Acute Metabolic Crisis Research Articles

TANGO2 Deficiency Disorder: Two Cases of Developmental Delay Preceding Metabolic Crisis

BackgroundTANGO2 deficiency disorder is a rare genetic disease caused by biallelic defects in TANGO2 gene. MethodsWe report the clinical phenotype of two children with TANGO2 deficiency disorder. ResultsPatient 1 is a female child presenting with developmental delay and microcephaly during the second year of life, who evolved with severe cognitive impairment, facial dysmorphisms, spastic paraparesis, and atonic seizures. At age 13 years, she was hospitalized due to an episode of rhabdomyolysis complicated with cardiac arrhythmia and hypothyroidism. Patient 2 is a female child with dysmorphic facial features, cleft palate, and developmental delay who was diagnosed with DiGeorge syndrome. At age three years, she presented with an acute episode of severe rhabdomyolysis in the context of human herpesvirus 6 infection. After the resolution of this acute episode, she maintained recurrent muscle weakness with axial hypotonia and progressive spasticity of the lower extremities. In both patients, diagnosis of TANGO2 deficiency disorder was only confirmed after an acute metabolic crisis. ConclusionsA high index of suspicion for TANGO2 deficiency disorder is needed in patients with developmental delay or other neurological symptoms and episodic rhabdomyolysis.

P040: Reducing delays of dextrose administration in patients in acute metabolic crisis

P040: Reducing delays of dextrose administration in patients in acute metabolic crisis

Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects in Drosophila and human cells.

Mutations in the Transport and Golgi Organization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model of TANGO2-related disease in the fruit fly Drosophila melanogaster that recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated with TANGO2 deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss-of-function in Drosophila and rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2-deficiency disease. Possible mechanisms for the rescue are discussed that may include restoration of lipid homeostasis.

Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold, p < 0.01) and lowered ATP levels (-1.9-fold, p < 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (-41%, p < 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FAinduced the accumulation of β-hydroxybutyrate (+ 1.4-fold, p < 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOSCI) (-20%, p < 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.

Clinical Characteristics of Pediatric Patients with Urea Cycle Disorders

Objective: Urea cycle disorders (UCDs) are inherited deficiencies of the enzymes or transport molecules involved in the cellular excretion of excess ammonia produced during protein metabolism. The aim of this study was to evaluate the clinical characteristics and long-term outcome of pediatric patients with UCDs. Material and Methods: Our research was conducted between September 2020-March 2021 in Dr. Sami Ulus Maternity and Child Health Training and Research Hospital. Clinical characteristics in 16 patients with UCDs [carbamoyl phosphate synthetase I deficiency (n=1), N-acetylglutamate synthase deficiency(n=1), argininosuccinate lyase deficiency (n=4), argininosuccinate synthetase deficiency (n=4), arginase deficiency (n=2), ornithine transcarbamylase deficiency (n=2), hyperammonemia hyperornithinemia homocitrullinuria syndrome (n=2)] were defined. The term “neonatal-onset” UCD was used if symptoms occurred within 28 days of life, and “late-onset” if symptoms started after the neonatal period. Results: Eight patients presented with acute metabolic crisis during newborn period. Core clinical phenotype in neonatal-onset UCDs included sepsis-like findings, whereas epilepsy and mental retardation was predominant in lateonset UCDs. For patients with neonatal-onset UCDs, hyperammonemia was more severe at the initial period. Conclusion: Despite evolving treatment opportunities, still high mortality rates were found in neonatal-onset UCD. UCDs should be suspected in pediatric patients with hyperammonemia and metabolic investigations should be performed immediately to enlighten diagnosis. Neonatal-onset UCD usually present with symptoms of acute hyperammonemia, while moresubtle neurological manifestations are frequent initial findings in the late onset UCD.

Severe Hyperammonaemia with Metabolic Acidosis in a Neonate: a Case Report of Ornithine Transcarbamylase Deficiency (OTCD)

Ornithine transcarbamylase (OTC) deficiency (OTCD), the most common urea cycle disorder, is an X-linked genetic disorder due to complete or partial lack of the OTC enzyme. Its clinical presentation depends on the degree of enzyme deficiency and ranges from an acute neonatal metabolic crisis with a high mortality rate through to an asymptomatic adult. We present a case of a newborn baby boy who presented with poor feeding, vomiting, lethargy, and respiratory distress. Laboratory investigations revealed severe hyperammonaemia, hyperglutaminaemia, hyperalaninaemia, absence of citrulline, and marked orotic aciduria. Family screening confirmed the presence of an OTC disease-causing mutation in his mother. It was a heterozygous mutation, c.316G&gt;A. p. Gly106Arg in exon 4.

Severe Hyperammonaemia with Metabolic Acidosis in a Neonate: a Case Report of Ornithine Transcarbamylase Deficiency (OTCD)

Ornithine transcarbamylase (OTC) deficiency (OTCD), the most common urea cycle disorder, is an X-linked genetic disorder due to complete or partial lack of the OTC enzyme. Its clinical presentation depends on the degree of enzyme deficiency and ranges from an acute neonatal metabolic crisis with a high mortality rate through to an asymptomatic adult. We present a case of a newborn baby boy who presented with poor feeding, vomiting, lethargy, and respiratory distress. Laboratory investigations revealed severe hyperammonaemia, hyperglutaminaemia, hyperalaninaemia, absence of citrulline, and marked orotic aciduria. Family screening confirmed the presence of an OTC disease-causing mutation in his mother. It was a heterozygous mutation, c.316G&gt;A. p. Gly106Arg in exon 4.

Mitochondrial hepatopathy: Respiratory chain disorders- 'breathing in and out of the liver'.

Mitochondria, the powerhouse of a cell, are closely linked to the pathophysiology of various common as well as not so uncommon disorders of the liver and beyond. Evolution supports a prokaryotic descent, and, unsurprisingly, the organelle is worthy of being labeled an organism in itself. Since highly metabolically active organs require a continuous feed of energy, any dysfunction in the structure and function of mitochondria can have variable impact, with the worse end of the spectrum producing catastrophic consequences with a multisystem predisposition. Though categorized a hepatopathy, mitochondrial respiratory chain defects are not limited to the liver in time and space. The liver involvement is also variable in clinical presentation as well as in age of onset, from acute liver failure, cholestasis, or chronic liver disease. Other organs like eye, muscle, central and peripheral nervous system, gastrointestinal tract, hematological, endocrine, and renal systems are also variably involved. Diagnosis hinges on recognition of subtle clinical clues, screening metabolic investigations, evaluation of the extra-hepatic involvement, and role of genetics and tissue diagnosis. Treatment is aimed at both circumventing the acute metabolic crisis and long-term management including nutritional rehabilitation. This review lists and discusses the burden of mitochondrial respiratory chain defects, including various settings when to suspect, their evolution with time, including certain specific disorders, their tiered evaluation with diagnostic algorithms, management dilemmas, role of liver transplantation, and the future research tools.

Variable clinical severity in TANGO2 deficiency: Case series and literature review.

Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

Continuous Glucose Monitoring in the Management of Hypoglycemia in TANGO2

Abstract Introduction: The TANGO2 gene encodes a transport and Golgi organization protein of unclear function; mutations should be considered in patients presenting with acute metabolic crisis, hypoglycemic episodes, cardiac arrhythmias, and other endocrinopathies. We report the novel use of a continuous glucose monitor (CGM) to help predict and prevent significant hypoglycemic episodes in a patient with TANGO2 mutation. Clinical Case: A 14-month old previously healthy, developmentally normal female who presented with unresponsive hypoglycemia (glucose 26 mg/dL) was demonstrated by Next Generation Sequencing to have a pathogenic 31.8 kb deletion of exon 3 to 9 in the TANGO-2 gene and a suspected pathogenic hemizygous c.569_592dup, p.Ile190_Leu197dup in TANGO-2. Her hospital course was notable for MRI showing hypoxic ischemic encephalopathy and both physical and electrical cardiac dysfunction. Continuous intravenous dextrose corrected the hypoglycemia, and transient hyperglycemia followed after several days of a glucose infusion rate between 3.2 to 5.8 mg/kg/min. After transitioning to ad lib oral feeds without restrictions, she was discharged. A second admission for acute unresponsive hypoglycemia and metabolic acidosis (glucose 30 mg/dL) occurred at 17 months of age with no clear inciting cause. Continuous IV dextrose at 9.9 mg/kg/min corrected the hypoglycemia and again resulted in transient hyperglycemia up to 271 mg/dl. Levothyroxine was also started for a TSH of 27 mIU/mL and a T4 of 4.6 ug/dL. Immediately after discharge, a DexCom G6 CGM was placed. Data over 2 weeks shows an average glucose of 104 ng/dL with 99% of the BS in target range. Parents report that CGM predictive low alerts have allowed intervention to abort fasting-related metabolic crises. Conclusion: In TANGO-2 deficiency, the liver may not adequately store and/or release glycogen in response to glucagon due to abnormal endoplasmic reticulum, Golgi apparatus, and mitochondrial functioning in states of stress or illness. Recent reports are conflicting with some showing reduced mitochondrial respiration in TANGO-2 patients in steady state with others finding normal values, opening the possibility that a combination of factors in the setting of stress may precipitate a metabolic crisis. Our patient quickly returns to near-normal physiological functioning; consequently, we suggest that use of a CGM can help prevent fasting related metabolic crisis in TANGO2 patients and can help guide feeding schedule and food choices to limit hyper- and hypoglycemia. In addition, CGM data can help further investigate if any beta cell dysregulation exists in non-acute states.

Evaluation of Neonatal Acute Metabolic Crisis in Maple Syrup Urine Disease with MR Diffusion and MR Spectroscopy: Case Series and Review of the Literature

AbstractMagnetic resonance imaging (MRI) findings of acute metabolic crisis in maple syrup urine disease (MSUD) in neonates were reviewed. This case cohort study included six MSUD neonates imaged during acute metabolic decompensation. Specific diffusion imaging and proton spectroscopic findings were reviewed. All patients revealed extensive intramyelinic cytotoxic edema typically involving myelinated white matter structures. Brainstem, cerebellar white matter and peduncles, midbrain, posterior limbs of internal capsules, central portions of periventricular, and perirolandic white matter regions showed typical MSUD edema. Gray matter structures such as dentate nucleus and thalamus were involved in all patients. Involvement of other deep nuclei was also noted in a few patients. None of the patients showed involvement of the superficial cortex. Reduction in N-acetyl aspartate, a prominent lactate peak, and a peak representing methyl groups of amino acids were characteristic findings seen on intermediate short echo time MR spectroscopy. Our case series outlines the importance of diffusion and spectroscopy MR techniques in the diagnosis of acute neonatal MSUD metabolic crisis.

Lifestyle, Nutritional and Psychological Changes in Adult Patients with Inborn Errors of Metabolism during COVID 19 Pandemic: Results from an Online Survey

When COVID-19 pandemic out broke in Italy, during the lockdown from March to May 2020, Inborn Errors of Metabolism (IEM) patients were at risk of not getting their dietary special products and routine visits. Moreover, during pandemic, psychological difficulties might have arose in these subjects, even more severe than in the general population due to the worries about acute decompensation caused by a possible COVID-19. In order to evaluate the patients’ perception of the outbreak situation and their related needs, three simple online anonymous surveys drawn up by Google Forms were sent to patients and families referring to our Adult IEM Center. Answers were collected between April and May 2020. Questionnaires investigated nutritional and lifestyle changes and psychological status using validated psychological tools. 19 patients with IEM filled out our survey (Median age 26-30 years). The most common nutritional therapy was low protein diet. During quarantine 12% patients failed to follow their usual medical diet, 65% reduced their physical activity and no one underwent an acute metabolic crisis. 57% of patients asked for more frequent access to the reference center. 33% of patients showed stress perceived of clinical relevance and general health perception were out of normal in 40% of patients. In conclusion, during quarantine some patients reported difficulty in following their medical diet or physical activity and were clinically stressed. Despite this, no one experienced a metabolic crisis, but asked for contacting the Metabolic Team in different ways than usual due to worries about their health condition. Telemedicine, the possibility of clinical follow-up at home patient (Including blood tests) and reservation of non-COVID-19 beds for hospital admission of IEM patients may have contributed to help IEM adult patients in better face this emergency time.

Management of diabetic ketoacidosis: Role of Rapid Acting Insulin Analogs in comparison to regular intravenous insulin.

Background: Diabetic ketoacidosis (DKA) is an acute metabolic healthcare crisis in patients with diabetes mellitus. The current study aimed to compare the effectiveness of rapid-acting insulin analog administered subcutaneously with regular insulin infused intravenously among the DKA patients.&#x0D; Methodology: In this prospective open labelled study, 100 consecutive DKA patients were randomly assigned to two groups. Group 1 patients were admitted to the intensive care unit (ICU) and treated with intravenous regular insulin infusion. Group 2 patients were managed in the emergency medical ward with subcutaneous rapid-acting insulin. Response to the therapy was assessed by the follow-up investigations of the biochemical parameters, including blood glucose concentration, serum ketones, pH, serum electrolytes including bicarbonates, sodium and potassium concentration until the resolution of DKA. Furthermore, the overall duration of therapy (blood glucose level &lt; 250 mg/dl), time and amount of insulin administered until the resolution of DKA, were also assessed.&#x0D; Results: The baseline clinical and biochemical parameters were similar between the two treatment groups except for blood glucose and sodium concentration. The mean random blood sugar (RBS), acid-base parameters and concentration of ketone bodies were significantly improved from admission until the resolution of DKA. There was no significant difference in the duration of therapy (p=0.07). While the time and amount of insulin therapy required until resolution of DKA were significantly reduced among the patients treated subcutaneously with rapid-acting insulin, i.e. 16.36 ± 6.92 hrs and 59.28 ± 30.05 units (p&lt;0.05).&#x0D; Conclusion: The patients with less complicated DKA can be managed with rapid-acting insulin analog in the medical wards obviating the need for admission to the ICU. With relatively better outcomes, it is an effective alternative to regular intravenous insulin infusion for DKA resolution.

Neonatal Presentations of Metabolic Disorders.

Metabolic disorders in a neonate can present with involvement of any organ system and can be challenging to diagnose. A newborn can present with an acute metabolic crisis such as hyperammonemia or seizures needing immediate management, with a more chronic clinical picture such as cholestatic liver disease, or with structural abnormalities such as skeletal manifestations. Early detection of treatable metabolic conditions is important to improve outcomes. Newborn screening has facilitated early detection and initiation of therapy for many metabolic disorders. However, normal testing does not rule out a metabolic disorder and a high index of suspicion should remain when caring for any critically ill neonate without a diagnosis. Whole exome sequencing (WES) or whole genome sequencing (WGS) can be powerful tools in rapid diagnosis of a potentially treatable metabolic condition in a critically ill neonate. This review presents classic clinical presentations of neonatal metabolic disorders and also highlights some uncommon neonatal manifestations of metabolic disorders to improve the recognition and diagnosis of these conditions.

Biochemical and anaplerotic applications of in vitro models of propionic acidemia and methylmalonic acidemia using patient-derived primary hepatocytes

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, which are caused by a deficiency in the enzyme propionyl-CoA carboxylase or the enzyme methylmalonyl-CoA (MM-CoA) mutase, respectively. The functional consequence of PA or MMA is the inability to catabolize P-CoA to MM-CoA or MM-CoA to succinyl-CoA, resulting in the accumulation of P-CoA and other metabolic intermediates, such as propionylcarnitine (C3), 3-hydroxypropionic acid, methylcitric acid (MCA), and methylmalonic acid (only in MMA). P-CoA and its metabolic intermediates, at high concentrations found in PA and MMA, inhibit enzymes in the first steps of the urea cycle as well as enzymes in the tricarboxylic acid (TCA) cycle, causing a reduction in mitochondrial energy production. We previously showed that metabolic defects of PA could be recapitulated using PA patient-derived primary hepatocytes in a novel organotypic system. Here, we sought to investigate whether treatment of normal human primary hepatocytes with propionate would recapitulate some of the biochemical features of PA and MMA in the same platform. We found that high levels of propionate resulted in high levels of intracellular P-CoA in normal hepatocytes. Analysis of TCA cycle intermediates by GC–MS/MS indicated that propionate may inhibit enzymes of the TCA cycle as shown in PA, but is also incorporated in the TCA cycle, which does not occur in PA. To better recapitulate the disease phenotype, we obtained hepatocytes derived from livers of PA and MMA patients. We characterized the PA and MMA donors by measuring key proximal biomarkers, including P-CoA, MM-CoA, as well as clinical biomarkers propionylcarnitine-to-acetylcarnitine ratios (C3/C2), MCA, and methylmalonic acid. Additionally, we used isotopically-labeled amino acids to investigate the contribution of relevant amino acids to production of P-CoA in models of metabolic stability or acute metabolic crisis. As observed clinically, we demonstrated that the isoleucine and valine catabolism pathways are the greatest sources of P-CoA in PA and MMA donor cells and that each donor showed differential sensitivity to isoleucine and valine. We also studied the effects of disodium citrate, an anaplerotic therapy, which resulted in a significant increase in the absolute concentration of TCA cycle intermediates, which is in agreement with the benefit observed clinically. Our human cell-based PA and MMA disease models can inform preclinical drug discovery and development where mouse models of these diseases are inaccurate, particularly in well-described species differences in branched-chain amino acid catabolism.

Validation of ELISA and cellular uptake inhibition assays to detect and quantify antibodies raised against sebelipase alfa in lysosomal acid lipase deficiency

Propionic acidemia (PA) and methylmalonic acidemia (MMA) are autosomal recessive disorders of propionyl-CoA (P-CoA) catabolism, which are caused by a deficiency in the enzyme propionyl-CoA carboxylase or the enzyme methylmalonyl-CoA (MM-CoA) mutase, respectively. The functional consequence of PA or MMA is the inability to catabolize P-CoA to MM-CoA or MM-CoA to succinyl-CoA, resulting in the accumulation of P-CoA and other metabolic intermediates, such as propionylcarnitine (C3), 3-hydroxypropionic acid, methylcitric acid (MCA), and methylmalonic acid (only in MMA). P-CoA and its metabolic intermediates, at high concentrations found in PA and MMA, inhibit enzymes in the first steps of the urea cycle as well as enzymes in the tricarboxylic acid (TCA) cycle, causing a reduction in mitochondrial energy production. We previously showed that metabolic defects of PA could be recapitulated using PA patient-derived primary hepatocytes in a novel organotypic system. Here, we sought to investigate whether treatment of normal human primary hepatocytes with propionate would recapitulate some of the biochemical features of PA and MMA in the same platform. We found that high levels of propionate resulted in high levels of intracellular P-CoA in normal hepatocytes. Analysis of TCA cycle intermediates by GC–MS/MS indicated that propionate may inhibit enzymes of the TCA cycle as shown in PA, but is also incorporated in the TCA cycle, which does not occur in PA. To better recapitulate the disease phenotype, we obtained hepatocytes derived from livers of PA and MMA patients. We characterized the PA and MMA donors by measuring key proximal biomarkers, including P-CoA, MM-CoA, as well as clinical biomarkers propionylcarnitine-to-acetylcarnitine ratios (C3/C2), MCA, and methylmalonic acid. Additionally, we used isotopically-labeled amino acids to investigate the contribution of relevant amino acids to production of P-CoA in models of metabolic stability or acute metabolic crisis. As observed clinically, we demonstrated that the isoleucine and valine catabolism pathways are the greatest sources of P-CoA in PA and MMA donor cells and that each donor showed differential sensitivity to isoleucine and valine. We also studied the effects of disodium citrate, an anaplerotic therapy, which resulted in a significant increase in the absolute concentration of TCA cycle intermediates, which is in agreement with the benefit observed clinically. Our human cell-based PA and MMA disease models can inform preclinical drug discovery and development where mouse models of these diseases are inaccurate, particularly in well-described species differences in branched-chain amino acid catabolism.

Eight novel mutations detected from eight Chinese patients with isovaleric acidemia

BackgroundIsovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China. MethodsEight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined. ResultsThe patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and “dirty sock” odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study). ConclusionsWe described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population.

Life-threatening lactic acidosis occurring in adults with mitochondrial disorders

Although relatively common in children, severe acute lactic acidosis is rare in adults with mitochondrial myopathies. We report here three cases, aged 27, 32 and 32 years, who developed life-threatening metabolic crisis with severe lactic acidosis, requiring hospitalisation in intensive care unit. Plasma lactates were elevated 10 to 15 fold normal values, necessitating extra-renal dialysis. By contrast CK levels were moderately increased (3 to 5N). No triggering factor was identified, but retrospectively all patients reported long-lasting mild muscle fatigability and weakness before their acute metabolic crisis. All of them recovered after prolonged intensive care but resting lactate levels remained elevated. Muscle biopsy showed ragged-red and COX-negative fibers in two patients and mild lipidosis in the third one. Heteroplasmic pathogenic point mutations were detected in MT-TL1 (m.3280G>A;m.3258C>T) and MT-TK (m.8363A>G). Life-threatening lactic acidosis may thus be a major inaugural clinical manifestation in adults with mitochondrial myopathies. Prolonged intensive care may lead to a dramatic and sustained improvement and is mandatory in such cases.

Diagnosis and treatment of a child with propionic acidemia - an issue both near and distant

Propionic acidemia (PA) is a genetic heterogeneous hereditary disease, that is due to deficiency of the mitochondrial enzyme propionyl-CoA carboxylase. As a result of the inherited genetic error of metabolism, propionic acid and propionyl-CoA-related metabolites accumulate in the body. The clinical manifestation of PA is caused by the toxic effect of the formed substances. PA presents with acute encephalopathy, progressive eating disorders, vomiting, dehydration and hypotension, running against the background of severe metabolic ketoacidosis, an increased anion gap (AnGap) ≥15 and hyperammonemia. The clinical condition is defined as an acute metabolic crisis of PA. The early diagnosis and the timely treatment are crucial for the outcome of the disease. We present a clinical case of PA in a two-month-old infant who was admitted to the Pediatric Intensive Care Unit in St. Marina University Hospital, Varna with seizures and disturbance of consciousness. The current clinical case is presented with the aim of focusing on the problems of hereditary diseases of the metabolism, in particular organic acidemias and the critical importance of the initial stabilization and adequate management of the lives of the affected patients.

Continuous venovenous hemodiafiltration in the treatment of newborns with an inborn metabolic disease: a single center experience

Background/aim Most inborn metabolic diseases are diagnosed during the neonatal period. The accumulation of toxic metabolites may cause acute metabolic crisis with long-term neurological dysfunction and death. Renal replacement therapy (RRT) modalities allow the efficient removal of toxic metabolites. In this study, we reviewed our experience with continuous venovenous hemodiafiltration (CVVHDF) as RRT for newborns with an inborn metabolic disease.Materials and methods Patients diagnosed with an inborn metabolic disease and who received CVVHDF treatment at our neonatal intensive care unit between January 2014 and December 2017 were included in this study. Their demographic and clinical data were collected, and the efficacy and safety of CVVHDF was evaluated.ResultsA total of nine continuous RRT (CRRT) sessions as CVVHDF were performed in eight newborns with a diagnosis of urea cycle defect (n = 5), maple syrup urine disease (n = 2), or methylmalonic acidemia (n = 1). The mean age at admission was 10 ± 8.6 days (range: 3–28 days). The mean plasma levels of ammonium were 1120 ± 512.6 mg/dL and 227.5 ± 141.6 mg/dL before and at the end of the treatment, respectively. Plasma levels of leucine were 2053.5 ± 1282 µmol/L and 473.5 ± 7.8 µmol/L before and at the end of the treatment, respectively. The CVVHDF duration was 32.3 ± 11.1 h (median: 37 h; range: 16–44 h), and the mean length of hospitalization was 14.6 ± 12.9 days. The mean duration of CVVHDF was 32.3 ± 11.1 h (range: 16–44 h). Circuit clotting was the most common observed complication (37.5%) and the survival rate was 50%. Among surviving patients, two developed severe and two developed mild mental and motor retardation. Conclusion CVVHDF is a CRRT modality that can be used to treat newborns with an inborn metabolic disease. Early diagnosis, commencement of specific medical therapy, diet, and extracorporeal support, if needed, are likely to result in improved short and long-term outcomes.