Fructose-1,6-bisphosphatase deficiency is a rare inherited metabolic disorder of gluconeogenesis characterized by recurrent hypoglycemia and lactic acidosis, typically triggered by inadequate glucose intake or increased consumption of fructose, sucrose, or sorbitol. During pregnancy, the risk of hypoglycemia and lactic acidosis increases because endogenous glucose production is limited while fetal glucose demand rises. Here we report three patients with fructose-1,6-bisphosphatase deficiency who had successful pregnancies and deliveries. These patients were managed by a multidisciplinary team of obstetricians, maternal-fetal medicine specialists, metabolic physicians, and metabolic dieticians. All patients were obese; one had morbid obesity. Two patients developed gestational diabetes mellitus. One responded to dietary intervention, whereas the patient with morbid obesity had poor dietary adherence, suboptimal glycemic control, and experienced an episode of severe life-threatening hypoglycemia with lactic acidosis requiring intensive care. She recovered fully, with no adverse maternal or fetal effects. All patients had normal vaginal deliveries and were closely monitored during labor, delivery, and the postpartum period. Both patients with gestational diabetes developed lactic acidosis immediately after delivery despite stable blood glucose levels. Managing gestational or type 2 diabetes in patients with fructose-1,6-bisphosphatase deficiency is particularly challenging because the disorder predisposes them to hypoglycemia. This case series contributes to the limited literature on pregnancy outcomes and highlights key management challenges in this rare condition.
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) classically presents with hypoketotic hypoglycaemia; however, this presentation is now rare following the introduction of newborn screening. While children with MCADD may produce some ketones, severe ketoacidosis has not been previously described. Here we report two patients with MCADD presenting with severe ketoacidosis in the neonatal period prior to results of newborn screening. Patient 1 presented on Day 5 with hypoglycaemia, profound ketoacidosis and circulatory shock, and developed refractory ventricular tachycardia requiring extra-corporeal membrane oxygenation. Patient 2 presented on Day 4 with severe ketoacidosis, but only borderline hypoglycaemia. The diagnosis of MCADD was rapidly confirmed in both by analysis of acylcarnitines and urine organic acids, with subsequent genetic confirmation of ACADM mutations. We conclude that MCADD should be included in the differential diagnosis of neonatal ketoacidosis, with or without hypoglycaemia.
Enzyme Replacement Therapy (ERT) is the clinical standard for Mucopolysaccharidosis II (MPSII), yet its limited penetration into poorly vascularised tissues such as bone, cartilage and heart valves leaves participants with significant musculoskeletal morbidity. This small study evaluated the feasibility of hydrotherapy as an adjunct to ERT in addressing these therapeutic gaps and improving Health-Related Quality of Life (HRQoL). Using a crossover design, the study assessed five male participants with MPSII. Key outcomes included HRQoL via the Short Form Health Survey (SF-36), functional mobility by the 6-Minute Walk Test (6MWT) and pain interference through the Brief Pain Inventory (BPI). Data from the SF-36 and BPI showed improvements, including a mean improvement in Physical Functioning, Role Physical and Social Functioning and a mean reduction of 16.2 in pain interference. Analgesic relief over 24 h was 45.8% in the hydrotherapy arm, compared to 18% in the observation arm. Psychological conditions including anxiety, depression and kinesiophobia were also analysed. Participants demonstrated a mean increase of 44.5 m in the 6MWT, suggesting that the 'unloading' effect of water facilitated gait speed and endurance (compared to observation arm: mean difference 55.8 m 95% CI -51.6 to 163.1). Participants achieved a mean strength increase of 6.1 lb. during the hydrotherapy arm without adverse effects, corroborating the safety of aquatic resistance training in fragile populations. Our findings demonstrate the feasibility of hydrotherapy as an adjunct to ERT in participants with MPSII. By managing pain and improving HRQoL, hydrotherapy addresses physical and psychological burdens that ERT alone cannot achieve.
Adult patients with inherited metabolic diseases are often overlooked. Limited data on this population hinder adequate planning of their clinical and social care. In this retrospective, observational, cross-sectional service evaluation study, we reviewed the electronic medical records of adult patients with inherited neurometabolic diseases (NIMD) managed at Skåne University Hospital between 2020 and 2024. Skåne University Hospital, located in Region Skåne in Southern Sweden, is one of three specialized tertiary centers for inherited metabolic diseases in Sweden. The aim of this study was to characterize these patients demographically and clinically and to describe their treatment profiles, functional status, and social support. We identified 59 patients. Most patients had disorders of intermediary energy metabolism (21/59; 35.6%) or lipid metabolism (14/59; 23.7%), including 10 patients (16.9%) with adrenoleukodystrophy. Disease-specific treatments were provided to 65.4% of patients, and 83.6% were under continuous follow-up. Sixteen patients (27.1%) were fully independent, lived in their own homes, did not require societal support nor mobility aid, and worked/studied full time/retired due to old age. More than half of the patients (50.8%) received no disability or social support. In conclusion, adult patients with NIMD represent a heterogeneous group with variable clinical and social needs. Despite the rarity of individual NIMDs, disease-specific treatments were commonly used in our center. Further studies, particularly long-term follow-up studies, are required to better understand NIMD clinical trajectories and to optimize both medical management and social support for adults with NIMD.
ABSTRACT Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inherited metabolic diseases causing deficiency in the catabolism of amino acids, cholesterol, and odd‐chain fatty acids. Both patient groups report exercise intolerance and fatigue. We recently reported findings of impaired lipolysis and blunted fat oxidation during exercise in a patient with PA, suggesting a metabolic myopathy phenotype. To further investigate this phenomenon, we conducted a new study to investigate fat and glucose metabolism during exercise in patients with PA and MMA. We included two patients with MMA and two with PA. The patients performed a low‐intensity exercise test on a cycle ergometer, working at a workload corresponding to 50% of their maximal oxygen capacity. Fat and glucose metabolism were quantified at rest and during exercise via continuous infusion of stable isotope‐labeled glucose and palmitate, and indirect calorimetry. The results were compared to those of matched healthy controls. Lipolysis and fatty acid oxidation were close to normal at rest, but impaired during exercise in the patients vs. healthy controls exercising at the same absolute workload: Lipolytic rate (1.5 ± 0.6 vs. 4.0 ± 1.4 μmol kg −1 min −1 , p = 0.001) and palmitate oxidation (0.8 ± 0.6 vs. 2.1 ± 1.0 μmol kg −1 min −1 , p = 0.018). To compensate, the patients increased carbohydrate oxidation (68.2 ± 18.1 vs. 44.9 ± 16.4 μmol kg −1 min −1 ). Our findings indicate that both PA and MMA should be considered metabolic myopathies, which may explain the reported exercise intolerance and fatigue.
ABSTRACT Enzyme replacement therapy (ERT) with elosulfase alfa is the only approved treatment for mucopolysaccharidosis type IVA. This case report delineates the 5‐year outcomes of ERT in two Korean siblings with mucopolysaccharidosis type IVA, with the younger sibling initiating treatment at 0.8 years of age and the older one at 5.4 years. Both patients exhibited a progressive decline in their height standard deviation scores, with trajectories paralleling the natural history curves of the disease. At 5.2 years of age, persistent skeletal dysplasia was evident in both siblings. However, the younger sibling demonstrated attenuated disease severity, lacking cervical myelopathy or spinal stenosis requiring C1 laminoplasty. Cardiorespiratory assessment revealed normalized left ventricular mass index z‐scores, stable ejection fractions, and the absence of valvular pathology. Overall, these findings suggest that early ERT attenuates severe spinal and upper body manifestations but does not prevent lower limb skeletal progression, highlighting the need for early therapeutic initiation along with orthopedic intervention to preserve cardiorespiratory parameters and functional independence.
ABSTRACT Both citrin deficiency (CD) and citrullinemia type I (CTLN1) may be detected by elevated citrulline through newborn screening (NBS) or present as acute liver failure in later infancy, but they differ significantly in management. This may pose therapeutic challenges in the early period after presentation while awaiting diagnostic confirmation. We report a Chinese girl (birth weight 1.98 kg at 37 weeks) who was recalled on day 5 for elevated citrulline (47 μmol/L; cutoff < 25) and citrulline/arginine ratio of 7.34 at NBS on day 2. Citrulline rose to 264 μmol/L upon retesting on day 5. Initial investigations revealed INR of 3.4 and raised alkaline phosphatase, while ammonia, conjugated bilirubin, glucose, albumin, gamma‐glutamyl transferase, and transaminases were normal. Suspected CTLN1 led to halting protein intake and starting high glucose infusion. Within 17 h, INR increased to 6.5 and albumin dropped. Worsening hepatic function following high‐glucose intake and her small for gestation age status suggested CD. She improved rapidly after switching to lactose‐free MCT‐enriched formula. Genetic analysis revealed compound heterozygous known pathogenic mutations in the SLC25A13 gene, confirming the diagnosis of CD. This is the first report of CD presenting with neonatal acute liver failure without cholestasis. It highlights the importance of prompt differentiation between CD and CTLN1 in NBS recalls for safe and effective interim treatment.
ABSTRACT 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.
ABSTRACT 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.
ABSTRACT 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.
ABSTRACT 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.
ABSTRACT Hyperammonemic 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 (ΔNH 3 ) 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 (NH 3 ) > 150 μg/dL (88.1 μmol/L). For each patient, ΔGln and ΔNH 3 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 ΔNH 3 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 ΔNH 3 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.
ABSTRACT Sodium 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 (AUC NH3,0–24 ). 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) AUC NH3,0–24 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 AUC 0–24 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.
ABSTRACT 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.
ABSTRACT 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 in vivo, 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.
ABSTRACT Classical 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.
ABSTRACT Incorporating patient preferences into drug development is crucial, particularly, for rare diseases with significant unmet needs. This study used Best‐Worst Scaling type 2 (BWS‐2) to explore benefit–risk trade‐offs for patients and caregivers in two rare neuromuscular diseases (NMDs), myotonic dystrophy type 1 (DM1), and mitochondrial myopathy (MM). Patients with DM1 and MM, along with caregivers, completed a BWS‐2 survey assessing four treatment benefits (muscle strength, energy and endurance, balance, cognition) and two risks (permanent liver damage, temporary blurring of vision). Participants were stratified by disease group and age of onset (< 20, ≥ 20 years). A latent class analysis was used to calculate the relative importance of each treatment attribute. Sociodemographic and disease‐related data were also collected. A total of 270 participants (DM1 n = 143, MM n = 127, including 37 caregivers) were included. BWS‐2 results revealed a priority for improvements in muscle strength (24%), and energy and endurance (23%) across all groups, with caregivers placing a higher priority on cognition improvements (17%) compared to patients. There were no significant differences between disease groups or by age of onset. This study underscores the importance of patient preferences in drug development for rare NMDs. The consensus on treatment priorities across both diseases suggests that overlapping clinical features can inform and expedite future NMD or rare disease drug development.
Isovaleric acidemia (IVA) is a rare autosomal recessive disorder caused by isovaleryl-CoA dehydrogenase deficiency, leading to toxic metabolite accumulation and potentially life-threatening metabolic crises. Newborn screening (NBS) has enabled early detection through elevated C5 acylcarnitine levels, yet the prognostic value of initial C5 concentrations remains unclear. This single-center retrospective study examined 10 Australian patients diagnosed with IVA via NBS between 2004 and 2025. Patients were stratified as "mild" or "classic" based on initial C5 levels and clinical severity. Developmental outcomes were assessed using standardized tools and clinical evaluations. Despite biochemical evidence of metabolic instability, including hyperammonemia, acidosis, and hospitalizations, no patients demonstrated neurological impairment on follow-up. Notably, individuals with markedly elevated C5 levels (up to 63.6 μmol/L) remained neurologically intact, suggesting that early diagnosis and timely metabolic management (protein restriction, carnitine/glycine supplementation, emergency protocols) may mitigate long-term CNS involvement. Dietary practices varied, with some patients maintaining protein restriction due to self-limited intake. Our findings reveal substantial heterogeneity in biochemical profiles and clinical trajectories, with minimal correlation between initial C5 levels and neurodevelopmental outcomes. These results align with prior studies questioning the predictive value of isolated NBS markers and support a more nuanced, individualized approach to IVA management. Limitations include small sample size, retrospective design, and incomplete standardized neurocognitive testing. Further prospective studies incorporating genotype data and formal assessments are needed to refine risk stratification and optimize long-term care strategies.
Seryl-tRNA synthetase 1 (SARS1) deficiency is a rare autosomal recessive disorder presenting with neurodevelopmental delay, deafness, cardiomyopathy, and fatal metabolic decompensation triggered by febrile episodes. While amino acid chronic supplementation is established, no guidelines exist for acute management. We report the case of a 9-year-old male of Turkish origin with genetically confirmed SARS1 deficiency, admitted with fever, vomiting, hypotonia, and seizures. The clinical course rapidly progressed to metabolic decompensation and severe acute cardiac failure, characterised by a left ventricular ejection fraction of 20%, necessitating mechanical ventilation and vasopressor support. Notably, the patient's family history included the death of three siblings during similar febrile episodes. During hospitalisation, the patient's specific L-serine supplementation dosage was progressively tripled concurrently with standard supportive care. Unlike the fatal outcomes observed in his siblings, untreated by L-serine, the patient survived and recovered following this high-dose regimen. Cardiac biomarkers normalised within 20 days, and follow-up echocardiography at 1 month demonstrated complete resolution of myocardial oedema. However, a year later, the patient presented with another febrile crisis at 10 years old, and despite an emergency protocol, the patient developed severe biventricular dysfunction progressing to fatal cardiogenic shock. This constitutes the first documented survival of a SARS1-related metabolic crisis managed with high-dose L-serine. The findings strongly suggest that early, aggressive escalation of L-serine dosage can be a viable therapeutic strategy for acute decompensation in SARS1 deficiency.
