This study evaluated the role of urine organic acid (UOA) analysis in eight infants initially flagged by California newborn screening and later diagnosed with Zellweger spectrum disorder (ZSD). Retrospective evaluation o...This study evaluated the role of urine organic acid (UOA) analysis in eight infants initially flagged by California newborn screening and later diagnosed with Zellweger spectrum disorder (ZSD). Retrospective evaluation of UOA during workup of all patients with ZSD identified a consistent pattern of 2-hydroxysebacic acid, 3,6-epoxydeodecanedioic and 3,6-epoxytetracanedioic acids. These results highlight the value of UOA analysis in the evaluation of ZSD and provide images of clinically relevant peaks on UOA chromatograms.
Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found th...Neuroinflammation underlies neurodegenerative processes in neuronopathic mucopolysaccharidoses (MPS), with innate immunity known to have a dominating role. Here, by studying mouse models of neuronopathic MPS, we found that the neurotoxic reactive astrocytes A1 are present in the brain of MPS mice and progressively increase with age. Such A1 phenotype is associated to activated microglia and to microglia-mediated release of a subset of specific cytokines involved in the A1 phenotype. Additionally, in the mouse model of MPS-IIIA, one of the most severe neuronopathic MPS in humans, we also found that neuroinflammation proceeded concomitantly with the activation of transglutaminase 2, a multifunctional enzyme involved in a variety of cellular processes, mostly in the microglia. Moreover, amyloid deposition appears to be associated to the maintenance of these processes, indeed, inhibiting amyloid deposition in MPS-IIIA mice reduced TG2 expression, microglia activation and the relative amount of astrocyte A1 phenotype. Our results shed light on the microglia-astroglia crosstalk in neuronopathic MPS and on its implication in neuroinflammation and neurodegeneration in MPS, thus also suggesting new therapeutic targets for these diseases.
Citrin deficiency is an autosomal recessive disorder caused by mutations in SLC25A13, encoding the inner mitochondrial membrane protein citrin. This disease manifests in age-dependent forms: neonatal intrahepatic cholest...Citrin deficiency is an autosomal recessive disorder caused by mutations in SLC25A13, encoding the inner mitochondrial membrane protein citrin. This disease manifests in age-dependent forms: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency, and adolescent and adult citrin deficiency (AACD). While NICCD often resolves with early treatment, AACD symptoms tend to persist or worsen over time. However, the long-term outcome in adult patients with citrin deficiency, particularly those affected by the symptoms of AACD, is not well understood. To address this gap, we conducted a new study from 2022 to 2024 that focused specifically on adult patients with citrin deficiency. This retrospective study investigated the long-term outcomes in a total of 128 adult patients, categorized depending on their onset of disease into NICCD, Post-NICCD, and AACD groups. Significant differences in height were observed: NICCD patients had taller median heights than AACD patients (Males: 170.6 cm vs. 168.0 cm, P = 0.016; Females: 156.0 cm vs. 153.0 cm, P = 0.007). Former NICCD patients generally achieved favorable long-term outcomes with early intervention, while AACD patients often experienced persistent or worsening symptoms, including irreversible liver damage with impaired urea cycle function. In conclusion, this study suggests that early intervention during infancy or childhood may improve long-term prognosis in citrin deficiency, particularly for NICCD patients. Conversely, outcome for AACD patients remains a concern, highlighting the need for improved management strategies in adulthood. This study emphasizes the importance of timely diagnosis and treatment to mitigate the progressive nature of citrin deficiency.
Fabry disease is an X-linked condition that historically was thought to only affect males, but it is well known that females can also be equally affected. With the advent of newborn screening, understanding genotype-phen...Fabry disease is an X-linked condition that historically was thought to only affect males, but it is well known that females can also be equally affected. With the advent of newborn screening, understanding genotype-phenotype correlations, especially among variants of uncertain significance, has become essential. Two such GLA variants, p.Ile198Thr (I198T) and p.Ala143Thr (A143T) are associated with later-onset disease, though their pathogenicity remains debated. A cohort of 21 individuals (4 males, 17 females; ages 8-79 years) with these two genotypes from the University of Minnesota is presented here with their phenotypic characterization. In the I198T subgroup, males exhibited higher Lyso-GL3 levels and lower enzymatic activity than females, consistent with X-linked inheritance. A mild cardiac phenotype was observed on imaging in three out of four females over the age of 60, suggesting a potential association between this genotype and a later-onset cardiac risk. The predominant early presenting symptoms and signs included numbness and tingling suggestive of small fiber neuropathy and angiokeratomas, respectively. None of the males in this cohort had any evidence of end-organ damage. Our cohort of p.A143T exhibited no signs of end organ damage, except for one female who presented with concentric left ventricular hypertrophy at a young age. Gastrointestinal symptoms and recurrent headaches were common presenting features. The limited number of males in both cohorts restricts generalizability and underscores the need for larger studies. Given their uncertain pathogenicity and diverse clinical presentations, we propose classifying p.I198T and p.A143T as Variants of Varying Clinical Consequence (VVCC).
Maquet J, Pontoizeau C, Imbard A
… +15 more, Gobin-Limballe S, Arnoux JB, Le Guillou É, Dubot P, Brassier A, Bérat CM, Altenburger L, Bouchereau J, Servais A, Dao M, Bonnefont JP, Ottolenghi C, Benoist JF, de Lonlay P, Schiff M
INTRODUCTION: Regardless of its mechanism, hyperammonemia can cause coma and death, and requires urgent management. This study aims at describing the landscape of causes of hyperammonemia in adults and at evaluating the...INTRODUCTION: Regardless of its mechanism, hyperammonemia can cause coma and death, and requires urgent management. This study aims at describing the landscape of causes of hyperammonemia in adults and at evaluating the performance of targeted next-generation sequencing (NGS) in this setting. METHODS: We analyzed two cohorts. The first included patients aged ≥15 years presenting with hyperammonemia ≥100 μmol/L at Necker-Enfants Malades (NEM) University Hospital for 10 years and at Toulouse University Hospital for 1.5 years. The second cohort included patients who underwent genetic testing for inherited metabolic disease (IMD) via targeted NGS at NEM hospital over a 5 year-period, regardless of their inclusion in the first cohort, all with hyperammonemia ≥100 μmol/L after age 15. RESULTS: We included 184 patients in the first cohort, with a median peak ammonia concentration of 155 μmol/L. Among them, 61 patients (33 %) presented with coma. Non-genetic liver failure or portosystemic shunt was present in 133 patients. Twenty-three patients had received asparaginase treatment (none with coma despite a median ammonia level of 257 μmol/L), 7 had received valproic acid, 3 had undergone surgical ureterorectal anastomosis, 2 had multiple myeloma, 1 was receiving 5-Fluorouracil (5FU) for metastatic gastrointestinal cancer, 1 had disseminated atypical mycobacteriosis with Mycobacterium genavense (urease-producing bacteria) in a renal transplant setting and 13 had a genetically confirmed IMD diagnosed in adulthood. In the second cohort of 17 patients, genetic testing was positive in 5 of 6 patients with IMD-suggestive biochemical profiles (2 CPS1 deficiencies, 1 OTC deficiency, 1 multiple acyl-coA dehydrogenase deficiency, and 1 lysinuric protein intolerance), and negative in patients without biochemical profile suggesting an IMD. Among them, four patients suffered from protein malnutrition related to various severe conditions (gastric bypass, metastatic colorectal adenocarcinoma, Duchenne muscular dystrophy, and short bowel syndrome). CONCLUSION: The causes of hyperammonemia in adults are varied. In cases of acute episodes without unequivocal metabolic profiles (when unwell) and with an acquired identified cause of hyperammonemia, genetic investigations had a low yield.
Barth syndrome is an exceedingly rare and potentially fatal X-linked mitochondrial disease arising from pathogenic variants in TAFAZZIN (TAZ), leading to defects in mature cardiolipin synthesis and its integration into t...Barth syndrome is an exceedingly rare and potentially fatal X-linked mitochondrial disease arising from pathogenic variants in TAFAZZIN (TAZ), leading to defects in mature cardiolipin synthesis and its integration into the mitochondrial inner mitochondrial membrane. Clinical features that may be severe include cardiomyopathy, cyclic neutropenia, skeletal myopathy, and growth delay. Currently, no FDA-approved therapies exist. Elamipretide (ELAM) has been shown to stabilize cardiolipin and improve mitochondrial bioenergetics in pre-clinical and clinical studies in older individuals with Barth syndrome. Here we describe a case of prenatally identified Barth syndrome-related severe left ventricle (LV) non-compaction cardiomyopathy, where ELAM was initiated shortly after birth for clinical heart failure and was associated with significant and sustained clinical improvement leading to an inactive status on the heart transplant list with eventual anticipated delisting. We provide a review of the current literature including the pathophysiology of Barth syndrome, the mechanism of action of ELAM, and its clinical applications.
Bérat CM, Hully M, Rötig A
… +16 more, Barcia G, Assouline Z, Abi-Warde MT, Barnerias C, Payen E, Jaroussie M, Gaignard P, Lebigot E, Roubertie A, Boddaert N, Roux CJ, de Lonlay P, Desguerre I, Munnich A, Schiff M, Gitiaux C
Pathogenic variants in POLG are involved in a large spectrum of neurological, gastrointestinal and liver impairments. Children affected with POLG-related disorders rarely exhibit peripheral neuropathy, the latter being m...Pathogenic variants in POLG are involved in a large spectrum of neurological, gastrointestinal and liver impairments. Children affected with POLG-related disorders rarely exhibit peripheral neuropathy, the latter being most often described in adults as axonal polyneuropathy. Our aim was to focus on electrophysiological findings in young children affected with POLG-related disorder. We report herein 6 unrelated early-onset POLG patients presenting with an atypical and severe polyradiculoneuropathy mimicking Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). All these patients also exhibited severe intestinal dysmotility and liver disease. Different compound heterozygous pathogenic variants in POLG were found and 4/6 patients shared the same heterozygous R232H variation. POLG-related disorders should therefore be considered in the setting of atypical childhood onset CIDP with gastrointestinal and liver impairments.
INTRODUCTION: Cardiovascular complications are the primary cause of morbidity and mortality in Fabry disease. Despite disease-specific and adjuvant treatments, gaps in care exist. Cardiac imaging facilitates the understa...INTRODUCTION: Cardiovascular complications are the primary cause of morbidity and mortality in Fabry disease. Despite disease-specific and adjuvant treatments, gaps in care exist. Cardiac imaging facilitates the understanding of disease progression, however data on the clinical relevance of imaging endpoints in Fabry disease are scant. Therefore, we evaluated the association between left ventricular mass index (LVMi) measured via echocardiography and risk of subsequent clinical events. METHODS: Adult patients from the Fabry Registry treated with enzyme replacement therapy, with echocardiography measurements and no prior kidney events were analyzed. Composite clinical events included cardiac, cerebrovascular, and kidney events, or death. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for the association between (1) baseline LVMi and (2) LVMi progression (i.e., slopes) with the risk of subsequent clinical events. RESULTS: Baseline LVMi analysis included 809 patients (53.1 % females) with median age at diagnosis [25, 75 percentile]: 39.5 years [26.7, 52.2]) who had 248 clinical events, including 170 cardiac events, over 4752 and 5128 person-years, respectively. Higher baseline LVMi was associated with greater risk of composite clinical and cardiac events (adjusted HR per 10 % higher baseline LVMi: 1.09 [95 % CI: 1.04-1.13; p < 0.001] and 1.11 [95 % CI: 1.06-1.17; p < 0.0001], respectively). LVMi slope analysis included 377 patients with median 3-year LVMi slope [25, 75 percentile] of -0.5 g/m/year [-7.8, 7.2]; and evaluated 86 composite clinical events and 57 cardiac events, over 1899 and 2028 person-years, respectively. Increasing LVMi slope was associated with higher incidence of clinical events in key subgroups including in those with the classic Fabry phenotype, those with left ventricular hypertrophy (LVH) at baseline, those with pre-baseline clinical events and in patients with history of hypertension; adjusted HR per 10 g/m/year increase in LVMi slope ranged from 1.16 to 1.64 (p < 0.05). CONCLUSIONS: Our study quantifies the biologically plausible association between LVMi and its progression with composite clinical events, including in key subgroups of Fabry patients.
A patient registry facilitates collection of data on a group of patients with similar conditions. While some registries collect clinician-input data, patient-entered registries prioritize the perspective of patients and...A patient registry facilitates collection of data on a group of patients with similar conditions. While some registries collect clinician-input data, patient-entered registries prioritize the perspective of patients and families. To better support research for phenylketonuria (PKU), National PKU Alliance (NPKUA) launched the PKU Patient Registry in 2017 to collect patient-entered lived experience and natural history data. It gathers medical information and queries the lived experience of PKU through the completion of surveys, developed by a group of key stakeholders, individuals with PKU, and healthcare providers which includes validated tools and patient surveys. The data collected provide insights about the needs of the community and assist in recruitment for external research studies. This Registry uses the National Organization for Rare Disorders' IAMRARE® platform, as it is a secure, user-friendly system compliant with federal and state information privacy laws. The Registry and participant data are owned by NPKUA on behalf of the PKU community and are governed by NPKUA and the Registry Advisory Committee. As of November 2024, there are 1125 consented participants representing 46 states plus the District of Columbia and 36 different countries with the completion of 123,044 surveys over the past seven years. Since the Registry's inception, it has supported recruitment for over 35 external research studies and shared anonymized data through industrial and federal collaborations. The PKU Patient Registry collects longitudinal patient-entered data and allows for collaboration with other PKU datasets, permitting an improved understanding of the natural history of this condition.
Yeo M, Goh JLK, Koh AL
… +22 more, Fong N, Tan ES, Jamuar S, Goh CYJ, Lim E, Poh S, Lim SCJ, Kam S, Cham B, Lim JY, Phua KB, Chiou FK, Logarajah V, Ho CWW, Ng LQ, Wong SA, Goh L, Ong C, Quek G, Ong C, Phuah KY, Ting TW
BACKGROUND: Citrin deficiency (CD) is a pan-ethnic autosomal recessive inborn error of metabolism due to-pathogenic variants in the SLC25A13 gene which results in disruptions of multiple metabolic pathways including glyc...BACKGROUND: Citrin deficiency (CD) is a pan-ethnic autosomal recessive inborn error of metabolism due to-pathogenic variants in the SLC25A13 gene which results in disruptions of multiple metabolic pathways including glycolysis, gluconeogenesis, lipogenesis, the urea cycle, and tricarboxylic cycle. METHODS: A retrospective observational study of CD patients managed according to standard clinical practice at a single centre in Singapore (KK Women's and Children's Hospital, KKH) was undertaken from August 2016-August 2024. We present the largest cohort of patients reported in Southeast Asia focusing on clinical, biochemical and imaging findings at diagnosis, and long-term outcomes/management (including drug therapy, food preferences/adherence, hospital admissions, growth, neurodevelopmental, biochemical, and imaging outcomes). We also explore the utility of newborn screening (NBS) as a means for early detection of CD. RESULTS: Eighteen CD patients (9 males; 2 sibling pairs) majority of Chinese ethnicity (n = 16) with a median duration of follow up 5 years 5 months, participated in this study. Median age at first presentation and at diagnosis was 50 days and 82 days, respectively. Fourteen patients presented with neonatal intrahepatic cholestasis caused by CD (NICCD), 2 asymptomatic from sibling screens, and two from abnormalities on NBS (one presenting with unconjugated hyperbilirubinaemia and the other with cholestasis and liver failure). Two patients had liver failure (one from NICCD group and another from NBS group). None required liver transplantation. All symptomatic patients had raised citrulline and threonine-serine ratios at presentation. None of the patients was prescribed any regular concomitant medications except for MCT oil. No genotype phenotype correlation was observed. At final assessment, all patients showed normalisation of liver parameter, galactose and plasma amino acids. Abnormalities in lipid profile in 9 patients (age 5-16 years) showed borderline high total cholesterol (median 5.4 mmol/L) and LDL (median 3.0 mmol/L) which was on the higher end of the normal range. Sixty-six percent of patients liver imaging findings were normal or showed stable changes. Food preferences (assessed in ≥1-year olds) did not reflect a clear bias towards high protein/fat diet. Adherence appeared to improve with a more prescriptive approach, it waned with age (more so in dietary aspects versus the use of MCT oil). Hospital admissions were few (median 1/patient) and unrelated to CD. Overall improvements were seen in weight, height and BMI for age z-scores, showing median weight/height/BMI for age z-scores to be -0.72, -0.83, 0.08, respectively. None had neurodevelopmental concerns. CONCLUSION: CD remains challenging to diagnose biochemically at all ages. Current NBS strategies require further refining to increase pick up rates of CD. Cascade screening utilising genetic testing is recommended due to the presence of phenotypic heterogeneity among patients with the same genotype. However, in the absence of available genetic testing, CD should be considered in all children presenting with prolonged conjugated hyperbilirubinaemia in the presence of elevated ALP, total galactose, with/without transaminitis and typical PAA profile. With our standard treatment for CD, we observed: (i) normalisation of biochemical parameters, (ii) normalisation/stabilisation of liver imaging findings, (iii) improvements in weight/height/BMI for age scores. Adoption of a prescriptive approach appeared to encourage treatment adherence. SYNOPSIS: This retrospective study examines 18 patients with citrin deficiency at KK Women's and Children's Hospital in Singapore, the largest cohort reported in Southeast Asia. The study assesses clinical, biochemical, imaging findings, and outcome measures. Results showed improvements in growth, biochemical normalisation, and stable liver imaging with standard treatment (dietary adjustments and MCT oil). While NBS detected some cases, there remains a need for better screening strategies. This study also demonstrated a lack of genotype-phenotype correlation, suggesting that cascade screening utilising genetic testing are crucial for early diagnosis.
Mol Genet Metab
· 2025 · PMID 40763653
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The landscape of therapeutic options for rare diseases is rapidly expanding, including a range of novel treatments such as antisense oligonucleotides, enzyme replacement therapies, targeted small molecules, mRNA, and gen...The landscape of therapeutic options for rare diseases is rapidly expanding, including a range of novel treatments such as antisense oligonucleotides, enzyme replacement therapies, targeted small molecules, mRNA, and gene replacement therapies. The integration of these high-cost, advanced therapeutics into clinical practice presents significant challenges. This focused review aims to outline the practical aspects of implementing non-gene therapy therapeutics that have been recently approved for rare diseases in a clinical setting, focusing on the multidisciplinary efforts required for successful integration, the coordination with various healthcare specialists, and the management of institutional and insurance-related barriers. Effective implementation necessitates strong institutional support and comprehensive infrastructure, including specialized clinics and dedicated pharmacy services. Key strategies involve developing new treatment protocols, ensuring robust payor support, and coordinating with pharmaceutical companies. The successful deployment of these new to market therapeutics hinges on a well-coordinated, institution-wide approach that addresses both clinical and logistical challenges. Emphasizing multi-disciplinary collaboration and patient-centric care, institutions can navigate the complexities of recently approved rare disease treatments, improving outcomes and access for this vulnerable patient population.
Meta-analyses were used to track cognitive outcomes in early treated people with phenylketonuria. We compared impairment sizes and possible modulations by blood Phe in young adults and children/early adolescents. We iden...Meta-analyses were used to track cognitive outcomes in early treated people with phenylketonuria. We compared impairment sizes and possible modulations by blood Phe in young adults and children/early adolescents. We identified results for 29 adult PKU groups and 21 child groups (N-participants = 904 and 460; mean age 27 and 11 years; mean current blood Phe: 1010; and 527; median 899 and 494; SD= =396 and 159) with 278 separate outcome measures available for adults and 175 for children. Results demonstrated a similar overall level of impairment across ages, corresponding to approximately 0.5 of a standard deviation difference from controls. However, children showed more homogeneous impairments across functions compared to adults who showed a larger difference between the most and least impaired measures and a stronger difference of impairment between speed measures (impaired) and accuracy measures (preserved). In both age groups, blood Phe level modulated the effect size of the impairment in several conditions, but speed of processing appeared to be affected more by childhood levels than current adult levels consistent with previous results. Results indicate that negative effects of PKU persist across the lifespan, but that adults with PKU may rely on relatively unaffected learning skills and on prioritization of resources to achieve good accuracy and good performance in tasks tapping crystallized intelligence, even if speed remains impaired. This has positive implications for educational and employment prospects, but it is unclear how positive trends generalize to the whole PKU population beyond groups engaged in research.
Muffels IJJ, Budhraja R, Shah R
… +3 more, Radenkovic S, Morava E, Kozicz T
Mol Genet Metab
· 2025 · PMID 40743674
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BACKGROUND: Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective...BACKGROUND: Congenital Disorders of Glycosylation (CDG) are a rapidly expanding group of inherited metabolic diseases caused by defects in glycosylation. Although over 190 genetic defects have been identified, effective treatments remain available for only a few. We hypothesized that integrative analysis of multi-omics datasets from individuals with various CDG could uncover common molecular signatures and highlight shared therapeutic targets. METHODS: We compiled all publicly available RNA sequencing, proteomics and glycoproteomics datasets from patients with PMM2-CDG, ALG1-CDG, SRD5A3-CDG, NGLY1-CDDG, ALG13-CDG and PGM1-CDG, spanning different tissues, including induced cardiomyocytes, human cortical organoids, fibroblasts, and lymphoblasts. Differential expression and glycosylation analyses were performed, followed by Gene Set Enrichment Analysis (GSEA) to identify commonly dysregulated pathways. We then applied the EMUDRA drug prediction algorithm to prioritize candidate compounds capable of reversing these shared molecular signatures. RESULTS: We identified four glycoproteins with consistent differential glycosylation across all eight glycoproteomics datasets. Six glycosylation sites and glycan structures were recurrently altered across CDG and showed partial correction with treatment. Pathway analysis revealed shared disruptions in autophagy, vesicle trafficking, and mitochondrial function. EMUDRA predicted several repurposable drug classes, including muscle relaxants, antioxidants, beta-adrenergic agonists, antibiotics, and NSAIDs, that could reverse key pathway abnormalities, particularly those involving autophagy and N-glycosylation. CONCLUSION: Most dysregulated pathways were shared across CDG, suggesting the potential for common therapeutic strategies. Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies.
Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) accounts for about 60 % of all CDGs and is caused by pathogenic variants of the gene encoding PMM2, which catalyzes an essential early step in N-linked...Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) accounts for about 60 % of all CDGs and is caused by pathogenic variants of the gene encoding PMM2, which catalyzes an essential early step in N-linked glycosylation. Efforts to derive an accurate prevalence estimate for this often life-threatening disorder, for which there are currently no approved therapies, are hampered by the wide spectrum of clinical manifestations, the rarity of the disease, and the lack of a central global patient registry. Here, we calculated new estimates of PMM2-CDG incidence and prevalence in North America and Europe based on the frequency of disease-causing alleles using the Hardy-Weinberg equation. Allele frequencies were obtained from the Genome Aggregation Database (gnomAD v4.0) and the likelihood of specific allele combinations resulting in a live birth was adjusted based on the occurrence of genotypes in patient datasets and the expected consequences for protein function. New incidence and prevalence estimates were then calculated in the context of historical ethnicity and birth data from national statistical databases, combined with estimated patient mortality rates. The calculated new incidence estimate was 1 in 33,576 for North America and Europe combined (1 in 40,375 and 29,043, respectively), which predicts an average of 303 live births per year for both regions combined since 1980. The new prevalence estimate was 1 in 63,694 (1 in 76,183 and 57,022 in North America and Europe, respectively), which translates to a total of 14,154 patients living with PMM2-CDG in North America and Europe. Notably, this prevalence is more than 5-fold higher than the current estimate of 2447 diagnosed cases combined, and 10-fold higher than the worldwide prevalence most frequently quoted in the literature. These striking differences highlight the underdiagnosis of the disease and the critical need for improved diagnostic and therapeutic strategies for PMM2-CDG.
Primary mitochondrial diseases are a heterogeneous group of disorders caused by impaired mitochondrial respiratory chain function due to pathogenic variants in nuclear or mitochondrial DNA. These variants disrupt enzyme...Primary mitochondrial diseases are a heterogeneous group of disorders caused by impaired mitochondrial respiratory chain function due to pathogenic variants in nuclear or mitochondrial DNA. These variants disrupt enzyme activity, membrane integrity, or mitochondrial genome maintenance. Phosphodiesterase type 5 (PDE5) inhibitors have recently emerged as potential modulators of mitochondrial function. Prompted by self-reported symptom improvement in an individual with mitochondrial disease taking tadalafil, we investigated the effects of PDE5 inhibitors in this context. Using high-resolution respirometry, we analyzed mitochondrial function in fibroblasts from six individuals with primary mitochondrial disease following treatment with sildenafil or tadalafil. We hypothesized that PDE5 inhibition would improve mitochondrial respiratory function and alleviate clinical symptoms. Clinical outcomes were also assessed in three individuals receiving off-label tadalafil therapy. Patient-derived fibroblasts showed elevated basal and non-mitochondrial respiration, along with increased glycolytic flux. Treatment with PDE5 inhibitors reduced proton leak-associated OCR, improved coupling efficiency, and normalized metabolic profiles. Off-label tadalafil use was associated with acute, dose-dependent, and sustained symptom improvements in all three individuals, with no adverse effects reported. In MELAS fibroblasts responses varied with m.3243 A > G heteroplasmy levels. These findings suggest PDE5 inhibitors may offer safe, accessible, and personalized therapeutic options for mitochondrial diseases, particularly those involving mitochondrial DNA pathogenic variants.
Goorden SMI, van Haaften-Visser DY, Trętowicz MM
… +13 more, Bonte R, Bogaerts E, Jamal Y, Vrieswijk S, Huijser E, Bökenkamp R, van der Palen RLF, Hoffer MJV, Houtkooper RH, Vaz FM, Santen GWE, Bierau J, Oussoren E
Congenital NAD deficiency disorders (CNDD) represent a novel category of hereditary diseases that affect NAD biosynthesis from tryptophan. CNDD include kynureninase (KYNU) deficiency with only ten documented patients to...Congenital NAD deficiency disorders (CNDD) represent a novel category of hereditary diseases that affect NAD biosynthesis from tryptophan. CNDD include kynureninase (KYNU) deficiency with only ten documented patients to date. Here, we report two new cases. In addition to the previously described clinical phenotype of congenital heart defects, skeletal abnormalities, hearing loss and airway malacia, our patients also had hypothyroidism, recurrent infections, and necrotizing enterocolitis. The first patient's exome analysis identified compound heterozygosity for two novel KYNU variants, pathogenicity being supported by extensive metabolic profiling. The second patient was homozygous for a known KYNU missense variant. For the first time we describe a potential treatment of KYNU deficiency as both patients were treated with oral nicotinamide (a B3 vitamer and NAD precursor) and pyridoxine (a vitamin B6, cofactor of KYNU) from young age, which improved biochemistry without evident short-term adverse effects. Furthermore, we show that maternal supplementation with nicotinamide riboside (another B3 vitamer and NAD precursor) during pregnancy appears to be safe. In conclusion, KYNU deficiency is an extremely rare disorder associated with severe congenital defects, demonstrating the indispensable role of de novo NAD biosynthesis in foetal development. Metabolomic profiling is a valuable tool in the analysis of new genetic variants. NAD precursor supplementation in the form of nicotinamide, combined with pyridoxine, may be a novel therapeutic approach.
Acyl-coenzyme A (CoA) thioesters occupy key positions in normal metabolism and are directly related to many inborn errors of metabolism. The degradation pathways of the branched-chain amino acids (BCAAs) are rich in acyl...Acyl-coenzyme A (CoA) thioesters occupy key positions in normal metabolism and are directly related to many inborn errors of metabolism. The degradation pathways of the branched-chain amino acids (BCAAs) are rich in acyl-CoA intermediates, many of which give rise to diagnostically important organic acids and acylcarnitines. Because several such acyl-CoAs are not routinely commercially available, they cannot be identified and quantified in biological samples. This leaves a gap in the characterization of BCAA-related inborn errors of metabolism. We attempted the enzymatic synthesis of BCAA-related 3-hydroxyacyl-CoAs, starting with the corresponding 2,3-enoyl free acids. First the 2,3-enoyl free acid is linked to CoA by purified recombinant glutaconate coenzyme A-transferase (GctAB), a bacterial CoA transferase active toward short chain acids. Then, hydration of the resulting 2,3-enoyl-acyl-CoA is catalyzed by recombinant human short-chain enoyl-CoA hydratase (ECHS1, gene ECHS1), producing a 3-hydroxyacyl-CoA. In this fashion, we synthesized 3-hydroxyisovaleryl-CoA, 3-hydroxyisobutyryl-CoA, 2-methyl-3-hydroxybutyryl-CoA and 3-hydroxypropionyl-CoA. All of these are detectable in normal mouse liver. We also found an unexpected peak with the same mass/charge ratio as 2-methyl-3-hydroxybutyryl-CoA. This proved to be 3-hydroxyvaleryl-CoA, an intermediate of odd chain fatty acid oxidation. All 3-hydroxyacyl-CoA intermediates of BCAA degradation are either commercially available or can be synthesized by the methods described.