accumulation of autofluorescent lysosomal storage and a massive loss of neurons with gliosis in the brain. The major component of the storage is subunit c of mitochondrial ATP synthase, a highly hydrophobic, 75-aminoacid polypeptide. We developed an in vitro model of CLN2 disease by knocking out CLN2 in the human neuroblastoma cells SH-SY5Y by using CRISPR/cas9 technology. We focused on defining the pattern of deposition of subunit c, factors contributing to subunit c accumulation, and subcellular morphometry to identify differences between the model cells knockout (KO) and controls. Implementation of acetone for cell fixation allowed us to: i. identify higher levels of subunit c in the mitochondria of KO cells than controls; ii. characterize in detail subunit c inclusions, also present in controls; iii. identify other mitochondrial proteins colocalizing with subunit c in inclusions; and iv. detect mitochondrial pathology in degenerating cells often accompanied by deposition of subunit c. Differentiation of cells with retinoic acid and brain-derived neurotrophic factor led to a substantial increase in the levels of subunit c and to significant differences in the levels of autophagy-related proteins between KO and control cells. Inhibition of induced autophagy by bafilomycin A1 (Baf.A1) decreased subunit c levels in controls but not in KO cells, whereas the levels of subunit c were unaffected by Baf.A1 treatment upon basal autophagy. Finally, subcellular morphometry showed differences in the number and size of vesicular structures immunostained for autophagy-related proteins between KO cells and controls upon both induced and basal autophagy, further supporting the association of TPP1 deficiency with autophagy.
AAV9/hGLA gene therapy reduces podocyte GL-3 accumulation in a Fabry disease mouse model.
Kanai T, Hayashi Y, Sehara Y … +5 more , Yoshino M, Kurosaki M, Kubota N, Mizukami H, Yamagata T
Mol Genet Metab · 2026 Jul · PMID 42102430 · Publisher ↗
BACKGROUND: Fabry disease is a hereditary disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of globotriaosylceramide (GL-3) in multiple cell types throughout the body. Terminally different...
BACKGROUND: Fabry disease is a hereditary disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of globotriaosylceramide (GL-3) in multiple cell types throughout the body. Terminally differentiated non-dividing cells, such as podocytes, are particularly susceptible to such accumulation and therefore require effective therapeutic intervention. Gene therapy is an ideal therapeutic intervention for replacing the deficient enzyme; however, one of the major challenges is maintaining long-term expression of episomal transgenes during cell division. In this regard, podocytes, as non-dividing cells, represent an ideal target for gene therapy in Fabry disease. Nevertheless, it has not been confirmed yet whether gene therapy vectors can transduce podocytes and reduce GL-3 accumulation especially in podocytes. METHODS: Male Fabry disease model mice (TgG3S/GLA knockout mice) received an intravenous injection of 2 × 10 vector genomes of AAV9 encoding human GLA at 6 weeks of age. Kidney tissues were analyzed 8 weeks after administration by electron microscopy (EM) and immunogold EM. RESULTS: In AAV9/hGLA-treated mice, GL-3 accumulation was markedly reduced in most podocytes, endothelial cells, and tubular epithelial cells, whereas it was evident in untreated mice. Virus-like particles were detected only in treated mice. Furthermore, immunogold EM confirmed the presence of AAV9 particles in the podocytes of treated mice. CONCLUSIONS: AAV9/hGLA gene therapy may reduce podocyte GL-3 accumulation in a Fabry disease mouse model, potentially through AAV9 transduction of podocytes; however, given the technical limitations of our approach, the precise cellular mechanisms remain to be determined.
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