Evidence That Long-Term Treatment Prevents Tissue Oxidative Damage in Patients With Inherited Disorders of the Propionate Pathway.

Propionic and methylmalonic acidemias (PAcidemia and MMAcidemia, respectively) are genetic disorders clinically characterized by metabolic decompensation associated with life-threatening encephalopathic episodes in the neonatal period. Adequate and rapid therapeutic management is essential for patients' survival and prognosis. In this study, a restricted protein diet associated with L-carnitine (LC) supplementation was shown to decrease mortality and morbidity in patients affected by these disorders probably by decreasing the accumulation of the major metabolites and therefore their toxicity. Since oxidative stress was proposed as a contributing mechanism of tissue damage in PAcidemia and MMAcidemia and LC has potent antioxidant properties, our objective in this work was to investigate the effects of a long-term therapy consisting of reduced protein intake associated with LC supplementation on oxidative damage markers in patients affected by these diseases. We measured urinary isoprostanes, di-tyrosine, and oxidized guanine species, which reflect oxidative damage to lipids, proteins, and DNA/RNA, respectively, as well as the concentrations of NO products (nitrate plus nitrite) in patients untreated or submitted to short-term or a long-term treatment. Results revealed significant increases of isoprostanes, di-tyrosine, and oxidized guanine species, as well as a moderate nonsignificant increase of NO levels in the untreated patients, relatively to controls. Furthermore, these altered markers were attenuated after short-term treatment and normalized after prolonged treatment. In conclusion, data from this work show for the first time that long-standing treatment of patients with disorders of the propionate pathway can protect against oxidative damage. However, it remains to be elucidated whether oxidative stress identified in this study directly correlates with the clinical conditions of the affected patients.

Prenatal Ultrasound and Magnetic Resonance Findings of Glutaric Acidemia Type 1 and Its Challenges in Prenatal Diagnosis.

Glutaric acidemia type 1 (GA1) presents unique challenges in prenatal diagnosis, especially in cases with no family history. This review article aims to review and present the prenatal ultrasound and magnetic resonance findings of GA1 and consolidate key insights into the difficulties associated with GA1 prenatal diagnosis and the neuroimaging features that require careful differentiation during the diagnostic process.

Use of the Novel Site-Directed Enzyme Enhancement Therapy (SEE-Tx) Drug Discovery Platform to Identify Pharmacological Chaperones for Glutaric Acidemia Type 1.

Allosteric regulators acting as pharmacological chaperones hold promise for innovative therapeutics since they target noncatalytic sites and stabilize the folded protein without competing with the natural substrate, resulting in a net gain of function. Exogenous allosteric regulators are typically more selective than active site inhibitors and can be more potent than competitive inhibitors when the natural substrate levels are high. To identify novel structure-targeted allosteric regulators (STARs) that bind to and stabilize the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH), the computational site-directed enzyme enhancement therapy (SEE-Tx) technology was applied. SEE-Tx is an innovative drug discovery platform with the potential to identify drugs for treating protein misfolding disorders, such as glutaric acidemia type 1 (GA1) disease. Putative allosteric regulators were discovered using structure- and ligand-based virtual screening methods and validated using orthogonal biophysical and biochemical assays. The computational approach presented here could be used to discover allosteric regulators of other protein misfolding disorders.

Amyloid-like Aggregation Propensities of Metabolites - Homogentisic acid, N-Acetyl aspartic acid and Isovaleric acid.

The transformation of metabolites into amyloidogenic aggregates represent an intriguing dimension in the pathophysiology of metabolic disorders, including alkaptonuria, canavan disease, and isovaleric acidemia. Central to this phenomenon are the metabolites homogentisic acid (HA), N-acetyl aspartic acid (NAA), and isovaleric acid (IVA), which we found, weave an intricate network of self-assembled structures. Leveraging an array of microscopy techniques, we traced the morphological behavior of these assemblies that exhibit concentration and time-dependent morphological transitions from isolated globules to clustered aggregates. MD simulation studies suggest significant role of hydrogen bonding interactions in the aggregation process. While displaying strong amyloidogenic propensity in solution, these aged aggregates were significantly cytotoxic to mouse neural N2a cell lines.  In vivo effect in Caenorhabditis elegans (C. elegans) nematode further validated cytotoxicity of aggregates. Our findings provide fresh insights to amyloidogenic nature of HA, NAA, and IVA aggregates and their possible role in associated metabolic disorders such as alkaptonuria, canavan disease and isovaleric acidemia.

Backbone assignments of the biotin carboxyl carrier protein domain of Propionyl CoA carboxylase of Leishmania major and its interaction with its cognate Biotin protein ligase.

Propionyl CoA carboxylase (PCC) is a multimeric enzyme composed of two types of subunits, α and ß arranged in α6ß6 stoichiometry. The α-subunit consists of an N-terminal carboxylase domain, a carboxyl transferase domains, and a C-terminal biotin carboxyl carrier protein domain (BCCP). The ß-subunit is made up of an N- and a C- carboxyl transferase domain. During PCC catalysis, the BCCP domain plays a central role by transporting a carboxyl group from the α-subunit to the ß-subunit, and finally to propionyl CoA carboxylase, resulting in the formation of methyl malonyl CoA. A point mutation in any of the subunits interferes with multimer assembly and function. Due to the association of this enzyme with propionic acidemia, a genetic metabolic disorder found in humans, PCC has become an enzyme of wide spread interest. Interestingly, unicellular eukaryotes like Leishmania also possess a PCC in their mitochondria that displays high sequence conservation with the human enzyme. Thus, to understand the function of this enzyme at the molecular level, we have initiated studies on Leishmania major PCC (LmPCC). Here we report chemical shift assignments of LmPCC BCCP domain using NMR. Conformational changes in LmPCC BCCP domain upon biotinylation, as well as upon interaction with its cognate biotinylating enzyme (Biotin protein ligase from L. major) have also been reported. Our studies disclose residues important for LmPCC BCCP interaction and function.

Peroxisomal leukodystrophy.

Peroxisomal disorders can be classified as single-enzyme deficiencies or peroxisomal biogenesis disorders (characterized by multiple peroxisomal enzyme deficiencies or complete absence of peroxisomes). Most peroxisomal disorders give rise to complex multisystem disorders. Peroxisomal disorders associated with leukodystrophy are discussed in more detail, specifically X-linked adrenoleukodystrophy, Zellweger spectrum disorders, D-bifunctional protein deficiency, Acyl-CoA oxidase 1 deficiency, and Alpha-Methylacyl-CoA Racemase (AMACR) deficiency.

Long-term follow-up of Chinese patients with methylmalonic acidemia of the cblC and mut subtypes.

BACKGROUND: Methylmalonic acidemia (MMA) is the most common organic acidemia in China, with cblC (cblC-MMA) and mut (mut-MMA) being the predominant subtypes. The present study aimed to investigate the prognostic manifestations and their possible influence in patients with these two subtypes. METHODS: A national multicenter retrospective study of patients with cblC-MMA and mut-MMA between 2004 and 2022 was performed. We compared the clinical features between patients with two subtypes or diagnosed with or without newborn screening (NBS) and further explored the potentially influential factors on the prognosis. RESULTS: The 1617 enrolled MMA patients included 81.6% cblC-MMA patients and 18.4% mut-MMA patients, with an overall poor prognosis rate of 71.9%. These two subtypes of patients showed great differences in poor prognostic manifestations. The role of NBS in better outcomes was more pronounced in cblC-MMA patients. Predictors of outcomes are "pre-treatment onset", "NBS", variants of c.80A > G and c.482G > A and baseline levels of propionylcarnitine and homocysteine for cblC-MMA; "pre-treatment onset", "responsive to vitB12", variants of c.914T > C and baseline propionylcarnitine and propionylcarnitine/acetylcarnitine ratio for mut-MMA. Besides, prognostic biochemical indicators have diagnostic value for poor outcomes in mut-MMA. CONCLUSIONS: The study provided potential predictors of the long-term outcome of patients with cblC-MMA and mut-MMA. IMPACT: Predictors of outcomes are "pre-treatment onset", "NBS", MMACHC variants of c.80A > G and c.482G > A and baseline propionylcarnitine and homocysteine for cblC-MMA, "pre-treatment onset", "responsive to vitB12", MMUT variants of c.914T > C and baseline propionylcarnitine and propionylcarnitine/acetylcarnitine ratio for mut-MMA. This study with larger sample sizes effectively validated the prediction power and emphasized the importance of NBS in improving the outcomes of both MMA subtypes. The study enhances understanding of the phenotypic and prognostic variations of MMA disease and the predictors will help in the improvement of diagnosis and treatment strategies to achieve a better prognosis for MMA.

[The current diagnosis and treatment situation of rare disease in the pediatric intensive care unit].

Objective: To analyze the diagnosis and treatment of children with rare diseases in the pediatric intensive care unit (PICU), the distribution of disease types and populations, clinical characteristics, and the use of orphan drugs. Methods: A retrospective case summary was conducted. Data were collected from 105 children aged 29 days to <18 years with a confirmed diagnosis of rare diseases according to the "First Batch of Rare Disease Catalogue in China" who were admitted to the PICU of Beijing Children's Hospital, Capital Medical University from January 2020 to December 2022. Data including general information, auxiliary examinations, and treatment details for each patient were collected from the hospital's electronic medical record system. Patients were divided into age groups: infancy (29 days to<1 year), early childhood (1 to <3 years), preschool age (3 to<7 years), school age (7 to<13 years), and adolescence (13 to<18 years). The chi-square test was used to compare gender distribution differences among various rare diseases. Results: A total of 105 patients with 130 cases meeting the diagnostic criteria were included, accounting for 4.7% (130/2 754) of the total admissions to the PICU. The age at PICU admission was 5.3 (0.8, 9.5) years and there were 81 cases in male. The 3 most common types of diseases were endocrine, nutritional, and metabolic diseases (37 cases); followed by neurological disorders(32 cases); and congenital malformations, deformities, and chromosomal abnormalities(17 cases). The 5 most common rare diseases were methylmalonic acidemia (14 cases), mitochondrial encephalomyopathy (14 cases), atypical hemolytic uremic syndrome (12 cases), autoimmune encephalitis (12 cases), and idiopathic cardiomyopathy (9 cases). The distributions of common rare diseases varied among different age groups. In infants, atypical hemolytic uremic syndrome was most common (6 children). There was no statistically significant difference regarding gender among children with mitochondrial encephalomyopathy (13.6% (11/81) vs. 6.1% (3/49), χ2=1.77, P=0.184). Respiratory failure (36 cases) was the primary reason for rare diseases children to be admitted to the PICU. A total of 95 cases underwent mechanical ventilation, 39 cases received multidisciplinary collaborative diagnosis and treatment, and only 6 children received orphan drug therapy during their stay in the PICU. Conclusions: Rare diseases are not uncommon in PICU. Endocrine, nutritional and metabolic disorders, neurological disorders, congenital malformations, deformities, and chromosomal abnormalities were common. Methylmalonic acidemia, mitochondrial encephalomyopathy, atypical hemolytic uremic syndrome and autoimmune encephalitis have higher cases. Many children with rare diseases in the PICU have complex conditions those are challenging to treat, requiring multidisciplinary collaboration. The utilization rate of orphan drugs among children with rare diseases in PICU needs to be improved.

The in vitro effects of acidemia and acidemia reversal on coagulation in dogs.

Background: The effect of acidemia on blood coagulation remains inadequately understood in veterinary medicine. Therefore, we assessed the effect of in vitro acidification of canine whole blood on coagulation and investigated whether acidemia-induced coagulopathy could be reversed by reversing acidemia. Methods: Citrated whole blood samples were taken from six healthy Beagle dogs and categorized, based on pH adjustment, into neutral, weak acidemia (WA), strong acidemia (SA), and reversal from SA. Then, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, conventional thromboelastography (TEG) parameters, and velocity curve (V-curve) variables of TEG were assessed. Results: The PT, aPTT, and most TEG parameters showed significant coagulopathy in the SA group compared to the neutral group, with additional significant changes in reaction time (R), clot kinetic (K), maximum amplitude (MA), split point (SP), elasticity (E), thrombodynamic potential index (TPI), and coagulation index (CI) between the SA and WA groups. Among V-curve variables, the maximum rate of thrombus generation (MRTG) and total thrombus generation were significantly inhibited in the SA group compared to the neutral group, with significant differences in the time to maximum rate of thrombus generation (TMRTG) between the WA and SA groups. In the reverse group, aPTT, R, K, α-angle, MRTG, TMRTG, SP, TPI, and CI exhibited significant recovery compared to the SA group. Conclusion: The in vitro induction of acidemia in canine whole blood leads to impairment of coagulation profiles, and pH correction can reverse most acidemia-induced coagulopathy.

Acute Metabolic Decompensation of Isovaleric Acidemia Presenting as Persistent Metabolic Acidosis in a Middle-Aged Man: A Case Report.

Isovaleric acidemia is a rare autosomal recessive inborn error of metabolism that affects the breakdown of the essential amino acid leucine. Acute metabolic decompensation is often triggered by stressors such as surgery, concurrent illness, excessive protein intake, or dehydration. This can lead to a catabolic state with increased endogenous protein turnover, posing a risk of potentially life-threatening crises due to the accumulation of toxic metabolites from incomplete leucine breakdown. Such episodes are rarely observed beyond childhood and adolescence, and the disease's rarity typically prevents single centers from gaining extensive experience with its full spectrum. This lack of familiarity can be challenging for adult physicians, who may not be well versed in the appropriate management strategies. This case report describes an acute metabolic crisis in a middle-aged man in his late 30s, triggered by an influenza virus infection and presenting as persistent and unresolved metabolic acidosis. We aim to emphasize the importance of early and prompt recognition of metabolic crises in metabolically stable adults with inborn errors of metabolism, particularly for intensivists and acute care physicians.

Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid and amino acid oxidation with an incidence of 1 in 200,000 live births. MADD has three clinical phenotypes: severe neonatal-onset with or without congenital anomalies, and a milder late-onset form. Clinical diagnosis is supported by urinary organic acid and blood acylcarnitine analysis using tandem mass spectrometry in newborn screening programs. MADD is an autosomal recessive trait caused by biallelic mutations in the ETFA, ETFB, and ETFDH genes encoding the alpha and beta subunits of the electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase enzymes. Despite significant advancements in sequencing techniques, many patients remain undiagnosed, impacting their access to clinical care and genetic counseling. In this report, we achieved a definitive molecular diagnosis in a newborn by combining whole-genome sequencing (WGS) with RNA sequencing (RNA-seq). Whole-exome sequencing and next-generation gene panels fail to detect variants, possibly affecting splicing, in deep intronic regions. Here, we report a unique deep intronic mutation in intron 1 of the ETFDH gene, c.35-959A>G, in a patient with early-onset lethal MADD, resulting in pseudo-exon inclusion. The identified variant is the third mutation reported in this region, highlighting ETFDH intron 1 vulnerability. It cannot be excluded that these intronic sequence features may be more common in other genes than is currently believed. This study highlights the importance of incorporating RNA analysis into genome-wide testing to reveal the functional consequences of intronic mutations.

Development of a signs and symptoms outcome measure for caregivers of patients with methylmalonic acidemia and propionic acidemia (MMAPAQ).

BACKGROUND AND OBJECTIVE: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare inborn errors of metabolism with shared signs and symptoms that are associated with significant morbidity and mortality. No disease-specific clinical outcomes assessment instruments for MMA and/or PA currently exist to capture the patient perspective in clinical trials. Because patients with these conditions are generally young and have cognitive impairments, an observer-reported outcome (ObsRO) instrument is crucial. We report results from qualitative research supporting development of the Methylmalonic Acidemia and Propionic Acidemia Questionnaire (MMAPAQ), a signs and symptoms ObsRO measure for caregivers of patients with MMA and/or PA. METHODS: Concept elicitation (CE) interviews were conducted with 35 participants across 2 studies who were aged ≥18 years and caregivers of patients with a confirmed diagnosis of MMA or PA, and an additional 5 patients aged ≥6 years with MMA or PA in Study 1, to identify core signs/symptoms for inclusion in the MMAPAQ. All interviews were conducted in English. Study 2 included cognitive interviews (CI) with caregivers and clinical experts to further assess content validity. CE and a conceptual framework review were also conducted with clinical experts to further support findings. RESULTS: A consistent set of signs/symptoms of MMA and PA were reported by eligible caregivers interviewed in study 1 (n = 21) and study 2 (n = 14), representing 11 patients with MMA and 20 with PA. Based on concepts reported in study 1, a draft instrument was constructed and compared with the Pediatric Quality of Life Inventory™ (PedsQL™) and Family Impact module, demonstrating face validity for measuring key signs/symptoms important to patients and caregivers. The PedsQL™ and Family Impact modules were preferred to assess patient and caregiver impacts. Two waves of CE and CIs were conducted in study 2, with wave 1 resulting in removal of 7 items and other revisions to improve clarity, and wave 2 resulting in modification of examples used for 2 items. The final instrument consisted of the following 7 items assessed over the past 7 days using a Likert-type response scale ranging from "never" to "very often": uncontrollable or involuntary movements, dehydration, rapid breathing at rest, appearing lethargic, appearing disinterested in eating, refusing to eat, and vomiting. CONCLUSIONS: This study establishes the content validity of the MMAPAQ as the first ObsRO questionnaire for measuring core signs and symptoms of MMA and PA in clinical trials and community research. Scoring and psychometric measurement properties of the MMAPAQ will be established in future studies. The PedsQL™ was found to have face validity in measuring concepts that affect the MMA and PA patient populations and should also be considered for use in clinical trials in MMA and PA.

Outcome of Expanded Newborn Screening Among 194 000 Neonates at Northeast México.

Objectives. To describe the results of a 16-year experience of a state-coverage expanded newborn screening program (NBSP) in Northeast México. Methods. Between 2002 and 2017, dried blood spots of newborns were screened for congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), biotinidase deficiency, galactosemia, cystic fibrosis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency via immunofluorescence and amino and fatty acid disorders and organic acidemias using tandem mass spectrometry. Frequency rates were determined. Results. Overall, 192 487 samples were processed; 99.4% had negative results, and 598 were diagnosed. The frequency was 3.01/1000 newborns. G6PD deficiency, CH, amino acidemia, organic acidemia, cystic fibrosis, CAH, fatty acid oxidation disorder, galactosemia, and biotinidase deficiency cases were 1:773, 1:962, 1:4277, 1:4476, 1:11,322, 1:10,693, 1:10,693, 1:38,497, and 1:64,162, respectively. Conclusion. Using different technologies in NBSP increased the number of conditions detected, facilitating infant morbidity and mortality prevention. The frequency of disorders depends on the population's genetic background and diagnostic capacity.

Newborn screening algorithm distinguishing potential symptomatic isovaleric acidemia from asymptomatic newborns.

Newborn screening (NBS) for isovaleric acidemia (IVA) reduces mortality and morbidity; however, it has also resulted in the detection of individuals with an asymptomatic or mild presentation for which early detection via newborn screening has not been proven to alter neurological outcome. We reevaluated biochemical and molecular data for newborns flagged positive for IVA in aim of developing a new screening algorithm to exclude the latter from positive screening. Among 2 794 365 newborns underwent routine newborn screening in Israel, 412 flagged positive for IVA, of which, 371 were false positives on recall sample testing and 41 positive newborns were referred to the clinic. 38/41 have biochemical and molecular confirmation in keeping with IVA. Among the 38 patients, 32% (12/38) were classified as symptomatic while, 68% (26/38) were classified as asymptomatic. 69% of the latter group harbor the known variant associated with mild potentially asymptomatic phenotype, c.932C>T; p. Ala311Val. Among asymptomatic patients, only 46% (12/26) are currently treated. Two novel variants have been detected in the IVD gene: c.487G>A; p. Ala163Thr and c.985A>G; p. Met329Val. Cut-off recalculation, of referred newborns' initial biochemical results, after classifying the referred patients to two binary groups of symptomatic and asymptomatic, resulted in an improved NBS algorithm comprising of C5 >5 µM and C5/C2>0.2 and C5/C3>4 flagging only those likely to have the classic symptomatic phenotype.

Evaluation of the clinical, biochemical, and molecular spectrum of Cobalamin C (CblC) defect in 33 patients from Pakistan.

BACKGROUND: Cobalamin C is the most common inborn error of intracellular cobalamin metabolism caused by biallelic pathogenic variants in the MMACHC gene, leading to impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Biochemical hallmarks are elevated plasma total homocysteine (HCYs) and low methionine accompanied by methylmalonic aciduria. This study aimed to evaluate the clinical, biochemical, and molecular analysis of Pakistani patients with CblC defect. METHODS: Medical charts, urine organic acid (UOA) chromatograms, plasma amino acid levels, plasma tHcy and MMACHC gene results of patients presenting at the Biochemical Genetics Clinic, AKUH from 2013-2021 were reviewed. Details were collected on a pre-structured questionnaire. SPSS 22 was used for data analysis. RESULTS: CblC was found in 33 cases (Male:Female 19:14). The median age of symptoms onset and diagnosis were 300 (IQR:135-1800) and 1380 (IQR: 240-2730) days. The most common clinical features were cognitive impairment (n = 29), seizures (n = 23), motor developmental delay (n = 20), hypotonia (n = 17), and sparse/hypopigmented scalp hair (n = 16). The MMACHC gene sequencing revealed homozygous pathogenic variant c.394C > T, (p.Arg132*) in 32 patients, whereas c.609G > A, (p.TRP203*) in one patient whose ancestors had settled in Pakistan from China decades ago. The median age of treatment initiation was 1530 (IQR: 240-2790). The median pre-treatment HCYs levels were 134 (IQR:87.2-155.5) compared to post-treatment levels of 33.3 (IQR: 27.3-44.95) umol/L. CONCLUSIONS: Thirty-three cases of CblC defect from a single center underscores a significant number of the disorder within Pakistan. Late diagnosis emphasizes the need for increased clinical awareness and adequate diagnostic facilities.

Neurological outcomes and associated perinatal factors in infants born between 22 and 25 weeks with active care.

OBJECTIVES: To elucidate the outcomes of periviable infants receiving active care (AC) and explore perinatal factors associated with neurodevelopmental outcomes. METHODS: This is a single-center retrospective study on infants born at 22-25 weeks of gestation, all of whom received AC. A developmental quotient (DQ) ≥ 85 at corrected 18 months was judged as normal. RESULTS: Fifty-seven infants were included in the study. The survival rates at discharge were 83%, 86%, 93%, and 93% at 22, 23, 24, and 25 gestational weeks, respectively. The overall percentage of normal DQ was 26/47 (55%). Acidemia in the arterial blood gas measured within 6 h after birth was identified as a factor significantly associated with subnormal DQ. CONCLUSIONS: Not only high survival rates, but also favorable neurodevelopmental outcomes may be achieved by AC in periviable infants. Moreover, impaired neurodevelopmental outcomes may be associated with early postnatal acidemia following initial resuscitation.

Left Ventricular Systolic Dysfunction in NBCe1-B/C-Knockout Mice.

Congenital proximal renal tubular acidosis (pRTA) is a rare systemic disease caused by mutations in the SLC4A4 gene that encodes the electrogenic sodium bicarbonate cotransporter, NBCe1. The major NBCe1 protein variants are designated NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A expression is kidney-specific, NBCe1-B is broadly expressed and is the only NBCe1 variant expressed in the heart, and NBCe1-C is a splice variant of NBCe1-B that is expressed in the brain. No cardiac manifestations have been reported from patients with pRTA, but studies in adult rats with virally induced reduction in cardiac NBCe1-B expression indicate that NBCe1-B loss leads to cardiac hypertrophy and prolonged QT intervals in rodents. NBCe1-null mice die shortly after weaning, so the consequence of congenital, global NBCe1 loss on the heart is unknown. To circumvent this issue, we characterized the cardiac function of NBCe1-B/C-null (KOb/c) mice that survive up to 2 months of age and which, due to the uninterrupted expression of NBCe1-A, do not exhibit the confounding acidemia of the globally null mice. In contrast to the viral knockdown model, cardiac hypertrophy was not present in KOb/c mice as assessed by heart-weight-to-body-weight ratios and cardiomyocyte cross-sectional area. However, echocardiographic analysis revealed reduced left ventricular ejection fraction, and intraventricular pressure-volume measurements demonstrated reduced load-independent contractility. We also observed increased QT length variation in KOb/c mice. Finally, using the calcium indicator Fura-2 AM, we observed a significant reduction in the amplitude of Ca2+ transients in paced KOb/c cardiomyocytes. These data indicate that congenital, global absence of NBCe1-B/C leads to impaired cardiac contractility and increased QT length variation in juvenile mice. It remains to be determined whether the cardiac phenotype in KOb/c mice is influenced by the absence of NBCe1-B/C from neuronal and endocrine tissues.

Unusual Presentation of Propionic Acidemia Mimicking Botulism in an Infant: A Case Report and Literature Review.

Propionic acidemia (PA) is a rare metabolic disorder stemming from genetic mutations, often causing hyperammonemia, acidosis, and basal ganglia issues. Its symptoms range from vomiting to neurological abnormalities, with severe cases presenting in neonates. Neurological complications including stroke-like episodes are common, requiring immediate attention. An eight-month-old boy with PA presented to the emergency department with respiratory distress, cough, and lethargy. Initial evaluation showed acidemia and elevated ammonia levels. He tested positive for rhinovirus and was diagnosed with acute viral bronchiolitis. While his respiratory symptoms improved, he developed neurological deficits, including hypotonia and weakness. Neurology consultations explored possible diagnoses such as botulism or acute inflammatory demyelinating polyneuropathy (AIDP). Imaging revealed basal ganglia abnormalities consistent with PA progression. Due to aspiration risk, he was transferred to the pediatric intensive care unit for supportive care. Despite unremarkable lumbar puncture and MRI results, new metabolic brain changes were noted, particularly in the basal ganglia. He was managed for weakness and feeding difficulties due to a metabolic stroke. After adjusting nutritional support and discussing long-term feeding options, he was discharged on day 29 with a nasogastric tube due to his inability to meet caloric goals orally. Neurological complications in PA, such as basal ganglia abnormalities and stroke-like episodes, are well-documented. Our case illustrates how an acute respiratory illness can obscure underlying neurological deficits, leading to delayed diagnosis. Symptoms resembling other conditions, such as descending hypotonia in our case, broaden the differential diagnosis to include botulism toxicity and AIDP. This report demonstrates the variety of clinical features patients with PA can present with and the importance of working up a metabolic crisis in addition to conditions with overlapping symptoms.

Intrafamilial phenotypic variability due to a missense pathogenic variant in FBP1 gene.

Background: FBPase deficiency as an autosomal recessive disorder is due pathogenic variants in the FBP1 gene. It usually presents with hyperlactic acidemia and hypoglycaemia starting from early childhood. Here, genotypes and phenotypes of all reported patients and their distributions are presented. In addition, we present an Iranian family with two affected children presenting with unusual symptoms due to pathogenic variants in the FBP1 gene.Clinical evaluations and laboratory assessments were performed for the affected members. Whole exome sequencing (WES) was applied in order to find the causal variant. In addition to segregation analysis within the family, variant pathogenicity analyses and predictions were done via bioinformatics tools and according to ACMG guidelines. The genotypes and detailed clinical features were documented for all patients. Results: The study included a population of 104 patients with different variants of the FBP1 gene; 75 were homozygotes. The average age of onset was 14.97 months. The most frequent clinical features were metabolic acidosis (71 cases), hypoglycemia (70 cases), vomiting (46 cases), hyperuricemia (37 cases), and respiratory distress (25 cases). 74 families were from Asia. The most common genotypes were c.841G > A/c.841G > A and c.472C > T/c.472C > T. WES test showed a pathogenic homozygous variant, c.472C > T in two cases of a family: a six-and-a-half-year-old girl with an older brother with different symptoms. All laboratory evaluations in the patient were normal except for the blood sugar. The patient experienced her first hypoglycemic episode at age 3. Conclusions: This is an unusual presentation of FBPase deficiency with intrafamilial phenotypic variability.