BACKGROUND:Primary mitochondrial diseases (PMDs) comprise a genetically and clinically heterogeneous group of disorders for which evidence-based therapeutic options remain limited. Despite advances in molecular diagnosis and the identification of gene-specific therapeutic targets for selected conditions, vitamin and cofactor supplementation continues to be frequently prescribed. We aimed to evaluate prescribing patterns, dosing practices and the balance between PMDs with established genotype-directed metabolic therapy and PMDs managed with empirical supplementation in a genetically confirmed PMD cohort. MATERIALS AND METHODS:We retrospectively reviewed 62 patients with genetically confirmed PMDs followed at a tertiary pediatric metabolism center between 2015 and 2025. Demographic, genetic and treatment-related data were collected, including vitamin and cofactor use and dosing regimens. Patients were categorized as PMDs with genotype-directed therapies and PMDs managed with empirical supplementation. RESULTS:Sixty-two patients were included (43.5% female; mean age 10.7 years). Oxidative phosphorylation (OXPHOS) complex defects were the most common genetic category (35.5%). Overall, 71% of patients received at least one vitamin or cofactor supplement. Coenzyme Q10 (62.9%), carnitine (53.2%), riboflavin (48.4%), biotin (37.1%) and thiamine (35.5%) were the most frequently prescribed agents. Thirteen patients (21%) had PMDs with established targeted therapies and received genotype-directed treatment. Among the remaining 49 patients, who lacked a defined genotype-directed therapeutic option and were therefore classified as being managed with empirical supplementation, 63.2% (31/49) received at least one vitamin or cofactor supplement. CONCLUSION:Despite advances in molecular diagnosis, empirical vitamin and cofactor supplementation remains frequently used in patients with PMDs who lack established gene- or pathway-specific therapeutic options. These findings underscore the persistent gap between molecular diagnosis and evidence-based therapy and support the need for prospective multicenter studies to guide standardized treatment approaches in PMDs.
PURPOSE:Hypophosphatasia (HPP) is a multi-system genetic disorder that affects mineralization of the skeleton and dentition. Despite the success of postnatal enzyme replacement therapy (ERT), children with life-threatening presentations (LT-HPP) experience significant morbidity, decreased quality of life, and risk of death. Recent evidence suggests that in-utero ERT (IU-ERT) may further improve outcomes; however, acceptability within the HPP community has not been assessed. This study aimed to explore patient and caregiver attitudes toward IU-ERT for LT-HPP. METHODS:We surveyed adults with lived experience with HPP. The survey was distributed through patient advocacy organizations. RESULTS:Ninety-two individuals completed the survey. Most participants supported availability of IU-ERT following prenatal detection of LT-HPP and further research in this area. Predominant concerns were potential risks for the baby or mother, long-term side effects, and uncertainty regarding treatment effectiveness. Frequent reasons cited for one to pursue IU-ERT were reduced disease severity, a potential cure, and reduced mortality. Potential barriers included perceived risks, uncertainty regarding safety or benefits, and financial burden. CONCLUSIONS:Participants were supportive of further research and clinical trials for IU-ERT for LT-HPP. These results provide preliminary evidence that can be used to inform the development and implementation of IU-ERT for LT-HPP.
Lysinuric protein intolerance (LPI) is a rare inherited metabolic disorder characterized by multisystem involvement, including failure to thrive, protein intolerance, hepatosplenomegaly, osteoporosis, pulmonary and renal disease, neurological impairment, and immune-dysregulation. Although immune-abnormalities are increasingly recognized in LPI, the immunological consequences of altered amino acid homeostasis remain incompletely understood. According to this, we aimed to characterize the immunologic-phenotype of patients with LPI. Patients with LPI and age-matched healthy controls were enrolled. Peripheral lymphocyte subsets, intracellular protein and cytokine expression, and lymphocyte-proliferative responses were assessed by flow cytometry. Serum immunoglobulin levels and amino acid profiles were analyzed using high-performance-liquid-chromatography. A total of 10 patients with LPI and 18 healthy-controls were included. Patients exhibited a combined immunological and metabolic phenotype characterized by reduced B-cell and class-switched memory B-cell compartments with IgG deficiency, together with impaired lymphocyte-proliferative responses despite preserved T-cell numbers. Cytokine profiling demonstrated decreased IL-17 and IL-4 responses, whereas IFN-γ production was relatively preserved. In parallel, stimulation-dependent alterations in amino acid profiles and disease-specific correlations between amino acids and immune-parameters suggested a direct link between disrupted amino acid homeostasis and immune dysfunction. Beyond quantitative immune defects, our findings reveal disease-specific metabolic signatures accompanying lymphocyte activation in LPI. Mitogenic stimulation induced coordinated amino acid changes in healthy controls, whereas this response was altered and accompanied by distinct metabolic changes, including increased citrulline levels. Overall, our findings indicate that lysinuric protein intolerance is associated with an immune phenotype characterized by humoral and cellular immune abnormalities accompanied by metabolic alterations. Together with previous studies describing innate immune dysfunction, these findings further support immune dysregulation as an important feature of LPI.
Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by pathogenic variants in AGL, which encodes the glycogen debranching enzyme (GDE). Loss of GDE function impairs glycogen degradation, leading to accumulation of abnormal glycogen in liver and skeletal muscle. Clinical manifestations arise in early childhood and include hypoglycemia, hepatomegaly, and progressive myopathy. Despite significant morbidity, no disease-modifying therapies exist, due in part to a lack of rigorously validated cellular models. Patient-derived fibroblasts provide an accessible and scalable system that preserves each patient's endogenous AGL genotype and broader genetic background, enabling investigation of disease heterogeneity, genotype-phenotype relationships, and potential genetic modifiers. We performed whole-genome sequencing and phenotypic characterization of nine fibroblast lines originating from patients who were diagnosed with GSD III. Eight lines harbored biallelic pathogenic or likely pathogenic AGL variants, while one was reclassified based on absence of AGL variants and the presence of a pathogenic variant in an alternative metabolic gene. Validated GSD III fibroblasts exhibited consistent disease features, including absence of GDE protein, impaired glycogen utilization, and distinct lipidomic signatures. We generated an isogenic immortalized AGL-deficient fibroblast model which recapitulated these phenotypes. Together, these patient-derived and isogenic models provide a robust, genomically defined platform for studying the pathogenesis and phenotypic heterogenity of GSD III. Refined characterization and accessibility of these models will be useful to evaluate candidate GSD III therapeutics.
The advent of newborn screening for Pompe disease has led to a massive increase in the number of missense variants of uncertain significance (VUS) reported in GAA. Molecular diagnostic testing may be inconclusive in the presence of one or more VUS, posing a significant challenge since most positive NBS occur in healthy infants with no apparent disease-related symptoms. It then becomes challenging to distinguish between pre-symptomatic infants with late-onset Pompe disease who require close monitoring and follow-up, and those who may just be carriers or have a partially functional pseudodeficiency variant. Missense variants are notoriously difficult to interpret in a clinical setting. Thus, there is a high demand for functional evidence to predict their impact in the absence of documented clinical evidence. To address this rapidly growing need, we have developed and validated a cell-based in vitro assay to test individual missense variants and their impacts on GAA enzyme activity and protein processing. Using this assay, we characterized 42 missense GAA VUS. We found that residual enzyme activity spanned the full GAA activity range, from complete loss of product to near wild type, with 66% of these variants falling below established cutoffs for a potentially deleterious effect. In addition, we provide case examples from individuals evaluated at the Duke Pediatric Medical Genetics clinic with GAA VUS and describe the utility of this functional assay in solving clinical conundrums. While variant classification cannot rely on a single line of evidence, our assay adds functional evidence to support classifications and clinical decision making, especially in the setting of novel variants not previously reported in patients with Pompe disease.
BACKGROUND:Beta-ketothiolase deficiency (BKTD) is a rare autosomal recessive metabolic disorder affecting isoleucine catabolism and ketone body utilization, demonstrating marked clinical and biochemical heterogeneity. This study aims to characterize the longitudinal clinical, biochemical, and genetic features of a single-center BKTD cohort and evaluate phase-dependent dynamics in metabolic biomarkers during acute crises and stable follow-up periods. METHODS:Twenty patients from 11 families diagnosed with BKTD were included in this retrospective study. Longitudinal clinical findings, plasma acylcarnitines via LC-MS/MS, and urinary organic acids via GC-MS were comprehensively evaluated during both acute catabolic crises and stable follow-up intervals. ACAT1 variants and genotype-phenotype correlations were statistically analyzed. RESULTS:The median age at diagnosis was 9.5 months, and parental consanguinity was present in 81.8% of families. Clinical manifestations ranged from asymptomatic disease to severe metabolic crises, with neurological involvement in 10% of patients and mortality in 5%. The most frequent ACAT1 variant was c.158G > A, accounting for 42.1% of cases. Plasma C5OH was the most consistent biomarker, remaining elevated in 100% of acute and 97.1% of stable samples. Plasma C5:1 was elevated in 85.7% and 73.5% of acute and stable samples, respectively. In contrast, C4OH elevation was observed only during acute crises (28.6%) and was absent during stable follow-up. Urinary 2M3HB and TIG were elevated in all acute samples but showed reduced positivity rates during remission. CONCLUSION:BKTD exhibits significant phase-dependent metabolic variability driven by catabolic stress. Longitudinal multi-marker evaluation is essential, as single-time-point biochemical assessments during stable remission carry a distinct risk of false-negative results.
BACKGROUND:This study analyzed tandem mass spectrometry (MS/MS) screening results from 404,990 newborns in Beijing (2022-2025) to determine the incidence, outcomes, genetic findings, and follow-up of inherited metabolic diseases (IMDs). METHODS:Dried blood spot samples were screened by MS/MS for amino acid (AAs), organic acid (OAs), and fatty acid β-oxidation disorders (FAs). Positive cases were recalled for confirmatory and genetic testing. RESULT:A total of 243 cases of IMDs were diagnosed, including 123 cases of AAs (1:3293), 76 cases of OAs (1:5329), and 44 cases of FAs (1:9204). The regional specific incidence rate was 1:1667. PAH deficiency was the most prevalent AAs, with 99 cases (incidence 1:4091). MMA was the most common OAs, with 55 cases (incidence 1:7363). PCD was the predominant FAs, with 19 cases (incidence 1:21,315). In total, 22 types of IMDs were identified, including nine AAs, eight OAs, and five FAs. Genetic analysis identified hotspot variant s in PAH (c.728G>A [p.Arg243Gln] and c.158G>A [p.Arg53His]) and MMACHC (c.609G>A [p.Trp203*], c.482G>A [p.Arg161Gln], and c.658_660delAAG [p.Lys220del]). Three novel variants were identified. Of 243 confirmed patients, 236 received continuous treatment; 7 died. CONCLUSIONS:This first large-scale MS/MS newborn screening in Beijing identified 22 IMDs types with a relatively high overall incidence. Three novel variants expand the variant spectrum. Early detection through MS/MS is critical for improving prognosis and represents a vital public health strategy. To further promote public health, future efforts will prioritize second-tier biochemical testing to improve PPV and diagnostic speed, and expand the panel only to clinically validated disorders. Genetic testing remains adjunctive for subtype confirmation; population-level application would require rigorous prospective evaluation.
OBJECTIVES:Differentiating primary mitochondrial disease (PMD) from disorders associated with secondary mitochondrial dysfunction may be challenging because of overlapping biochemical and clinical features. In the present study, the group designated as secondary mitochondrial dysfunction consisted specifically of lysosomal storage disorders. Single biomarkers, such as FGF-21 and GDF-15, may have limited discriminatory power in this setting. In this study, multivariate metabolite panels distinguishing PMD, lysosomal storage disorders associated with secondary mitochondrial dysfunction (SMD), and healthy controls (HC) were developed and internally validated using a leakage-controlled machine learning framework with interpretable outputs. METHODS:This prospective study included 88 participants: 28 patients with genetically confirmed PMD, 30 patients with genetically confirmed lysosomal storage disorders associated with secondary mitochondrial dysfunction, and 30 healthy controls (HC). Plasma amino acids were quantified by LC-MS/MS, urinary organic acids by GC-MS, and serum FGF-21 and GDF-15 by ELISA, yielding 77 variables. Three pairwise tasks were modeled using nested cross-validation, stability-ranked feature selection, and elastic net logistic regression. Performance was summarized using mean outer-fold AUC, accuracy, sensitivity, and specificity, with BCa confidence intervals; DeLong confidence intervals were calculated from pooled out-of-fold predictions. RESULTS:The comparison between the lysosomal storage disorder group and the PMD group showed the highest discrimination within the present cohort (mean outer-fold AUC, 0.988; pooled-OOF DeLong 95% CI, 0.952-1.000; mean outer-fold accuracy, 0.948). Parsimonious panels were identified: SMD vs. PMD-asparagine, lactate, GABA, homocystine, hydroxylysine; SMD vs. HC-asparagine, pyruvate, GDF-15, histidine, urinary 4-hydroxyphenylpyruvic acid; PMD vs. HC-GDF-15 and lactate. SHAP analysis supported the consistency in the mitochondrial redox and amino acid pathways. CONCLUSIONS:A multivariate metabolomic approach provided discriminatory information between genetically confirmed PMD, selected lysosomal storage disorders associated with secondary mitochondrial dysfunction, and healthy controls. The highest performance was observed between the two patient groups. However, these findings are specific to the diagnostic composition of the present cohort and should not be interpreted as establishing a universal distinction between primary and secondary mitochondrial dysfunction. External validation in larger, independent, and diagnostically broader cohorts is required before clinical implementation.
CLN1 Batten Disease is caused by mutations in the CLN1 gene resulting in a reduction or absence of enzyme activity. It is characterized by progressive cognitive, language and motor regression, seizures, loss of vision, and early death. There is currently no approved treatment for this rare disease apart from palliative care. Recombinant human palmitoyl-protein thioesterase-1 (rhPPT1, CPI-601) can be used as an enzyme replacement therapy (ERT) for CLN1. A good laboratory practice (GLP) repeat-dose toxicology and pharmacokinetic study was conducted in juvenile cynomolgus monkeys following intracerebroventricular (ICV) administration of CPI-601 to support clinical translation based on efficacy data seen in the CLN1-/- mouse preclinical efficacy model. Safety assessments included clinical observations, neurologic evaluations, clinical pathology, electrocardiography, ophthalmology, anti-drug antibody (ADA) analysis, pharmacokinetics, and comprehensive neuropathology. CPI-601 demonstrated rapid cerebrospinal fluid (CSF) exposure with peak concentrations observed approximately 0.5 h following administration. Exposure increased with dose, while systemic exposure remained limited. In CLN1 patient fibroblasts, CPI-601 exhibited a half-life of 21.38 h. No anti-drug antibodies (ADAs) were detected during the study. No treatment-related changes were observed in body weight, electrocardiography, ophthalmology, respiratory parameters, or clinical pathology. No comparable adverse findings were observed at lower dose levels. There were microscopic findings only at the highest dose tested, that were minor to moderate in nature and progressed from minimal microgliosis at the end of dosing to moderate neurodegenerative changes during recovery. This study now supports dosing of CPI-601 ICV in a pediatric clinical trial for which allometric scaling was used to enable dose selection. ONE SENTENCE SUMMARY: Safety evaluation and pharmacokinetics of CPI-601 as an enzyme replacement therapy for CLN1 Batten disease in non-human primates.
Fabry disease is an X-linked lysosomal disorder caused by deficient α-galactosidase A activity, leading to progressive tissue accumulation of globotriaosylceramide (Gb₃) and globotriaosylsphingosine (lyso-Gb₃) throughout the body, with vascular, renal, cardiac, and neural tissues considered the most prominently affected. Although renal and cardiac endpoints currently dominate therapeutic monitoring and regulatory assessment, accumulating evidence demonstrates that central nervous system (CNS) involvement begins early, evolves sub-clinically, and contributes significantly to long-term morbidity. CNS injury in Fabry disease reflects a convergence of multi-system consequences of substrate accumulation, manifesting into endothelial dysfunction, microvascular ischemia, neuroinflammation, oxidative stress, and impaired autophagy-lysosome homeostasis. This review synthesizes advances in fluid and imaging biomarkers that are directly or indirectly associated with mechanistic pathways, including lyso-Gb₃ analogues, inflammatory and oxidative stress mediators, and neurofilament light chain (NfL) as a dynamic marker of neuroaxonal injury. We further examine emerging neuroimaging modalities, e.g., diffusion tensor imaging (DTI), quantitative susceptibility mapping, perfusion magnetic resonance imaging (MRI), and volumetric analyses, that quantify microstructural white matter injury, thalamic vulnerability, and cerebrovascular dysfunction. The strengths, limitations, and translational readiness of these biomarker classes are evaluated in the context of therapeutic monitoring, clinical trial design, and biomarker qualification pathways. Taken together, a multidomain biomarker strategy integrating advanced MRI metrics, NfL, and substrate- or inflammation-linked markers provides a more complete assessment of CNS involvement and offers a promising direction for earlier detection, improved disease monitoring, and future development of surrogate endpoints relevant to neurologic outcomes in Fabry disease.
Beta-mannosidosis is a lysosomal storage disorder caused by pathogenic variants in the MANBA gene, resulting in deficiency of beta-mannosidase. This enzyme is essential for terminal glycoprotein degradation within lysosomes, and its deficiency leads to glycoprotein accumulation in the brain and other organs. Clinical manifestations are heterogenous and may include hearing loss, developmental delay, seizures, angiokeratomas, vision abnormalities, and intellectual disability. Currently, no disease-specific treatment exists. We previously reviewed clinical features in 46 individuals worldwide. This study highlights six new cases of beta-mannosidosis. Patient 1, an 8-year-old male, presented with a failed newborn hearing screening and compound heterozygote c.550-1G > A and c.562 T > G variants. Patient 2, a 40-year-old male, was diagnosed at age 3 with language delay, hearing loss and behavioral issues. He has c.375_378del, p.Tyr126Alafs*11 and c.1513 T > C variants. Patient 3, a 6-year-old female, developed gait disturbances and visual difficulties at 3 years and is homozygous for the c.188 A > G variant. She also has homocystinuria. Patient 4, a 15-year-old female with sensorineural hearing loss at age 2 years, carries variants c.1454_1455del and c.550-3C > A. Patient 5 presented at age 12 years with sensorineural hearing loss, intellectual disability, juvenile glaucoma and is homozygous for the c.1452_1453del variant. Patient 6, a 14-year-old male failed the newborn hearing screening. He is homozygous for variant c.378 + 1G > A. Analysis of these patients highlights marked phenotypic variability with no clear genotype-phenotype correlation. Early screening may enable prompt diagnosis, improve management, and support future therapeutic development.
Background Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by aldolase B deficiency (ALDOB). Patients with HFI require lifelong adherence to a fructose-restricted diet. However, despite strict dietary restriction, both HFI patients and mice with Aldob−/− exhibit hepatocellular accumulation of fructose 1-phosphate (F1P) and intrahepatic lipids (IHL). We studied whether endogenously produced fructose could account for these observations. Methods We first measured serum fructose levels during a 75 g oral glucose tolerance test (OGTT) in patients with HFI (n = 14) and matched healthy controls (n = 14). Furthermore, we quantified the incorporation of 13C6-glucose into F1P in Aldob−/− mice (n = 4) and wildtype mice (n = 4). Next, we examined the effects of inhibition of endogenous fructose production in Aldob−/− mice. Aldob−/− mice were treated for 9 days with an aldose reductase inhibitor (ARi; n = 9) or vehicle (n = 9) under fructose-free dietary conditions. Results Serum fructose concentrations increased significantly at 30 and 60 min compared to baseline in patients with HFI and controls (P < 0.05), indicating glucose-derived fructose production. Similar, 13C6-glucose was incorporated into F1P in Aldob−/− mice and wildtype mice. ARi-treatment significantly reduced hepatic fructose levels in Aldob−/− mice (P = 0.002), confirming effective inhibition of the polyol pathway, but did not reduce IHL content (P = 0.71). Conclusions Although endogenous fructose production contributes to circulating and hepatic fructose levels in Aldob−/−, inhibition of the polyol pathway does not reduce hepatic steatosis in Aldob−/− mice under fructose-free conditions.
People with mitochondrial disease (MD) associated with the m.3243 A > G mutation often experience gastrointestinal complaints and dysmotility, suggesting dysbiosis of the gut microbiome. A common phenotype of the m.3243 A > G mutation is Maternally Inherited Diabetes and Deafness (MIDD). Previous studies have shown that other forms of diabetes are associated with an altered gut microbiome. Therefore, our study aimed to investigate the gut microbiota of people with MD caused by the m.3243 A > G mutation compared to healthy controls (Lifelines®) and people with type 1 diabetes (T1D). Fecal samples of 30 people with the m.3243 A > G mutation were used for shotgun metagenomic sequencing. The MD group was compared with 60 healthy controls and 60 people with T1D from different datasets, and were matched for age, sex, and BMI. We found that the Bray-Curtis β-diversity of the gut microbiota differed significantly between MD compared to healthy controls and T1D, while there was a non-significant reduction in Shannon α-diversity in the MD group. The gut microbiota of the MD group was characterized by reduced Faecalibacterium prausnitzii, and increased Escherichia coli, Ruminococcus gnavus, and Ruminococcus torques levels compared to healthy controls and T1D. This pattern aligns with microbial signatures reported in inflammatory bowel disease, which is associated with mitochondrial dysfunction in intestinal epithelial cells. Overall, our explorative study suggest that people with the m.3243 A > G mutation exhibit a dysbiotic gut microbiota, which may pave the way for future research aimed at developing new therapies, dietary adjustments and their potentials to improve quality of life.
BACKGROUND:3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is an ultra-rare autosomal recessive disorder of leucine catabolism and ketogenesis. Evidence on its long-term course and management is limited, with no international consensus on treatment. We characterized the clinical, genetic, dietary, and long-term outcomes of HMGCLD in a Turkish cohort. METHODS:We retrospectively analyzed 12 patients with HMGCLD followed at a tertiary metabolic center in Turkey between 1996 and 2026. Cross-sectional and longitudinal clinical, biochemical, dietary, and neurocognitive data were collected. Variants were classified according to ACMG/AMP guidelines. RESULTS:Twelve patients (5 males, 7 females; 10 families; parental consanguinity, 75%; median age,19 years) were included. Eleven presented with symptoms, most within the first year of life; whereas one was identified through newborn screening abroad. Three had diagnostic delays of 5, 10, and 17 years. Five HMGCL variants were identified, including two previously unreported variants, one of uncertain significance. Six remained on a leucine-restricted diet; in four, the leucine-free amino acid mixture was discontinued under medical supervision after plasma leucine normalized. Growth was preserved, and eight of 11 assessed patients had borderline or better cognitive performance. Hepatic steatosis was present in 5/12 patients (42%). Three of six adults developed metabolic decompensation after age 18, including one fatal pregnancy-related crisis. CONCLUSIONS:HMGCLD is a lifelong disorder with preserved growth and variable cognitive outcomes. Our findings expand the HMGCL mutational landscape, identify hepatic steatosis as a potentially underrecognized finding warranting further study, and highlight the persistent risk of adult metabolic decompensation, particularly during pregnancy.
INTRODUCTION:Variegate Porphyria (VP) is the predominant porphyria in South Africa, historically linked to Dutch colonization, and is considered the second most common AHP. Data from Brazil remain scarce. This study aimed to describe the genetic findings in a case series of Brazilian VP patients. METHODS:We conducted a cross-sectional study including patients with VP from three different Brazilian tertiary centers. Medical records and previous genetic testing reports from commercial kits were reviewed and presented including literature review. RESULTS:A total of 35 patients from 19 families were identified. Twenty-three of these had experienced acute attacks, with first symptoms presenting between 17 and 62 years of age. All patients initially presented abdominal pain, and 20 developed severe attacks followed by acute flaccid paralysis. Genetic analysis revealed that fourteen (74%) families carried the same missense variant in exon 6 of PPOX gene (p.Arg168His). CONCLUSION:We describe the first case series of Brazilian VP patients with a recurrent variant p.Arg168His that may suggest a regional founder effect or uncharacterized ancestral links, which warrant further genetic and epidemiological studies.
Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive disorder of heme biosynthesis caused by severe deficiency of uroporphyrinogen decarboxylase (UROD). It typically presents in infancy or early childhood with marked photosensitivity, skin fragility, blistering, dyspigmentation, hypertrichosis, and dark urine. We report a girl from Brazil who developed blistering and ulcerative lesions of the face and upper extremities beginning at 10 months of age, along with dark urine and gray discoloration of the teeth. She was 2.5 years old when first evaluated at the Massachusetts General Hospital Porphyria Center. Prior genetic testing in Brazil had already identified two UROD variants, c.239C>G (p.Ala80Gly) and c.464C>T (p.Ala155Val). At our center, erythrocyte UROD activity was markedly reduced to approximately 5% of normal, and plasma, urine, stool, and erythrocyte porphyrins were all substantially elevated, confirming the diagnosis of HEP. Erythrocyte protoporphyrin was 83.5% zinc-chelated. The patient also had persistent mild hepatosplenomegaly and mild transaminase elevation. Management included strict photoprotection and sequential trials of cholestyramine and cimetidine, followed by serial therapeutic phlebotomy while continuing cimetidine. Neither cholestyramine nor therapeutic phlebotomy was associated with clear biochemical improvement, whereas cimetidine was temporally associated with a decline in urinary porphyrins, although other biomarkers were more variable. This case highlights the importance of considering HEP in children with blistering lesions on sun-exposed skin.
Galactosemias (GALAC) are rare inherited metabolic disorders with highly variable prevalence worldwide. Differences in newborn screening (NBS) implementation, diagnostic methodologies, and population-specific genetic factors contribute to heterogeneity in epidemiological estimates. We aimed to map the estimated global GALAC birth prevalence and explore the role of NBS in shaping epidemiological patterns. A scoping review was conducted following PRISMA-ScR guidelines. Studies reporting prevalence or incidence of GALAC were included regardless of country or screening context. Data were extracted on study design, population characteristics, screening strategies, diagnostic methods, and reported prevalence, standardized to cases per 100,000 live births when possible. Twenty-eight studies were included, predominantly from Europe, Asia, and North America. Birth prevalence estimates ranged widely, from undetected cases in some Asian populations to over 100 cases per 100,000 live births in isolated populations. Most studies reported one-to-five cases per 100,000 live births in regions with established NBS programs. Higher birth prevalence in specific populations was associated with founder effects, genetic isolation, and sociocultural factors including endogamy and consanguinity. Variability was also influenced by screening coverage, study design, and diagnostic approaches. Programs relying solely on biochemical methods showed limitations in detecting non-classical subtypes, while combined or multi-tier strategies improved diagnostic accuracy but affected the birth prevalence estimates through inclusion of variants. GALAC estimated global epidemiology reflects a complex interplay of genetic, demographic, and methodological factors. Standardization of screening strategies and NBS expansion, particularly in underrepresented regions, are essential to improve comparability of epidemiological data and accurately estimate disease burden.
