Practical aspects of therapy for glutaric aciduria type 1

Treatment of many of the diseases in the panel of expanded newborn screening includes dietary therapy. Glutaric aciduria type 1 (GA1) is a hereditary disorder caused by mutations in the gene GCDH, encoding glutaryl‑CoA dehydrogenase, an enzyme in the amino acid metabolic pathways. The decreased activity of the enzyme leads to accumulation of neuro‑ toxic metabolites. The recommended treatment approaches for GA1 are the prescription of specialized nutrition products, levocarnitine, and symptomatic management. In 2021, clinical guidelines for the treatment of this rear disease were published in Russian Federation. To provide for the timely treatment, it is essential for a practitioner involved in the care patients with such a rare disorder as GA1 to have the knowledge of the principles of management, as well as practical algorithms for diet calculation.The article gives a detailed case‑based description of management during metabolic decompensation and the choice of dietary therapy for GA1 patients of different age groups.

Abstract 17081: End Stage Mitochondrial Cardiomyopathy And Heart Transplantation Due To Pathogenic Biallelic C1QBP Variants

Case Presentation: A 29-year-old male with LVH diagnosed in childhood was admitted with acute HF. TTE showed LVEF 5-10% and LV thrombi for which he was anticoagulated. He received inappropriate ICD shocks due to T wave oversensing, leading to cardiogenic shock requiring VA-ECMO support. Serum lactate peaked at 17 mmol/L due to cardiac and metabolic decompensation. He underwent heart transplantation (HT) on hospital day (HD) 8 and tolerated standard immunosuppression. First endomyocardial biopsy showed acute cellular rejection requiring pulse steroids. He was discharged on HD 33. Trio whole exome and mitochondrial genome sequencing revealed biallelic variants in complement component 1Q subcomponent-binding protein ( C1QBP ), due to a maternally inherited likely pathogenic variant c.612C>G (p.F204L in exon 5) and an apparently de novo deletion of 17p13.2, spanning exons 4-6 of C1QBP and exon 6 of the RPAIN gene. Mitochondrial genome sequencing of the explanted heart revealed multiple large-scale mitochondrial DNA deletions at 33% heteroplasmy. Discussion: C1QBP variants are associated with mitochondrial and multi-organ dysfunction. Only 12 patients exhibiting biallelic C1QBP variants are reported. Four died in the peripartum period due to fetal hydrops or HF; 5 exhibited early-onset cardiomyopathy (CM); 3 others had late-onset ophthalmoplegia without CM. The p.F204L variant has been reported in 1 patient with compound C1QBP p.F204L/p.C186S heterozygosity who died from hydrops fetalis and a second with p.F204L homozygosity with late-onset ophthalmoplegia and skeletal myopathy without CM. Differences in the size, heteroplasmy, and tissue distribution of mitochondrial genome secondary deletions may explain variability in disease onset and progression. We present the first patient with biallelic pathogenic C1QBP gene variants with mitochondrial CM to undergo HT and highlight the diagnosis and management of an exceptionally uncommon genetic disorder.

ECMO for Metabolic Crisis in a Patient with Mitochondrial Disease

Patients with mitochondrial disease exhibit disrupted pyruvate oxidation, resulting in intraoperative and perioperative physiologic derangements. Increased enzymatic conversion of pyruvate via lactate dehydrogenase during periods of fasting or stress can lead to metabolic decompensation, with rapid development of fatal lactic acidosis. We describe the intraoperative management and postoperative critical care of a patient with mitochondrial disease who presented for repair of esophageal perforation following repair of a paraesophageal hernia. His surgery was complicated by the development of metabolic crisis and severe lactic acidosis which became resistant to conventional therapy before ultimately resolving with the initiation of venoarterial extracorporeal membrane oxygenation (VA-ECMO).

Methylmalonic acid impairs cell respiration and glutamate uptake in C6 rat glioma cells

ABSTRACTMethylmalonic acidemia is an organic acidemia caused by deficient activity of L-methylmalonyl-CoA mutase or its cofactor cyanocobalamin and it is biochemically characterized by an accumulation of methylmalonic acid (MMA) in tissue and body fluids of patients. The main clinical manifestations of this disease are neurological and observable symptoms during metabolic decompensation are encephalopathy, cerebral atrophy, coma, and seizures, which commonly appear in newborns. This study aimed to investigate the toxic effects of MMA in a glial cell line presenting astrocytic features. Astroglial C6 cells were exposed to MMA (0.1-10mM) for 24 or 48 hours and cell viability, glucose consumption and oxygen consumption rate, as well as glutamate uptake and ATP content were analyzed. The possible preventive effects of bezafibrate were also evaluated. MMA significantly reduced cell viability after 48-hour period and increased glucose consumption during the same period of incubation. Regarding the energy homeostasis, MMA significantly reduced respiratory parameters of cells after 48-hour exposition, indicating that cell metabolism is compromised at resting and reserve capacity state, which might influence the cell capacity to meet energetic demands. Glutamate uptake and ATP content were also compromised after exposition to MMA, which can be influenced energy metabolism impairment, affecting the functionality of the astroglial cells. Our findings suggest that these effects could be involved in the pathophysiology of neurological dysfunction of this disease.

Seasonal Variation in the Time of Disease Manifestation in Finnish Children with Type 1 Diabetes

We tested the hypothesis of a more aggressive disease process at diagnosis of type 1 diabetes during autumn and winter, the colder seasons with consistently observed higher incidence of type 1 diabetes, compared to spring and summer. Seasonality in the manifestation of type 1 diabetes was examined in 4993 Finnish children and adolescents participated in the nationwide register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed at clinical diagnosis. Significant seasonality was observed with higher number of new cases during autumn and winter (n=1353/27.1% and n=1286/25.8%) compared to spring and summer (n=1135/22.7% and n=219/24.4%) (p<0.001). The youngest children (aged 0.5-4 years) differed from the older ones (aged 5-14 years) as their frequency of diagnoses was highest in autumn and the fewest cases were found in winter (p=0.019) while the older children followed the same pattern as that seen in the total series. Ketoacidosis was more frequent in children diagnosed during spring or summer compared to those diagnosed in autumn (18.8% and 19.9% vs. 15.8%, respectively; p=0.036) and weight loss was highest if diagnosed in summer (6% vs. 4.7˗5.4%; p<0.001). No relationship was observed between the season of disease presentation and diabetes-associated autoantibodies or HLA genotypes.Conclusions: Contrary to our working hypothesis, more severe metabolic decompensation was seen during seasons with lower number of new cases. The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that there could be different environmental factors triggering the disease at different ages.Trial registration number: 454/E//2001Date of registration: 19.9.2001

Neonatal seizures as onset of Inborn Errors of Metabolism (IEMs): from diagnosis to treatment. A systematic review

Neonatal seizures (NS) occur in the first 28 days of life; they represent an important emergency that requires a rapid diagnostic work-up to start a prompt therapy. The most common causes of NS include: intraventricular haemorrhage, hypoxic-ischemic encephalopathy, hypoglycemia, electrolyte imbalance, neonatal stroke or central nervous system infection. Nevertheless, an Inborn Error of Metabolism (IEM) should be suspected in case of NS especially if these are resistant to common antiseizure drugs (ASDs) and with metabolic decompensation. Nowadays, Expanded Newborn Screening (ENS) has changed the natural history of some IEMs allowing a rapid diagnosis and a prompt onset of specific therapy; nevertheless, not all IEMs are detected by such screening (e.g. Molybdenum-Cofactor Deficiency, Hypophosphatasia, GLUT1-Deficiency Syndrome) and for this reason neonatologists have to screen for these diseases in the diagnostic work-up of NS. For IEMs, there are not specific semiology of seizures and EEG patterns. Herein, we report a systematic review on those IEMs that lead to NS and epilepsy in the neonatal period, studying only those IEMs not included in the ENS with tandem mass, suggesting clinical, biochemical features, and diagnostic work-up. Remarkably, we have observed a worse neurological outcome in infants undergoing only a treatment with common AED for their seizures, in comparison to those primarily treated with specific anti-convulsant treatment for the underlying metabolic disease (e.g.Ketogenic Diet, B6 vitamin). For this reason, we underline the importance of an early diagnosis in order to promptly intervene with a targeted treatment without waiting for drug resistance to arise.

Detection of Early Onset Carnitine Palmitoyltransferase II Deficiency by Newborn Screening. Should CPT II Deficiency Be a Primary Disease Target?

Early-onset carnitine palmitoyltransferase II deficiency (CPT II deficiency) (OMIM 600650) can result in severe outcomes, which are often fatal in the neonatal to infantile period. CPT II deficiency is a primary target in the Maritime Newborn Screening Program. We report a case of neonatal-onset CPT II deficiency identified through expanded newborn screening with tandem mass spectrometry. Identification through newborn screening led to early treatment interventions, avoidance of metabolic decompensation, and a better clinical outcome. Newborn screening for CPT II deficiency is highly sensitive and specific with no false positives identified. The only screen positive case detected identified a true positive case. This experience illustrates the importance of newborn screening for CPT II deficiency and demonstrates why reconsideration should be taken to add this disease as a primary newborn screening target.

Mucormycosis: A case series and review of the literature

Mucormycosis is an opportunistic, invasive fungal disease, which is most commonly found in patients with preexisting morbidity such as diabetes mellitus and prolonged steroidal therapy. During this COVID-19 pandemic, diabetic patient’s food and their lifestyle, as well as their access to medicine and regular medical care becomes disrupted. This could result in metabolic decompensation, resulting in hyperglycemia, and causes secondary bacterial and fungal infections such as Rhinocerebral mucormycosis and Staphylococcus sepsis. The most common cause of this condition is the extraction of maxillary posterior tooth, which accounts for more than 80% of all cases. In this article, five cases of mucormycosis have been documented after dental extractions in maxilla. Importance of understanding this disease, early diagnosis and appropriate aggressive treatment is emphasized in this article for a successful outcome modality associated with the surgeries are explained.

Severe anemia in patients with Propionic acidemia is associated with branched-chain amino acid imbalance

Background Propionic acidemia (PA), an inborn error of metabolism, is caused by a deficiency in propionyl-CoA carboxylase. Patients have to follow a diet restricted in the propiogenic amino acids isoleucine (Ile), valine (Val), methionine (Met) and threonine (Thr); proper adherence can prevent and treat acute decompensation and increase life expectancy. However, chronic complications occur in several organs even though metabolic control may be largely maintained. Bone marrow aplasia and anemia are among the more common. Materials and methods In this retrospective study, data for patients with PA being monitored at the Hospital Ramón y Cajal (Madrid, Spain) (n = 10) in the past 10 years were examined to statistically detect relationships between persistent severe anemia outside of metabolic decompensation episodes and dietary practices such as natural protein intake and medical food consumption (special mixture of precursor-free amino acids) along with plasma levels of branched-chain amino acids (BCAA). High ferritin levels were deemed to indicate that a patient had received repeated transfusions for persistent anemia since data on hemoglobin levels at the moment of transfusion were not always passed on by the attending centers. Results Three patients had severe, persistent anemia that required repeated blood transfusions. Higher medical food consumption and plasma Leu levels were associated with iron overload. Notably, natural protein intake and plasma Val were negatively correlated with ferritin levels. We also observed an inverse relationship between plasma Val/Leu and Ile/Leu ratios and ferritin. Conclusion The present results suggest that severe anemia in patients with PA might be associated with low natural protein intake and BCAA imbalance.

A Comparison of Familial and Sporadic Type 1 Diabetes Among Young Patients

<b>Objective </b>To investigate natural course, treatment and outcomes in familial versus sporadic type 1 diabetes (T1D). <p><b>Research design and methods </b>In a population-based study, we compared patients with onset of T1D before the age of 20 years who had a first-degree relative with T1D (familial diabetes) with patients who had no first-degree relative with T1D (sporadic diabetes) at diagnosis and over the first 10 treatment years, using multivariable regression and proportional-hazards models. Patients were identified from the Diabetes Prospective Follow-up (DPV) database between 1995 and 2018. </p> <p><b>Results </b>Of 57,371 patients with T1D, 53,606 (93.4%) had sporadic diabetes and 3,765 (6.6%) had familial diabetes. Familial diabetes, compared with sporadic diabetes, was associated with younger age (median 7.9 vs. 9.7 years, p<0.001), lower prevalence of ketoacidosis (11.9% vs. 20.4%, p<0.001) and lower HbA1c levels (9.7% vs. 11.1%, p<0.001) at onset, and higher prevalence of associated autoimmune disease (16.7% vs. 13.6%, p<0.001). Over 10 years, patients with familial diabetes, compared with sporadic diabetes, more often used insulin pumps (p<0.001) and had a lower rate of severe hypoglycemia (12.97 vs. 14.44 per 100 patient-years, p<0.001), but similar HbA1c levels (p≥0.08) and ketoacidosis rates (1.85 vs. 2.06 per 100 patient-years, p=0.11). In familial and sporadic diabetes, absence of ketoacidosis at onset predicted fewer events of severe hypoglycemia (hazard ratio 0.67, p<0.001, and 0.91, p<0.001, respectively) and of ketoacidosis (hazard ratio 0.64, p=0.007, and 0.66, p<0.001, respectively) after 10 years.</p> <b>Conclusions</b> Familial T1D, compared with sporadic T1D, is characterized by earlier disease manifestation and higher autoimmune comorbidity as well as less metabolic decompensation at onset likely related to higher disease awareness in affected families, while the course of disease is similar. These findings may have implications for the generalizability of results of diabetes prevention trials from familial to sporadic T1D patients.