With increased survival due to enzyme replacement therapy, children with classic infantile Pompe disease tend to develop a clinical phenotype with pronounced distal muscle weakness, while late-onset patients typically exhibit proximal muscle weakness. This MRI study aimed to characterize lower limb muscle involvement in classic infantile and young late-onset Pompe patients compared to healthy controls, and examine its relationship with motor function. Quantitative MRI (3-point Dixon and multi-echo spin-echo at 3T) was used to assess fat fraction (FF) and water T2 (T2water) in the leg muscles of eight classic infantile patients (6.6-15.0 years), 12 late-onset patients (6.8-27.3 years), and 13 healthy controls (6.5-26.9 years). Group comparisons were performed (Kruskal-Wallis, post hoc Dunn), and FF and T2water values were combined to identify the most frequently affected muscles. MRI findings were correlated with Quick Motor Function Test (QMFT) scores for thigh involvement and Medical Research Council (MRC) scores for foot dorsiflexion strength. MRI showed fat replacement and T2water abnormalities in numerous muscles in both patient groups. Fat replacement was generally mild (< 20%) but reached 69% in some cases. T2water values ranged from 21 to 37 ms. Classic infantile patients showed more frequent lower leg involvement (80% vs. 40%), while late-onset patients had predominant thigh involvement, particularly in the adductors. Extensive thigh involvement correlated with lower QMFT scores. Foot dorsiflexion weakness occurred only in classic infantile patients with tibialis anterior involvement. This data suggests a phenotype-specific pattern of muscle involvement and demonstrates the value of combining FF and T2water via quantitative MRI for detection of muscle involvement in Pompe disease.

Organic acidemias (OAs) are a group of inherited disorders, most commonly caused by defects in mitochondrial enzymes involved in amino acid and fatty acid metabolism. While they characteristically present with metabolic and neurological crises, growing evidence reveals a significant burden of chronic immune dysregulation in some disorders and patients. This review provides a synthesis of clinical and mechanistic evidence discussing immune dysregulation in OAs. Cytopenia can occur in OAs and predispose patients to recurrent and severe infections. Adaptive immune deficits, such as hypogammaglobulinemia, reduced B and T cell populations, and impaired vaccine-specific antibody responses, including to diphtheria and tetanus in MSUD and to the inactivated COVID-19 vaccine in propionic acidemia, have also been reported. Additionally, some case series note hyperinflammatory conditions, such as hemophagocytic lymphohistiocytosis. Mechanistic studies indicate that accumulated metabolites disrupt innate and adaptive hematopoietic progenitor function, mitochondrial homeostasis, and inflammatory signaling. Emerging therapeutic avenues, such as gene and mRNA-based therapies, hold the potential to improve or normalize the biochemical phenotype in OAs. While their impact on immune abnormalities remains largely unexplored, future clinical trials offer an opportunity to systematically assess potential effects on immune parameters. OAs are increasingly recognized as disorders with intrinsic immune dysregulation, extending beyond their well-characterized metabolic and neurological manifestations. Future clinical trials will benefit from including immunological endpoints to evaluate immunological recovery for novel therapies.

Vitamin-dependent cofactors are essential for numerous metabolic reactions, and defects affecting their uptake, conversion, utilisation, or regeneration constitute a heterogeneous group of inherited metabolic disorders (IMDs). Although dietary vitamin intake is sufficient to sustain coenzyme synthesis in healthy individuals, it is insufficient in vitamin-responsive IMDs, where pharmacological supplementation can restore deficient metabolic fluxes or stabilise impaired enzymes. This review provides an integrated overview of the biochemical pathways that convert vitamins into their active coenzymes and documents all currently known hereditary disorders responsive to vitamin or coenzyme therapy, along with recommended doses. For each vitamin group (B1, B2, B3, B6, B8, B9, and B12) and BH4, we outline absorption, intracellular trafficking, coenzyme formation and turnover, major clinical phenotypes, diagnostic biomarkers, and vitamin therapeutic considerations, including dose ranges, formulation constraints, and safety issues. The expected therapeutic benefit is graded to assist with clinical decision-making. As many conditions are rare and have only recently been described, the evidence is sometimes limited; therefore, systematic reporting of individual responses, including vitamin forms and dosing, remains essential. Early recognition of vitamin-responsive IMDs is critical, as timely treatment can dramatically alter disease trajectories and, in some cases, fully reverse symptoms.

Since the 1960s, phenylalanine hydroxylase (PAH) deficiency can be detected via newborn screening, allowing early start of treatment to prevent severe intellectual disability. Precise determination of PAH deficiency severity continues to be hampered by several factors. Nevertheless, as therapeutic options broaden, precise determination of PAH deficiency severity becomes critical to inform individualized treatment selection. Although various methods (hepatic PAH activity, pretreatment phenylalanine (Phe) levels, Phe loading test, Phe tolerance, invitro expression analysis, tracer studies, prediction models) have been used to assess and/or classify PAH deficiency, all of them still report inconsistencies in the correlation between genotype and biochemical phenotype. Establishing the genotype-phenotype correlation for different genotypes is complicated by the enormous genetic heterogeneity within the PAH gene. Furthermore, variability in the terminology applied to different phenotype strata further complicates interpretation. Here, we aim to summarize the methods that have been described in the literature to assess the classification of PAH deficiency and propose terminology to describe phenotype levels as a crucial step to overcome these issues.

Gaucher disease is a rare, autosomal recessive disease, with decreased activity of lysosomal glucocerebrosidase (GCase) due to changes in the GBA1 gene. There is no cure for Gaucher disease, and standard treatment involves the use of enzyme replacement therapy or substrate reduction therapy. We describe the first case of Gaucher disease that was treated with an autologous transplant of lentivirus-transduced CD34+ cells. Enzyme therapy was stopped 4 weeks prior to Day 0 of transplant. At 5 years of follow-up, dried blood spot GCase enzyme levels have remained in the normal range; there has been a consistent and sustained reduction of lyso-GB1 and liver volume, and hematological indices such as leukocyte count, hemoglobin, and platelet count have remained in the normal range despite no additional therapy for the Gaucher disease. This case shows a sustained response to a single dose of lentiviral gene therapy for Gaucher disease.

This guideline summarizes diagnostic and therapeutic approaches based on a systematic literature review and evidence evaluation using the GRADE methodology. Given the limited high-quality data, expert consensus was additionally obtained through a modified Delphi process. Remethylation disorders are rare inherited conditions that disrupt the methionine-homocysteine cycle and consecutively impair essential methylation dependent metabolic pathways. Remethylation disorders are caused by defects in the cobalamin or folate metabolism. The disorders typically result in elevated homocysteine and often low methionine; combined cobalamin-related defects also affect mitochondrial methylmalonic acid clearance. The cblC-MMACHC defect is the most common cobalamin-related remethylation disorder. Early-onset patients usually present with severe neurological and eye symptoms. Late-onset cases show variable symptoms (e.g., psychiatric, renal, thromboembolic events). Plasma total homocysteine, methionine, methylmalonic acid, serum vitamin B12 (and folates) should be assessed in suspected cases. Early detection through newborn screening is associated with improved clinical outcomes. Betaine as first-line therapy for methylenetetrahydrofolate reductase deficiency and parenteral hydroxocobalamin for cobalamin-related defects have reduced mortality and morbidity. Total homocysteine, methionine (and methylmalonic acid) should be kept as close to normal values as achievable. Emerging evidence suggests that early use of high-dose hydroxocobalamin (> 0.35 mg/kg/day) may improve neurocognitive impairment and may ameliorate eye disease in severe cobalamin-related defects. A major limitation in current practice is the lack of availability of high concentration hydroxocobalamin formulations for parenteral administration.

Almost all patients with mucopolysaccharidosis (MPS) develop respiratory dysfunction of varying severity during disease progression. While respiratory disease in MPS has traditionally been attributed to upper airway obstruction caused by glycosaminoglycan (GAG) accumulation in the trachea and bronchi, involvement of the intrapulmonary conducting airways and lung parenchyma remains poorly defined. Here, we characterised lung disease in a mouse model of MPS I using a combination of non-invasive X-ray Velocimetry (XV) functional lung imaging and gold-standard flexiVent respiratory mechanics testing, complemented by lung volume measurements and histological analysis. XV provides regional ventilation information across the entire lung during tidal breathing. MPS I mice demonstrated reduced mean specific ventilation (the average regional expansion of lung tissue across the respiratory cycle), driven predominantly by reduced ventilation in the inner (mediastinal-adjacent) lung regions, with evidence of spatially heterogeneous ventilation distribution. Lung mechanics testing showed increased conducting airway resistance, increased respiratory system compliance and reduced tissue elastance, consistent with impaired elastic recoil and expiratory flow limitation. Lung volume analysis revealed reduced opening pressure following degassing together with increased residual volume, functional residual capacity and vital capacity. Histological analysis demonstrated heterogeneous parenchymal architecture with regions of enlarged airspaces. Together, these findings demonstrate that respiratory dysfunction in MPS I is not limited to upper airway obstruction but also involves intrinsic abnormalities of the intrapulmonary conducting airways and lung parenchyma. This intrinsic pulmonary pathology likely contributes to obstructive lung disease and may underlie the susceptibility to respiratory failure observed in patients with MPS I.

Tetrahydrobiopterin (BH4; sapropterin) responsiveness in phenylalanine hydroxylase (PAH) deficiency is genotype dependent, yet many patients remain untested. Allelic phenotype values (APV) summarize allele severity, but responsiveness can be heterogeneous within APV strata. We assessed whether integrating functional consequence annotation from Ensembl variant effect predictor (VEP) improves genotype-based prediction of BH4 response. We analyzed 23 640 individuals with biallelic PAH genotypes and BH4 status (RESP, S-RESP, N-RESP, or not tested). Tested individuals were used for model development (responders defined as RESP+S-RESP; nonresponders as N-RESP). APV values were assigned from published APV resources and merged at the variant level. Functional consequence predictors were derived from VEP output and included strict predicted loss-of-function (pLoF) flags, splice-impact scores (SpliceAI maximum delta score), and missense pathogenicity predictions (SIFT and PolyPhen). Genotype predictors were constructed using a milder-versus-severer allele framework, with the milder allele defined as the allele with the higher APV. Models were evaluated using genotype-held-out cross-validation (GroupKFold by genotype). Among 4640 tested individuals, 2044 (44.1%) were BH4 responders. Responder rates were enriched in milder phenotypes and increased monotonically across milder-allele APV bins. In genotype-held-out evaluation, integrating functional consequence predictors with APV improved discrimination modestly overall and more clearly in intermediate APV genotypes. Genotype predicts BH4 responsiveness with high performance under stringent genotype-held-out validation, and VEP-derived functional consequence annotation provides modest complementary value beyond APV, particularly for intermediate-severity genotypes.

Niemann-Pick type C (NPC) is a childhood dementia characterized by lysosomal lipid accumulation. In Npc1-/- mice, Rapamycin, an autophagy inductor, yielded opposite results depending on genetic background, suggesting the presence of pharmacogenomic modifiers. To identify them, we used a genotyped yeast panel designed for gene mapping and the NPC-mimetic U18666A (U18-drug) in the presence and absence of rapamycin. We evaluated cell growth, vacuolar fragmentation, and transcriptomics across diverse strains. Linkage analysis based on cell growth identified a significant locus, leading to the prioritization of nine genes. Notably, ccs1 (copper chaperone for superoxide dismutase) and avo2 (TORC2 subunit) deletions decreased cell growth compared to U18-Rapa in WT cells, while irc21 (DNA damage and ceramide metabolism) increased it. Our results suggest that genomic variants within these genes should be assessed before using rapamycin for NPC. This study represents a crucial step towards personalized rapamycin therapeutics.

Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disorder caused by deficient activity of lysosomal alpha-galactosidase A (AGAL, E.C. 3.2.1.22) due to pathogenic variants in the GLA gene (HGNC:4296, Xq22.1). Plasmatic deacylated globotriaosylceramide (lysoGb3) is elevated in FD patients as a reflection of lysosomal accumulation of Gb3. Specific (AGALopathic) GLA variants have been recently shown to accumulate within the secretory pathway and trigger endoplasmic reticulum stress and unfolded protein response rather than result in profound enzymatic deficiency. In part due to lack of integrative measures of clinical severity and biochemical/molecular parameters, specific impacts and consequences of X-chromosomal inactivation (XCI) on clinical manifestation in FD female heterozygotes still remain to be fully understood. Our study aimed at evaluation of XCI (% of inactive wt GLA allele) in untreated female FD heterozygotes with classic FD (n = 17), late-onset FD (n = 19) and individuals carrying GLA variants (p.(L394P) (n = 7), p.(A143T) (n = 4), and p.(D313Y) (n = 4)) with predominant AGALopathic effects. XCI was correlated with age of the patients, clinical phenotype, (residual) AGAL activity, and lysoGb3. AGAL activity corresponded to XCI independently of the type of the GLA mutation. The best separation of the clinical phenotypes (classic FD, late-onset FD and AGALopathy) was achieved by correlating XCI to the ratio of AGAL activity to lysoGb3. This three parametric calculated marker was then confronted with the Mainz Severity Score Index (MSSI) to generate an Integrative Clinical-Laboratory quotient (ICLq). ICLq discriminated the three female patient groups and demonstrated group-dependent differences in its average age-related increase.