Background:Propionic acidemia (PA) is a severe metabolic disorder that leads to multiorgan damage despite comprehensive management. Liver transplantation (LT), particularly living donor liver transplantation, has been proposed as an effective treatment, but evidence from large-scale studies is limited.Methods:This retrospective study analyzed clinical outcomes of 39 children with PA who underwent LT at Shanghai Ren Ji Hospital between September 2017 and October 2023. The data included demographics, surgical details, biochemical/metabolic markers, and progression of symptoms. Patients were grouped based on the Diagnosis-to-Transplant Interval (<20 vs. ≥20 mo) for comparative analysis.Results:Among 39 patients, 38 (97.4%) underwent living donor liver transplantation, and 1 received split LT. At 6 months after transplant, significant reductions were observed in propionylcarnitine/acetylcarnitine ratio (1.4 to 0.8, p=0.01), urinary methylcitrate (35.4 to 15.2, p=0.03), and 3-hydroxypropionic acid (198.8 to 6.8, p=0.02). Symptoms such as gross motor delay, metabolic acidosis, hyperammonemia, and feeding difficulties significantly improved (all p<0.001). The 5-year patient and graft survival rates were 97.4%. Short Diagnosis-to-Transplant Interval time (<20 mo) and long Diagnosis-to-Transplant Interval time (≥20 mo) also affected the results of specific PA clinical problems before and after transplantation.Conclusions:This single-center study on PA transplantation suggests that LT, especially living donor liver transplantation, effectively reduces metabolic waste, promotes metabolic stability, and enhances quality of life in pediatric patients with PA. LT represents an effective therapeutic option for patients with metabolic instability.

Propionic acidemia is a rare autosomal recessive metabolic disorder caused by a deficiency of the enzyme propionyl-CoA carboxylase, leading to the accumulation of toxic levels of propionic acid in the blood. This accumulation can result in life-threatening metabolic crises and a wide range of systemic and neurological complications. In individuals with propionic acidemia, recurrent metabolic decompensations, altered neurological status, developmental delays, and psychomotor retardation are commonly observed, with significant variability in their clinical presentation. Visual impairment in propionic acidemia may arise due to the impact of these associated systemic and neurological disturbances on the optic nerve, visual pathways, and cortical visual processing areas, potentially leading to cerebral visual impairment. This case study presents the visual functioning of a seven-year-old girl with a confirmed diagnosis of propionic acidemia. It highlights her specific visual profile and describes individually designed adaptations that support visual access and processing. Observations over time in different settings revealed patterns such as delayed visual responses, fluctuations in visual performance depending on the time of day, color preferences, difficulties in object recognition within visually cluttered scenes, and stronger responses to moving versus static visual stimuli. Based on these findings, a targeted visual stimulation and (re)habilitation program was created, along with an individualised adaptation plan to enhance visual learning and interaction with the environment.

ABSTRACTMethylmalonic acidemia (MMA) is a rare metabolic disorder with various subtypes, including Cobalamin B (cblB) disease. While cardiac complications are well‐documented in propionic acidemia, their occurrence in MMA is less understood. Here, we report a 12‐year‐old child with cblB disorder who developed acute cardiomyopathy (CM). The patient presented with fever, tachycardia, and dyspnea. Echocardiography revealed depressed left ventricular function, which initially improved with standard treatment but rapidly deteriorated. Coenzyme Q10 (CoQ10) supplementation was initiated at a dose of 25 mg/kg/day, resulting in a remarkable improvement in cardiac function within 72 h. This report highlights the potential efficacy of CoQ10 in treating MMA‐related cardiomyopathy, suggesting mitochondrial dysfunction as a key factor. The successful use of CoQ10 in this context is novel, as previous literature mainly focused on its application in propionic acidemia. This report proposes CoQ10 supplementation as a promising adjuvant therapy for cardiomyopathy in MMA, particularly in cblB disorder, and calls for further research to validate its benefits.

In the Netherlands, the newborn screening (NBS) program includes screening for propionic aciduria (PA) and methylmalonic aciduria (MMA). When initial screening reveals elevated C3 concentrations or abnormal ratios (C3/C2, C3/C16), a second-tier test measuring methylcitric acid (MCA) for PA and methylmalonic acid (MMAmb) for MMA is performed. While this two-tier approach reduces false positives effectively, it can delay referral from the NBS program and diagnosis of propionic aciduria. We describe four early-onset PA cases in which the current Dutch screening algorithm negatively impacted clinical outcomes, highlighting the need for expedited referral. We investigated different alternative screening strategies to identify the most effective approach for improving timeliness, while maintaining the high specificity of Dutch PA NBS. This revised approach prioritizes the evaluation of the C3/C2 ratio in first-tier screening. Specifically, samples with a C3/C2 ratio ≥ 0.75 should be referred directly for medical consultation and confirmatory testing. For all other samples with less pronounced biochemical abnormalities, the existing two-tier screening algorithm remains an appropriate NBS protocol. To position our approach internationally, a survey of European NBS programs was conducted to compare screening and referral protocols for PA across the region.

Background/Objectives: Propionic acidemia (PA) and methylmalonic acidemia (MMA) affect methionine, threonine, valine (Val), and isoleucine (Ile) (MTVI) metabolism, leading to the production of highly neurotoxic organic acids. Treatment involves a diet restricted in natural proteins and supplemented with a protein substitute (PS) with traces of MTVI. The aim was to analyze natural protein and PS intake in relation to linear growth impairment in individuals with PA and MMA. Methods: We followed the PRISMA protocol. We considered articles published between 1970 and 2025. We determined the eligibility criteria for selecting articles and evaluated the quality. Results: Thirteen studies were selected: two case reports, eight longitudinal, three cohorts, and one cross-sectional. Articles demonstrated that natural protein intake decreases with age, consistent with previous reports, underscoring the need for PS supplementation to meet protein requirements. Subjects with PA and non-responsive MMA had greater restriction of natural proteins, and the majority required PS; a higher PS intake was negatively correlated with a higher height-for-age (H/A) z-score. When analyzing the ratio of protein to energy (P:E), a negative correlation was found between the intake of natural proteins and energy, and a positive correlation with H/A z-score (p-value &lt; 0.05). Supplementation with PS increased leucine levels, causing an imbalance with MTVI amino acids. This imbalance led to the paradoxical need to supplement L-Val and L-Ile, both propiogenic amino acids. As a result, a decrease in the H/A z-score was observed, particularly in PA and non-responsive MMA. Responsive MMA tolerated more natural proteins, received a lower intake of PS, and had a better H/A z-score. Conclusions: Restriction of natural proteins and PS is associated with a lower H/A z-score, primarily in subjects with PA and non-responsive MMA.

Several inborn errors of metabolism (IEMs) are known to affect immune function; the latter may arise from disruptions in metabolic pathways critical to immune cell development or from accumulation of toxic metabolites that impair immunity. This overlap can complicate diagnosis and management. We present seven patients with IEMs initially suspected of having inborn errors of immunity (IEIs) to highlight the phenotypic intersections between these disorders. All patients were referred for immunological evaluation due to recurrent infections, cytopenias, or abnormal immune profiles. Each was ultimately diagnosed with an IEM known to affect immune function. Results • Purine nucleoside phosphorylase deficiency: A 4-year-old female with CMV infection, seizures, and lymphopenia was diagnosed with this T cell defect associated with purine metabolism. Good clinical response with intravenous immunoglobulin, oral prednisolone, folic acid, vitamin B, and antiviral. • Propionic acidemia: Three patients presented with early-onset sepsis or viral infections. Immunologic findings included hypogammaglobulinemia, lymphopenia (particularly affecting B and natural killer cells), and neutropenia. Treated with carglumic acid, levocarnitine, protein-rich diet, and replacement immunoglobulin. • Transcobalamin II deficiency: Two patients had recurrent infections, cytopenias, and global lymphopenia. One showed hypogammaglobulinemia. Good response with intramuscular B12 vitamin and folic acid. • Thymidine phosphorylase deficiency: A 17-year-old male presented with ophthalmoparesis, severe abdominal pain, and angiographic images resembling vasculitis, with negative autoantibodies and poor response to immunosuppression. He died a few weeks after liver transplantation. Conclusion This series underscores the immunologic manifestations of IEMs, which can mimic IEIs and complicate diagnosis. Recognizing the bidirectional overlap is crucial: immune evaluation may uncover an underlying metabolic disorder, while persistent infections or immune alterations in IEMs warrant thorough immunological assessment. Immunologic interventions like immunoglobulins, antibiotic prophylaxis, vaccines, etc. may help to reduce the infectious burden in IEMs and improve quality of life. Timely diagnosis and comprehensive management are crucial for both groups of diseases.

This study evaluates the incidence of metabolic disorders detected from January 2005 to December 2024 and their clinical outcomes. Data were retrospectively collected from the Louisiana Newborn Screening database. Clinical outcomes were obtained through review of corresponding medical records. In addition, an electronic questionnaire assessing educational attainment and neurodevelopmental disorders was sent to the patients’ families. Of 1,230,356 infants screened, 478 were diagnosed with metabolic disorders, corresponding to an incidence of 1 in 2574 live births. The three most commonly identified conditions were biotinidase deficiency, phenylketonuria (PKU), and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). During the study period, at least 11 patients died. The program demonstrated a false-positive rate of 0.93%. Twelve patients (7%) were symptomatic before or at the time of NBS result notification. Recurrent metabolic decompensations occurred in 3 of 4 maple syrup urine disease (MSUD) cases, 7 of 7 methylmalonic acidemia (MMA) cases, 1 of 4 propionic acidemia (PA) cases and 1 of 7 urea cycle defect cases. Regarding long-term outcomes, 45.7% of survey respondents reported adverse neurodevelopmental outcomes of varying severity. Early detection and timely intervention have contributed to normal or near-normal outcomes in many cases. However, the morbidity and mortality observed in some patients despite early diagnosis highlights the severity and complexity of certain metabolic conditions. Additionally, the relatively high false positive rate underscores the need for ongoing efforts to improve the specificity of screening protocols to reduce unnecessary follow-ups and mitigate potential stress for families.

ABSTRACTMethylmalonic acidemia (MMA) and propionic acidemia (PA) are inherited metabolic disorders affecting valine and isoleucine catabolism. Long‐term therapy mainly involves dietary protein restriction. An amino acid mixture (AAM, medical food) free of the precursor amino acids is frequently used, especially when protein intake does not reach World Health Organization (WHO) recommendations. However, its clinical impact on disease control and patient outcomes remains unclear. Our study aimed to retrospectively review the dietary prescriptions in a cohort of vitamin B12‐unresponsive MMA and PA patients and to analyze their impact on clinical and laboratory parameters. Clinical data, anthropometric measurements and dietary prescriptions were collected from the patients' medical and dietary files. We included 71 patients (38 MMA and 33 PA). Fifty‐nine percent of the patients' dietary prescriptions did not reach the safe WHO‐recommended daily total protein intake. Among these, 28% included AAM supplementation versus 62% in the group of patients that met the WHO recommendations (p < 0.001). AAM was associated with a decrease in mean plasma concentrations of isoleucine and valine. These plasma amino acid concentrations were corrected by isoleucine and valine supplementation; however, leucine/isoleucine and leucine/valine ratios remained elevated in comparison to patients without AAM. Nutritional and clinical scores were worsened by AAM supplementation. We found that MMA/PA patients receiving AAM tend to have altered plasma amino acid concentrations, raising concerns about potential long‐term deleterious consequences of AAM. We recommend prioritizing natural protein intake over AAM when possible, and if not, to carefully monitor and moderately supplement valine and isoleucine to prevent deficiencies.

Propionic acidemia and methylmalonic aciduria: A portrait of the first 3years-Admissions and complications.

Heart and heart-liver transplantation in Amish patients with propionic acidemia.

Targeting pantothenate kinases in human diseases: Biochemistry and pharmacotherapy.

H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations.

Infantile epileptic spasms syndrome is an early-onset epileptic encephalopathy. Its association with inborn errors of metabolism is underrecognized, and the treatment can be complicated by the biochemical vulnerability. This report showed individualized treatment in 2 patients with inborn errors of metabolism. The first patient was found to have propionic acidemia in the setting of encephalopathy by third day of life. Infantile epileptic spasms syndrome was diagnosed at 10 months. Levetiracetam was started, and vigabatrin was introduced following liver transplant, which resulted in seizure freedom. The second patient presented at 6 months with hyperammonemia and elevated orotic acid consistent with ornithine transcarbamylase deficiency. Infantile epileptic spasms syndrome was diagnosed 3 weeks later. Treatment with vigabatrin, adjunctive to levetiracetam, led to a brief period of seizure cessation. The patient was later treated with two 4-week courses of enteral prednisolone, leading to the cessation of spasm. These cases emphasize the complexity in managing infantile epileptic spasms syndrome in patients at high risk for metabolic decompensation.

ABSTRACTImaging literature on propionic acidemia (PA) is predominantly concerned with deep gray matter changes. In order to investigate the spectrum and patterns of MRI changes, 45 MRI scans of 13 patients (0.31–33.2 years) were systematically analyzed. Deep and cortical gray matter changes were associated with acute metabolic decompensation. Striatum was affected in 10/13; T2‐hyperintensity was often mild, normalizing and becoming T2‐hypointense in one patient each without movement disorder. Pallidum was T2‐hyperintense in the 3 infants imaged for acute decompensation, with restricted diffusion in 2/3 and normalizing in 2/2 with follow‐up. Dentate and thalamus were T2‐hyperintense in 7/13 and 2/13, respectively, without resolution. Cerebellar watershed injury (4/13) and cortico‐subcortical involvement with transiently restricted diffusion, T2/FLAIR‐hyperintensity, and/or swelling (3/13) were more common with seizures during decompensation. A pattern of predominantly subcortical leukoencephalopathy was observed in 7/9 patients aged 9 years and above. Small foci of restricted diffusion, T2/FLAIR‐hyperintensity, and variable T1‐hypointensity evolved into bilateral, sometimes extensive changes with restricted and facilitated diffusion, decreasing in 3/6 with follow‐up MRI at 14.7–19.5 years. Volume deficit was common, including a thin brainstem in 9/13. Predominantly subcortical white matter changes are a characteristic finding in older children with PA, might reflect microvacuolation, and may improve. Transient pallidal changes in infants with acute decompensation might represent myelin splitting during active myelination of white matter‐rich pallidum. Cortico‐subcortical changes and cerebellar watershed injury during acute metabolic decompensation were more likely with seizures; like the more common striatal involvement they occurred without age‐predilection.

Nanoscale conformational dynamics of human propionyl-CoA carboxylase.

ABSTRACTPropionic aciduria (PA‐uria) and methylmalonic aciduria (MMA‐uria) are caused by defects in propionate catabolism. While chronic kidney disease (CKD) is a well‐established complication in MMA‐uria, renal involvement in PA‐uria has only come into focus more recently, and the underlying mechanisms remain poorly understood. We investigated human renal epithelial cells from patients with PA‐uria, MMA‐uria, and healthy controls under metabolic stress, induced by methylmalonic acid, methylcitric acid, high‐protein, or isoleucine/valine‐enriched media. Proteomic profiling revealed significant enrichment of extracellular matrix (ECM)‐related pathways in PA‐uria cells. Both PA‐uria and MMA‐uria cells exhibited increased deposition of fibronectin and collagen fibers, which were further amplified under metabolic stress conditions. Transforming growth factor beta (TGF‐β) signaling was identified as a key pro‐fibrotic pathway. Pharmacological inhibition of the TGF‐β receptor signaling normalized fibronectin and collagen deposition in both PA‐uria and MMA‐uria cells. Treatment with losartan, an angiotensin II type 1 receptor blocker known to modulate TGF‐β signaling, also reversed the enhanced ECM deposition. This is the first study to mechanistically link ECM remodeling and TGF‐β signaling to CKD pathogenesis in both PA‐uria and MMA‐uria. Our findings highlight fibrotic remodeling as a shared pathogenic feature and suggest that losartan, a widely available and well‐tolerated drug, could be repurposed to mitigate renal fibrosis in these disorders.

To retrospectively examine the clinical characteristics, magnetic resonance imaging (MRI) findings, and neurodevelopmental outcomes of infants diagnosed with an organic acidaemia during their first year of life. This was an observational retrospective study. Infants who were diagnosed with an organic acidaemia before the age of 1 year and underwent cranial MRI at Peking University First Hospital between 2010 and 2020 were included. Clinical and MRI data were collected, and prognoses were classified based on developmental assessments. Sixty-five children were included, with methylmalonic acidaemia combined with homocysteinaemia being the most prevalent type (40 of 65). Median age at onset was 2 months. Hydrocephalus was observed in 43% of children with methylmalonic acidaemia combined with homocysteinaemia, while thalamic and basal ganglia lesions were prominent in 83% of children with propionic acidaemia. All cases of glutaric aciduria type 1 exhibited extracerebral space widening. MRI findings were normal in eight children. Among the 47 children with available developmental data, 68% experienced severe neurodevelopmental impairments. Brainstem lesions may represent an independent risk factor for severe outcomes (odds ratio = 9.059, 95% confidence interval = 1.039-79.014, p = 0.046). MRI patterns are essential in the diagnosis and prognostication of organic acidaemias, with brainstem lesions serving as a potential indicator of prognosis.

Abstract Background Inborn errors of metabolism (IEM) are a phenotypically and genetically variable group of diseases produced by a variety of disorders in the metabolic pathway. They are more common in countries with a high consanguinity rate, such as Egypt. This study aimed to explore the frequency of IEM among eighty children who attend the Metabolic Outpatient Clinic at Alexandria University Children’s Hospital (AUCH) for follow-up from September 2019 to February 2023. Those children has been diagnosed clinically, radiologically and biochemically by using extended metabolic screening including amino acid screen, urine organic acids measurement and tandem mass spectrometry (TMS). Data about age, sex, birth order, area of residence, age at onset, presenting complaints, and family history of the same disease were all collected from caregivers and hospital records. Results There was a male predominance of 46 cases (57.5%), and females accounted for 34 (42.5%). Twenty percent of the studied cases had a history of a similar condition in their family. Specifically, 21 cases (26.3%) had maple syrup urine disease (MSUD), 19 cases (23.8%) had glutaric acidemia (GA) type 1, 13 cases (16.3%) had methylmalonic acidemia (MMA), and 8 (10%) had isovaleric acidemia (IVA). Only 2 cases (2.5%) of the studied cases had fatty acid oxidation defects (FAOD), and there was only one case (1.3%) of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA) and one cases (1.3%) of propionic acidemia (PA). Conclusion IEM are frequent among children, and further research studies are needed to gain a better understanding of their nature, highlighting the importance of neonatal screening and timely diagnosis to improve outcomes of affected children. As prevalence of some disorders seem to be more common, it is better to address on newborn screening program (NBS) to address them.

Objective: To evaluate bone mineral density (BMD) and the nutritional and biochemical factors affecting it in children with glycogen storage diseases (GSD) and organic acidemias (OA), which are rare metabolic disorders. Methods: This retrospective study included 31 pediatric patients with genetically confirmed diagnoses—15 with GSD (types I and III) and 16 with OA (methylmalonic and propionic acidemia). BMD was assessed using dual-energy X-ray absorptiometry (DXA) and reported as age-adjusted Z-scores. Anthropometric data, three-day dietary records (analyzed with BeBIS 8.2), and serum markers, including vitamin D, Parathyroid Hormone (PTH), calcium, phosphorus, and others, were analyzed. Malnutrition and stunting were defined using World Health Organization (WHO) growth standards. Pearson correlation analysis was used, with a significance level set at p30 ng/mL) achieved in only 20% of GSD and 31.2% of OA patients. Conclusion: Low bone mineral density is prevalent in both GSD and OA populations and appears to be influenced by modifiable factors such as calcium intake and vitamin D status. These findings highlight the importance of routine monitoring of bone health and nutrition in these patients. Multidisciplinary management is crucial for reducing long-term skeletal risks and optimizing clinical outcomes.

Toxic Storm Defused: Successful Use of Plasmapheresis and Continuous Renal Replacement Therapy in Propionic Acidemia.