2-oxyglutarate dehydrogenase (OGDH) encodes an E1 component of α-ketoglutarate dehydrogenase complex that plays a pivotal role in the Krebs cycle. Biallelic variants in OGDH have been reported to cause an early-onset neurodevelopmental and mitochondrial disorder. However, monoallelic OGDH variants have not been associated with human disease. Here, we identified de novo c.1909C>T (p.Arg637Trp) and heterozygous c.162T>G (p.Ser54Arg) variants in OGDH in unrelated individuals exhibiting late-onset neurological phenotypes, characterized by cerebellar ataxia, peripheral neuropathy and optic atrophy. In silico protein structure predictions suggest that the p.Arg637Trp mutation might influence protein function. To determine the functional effects of the OGDH variants invivo, we generated Drosophila models harboring UAS-dOgdh (p.Arg639Trp) and UAS-dOgdh (p.Thr58Arg) mutations, homologous to the human variants. While the mutant OGDH expression did not lead to defects in development, it did lead to age-dependent locomotion defects. Further, we found that p.Arg639Trp mutant leads to defective OGDH activity, while p.Thr58Arg causes abnormal proteolytic cleavage and impaired mitochondrial import. These findings suggest that the variants act as dominant-negative and toxic gain-of-function mutations, respectively. Our data provide evidence that monoallelic OGDH variants are involved in late-onset neurological disease in humans.

Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double-stranded RNA (mt-dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi-Goutières syndrome (AGS). We describe a 7-month-old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off-label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN-driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment-limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a "mitochondrial interferonopathy" and suggests that IFN-signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.

Mitochondrial carbonic anhydrase VA (CA-VA) deficiency is a rare inherited metabolic disorder caused by biallelic variants of the CA5A gene. It presents with hyperammonemia, lactic acidosis, and ketonuria, with or without hypoglycemia. We report the long-term follow-up of the first two reported cases of CA-VA deficiency: a 16-year-old female (case 1) and her 14-year-old brother (case 2), both of whom presented with neonatal hyperammonemic encephalopathy, hypoglycemia, elevated lactate, ketonuria, and compensated metabolic acidosis. The diagnosis was made in both cases through the TIDEX study, which identified a homozygous pathogenic variant in the CA5A gene (c.697T>C, (p.Ser233Pro)). The clinical course of the index patient revealed three additional metabolic decompensation episodes (MDEs) triggered by intercurrent illnesses, with the last episode occurring at 8 years of age, highlighting the unusual timing of her MDEs compared to previously reported cases. Case 2 remained metabolically stable without any additional MDEs. These episodes were successfully treated with parenteral dextrose, a single dose of enteral carglumic acid, and occasionally parenteral lipids. Management of intercurrent illness included a sick-day formula high in carbohydrates and fats. Currently, both cases show normal growth, development, and neurological outcomes, suggesting a favorable prognosis, and in keeping with previously reported cases. Early diagnosis of CA-VA deficiency allows prompt treatment and prevents severe complications. With proper management, long-term outcomes are favorable, although severe and fatal outcomes have been reported. The impact on longevity needs to be assessed over longer durations. The development of consensus management for CA-VA deficiency is warranted.

Wilson disease (WD) is a rare autosomal recessive disorder. Although hepatic and neurologic manifestations are characterized, long-term cardiac outcomes remain poorly defined. We report the first longitudinal study systematically assessing cardiac symptoms and events over nearly a decade in WD. In 2016, 61 WD patients underwent prospective cardiac evaluation including echocardiography, MRI and 24-h ECG. Nine years later, we re-contacted all surviving participants by telephone and emailed standardized questionnaires. Baseline characteristics of respondents and non-respondents were compared to assess selection bias; mortality data were obtained from family interviews and medical records. Outcomes were available for 31 of 61 patients (27 interviewed, 4 deceased; no cardiac-related deaths) after a mean follow-up of 9.1 years. Respondents did not differ from those lost to follow-up, except for fewer disease exacerbations. General and cardiac health remained unchanged in about half (48% and 52%), worsened in ~40%, and improved in ≤ 15%. Palpitations were frequent (70%), whereas dizziness (26%), syncope (7%), and leg oedema (15%) were infrequent and comparable to general-population estimates. Daily activity was unrestricted in 44%, mildly to moderately restricted in 52% and severely restricted in 4%. Only six patients (22%) remained in routine cardiology care. Baseline imaging, strain, autonomic and laboratory parameters did not predict symptoms at follow-up. Over 9 years, cardiac symptoms in WD were common but mostly mild to moderate. These findings support a symptom-guided cardiological assessment within interdisciplinary care. Whether systematic screening of asymptomatic patients is warranted remains uncertain and requires dedicated prospective study.

MRPS34 encodes a mitoribosomal protein essential for mitochondrial translation. Biallelic pathogenic variants in MRPS34 cause Combined Oxidative Phosphorylation Deficiency 32 (COXPD32), a rare mitochondrial disorder within the Leigh syndrome spectrum (LSS), ranging from fatal in infancy to adult survival. The objective is to describe two new individuals with MRPS34-related disease and expand the clinical, genetic, and phenotypic spectrum of COXPD32. Clinical, radiological, biochemical, and molecular evaluations were conducted in two individuals with Leigh Syndrome (LS). Exome and genome sequencing identified presumed biallelic MRPS34 variants. A systematic review of all previously reported cases was performed to assess possible genotype-phenotype correlations (n = 11). Individual 1, who died in infancy with LS, was presumed compound heterozygous for a novel splice-site variant (c.364 + 2 T>C, p.(?)) and a nonsense variant (c.94C>T, p.(Gln32*)). Individual 2 survived into mid childhood and was homozygous for the hypomorphic variant c.322-10G>A, p.(?). Among 11 individuals, key features included developmental delay (100%), lactic acidosis (91%), brainstem lesions (91%), and metabolic acidosis (83%). Homozygosity for c.322-10G>A, p.(?) correlated with longer survival. MRPS34-related disease presents with multisystemic features and genotype-dependent severity. Accurate genetic diagnosis is essential for prognosis and therapeutic strategies.

Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease, is a rare and potentially fatal lysosomal storage disease caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, which encodes acid sphingomyelinase (ASM). Deficient ASM activity results in dysregulation of cellular membrane homeostasis and accumulation of sphingomyelin in multiple organs. ASMD spans a broad clinical spectrum, with symptoms varying at presentation depending on age at onset and degree and type of organ/systemic involvement. To describe the diagnostic experience and clinical manifestations of ASMD in Argentina, a national retrospective case series was conducted across seven centers in patients diagnosed between 1988 and 2022. Diagnosis was confirmed by reduced ASM activity, with SMPD1 sequencing performed when possible. Nineteen patients (8 females/11 males; 0-76 years) were identified: Type A (4, 21%), Type B (12, 63%), Type A/B (2, 11%), and one unknown. Average age at symptom onset was 3.9 years, and average age at diagnosis was 11.4 years, corresponding to a diagnostic delay of 7.5 years. All patients presented with hepatosplenomegaly. Anemia (79%), pulmonary involvement (79%), thrombocytopenia (79%), and osteopenia (56%) were also reported in a majority of patients. Two patients were initially misdiagnosed with Gaucher disease. This series highlights the variety of clinical presentations and substantial diagnostic delays associated with ASMD in Argentina. Increasing awareness across specialties is essential to improve disease recognition, reduce time to diagnosis, and prevent misdiagnosis.

ABSTRACTHyperammonemic crisis (HAC) remains a major risk factor for urea cycle disorders (UCD), and practical outpatient predictors are limited. We tested whether short‐term changes in plasma glutamine (ΔGln) and ammonia (ΔNH3) predict HAC and whether effects differ by onset type. In a retrospective cohort (2014–2024) of 18 patients with UCD (neonatal‐onset [NO] nine; late‐onset [LO] nine), HAC was defined as ammonia (NH3) > 150 μg/dL (88.1 μmol/L). For each patient, ΔGln and ΔNH3 were calculated between sequential outpatient samples. Investigation 1 compared the changes observed between 31–60 days and 8–30 days before HAC, with stable period changes. Investigation 2 compared changes at 61–90 and 31–60 days before HAC with stable period changes. Associations were evaluated using generalized linear mixed‐effects models with onset‐specific effects. In NO, larger ΔGln during Investigation 1 was associated with higher HAC risk (p < 0.001) whereas ΔNH3 was not associated with HAC (p = 0.361). The probability of HAC in NO was estimated to reach 67.1% at ΔGln +500 μmol/L. In LO, neither ΔGln nor ΔNH3 during Investigation 1 showed a significant association with HAC, and the estimated probabilities remained low across the observed ranges. During Investigation 2, no significant associations between biomarkers and HAC were observed in either group. Progressive increases in plasma glutamine levels within the 31–60 and 8–30 days pre‐HAC window may serve as early markers of HAC risk in NO‐UCD, supporting the utility of longitudinal monitoring. These trends were not associated with LO‐UCD, suggesting the need for alternative surveillance strategies tailored to the onset phenotype.

ABSTRACTSodium phenylbutyrate (NaPBA) is used for nitrogen scavenging in urea cycle disorders (UCDs), but its volume, palatability, and sodium load affect adherence and ammonia control. Glycerol phenylbutyrate (GPB) offers an alternative option with demonstrated improvements in metabolic control and palatability. For a Japanese perspective, we undertook an open‐label, multicentre, prospective Phase 3 study of efficacy, pharmacokinetics (PK), and safety. In a switch‐over, 15 patients received NaPBA for 7 days, then GPB for 7 days. Primary endpoint: 24‐h blood ammonia AUC (AUCNH3,0–24). Secondary endpoints: blood ammonia and glutamine concentration; PK of scavenger metabolites in blood and urine; safety. Patients then received GPB for up to 12 months. For GPB and NaPBA, respectively, mean (SD) AUCNH3,0–24 was 627 (198) and 757 (307) μmol·h/L (ratio 0.849; 95% CI 0.723–0.997). Mean peak and mean blood ammonia were 37 and 26 μmol/L versus 52 and 32 μmol/L. Mean plasma AUC0–24 for phenylbutyrate (PBA), phenylacetate (PAA), and phenylacetylglutamine (PAGN) were 470, 1420, and 836 versus 425, 984, and 741 μg·h/mL. Mean PBA metabolite fluctuation was 297% versus 366%. One adverse event (hyperammonaemia) led to discontinuation in each treatment arm. In the extension (n = 14), mean (SD) blood ammonia at Month 12 was 21 (8) μmol/L. No new safety findings were observed. GPB demonstrated effective control of blood ammonia with a favourable safety profile. It offers a practical and clinically advantageous alternative to NaPBA, extending previous evidence to Japanese individuals with UCDs. Trial registration: jRCT2071220110.

ABSTRACTClassical homocystinuria (HCU) is an autosomal recessive disorder of methionine metabolism with a wide spectrum of severity and clinical presentation. Timely diagnosis facilitates prompt initiation of treatment, which reduces complications. Our aim was to identify the nature of the first clinical manifestation and time to subsequent diagnosis in our cohort of adults with HCU. This retrospective cross‐sectional study was conducted in two tertiary referral centres for adult inherited metabolic disorders in the United Kingdom. Fifty‐nine patients with sufficient clinical data for detailed analysis were included. 13/59 patients were detected asymptomatically through newborn or family screening and 46/59 were diagnosed on initial presentation with a clinical manifestation of HCU. For 15/54 (27.8%), the median time between initial presentation and diagnosis was 7 years (IQR, 2–11.9), the commonest first manifestation in the delayed group was lens subluxation (6/15, 40%) followed by venous thromboembolism (5/15, 33.3%) and skeletal deformities (2/15, 13.3%). 15/46 (32.6%) had two or more complications by the time of diagnosis. Lens subluxation is the commonest first manifestation of HCU in the group with delayed diagnosis. Early recognition, expanded screening and enhanced clinician awareness are essential for timely diagnosis and improved outcomes.