Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.

UNASSIGNED: Routine metabolic assessments for methylmalonic acidemia (MMA), propionic acidemia (PA), and homocysteinemia involve detecting metabolites in dried blood spots (DBS) and analyzing specific biomarkers in serum and urine. This study aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous detection of three specific biomarkers (methylmalonic acid, methylcitric acid, and homocysteine) in DBS, as well as to appraise the applicability of these three DBS metabolites in monitoring patients with MMA, PA, and homocysteinemia during follow-up.
UNASSIGNED: A total of 140 healthy controls and 228 participants were enrolled, including 205 patients with MMA, 17 patients with PA, and 6 patients with homocysteinemia. Clinical data and DBS samples were collected during follow-up visits.
UNASSIGNED: The reference ranges (25th-95th percentile) for DBS methylmalonic acid, methylcitric acid, and homocysteine were estimated as 0.04-1.02 μmol/L, 0.02-0.27 μmol/L and 1.05-8.22 μmol/L, respectively. Following treatment, some patients achieved normal metabolite concentrations, but the majority still exhibited characteristic biochemical patterns. The concentrations of methylmalonic acid, methylcitric acid, and homocysteine in DBS showed positive correlations with urine methylmalonic acid (r = 0.849, p < 0.001), urine methylcitric acid (r = 0.693, p < 0.001), and serum homocysteine (r = 0.721, p < 0.001) concentrations, respectively. Additionally, higher levels of DBS methylmalonic acid and methylcitric acid may be associated with increased cumulative complication scores.
UNASSIGNED: The LC-MS/MS method established in this study reliably detects methylmalonic acid, methylcitric acid, and homocysteine in DBS. These three DBS metabolites can be valuable for monitoring patients with MMA, PA, and homocysteinemia during follow-up. Further investigation is required to determine the significance of these DBS biomarkers in assessing disease burden over time.

In this study, peripheral blood mononuclear cells were contributed from a male infant with propionic acidemia (PA) verified by clinical and genetic diagnosis, who inherited compound heterozygous mutations in the propionyl-CoA carboxylase subunit beta (PCCB) gene. Here, this iPS was generated by non-integrated episomal vectors with SOX2, BCL-XL, OCT4, C-MYC and OCT4. Also, this iPSC line exhibited the morphology of pluripotent stem cells, upward mRNA and protein expression of pluripotency markers, conspicuous in vitro differentiation potency and regular karyotype, and carried PCCB gene mutations, which provided an excellent model for the research and drug screening of PA.

Propionic acidemia (PA) is a rare autosomal recessive congenital disease caused by mutations in the PCCA or PCCB genes. Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA. Early-onset PA can lead to acute deterioration, metabolic acidosis, and hyperammonemia shortly after birth, which can result in high mortality and disability. Late-onset cases of PA have a more heterogeneous clinical spectra, including growth retardation, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease. Timely and accurate diagnosis and appropriate treatment are crucial to saving patients\' lives and improving their prognosis. Recently, the number of reported PA cases in China has increased due to advanced diagnostic techniques and increased research attention. However, an overview of PA prevalence in China is lacking. Therefore, this review provides an overview of recent advances in the pathogenesis, diagnostic strategies, and treatment of PA, including epidemiological data on PA in China. The most frequent variants among Chinese PA patients are c.2002G > A in PCCA and c.1301C > T in PCCB, which are often associated with severe clinical symptoms. At present, liver transplantation from a living (heterozygous parental) donor is a better option for treating PA in China, especially for those exhibiting a severe metabolic phenotype and/or end-organ dysfunction. However, a comprehensive risk-benefit analysis should be conducted as an integral part of the decision-making process. This review will provide valuable information for the medical care of Chinese patients with PA.

Propionic acidemia (PA) is a genetic metabolic disorder caused by mutations in the mitochondrial enzyme, propionyl-CoA carboxylase (PCC), which is responsible for converting propionyl-CoA to methylmalonyl-CoA for further metabolism in the tricarboxylic acid cycle. When this process is disrupted, propionyl-CoA and its metabolites accumulate, leading to a variety of complications including life-threatening cardiac diseases and other metabolic strokes. While the clinical symptoms and diagnosis of PA are well established, the underlying pathophysiological mechanisms of PA-induced diseases are not fully understood. As a result, there are currently few effective therapies for PA beyond dietary restriction. This review focuses on the pathophysiological mechanisms of the various complications associated with PA, drawing on extensive research and clinical reports. Most research suggests that propionyl-CoA and its metabolites can impair mitochondrial energy metabolism and cause cellular damage by inducing oxidative stress. However, direct evidence from in vivo studies is still lacking. Additionally, elevated levels of ammonia can be toxic, although not all PA patients develop hyperammonemia. The discovery of pathophysiological mechanisms underlying various complications associated with PA can aid in the development of more effective therapeutic treatments. The consequences of elevated odd-chain fatty acids in lipid metabolism and potential gene expression changes mediated by histone propionylation also warrant further investigation.

Methylmalonic acidemia (MMA) is a series of rare inherited organic acid metabolic disorders with variable and nonspecific clinical manifestations, in particular neurological symptoms such as vomiting, lethargy, etc. Even with timely treatment, patients may still have various degrees of neurological complications and can even die. The prognosis is mainly related to the type of genetic variants, level of metabolites, newborn screening, onset of disease and early initiation of treatment. This article has reviewed the prognosis of patients with various types of MMA and factors that may affect it.

15岁患儿因“2个月余前运动后意识丧失伴心搏骤停1次”入北京大学第一医院，临床表现为运动后猝倒、意识丧失，呼吸、心搏骤停，外院予心肺复苏后自主呼吸、循环恢复，并予慢性抗心力衰竭、高压氧、肢体康复等治疗。超声心动图检查示左心室扩大伴心功能减低，全外显子测序发现PCCB基因复合杂合变异（c.184-2A>G和c.647T>C）。予慢性抗心力衰竭、饮食指导、能量合剂及大剂量辅酶Q10等治疗3个月后，心脏扩大及心功能较前改善。.

The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients.
We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients\' infection developments and liver functions.
Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1-13) years. The infection duration was 29 (Range: 18-40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05).
Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants.

OBJECTIVE: Newborn screening (NBS) for inborn errors of metabolism (IEMs) has been successfully implemented in China. However, the data on the IEM profiles in many regions are lacking. This study aimed to report the incidence, disease spectrum, and genetic profile of IEMs in northern China.
METHODS: A total of 36,590 newborns were screened using tandem mass spectrometry between January 2016 and April 2022. Newborns with positive results were referred for confirmatory testing.
RESULTS: Ten patients were confirmed to have IEMs, with an overall incidence of 1:3,539 in the Rizhao region. Five types of IEMs were detected, including four patients with propionic acidemia (PA), three patients with methylmalonic acidemia (MMA), one of each with citrin deficiency, primary carnitine deficiency, and isobutyryl-CoA dehydrogenase deficiency. PA was the most common IEM, with an unexpectedly high incidence of 1:8,848, followed by MMA, with an incidence rate of 1:11,797. All patients had abnormal screening markers and harbored biallelic variants in their respective causative genes. Two novel PCCB variants (c.505G>A and c.1123_1124insG) were identified in patients with PA. In silico analyses predicted that these two variants were potentially pathogenic.
CONCLUSIONS: This study preliminarily clarified the incidence, disease spectrum, and genetic profile of IEMs in the Rizhao region. PA is the most common IEM and MMA is the second most common in our region. The two novel identified PCCB variants further expand the variant spectrum of PA. More attention should be paid to NBS, early diagnosis, and management of PA and MA.

UNASSIGNED: Propionic acidemia (PA) is an inherited autosomal recessive metabolic disorder that is classified as early-onset or late-onset, depending on the onset time of clinical symptoms. It clinically manifests as numerous lesions in the brain, pancreas, liver, and muscle. Muscle biopsies show myopathic changes, which help to distinguish late-onset propionic acidemia from other metabolic diseases involving muscles.
UNASSIGNED: A 19-year-old Chinese girl was admitted to the hospital because of poor eating and fatigue. Head magnetic resonance imaging suggested metabolic diseases, and we administered symptomatic support treatment. Her symptoms gradually worsened, and she began to show convulsions and disturbances of consciousness. Muscle pathology showed myopathy-like changes. The presence of organic acids in the blood and urine suggested PA. Genetic analyses identified two compound heterozygous mutations in the patient\'s PCCB gene, confirming the diagnosis of delayed PA.
UNASSIGNED: The muscle pathological examination of late-onset PA provides valuable information that is helpful for distinguishing delayed-onset PA from metabolic diseases. In the absence of a history of trauma, subdural hematoma may be a very rare complication of late-onset PA and can be regarded as a poor prognostic sign; therefore, it is suggested to perform head computed tomography as part of the routine neurological evaluation of PA patients.