OBJECTIVE: 3-methylglutaconic aciduria (MEG), dystonia-deafness (D), (hepatopathy (H)), encephalopathy (E), and Leigh-like-syndrome (L) (MEGD(H)EL) syndrome is a rare, severely disabling progressive mitochondrial disease...OBJECTIVE: 3-methylglutaconic aciduria (MEG), dystonia-deafness (D), (hepatopathy (H)), encephalopathy (E), and Leigh-like-syndrome (L) (MEGD(H)EL) syndrome is a rare, severely disabling progressive mitochondrial disease associated with biallelic pathogenic variants in SERAC1. Knowledge about hearing loss (HL) and hearing rehabilitation is scarce but highly sought after for best possible care in the absence of causative treatment. METHODS: Retrospective cross-sectional study. RESULTS: This study analyzed the audiometric data of 36 MEGD(H)EL patients (14 unpublished). Bilateral HL was diagnosed in 31 individuals (86 %). Detailed audiometric data, available for 23 of 31 patients, did not allow for general statements on site and degree of HL. HL was mostly congenital (n = 14/31), pre-lingual in six and post-lingual in nine cases (median age 2 years, n = 15/31; age unknown in n = 2). In four of the five patients without HL, the severity of the other clinical-neurological symptoms was milder and less progressive, and their onset was significantly later than in the patients with HL. Five of 36 patients acquired spoken language, these were 4 of the 5 individuals without and one with HL. Twenty-two individuals received hearing rehabilitation with conventional hearing aids, followed by cochlear implant (CI) surgery in six. One of these six individuals acquired spoken language, which lessened in clarity as disease progressed. CONCLUSIONS: Congenital HL represents a ubiquitous symptom in severe types of MEGD(H)EL syndrome, being absent in late onset milder forms. Regularly, severely affected MEGD(H)EL patients do not achieve spoken language, even with CI. Hence, hearing rehabilitation with CIs needs to be discussed very critically.
Altassan R, Aldhahri SK, Macdonald G
… +2 more, Shah R, Morava E
Mol Genet Metab
· 2025 · PMID 40706141
·
Full text
GMPPA-Congenital Disorder of Glycosylation (CDG) is an ultra-rare autosomal recessive CDG caused by pathogenic variants in GMPPA that affects the N-linked glycosylation pathway. Affected individuals present with three ma...GMPPA-Congenital Disorder of Glycosylation (CDG) is an ultra-rare autosomal recessive CDG caused by pathogenic variants in GMPPA that affects the N-linked glycosylation pathway. Affected individuals present with three major symptoms: achalasia, alacrima, and impaired intellectual development during infancy. Current management of GMPPA-CDG is targeted to address patients' symptoms. To date, 23 individuals have been reported with GMPPA-CDG. This paper reviews the clinical, biochemical and genetic characteristics of the reported 23 patients and adds 3 patients with GMPPA-CDG. We also describe the effect of oral N-acetylglucosamine (GlcNAc) supplementation in 3 patients. Besides alacrima, achalasia and developmental/ intellectual disability, we noted in these patients also variable growth impairment, facial dysmorphism, hyperkeratosis, hypohidrosis, anodontia, and hearing deficit. Under treatment with GlcNAc (4-6 g/day), we noted improved tear production in our 3 patients. Given its effect on different developmental pathways, we emphasize the need for multidisciplinary care for this multisystem disorder. We did not find a genotype/phenotype correlation in our cohort of 26 patients.
Pyridoxine dependent epilepsy due to Antiquitin deficiency (PDE-ALDH7A1) is a disorder of lysine catabolism that results in accumulation of α- aminoadipic semialdehyde (α-AASA) and Δ1-piperideine 6-carboxylic acid (P6C)....Pyridoxine dependent epilepsy due to Antiquitin deficiency (PDE-ALDH7A1) is a disorder of lysine catabolism that results in accumulation of α- aminoadipic semialdehyde (α-AASA) and Δ1-piperideine 6-carboxylic acid (P6C). It is hypothesised that these metabolites are neurotoxic and that chronic exposure may have detrimental long-term effects, particularly on the young developing brain. Lysine reduction therapies in the form of lysine restricted diet (LRD) and arginine, have been used as an adjunct to pyridoxine for the treatment of PDE-ALDH7A1 for the last 15 years with an aim to improve long-term developmental outcomes by reducing α-AASA and P6C. We present the management and outcomes for a cohort of 17 PDE-ALDH7A1 patients from our centre. In this study we show that LRD leads to a reduction in plasma lysine levels and urine α-AASA concentrations and a correlation between these is seen in individual patients, supporting the treatment hypothesis. LRD alone was shown to be sufficient to reduce plasma lysine into the target treatment range and addition of arginine was not required. Transition to LRD and long-term adherence is easier to achieve in patients under 6 months of age, compared to older patients. Lysine reduction therapies did not offer any additional benefit on seizure control over pyridoxine monotherapy but in keeping with previous studies, this study supports early initiation of LRD in patients under 6 months with cognitive function scores maintained in some, although longer term follow up is required and ongoing.
Fabry nephropathy, a common complication of Fabry disease (FD), presents with a heterogeneous clinical phenotype. To date, genetic biomarkers associated with the progression of Fabry nephropathy have not been thoroughly...Fabry nephropathy, a common complication of Fabry disease (FD), presents with a heterogeneous clinical phenotype. To date, genetic biomarkers associated with the progression of Fabry nephropathy have not been thoroughly investigated. The aim of our study was therefore to identify genetic variants associated with nephropathy progression in FD. A total of 300 Caucasian patients were enrolled and stratified into two groups based on their estimated glomerular filtration rate (eGFR). Whole-exome sequencing was performed, and variants in a curated panel of 190 genes related to podocyte homeostasis were subjected to bioinformatic analysis. We identified six genetic variants with a false discovery rate (FDR) below 0.05. Five of these variants were located in non-coding regions: the 3' untranslated region (UTR) (YRDC: rs7686, TPPP: rs28364690), the 5' UTR (SNCA: rs1372518), an upstream region (COL4A2: rs7320419), and a non-coding exon (DLC1: rs10888175). Each of these variants was associated with an odds ratio less than one, suggesting a potential protective effect against nephropathy progression. In contrast, the coding variant rs749735949 in the FAT1 gene (FDR = 0.032) was associated with an odds ratio of 14.9, indicating a markedly increased risk of progressive nephropathy in carriers. These findings suggest that rs749735949 in FAT1 may serve as a predictive biomarker for accelerated eGFR decline, and could support the identification of biological targets for the prevention and improved management of Fabry nephropathy.
BACKGROUND: This paper presents efficacy and safety outcomes from the 48-month open-label extension (OLE) of the phase 2/3 NPC-002 trial (NCT02612129) which evaluated arimoclomol treatment in patients with Niemann-Pick d...BACKGROUND: This paper presents efficacy and safety outcomes from the 48-month open-label extension (OLE) of the phase 2/3 NPC-002 trial (NCT02612129) which evaluated arimoclomol treatment in patients with Niemann-Pick disease type C (NPC). Arimoclomol was recently approved by the US Food and Drug Administration for treatment of NPC in combination with miglustat. METHODS: Patients with NPC who completed the double-blind (DB) phase of the randomized controlled NPC-002 trial were eligible to continue in the OLE, during which all patients received arimoclomol in addition to routine clinical care. Primary efficacy outcomes were the 5-domain NPC Clinical Severity Scale (5DNPCCSS), and the rescored 4-domain NPCCSS (R4DNPCCSS), which was introduced post-hoc. Additional outcomes included NPC-specific measures (full scale NPCCSS, and NPC clinical database [NPC-cdb] score), and safety evaluations. RESULTS: Of the 50 patients who started the DB phase, 41 entered the OLE phase, with 29 completing 48 months. During the OLE, mean (SD) 5DNPCCS and R4DNPCCSS scores increased by 3.2 (4.8) and 2.7 (4.2) over 48 months, respectively. Among patients switching from placebo to arimoclomol after the DB phase, mean annual change in 5DNPCCSS decreased from 2.0 (on placebo) to 0.1 in the first year of receiving arimoclomol and mean annual change in R4DNPCCSS decreased from 1.9 to 0.2, indicating slowing of disease progression. Annual scores for both endpoints remained numerically smaller throughout the OLE than during the DB phase. The score pattern in the subset of patients who received miglustat as part of their standard care regime in addition to arimoclomol (N = 33) was similar to that seen in the total population. 17-domain NPCCSS (excluding hearing domains) and NPC-cdb results further supported sustained efficacy of arimoclomol. Arimoclomol was well-tolerated over 48 months, with no new safety concerns identified. CONCLUSION: The OLE of the NPC-002 trial provides evidence for a sustained reduction in disease progression for at least 5 years in a heterogeneous population of NPC patients receiving arimoclomol in addition to routine clinical care, with no new safety concerns. These results align with the statistically significant and clinically meaningful reduction in disease progression observed over 12-months in the DB phase, further highlighting the potential of arimoclomol as an effective and well tolerated disease modifying treatment for NPC.
Snyder MT, Divin K, Liu N
… +6 more, Sun Q, Wang Y, Luo X, Ben-Moshe Y, Burrage LC, Sutton VR
Mol Genet Metab
· 2025 Aug · PMID 40660651
·
Full text
False positives are an inherent part of newborn screening that can increase both costs to the healthcare system and parental anxiety. Previous studies primarily examined presumptive positive rates for medium-chain acyl-C...False positives are an inherent part of newborn screening that can increase both costs to the healthcare system and parental anxiety. Previous studies primarily examined presumptive positive rates for medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in places conducting one newborn screen (NBS), with predominantly white, non-Hispanic subjects. Texas performs two NBSs and there is a majority Hispanic population in our region. This study aims to analyze biochemical and DNA data to more easily distinguish affected individuals from carriers or healthy non-carriers and identify benefits and challenges of a second NBS for MCADD. Biochemical and targeted DNA data from NBS dried blood spots (DBS) were analyzed, alongside diagnostic biochemical and DNA testing. A Kruskal Wallis Test with Dunn's post-test was performed to compare the groups. Significant differences in all analyte values were observed among MCADD, carrier and non-carrier groups, and between carriers and non-p.Lys329Glu homozygous MCADD cases. Many false positives were detected due to low DBS C8 cutoff and the second NBS. An analyte algorithm including DBS C8, plasma acylcarnitine C6, and plasma C8/C10 was identified and discriminated MCADD cases from carrier and non-carrier cases. All cases with MCADD were identified on the first NBS demonstrating limited utility of a second NBS for MCADD.
OBJECTIVE: Phenylketonuria (PKU) is a metabolic disorder that is primarily treated with dietary phenylalanine (Phe) restriction and/or tetrahydrobiopterin (BH4) therapy. Dietary liberalization is often possible in BH4-re...OBJECTIVE: Phenylketonuria (PKU) is a metabolic disorder that is primarily treated with dietary phenylalanine (Phe) restriction and/or tetrahydrobiopterin (BH4) therapy. Dietary liberalization is often possible in BH4-responsive PKU patients; however, metabolic control may be impaired during catabolic stress such as illness or fever. The aim of this study was to investigate the efficacy of temporary protein substitution (Phe-free amino acid mixture; PFAAM) during intercurrent illness in BH4-responsive PKU patients managed without dietary protein restriction. METHODS: This retrospective case series, descriptive study included ten BH4-responsive PKU patients treated with BH4 monotherapy. All patients received PFAAM supplementation exclusively during febrile or disease-related episodes. Clinical, biochemical and genetic data were obtained from medical records. Blood Phe levels were determined before and after PFAAM intake during illness episodes. RESULTS: All patients experienced a significant increase in blood Phe levels during febrile illnesses despite receiving maximum BH4 dose (20 mg/kg/day). PFAAM supplementation initiated at a median dose of 0.3-1.5 g/kg/day resulted in a rapid decrease in blood Phe levels, often within a few days. In most cases, PFAAM was gradually discontinued once metabolic control was restored, and no patient required long-term dietary Phe restriction. The intervention allowed restoration of metabolic control while maintaining a liberal dietary regimen. CONCLUSIONS: Temporary PFAAM supplementation during intercurrent illness appears to be an effective adjunct to BH4 therapy to control transient elevations in blood Phe levels. This approach may support metabolic stability without the need for permanent dietary restriction in BH4-responsive PKU patients. Further prospective studies are needed to validate these results in larger cohorts.
Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodelin...Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodeling are mediated by a coordinated set of enzymes, and disruptions in this pathway are increasingly recognized as causes of inherited mitochondrial diseases. This review provides a comprehensive overview of the genetic disorders associated with defects in cardiolipin metabolism, highlighting genetic and molecular characteristics, clinical manifestations, and available models with which to study these diseases. We examine the roles of key genes involved in cardiolipin biosynthesis (PGS1, CRLS1) and remodeling (TAZ, AGK, among others), and describe how pathogenic variants disrupt mitochondrial function. The prototypical disorder, Barth syndrome, is discussed in depth alongside recently identified conditions linked to defects in related enzymes.
Urea cycle disorders (UCDs) are inherited metabolic conditions that lead to inadequate nitrogen detoxification due to defects in urea cycle enzymes or transporters. The severity of UCDs is classified into two types: neon...Urea cycle disorders (UCDs) are inherited metabolic conditions that lead to inadequate nitrogen detoxification due to defects in urea cycle enzymes or transporters. The severity of UCDs is classified into two types: neonatal onset (severe) and late onset (often milder). This cross-sectional study aimed to assess the levels of intelligence, developmental disabilities, and social functioning in adult patients with UCDs in Japan. A total of 116 adult patients with UCDs were enrolled in the study, including 10 with carbamoyl phosphate synthetase 1 deficiency, 69 with ornithine transcarbamylase deficiency (OTCD), 17 with argininosuccinate synthetase deficiency, 9 with argininosuccinate lyase deficiency, 4 with arginase 1 deficiency, and 7 with Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome. Of these, 25 (21.6 %) developed symptoms during the neonatal period (within 28 days after birth), while 86 (74.1 %) presented with symptoms after 28 days of age. The age of onset was unknown in 5 patients. This study included 111 surviving patients and 5 deceased patients (3 with OTCD and 2 with CPS1D). Fifty-three patients (45.7 %) experienced intellectual disabilities, while 48 (41.4 %) had non-intellectual disabilities. Additionally, learning disorders and communication disorders were common among many of the study participants. Sixty patients (51.7 %) graduated from regular high school, and most patients with intellectual disabilities graduated from special education schools. Almost half of the patients (51, 44.0 %) were able to obtain jobs, including simple tasks in supported workplaces, and received compensation for their work. Notably, more patients with OTCD could demonstrate higher social performance including experience of higher education and marriage. However, even OTCD patients without intellectual disabilities often struggled with specific neurobehavioral issues. This study provides information on the social situation of adult UCD patients and underlines the importance for clinicians, as well as society and communities, to understand the ongoing challenges faced by patients with UCDs in order to provide better support.
Huang Q, Trumpff C, Monzel AS
… +15 more, Rausser S, Devine J, Liu CC, Kelly C, Kurade M, Li S, Engelstad K, Tanji K, Lauriola V, Wang T, Wang S, Sloan R, Juster RP, Hirano M, Picard M
Mol Genet Metab
· 2025 Aug · PMID 40602037
·
Full text
Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Usin...Circulating growth differentiation factor 15 (GDF15) is a biomarker of mitochondrial diseases and aging, but its natural dynamics and response to acute stress in blood and other biofluids have not been well defined. Using extensive samples from MiSBIE participants with rare mitochondrial diseases (MitoD), we examined GDF15 biology in 290 plasma and 860 saliva aliquots from 40 subjects with the m.3243 A > G mutation (n = 25) or with single, large-scale mtDNA deletions (n = 15). Compared to healthy controls, both MitoD groups exhibited significantly elevated blood and saliva GDF15 (p < 0.0001). To examine the origin of GDF15 protein in saliva, we profiled GDF15 expression in 48 tissues from the GTEx dataset and identified high GDF15 expression in salivary gland secretory cells. Despite being chronically elevated in MitoD, saliva GDF15 further increased in response to experimental laboratory mental stress alone (without physical exertion), whereas the stress-induced plasma GDF15 reactivity was blunted in MitoD compared to controls. Using a home-based saliva collection protocol, we show that similar to other stress-related metabolic hormones, saliva GDF15 is highest upon awakening and declines rapidly by 61.2 % within 45 min. Elevated saliva GDF15 levels persisted throughout the day in MitoD. Clinically, saliva GDF15 correlated with neurological symptoms, fatigue, and functional capacity. Importantly, stress-evoked changes in GDF15 did not amplify noisy disease severity associations, but rather consistently increased the effects sizes for GDF15-symptoms connections, pointing to converging psychobiology underlying the responses to mitochondrial OxPhos defects and acute mental stress. These results open the door to exploring saliva GDF15 as a non-invasive monitoring approach for mitochondrial diseases and call for further studies examining the psychobiological processes linking mitochondria, mental stress, and GDF15 dynamics.
Newborn screening, while enabling early diagnosis, poses challenges to correctly identifying and typing otherwise asymptomatic infants with neuropathic Gaucher disease (nGD). Glucosylsphingosine (Lyso-GL1) may be elevate...Newborn screening, while enabling early diagnosis, poses challenges to correctly identifying and typing otherwise asymptomatic infants with neuropathic Gaucher disease (nGD). Glucosylsphingosine (Lyso-GL1) may be elevated at birth, but it does not help differentiate between nGD types. Neurofilament light chain (NfL), a neuronal cytoplasmic protein, is a marker for axonal damage and is associated with elevated levels in cerebrospinal fluid (CSF) and blood in lysosomal disorders characterized by neurodegeneration. In a prospective study (NCT02000310, 13-CFCT-07), NfL and Lyso-GL1 levels were assessed along with other neurological indicators in 35 GD patients (ages 6 months to 72 years: 8 GD1, 7 GD2, 20 GD3). Eighteen patients with other LSDs-with or without neurodegeneration-served as controls. In GD2, Lyso-GL1 was markedly elevated (range: 105-457 ng/mL), and all GD2 patients with neurological manifestations had elevated NfL. In GD3, Lyso-GL1 levels were highly variable, reflecting the clinical heterogeneity. NfL was elevated in 4 of 20 GD3 patients, all of whom had clinically discernable neurological involvement. All GD1 patients had normal NfL levels (max: 0.9 (ref:<1.63)) and near-normal Lyso-GL1 (maximum pretreatment: 10). Clinically, an abnormal Auditory Brainstem Response (ABR) correlated with neurodegeneration. ABR was abnormal in all GD2 infants tested, while 65 % (13/20) of GD3 patients had normal auditory function. The combination of elevated NfL and Lyso-GL1 levels, along with abnormal ABR, can aid in the early identification of severe nGD-even in the absence of characteristic neurological symptoms-supporting the need for earlier diagnosis and timely clinical intervention.
OBJECTIVE: The most common congenital disorders of glycosylation (CDG) is the phosphomannomutase 2 (PMM2) deficiency (PMM2-CDG). PMM2-CDG is a complex genetic disorder that often found in infancy or early childhood with...OBJECTIVE: The most common congenital disorders of glycosylation (CDG) is the phosphomannomutase 2 (PMM2) deficiency (PMM2-CDG). PMM2-CDG is a complex genetic disorder that often found in infancy or early childhood with a clinically heterogeneous variety of neurological and non- neurological symptoms. To expand the phenotypic and genetic spectrum of PMM2-CDG, we summarized the characteristics of 20 Chinese patients. METHODS: All patients were diagnosed by genetic analysis. Clinical characteristics, genotypes, imaging, electrophysiological, and metabolic data were analyzed retrospectively. RESULTS: Twelve males and eight females with PMM2-CDG were included. The median age at diagnosis was 12.0 (ranging from 6.0 to 52.0) months, while the median age at final follow-up was 10.3 (ranging from 5.1 to 12.8) years. All patients exhibited multisystem symptoms and various neurological symptoms were observed. Developmental delay was the primary initial symptoms. Dystaxia, growth retardation and liver damage were also common phenotypes. Cerebellar atrophy was the characteristic abnormality on brain imaging. Fourteen variants of the PMM2 gene were identified, of which five, c.82A > G (p.M28V), c.551C > T (p. P184L), c.640G > T (p.G214C), c.656A > T (p.E219V) and c.712C > G (p.R238G), were newly reported. The most prevalent variant was c.430 T > C (p.F144L), which was identified in 65.0 % of patients, followed by c.395 T > C (p.I132T). Consistent with reports from other populations, missense variants constituted the predominant type of PMM2 gene alterations. CONCLUSION: PMM2-CDG presents as a multi-system disease with diverse clinical phenotypes, posing challenges to early identification and diagnosis. The most common pathogenic variant in this Chinese cohort was c.430 T > C (p.F144L), which is close to, but different from, the common pathogenic variant c.422G > A (p.R141H) among European PMM2-CDG patients.
BACKGROUND: Combined methylmalonic acidemia and homocystinuria cblC type (cblC) is a multisystemic disease with diverse clinical presentations and known genotype-phenotype correlations. This study aims to define and expl...BACKGROUND: Combined methylmalonic acidemia and homocystinuria cblC type (cblC) is a multisystemic disease with diverse clinical presentations and known genotype-phenotype correlations. This study aims to define and explain the phenotypes and outcomes associated with the MMACHC variant c.1A>G (p.M1V), previously reported in several cases. METHODS: A retrospective review of 54 Chinese patients with cblC carrying the MMACHC c.1A>G variant was conducted. Clinical features, including onset age, initial symptoms, biochemical index and prognosis were analyzed and compared with 100 cblC patients without this variant. The variant's pathogenicity was investigated by in vitro experiments. RESULTS: Twenty-nine (54 %) of 54 individuals with the c.1A>G variant were diagnosed via newborn screening (NBS) and 23 (79 %) remained asymptomatic. Among 19 symptomatic patients, 12 (63 %) developed symptoms after 1 year of age, with cognitive decline being the most common initial symptom (55 %). Before treatment, all analyzed biochemical indexes except homocysteine showed reduced levels in the c.1A>G group compared to the Control group. Post-treatment, the poor prognosis rate and some metabolite levels in the c.1A>G group were significantly decreased compared to those in the Control group. Western blotting indicated that c.1A>G significantly reduced MMACHC protein expression, and co-immunoprecipitation provided evidence for impaired interaction between the variant MMACHC and methionine synthase (MTR). CONCLUSIONS: The c.1A>G variant in MMACHC is associated with later-onset disease, milder phenotypes and improved clinical outcomes in cblC patients. Functional studies suggest that this variant reduces MMACHC translation efficiency and disrupts its interaction with MTR. Our findings underscore the utility of NBS for early diagnosis and better management in c.1A>G-associated cblC.
Kell P, Mishra S, Gray-Edwards HL
… +8 more, Martin DR, Gaudioso A, Ledesma MD, Bongarzone ER, Sands MS, Sidransky E, Ory DS, Jiang X
Mol Genet Metab
· 2025 Aug · PMID 40543381
·
Full text
Lysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulati...Lysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulation of undegraded substrates or obstructed substances in lysosomes, serving as primary storage materials. However, in certain LSDs, secondary storage products-such as glycosphingolipids, phospholipids, and cholesterol-can also accumulate in tissues, independent of the primary enzyme or protein defect. In our recent studies, we identified lyso-platelet activating factors (lyso-PAFs) as secondary storage compounds in multiple LSDs, including Niemann-Pick disease type C1 (NPC1), GM2 activator deficiency, and GM1 gangliosidosis (GM1). Our ongoing work suggests that lyso-PAFs are also prevalent secondary storage products in Niemann-Pick disease type A (NPA), Sandhoff disease (SD), Tay-Sachs disease (TSD), and Krabbe disease (KD). We observed that elevated lyso-PAF levels were significantly correlated with the accumulation of primary storage substances in these disorders, indicating their potential as biomarkers for disease progression in these LSDs. Moreover, treatment with adeno-associated virus (AAV)-based gene therapies led to a reduction in lyso-PAF levels in the central nervous systems of TSD sheep and GM1 cats, further supporting their potential as biomarkers for therapeutic efficacy. While it remains unclear whether changes in lyso-PAFs contribute directly to disease pathology or simply reflect disease progression, further research into the enzymes involved in their synthesis and degradation is essential for uncovering their functional role in the cellular physiology and pathology of LSDs. Thus, further exploration of lyso-PAF in biofluids as prognostic and pharmacodynamic biomarkers is warranted.
Oxidative stress contributes to the pathophysiology of several inherited metabolic diseases (IMDs). The quality and extent of clinical evidence for the use of antioxidant therapies in IMDs have yet to be ascertained. Des...Oxidative stress contributes to the pathophysiology of several inherited metabolic diseases (IMDs). The quality and extent of clinical evidence for the use of antioxidant therapies in IMDs have yet to be ascertained. Despite frequent clinical use, robust evidence from large-scale trials is limited. The strongest support comes from studies on idebenone in Leber's hereditary optic neuropathy, showing improvements in visual outcomes. For other antioxidants and conditions, evidence is mixed or constrained by small sample sizes and short trial durations. Coenzyme Q10 in mitochondrial diseases, vitamin E in lipid disorders, and N-acetylcysteine in various IMDs have shown some promise, but evidence is heterogeneous. Challenges include optimizing dosing, dissecting oxidative stress mechanisms across disorders, and overcoming pharmacokinetic limitations. High-grade evidence exists for the clinical efficacy of N-acetyl-L-leucine for both Niemann Pick type C disease and other lysosomal storage diseases, though its potential antioxidant effect is indirect. This review highlights the need for larger trials with standardized, clinically relevant outcomes. Future research should explore oxidative stress mechanisms, targeted therapies, and combination approaches. While antioxidants hold potential, evidence remains limited, warranting cautious use and further investigation to define their role in these rare but cumulatively impactful disorders. SYNOPSIS: This review finds limited robust evidence for antioxidant therapies in inherited metabolic diseases, highlighting the need for larger trials and more targeted approaches.
Ali S, Nisar A, Zhang A
… +12 more, Nagamani S, Aceves-Ewing NM, Rawls B, Quan T, Enns G, Goss J, Leung DH, Shneider BL, Jain S, Hazard FK, Schady D, Burrage LC
Mol Genet Metab
· 2025 Aug · PMID 40540899
·
Full text
BACKGROUND: Various forms of liver disease have been increasingly reported in individuals with urea cycle disorders (UCDs). In this study, we performed the first systematic and standardized histopathological assessment o...BACKGROUND: Various forms of liver disease have been increasingly reported in individuals with urea cycle disorders (UCDs). In this study, we performed the first systematic and standardized histopathological assessment of the prevalence of fibrosis and steatosis in a large sample of hepatic explants and biopsies from individuals with UCDs at two liver transplantation centers. METHODS: Sixty-seven hepatic tissue samples from 66 individuals with UCDs were staged by two pathologists for hepatic fibrosis and steatosis using standard scoring systems at two large liver transplantation centers in the United States. Histopathological findings were correlated with clinical parameters, including UCD type, laboratory parameters, and imaging findings. RESULTS: Overall, 23 % (n = 15) of individuals demonstrated clinically significant hepatic fibrosis (≥ F2 according to Metavir staging). Of these, 12 were diagnosed with argininosuccinate lyase deficiency (ASLD) leading to an 80 % prevalence of clinically significant fibrosis in this disorder in this cohort. Eighteen percent of the patients (n = 12) had microvesicular and/or macrovesicular hepatic steatosis. No clinical parameters including routine laboratory testing or imaging were significantly associated with clinically significant hepatic fibrosis in individuals with ASLD. CONCLUSION: In this large study of hepatic histopathology in UCDs, our findings demonstrate a high prevalence of clinically significant hepatic fibrosis in ASLD. These findings emphasize the importance of monitoring for liver disease and promoting liver health in UCDs and may have implications for long-term monitoring for individuals with ASLD.