Episodes Of Metabolic Decompensation Research Articles

Contribution of Brain Intrinsic Branched-Chain Amino Acid Metabolism in a Novel Mouse Model of Maple Syrup Urine Disease.

Maple syrup urine disease (MSUD) results from loss of branched-chain ketoacid dehydrogenase (BCKDH) activity, the committed, rate-limiting step of branched-chain amino acid (BCAA) oxidation. Current treatments, including a low protein diet and liver transplantation, improve peripheral biochemistry and limit episodes of metabolic decompensation but do not fully prevent chronic neuropsychiatric symptoms. The mechanisms underlying chronic neurologic phenotypes remain poorly understood. Currently available MSUD mouse models do not survive long enough to evaluate chronic central nervous system (CNS) pathology. To investigate if loss of brain-intrinsic BCAA metabolism contributes to chronic neurologic disease, we developed a new brain-specific knockout mouse model of MSUD. First, we generated a mouse harboring a floxed Dbt allele (Dbtflox/flox). Then we crossed this line with Cre recombinase driver lines to induce loss of Dbt expression in (1) all developing CNS cell populations (2) neurons alone or (3) astrocytes alone. We found that brain-specific KO mice have elevations in BCAA levels in cortex that are exacerbated by a high protein diet. They also have secondary changes in amino acids in brain that are important for neuronal function, including glutamine and glycine. These metabolic differences result in subtle functional deficits as measured by electroencephalogram and behavioral testing. Astrocyte and neuron-specific KO mice each also demonstrate mild biochemical features of MSUD in the cortex, suggesting that both cell populations may contribute to disease pathology. Collectively, these data suggest that therapies targeting the CNS directly, in addition to the periphery, may improve outcomes in MSUD.

The Impact of Early Indication of Living Donor Liver Transplantation on the Outcomes of Patients With Propionic Acidemia: A Single-Center Experience.

Liver transplantation has been indicated for propionic acidemia (PA) patients with frequent metabolic decompensation and performed as an enzyme replacement therapy. We retrospectively evaluated the outcomes of patients with PA and analyze the appropriate timing of living donor liver transplantation (LDLT). We reviewed 12 children with PA who underwent LDLT, who were divided into early (period from the first episode of metabolic decompensation to LDLT < 1 year; n = 6) and late (> 1 year; n = 6) indication groups depending on the timing of LDLT. The patient and graft survival rates were 100% in 12 children with PA, and the median observation period was 61 months (5-193 months). None of the patients experienced any episodes of metabolic decompensation after LDLT. The timing of LDLT did not influence the incidence of surgical complications. Two patients in the late indication group had episodes of cardiac arrest and long QT syndrome before LDLT, and one patient showed prolongation of QT interval after LDLT. Two of the six patients in the late indication group had findings of metabolic stroke of the brain on MRI before LDLT. Although LDLT improved the findings of metabolic stroke, a decrease in development quotient score was shown in the post-LDLT course. LDLT may be an effective therapeutic option for improving metabolic control. Early LDLT might be help prevent cardiomyopathy and neurological impairment.

Triheptanoin in patients with long-chain fatty acid oxidation disorders: clinical experience in Italy

BackgroundLong-chain fatty acid oxidation disorders (LC-FAOD) are rare and potentially life-threatening diseases that cause deficient energy production and accumulation of toxic metabolites. Despite dietary management, adherence to maximum fasting guidelines, restricted long-chain triglyceride intake and supplementation with medium-chain triglyceride (MCT) oil (current standard of care), most patients experience recurrent decompensation episodes that can require hospitalisation. Herein, we analysed the effectiveness and safety of triheptanoin (a highly purified, synthetic medium odd-chain triglyceride) treatment in a cohort of Italian patients with LC-FAOD.MethodsThis retrospective, nationwide study included nine patients with LC-FAOD who switched from standard therapy with MCT oil to triheptanoin oral liquid. Data were collected between 2018 and 2022. Clinical outcome measures were the number and duration of intercurrent catabolic episodes and number and duration of metabolic decompensation episodes requiring hospitalisation. Creatine kinase (CK) levels and treatment-related adverse effects were also reported.ResultsPatients were provided a mean ± standard deviation (SD) triheptanoin dose of 1.5 ± 0.9 g/kg/day in four divided administrations, which accounted for 23.9 ± 8.9% of patients’ total daily caloric intake. Triheptanoin treatment was started between 2.7 and 16 years of age and was continued for 2.2 ± 0.9 years. The number of intercurrent catabolic episodes during triheptanoin treatment was significantly lower than during MCT therapy (4.3 ± 5.3 vs 22.0 ± 22.2; p = 0.034), as were the number of metabolic decompensations requiring hospitalisation (mean ± SD: 2.0 ± 2.5 vs 18.3 ± 17.7; p = 0.014), and annualised hospitalisation rates and duration. Mean CK levels (outside metabolic decompensation episodes) were lower with triheptanoin treatment versus MCT oil for seven patients. No intensive care unit admissions were required during triheptanoin treatment. Epigastric pain and diarrhoea were recorded as adverse effects during both MCT and triheptanoin treatment.ConclusionsThe significant improvement in clinical outcome measures after the administration of triheptanoin highlights that this treatment approach can be more effective than MCT supplementation in patients with LC-FAOD. Triheptanoin was well tolerated and decreased the number of intercurrent catabolic episodes, metabolic decompensation episodes requiring hospitalisation, and the annualised rate and duration of hospitalisations.

Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

BackgroundGenerating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits.MethodsWe used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death.ResultsThe frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3–3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9–1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients’ metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated.ConclusionsOpportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

A different perspective into clinical symptoms in CPT I deficiency

Carnitine palmitoyltransferase I (CPT I) deficiency is an autosomal recessive disorder causing long-chain fatty acid oxidation defect, characterized by metabolic decompensation episodes accompanied by hypoketotic hypoglycemia, hepatomegaly, seizures, renal tubular acidosis, and hyperammonemia. The aim of this study was to investigate the neurological symptoms in CPT I deficiency and different outcomes with respect to predisposing factors for sequela and to draw attention to the neurological impairment that may develop during the course of the disease. The retrospective study reviewed clinical characteristics of 14 patients. Mean follow-up period was 10.3 ± 4.7 (range: 8 months-18.6 years; median: 10 years) years. Three patients were diagnosed with newborn screening. In the symptomatic group (n = 12) most common presenting symptoms were psychomotor retardation (n = 6), seizures (n = 5), encephalopathy (n = 5), dystonia (n = 1), Reye-like syndrome (n = 5), muscle weakness (n = 3), and autism (n = 1). Neurologic findings detected in the follow-up period included speech disorder (n = 9), abnormal cranial MRI findings (n = 5), neuropathy (n = 1), and attention deficit hyperactivity disorder (n = 1). Speech disorders collectively included delayed expressive language development, speech articulation disorder, speech delay, stuttering, and specific speech difficulties. After starting treatment for CPT I deficiency, speech disorders improved in 3 patients. Our findings confirmed that the clinical manifestations of CPT I deficiency is wider than previously thought, causing specific neurologic dysfunction, mainly speech disorders at a large scale, that were unexpected in a fatty acid oxidation disorder. We suggest that early diagnosis and treatment is the key factor to prevent neurologic sequelae while an extensive neurological evaluation is essential in patients with CPT I deficiency both at the time of diagnosis and during the follow-up period.

UPDATED CLINICAL PROTOCOLS OF INHERITED FATTY ACID OXIDATION DISORDERS IN NEWBORNS: CONSOLIDATED DATA FROM THE INTERNATIONAL CLINICAL GUIDELINES

Fatty acid oxidation disorders (FAODs) are a group of inherited metabolic diseases (IMDs) caused by impairments in mitochondrial β-oxidation of fatty acids (FA) due to defects in genes encoding enzymes, transporters, membrane channels, and receptors that mediate this process. A common characteristic of this group of IMDs is an energy deficit associated with suppression of energy metabolism in mitochondria due to a decrease in the production of ketone bodies and the substrate of the tricarboxylic acid cycle – acetyl-coenzyme A. Since energy deficiency is a common pathogenetic factor of the entire group of FAODs, the manifestation of these inherited diseases is similar, and only certain nosologies have specific differences in the clinical picture, accordingly, these disorders require similar treatment. Initial manifestations of FAODs in neonatal and early childhood most often include cardiomyopathy, liver dysfunction, and hypoketotic hypoglycemia. For newborns with FAOD, the main danger is rapidly progressing crisis states of metabolic decompensation with severe, often fatal consequences. In adolescence, in addition to the above severe symptoms, episodes of rhabdomyolysis may also occur.Since long intervals between meals are one of the main factors provoking episodes of metabolic decompensation in patients with FAODs, the key tool for their prevention is the avoidance of prolonged fasting. In cases of the development of metabolic crisis states, symptomatic treatment is used with the introduction of carnitine according to indications. The special role of carnitine is its involvement in the transport of long-chain fatty acids through the mitochondrial membrane. Treatment of FAODs caused by a deficiency of enzymes whose substrates are long-chain fatty acids involves the use of a low-fat diet and the addition of medium-chain triglycerides and docosahexaenoic acid to the diet. Success in treating IMDs as such and FAODs, particularly, is directly related to early detection of the disease and treatment beginning since the destructive effect of toxic metabolites on internal organs and the brain increases according to the duration of exposure, leading to their progressive damage and delay in physical and mental development.An effective tool for the early detection of newborns with IMDs is the extended neonatal screening program, the implementation of which, according to the WHO, has become the greatest achievement of the health care systems of the developed countries of the world in reducing the levels of child mortality and disability in the first 10 years of the 21st century. In 2019, the program of extended newborn screening of IMDs was started in Ukraine at the initiative of the State Institution “Institute of Pediatrics, Obstetrics and Gynecology named after Academician O.M. Lukyanova of the National Academy of Medical Sciences of Ukraine”, “Association of Neonatologists of Ukraine” and “CDC Pharmbiotest” (Baby Screen, https://baby-screen.com.ua).One of the main reasons that limit the general use of this diagnostic procedure is doctors' lack of awareness and attention regarding IMDs, the causes of these serious diseases, diagnostic search algorithms, approaches to treatment, and patient follow-up. There is an urgent need for concise medical information that includes: a brief description of the individual genetic defect; characteristics of biochemical disorders and a list of marker substances that accumulate in the blood and urine of a newborn with IMDs; procedures of primary and clarifying laboratory studies; clinical manifestations of the disease; treatment strategy and prognosis. At the discretion of the Baby Screen team, this information is provided in the form of concise protocols.In this publication, we present eight Clinical Protocols, which were prepared by a team of specialists in metabolic pediatrics, medical genetics, and laboratory analytics, who were trained in the leading medical and genetic centers of the EU countries and regularly participate in training and scientific-practical seminars on this topic. The sources of information given in the protocols are international and national guidelines on extended neonatal screening, websites of leading organizations specializing in the diagnosis and treatment of IMDs, and well-known monographs and periodicals.

Novel AAV-mediated genome editing therapy improves health and survival in a mouse model of methylmalonic acidemia.

Methylmalonic acidemia (MMA) is an inborn error of metabolism mostly caused by mutations in the mitochondrial methylmalonyl-CoA mutase gene (MMUT). MMA patients suffer from frequent episodes of metabolic decompensation, which can be life threatening. To mimic both the dietary restrictions and metabolic decompensation seen in MMA patients, we developed a novel protein-controlled diet regimen in a Mmut deficient mouse model of MMA and demonstrated the therapeutic benefit of mLB-001, a nuclease-free, promoterless recombinant AAV GeneRideTM vector designed to insert the mouse Mmut into the endogenous albumin locus via homologous recombination. A single intravenous administration of mLB-001 to neonatal or adult MMA mice prevented body weight loss and mortality when challenged with a high protein diet. The edited hepatocytes expressed functional MMUT protein and expanded over time in the Mmut deficient mice, suggesting a selective growth advantage over the diseased cells. In mice with a humanized liver, treatment with a human homolog of mLB-001 resulted in site-specific genome editing and transgene expression in the transplanted human hepatocytes. Taken together, these findings support the development of hLB-001 that is currently in clinical trials in pediatric patients with severe forms of MMA.

Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease.

BackgroundMetabolic decompensation episodes (DEs) in Maple Syrup urine disease (MSUD) result in brain accumulation of toxic branched-chain amino acids (BCAAs) and their respective branched-chain α-keto acids that could induce neuroinflammation, disturb brain bioenergetics, and alter glutamate and glutamine synthesis. These episodes require immediate intervention to prevent irreversible neurological damage. Intravenous (IV) administration of BCAA-free solution could represent a powerful alternative for emergency treatment of decompensations.MethodsThis pediatric series discusses the management of DEs in MSUD patients with IV BCAA-free solution, as an emergency treatment for DEs or as a prophylactic in cases requiring surgery. Clinical evolution, amino acid profile and adverse effects were evaluated.ResultsWe evaluated the use of BCAA-free solution in 5 DEs in 5 MSUD pediatric patients, all with significantly elevated plasma leucine levels at admission (699–3296 μmol/L) and in 1 episode of risk of DE due to surgery. Leucine normalization was achieved in all cases with resolution or improvement of clinical symptoms following IV BCAA-free solution. The duration of administration ranged from 3–20 days. Administration of IV BCAA-free solution at the beginning of a DE could reverse depletion of the amino acids that compete with BCAAs for the LAT1 transporter, and the observed depletion of alanine, despite IV alanine supplementation. No related adverse events were observed.ConclusionsAdministration of standardized IV BCAA-free solution in emergency settings constitutes an important and safe alternative for the treatment of DEs in MSUD, especially in pediatric patients for whom oral or enteral treatment is not viable.

Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

Intravenous administration of a branched-chain amino-acid-free solution in children and adults with acute decompensation of maple syrup urine disease: a prospective multicentre observational study

BackgroundPatients with maple syrup urine disease (MSUD) experiencing metabolic decompensations have traditionally been treated with branched-chain amino acid (BCAA)-free mixture via oral or nasogastric administration routes. In some patients, enteral administration is not possible, either because the patient presents with vomiting, coma, or refuses nasogastric administration, thus intravenous (IV) BCAA-free solution is an appropriate intervention for these challenging cases.AimsThis study aimed to evaluate the effectiveness and safety of managing metabolic decompensations by administering an IV BCAA-free solution.MethodsThis is an observational prospective study of data from MSUD patients hospitalised for decompensation episodes between 2010 and 2016 at 6 centres for rare metabolic diseases in France.ResultsA total of 24 patients (16 males; 8 females) experiencing 126 MSUD metabolic decompensation episodes (39 in children; 87 in adults) were admitted to hospital. At presentation, mean leucine plasma concentration was ≥ 381 µmol/L in 113/126 (89.7%) episodes. Children were treated with continuous IV BCAA-free solution at doses of 0.8 to 2.0 g/kg/day, for 4.8 days and adults for 3.8 days at doses of 0.5 to 2.6 g/kg/day. In the efficacy set of 102 analysable episodes leucine concentrations were normalised (to below 381 µmol/L) in 82% (n = 18/22) of episodes in children and in 84% (n = 67/80) of episodes in adults. Mean time to leucine normalisation was 3.0 days. This was significantly (p < 0.001) shorter than the algorithmically predicted time to leucine normalisation with traditional BCAA-free mixture. Duration of hospitalisation was significantly longer for children than for adults (7.1 days in children vs 5.2 days in adults, p = 0.012). No treatment-related adverse events were reported in any patients on IV BCAA-free solution.ConclusionThe IV BCAA-free solution is safe and effective in normalising leucine concentrations during MSUD decompensation episodes in both children and adults, offering a practical treatment alternative for those patients who cannot receive BCAA-free mixture via oral or nasogastric routes.

Mitochondrial stroke-like episodes: The search for new therapies

A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym “MELAS” (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes.

Pyruvate Dehydrogenase Deficiency: With More Phenotypes Than We Believe

Introduction: The pyruvate dehydrogenase complex (PDC) is a multienzyme complex responsible for catalyzing the oxidative decarboxylation of pyruvate to Acetyl-CoA. A defect in any of its components can interfere with the production of energy on a cellular level; within these disorders we find pyruvate dehydrogenase (PDH) deficiency characterized by clinical neurological and systemic signs of varying severity, highlighting lactic acidosis, neurological and progressive neuromuscular deterioration. Objective: Describe the case of a female, school aged patient with characteristic craniofacial dysmorphology, neurodevelopmental delay and episodes of metabolic decompensation due to infections, with a mutation in the PDHX gene, treated with a ketogenic diet, thiamine, lipoic acid and carnitine. Results: The findings that made it possible to focus the diagnosis were elevated plasma and CSF lactate levels associated with persistent metabolic acidosis with accentuation of hyper intensity in the cortical sulci and in the in the bilateral basal ganglia and lenticular nuclei region of the brain on magnetic resonance imaging. Magnetic resonance imaging with spectroscopy showed a negative peak of lactate. Confirming the diagnosis with an exome of 6000 genes where a homozygous pathogenic variant is found in the PDHX gene position c.1426C&gt; T. Conclusion: PDH deficiency should be considered in cases of neurodevelopmental delay associated with intermittent episodes of neurological deterioration and elevated blood lactate and as well as elevated lactate in magnetic resonance spectroscopy of the brain. Unlike those affected by other subtypes, patients with E3-binding protein deficiency often survive childhood and even adulthood due to the presence of assembly to a certain extent of some of the pyruvate dehydrogenase complex. Prompt diagnosis opens the possibility of starting early supportive management, providing genetic counseling to parents, as well as establishing prognosis.

Interorgan amino acid interchange in propionic acidemia: the missing key to understanding its physiopathology

BackgroundPropionic acidemia is an inborn error of metabolism caused by a deficiency in the mitochondrial enzyme propionyl-CoA carboxylase that converts the propionyl CoA to methyl malonyl CoA. This leads to profound changes in distinct metabolic pathways, including the urea cycle, with consequences in ammonia detoxification. The implication of the tricarboxylic acid cycle is less well known, but its repercussions could explain both some of the acute and long-term symptoms of this disease.Materials and methodsThe present observational study investigates the amino acid profiles of patients with propionic acidemia being monitored at the Hospital Ramón y Cajal (Madrid, Spain), between January 2015 and September 2017, comparing periods of metabolic stability with those of decompensation with ketosis and/or hyperammonemia.ResultsThe concentrations of 19 amino acids were determined in 188 samples provided by 10 patients. We identified 40 metabolic decompensation episodes (22 only with ketosis and 18 with hyperammonemia). Plasma glutamine and alanine levels were reduced during these metabolic crises, probably indicating deficiency of anaplerosis (p < 0.001 for both alanine and glutamine). Hypocitrulllinemia and hypoprolinemia were also detected during hyperammonemia (p < 0.001 and 0.03, respectively).ConclusionsThe amino acid profile detected during decompensation episodes suggests deficient anaplerosis from propionyl-CoA and its precursors, with implications in other metabolic pathways like synthesis of urea cycle amino acids and ammonia detoxification.

Inborn error of metabolism patients after liver transplantation: Outcomes of 35 patients over 27 years in one pediatric quaternary hospital.

Liver transplantation (LT) has been used for many years as a therapeutic option for certain inborn errors of metabolism (IEMs). Here we present one institution's 27 years of experience with LT in IEMs. Our objective is to assess the outcomes of IEM patients who have undergone LT, which we hypothesize to be generally successful for prevention of metabolic decompensation. A retrospective chart review was performed on patients with urea cycle defects, organic acidemias, and amino acidopathies who underwent LT at the Children's Hospital of Philadelphia. Thirty-five patients with the following conditions have undergone LT: tyrosinemia (8), methylmalonic acidemia (7), maple syrup urine disease (6), citrullinemia (6), ornithine transcarbamylase deficiency (4), propionic acidemia (2), and argininosuccinate lyase deficiency (2). Average age at transplantation was 3.6 years. Three patients are now deceased. One patient suffered a metabolic stroke posttransplant. No episodes of metabolic decompensation have been noted. Thirty-five patients received LT with generally favorable outcome. None sustained metabolic decompensation posttransplant. As has been reported previously, LT does not ameliorate pre-existing developmental differences or risk to other organ systems. Further research is needed to aid in standardization of care and follow-up, as most patients no longer follow with a geneticist.

Enlargement of the Optic Chiasm: A Novel Imaging Finding in Glutaric Aciduria Type 1.

Patients with glutaric aciduria type 1, without early diagnosis and initiation of preventive treatment, often develop movement disorders and various degrees of motor disability due to striatal area-specific damage induced by an acute episode of metabolic decompensation. The neuroimaging phenotype of patients with glutaric aciduria type 1 includes characteristic cyst-like bilateral enlargement of the Sylvian fissures and anterior subarachnoid spaces and signal abnormalities including supratentorial white matter and deep gray matter structure T2 hyperintensities, frequently associated with restricted diffusion. In this retrospective study, we add to the neuroimaging spectrum of glutaric aciduria type 1, a novel imaging finding present regardless of a previous metabolic crisis: the enlargement of the optic chiasm associated with signal abnormalities in the anterior intracranial visual structures observed in 6 of 10 patients. These optic pathway abnormalities are suggested as useful diagnostic clues for glutaric aciduria type 1, and possible pathophysiologic mechanisms are discussed.

Clinical, biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations in the GCDH gene.

Glutaric aciduria type 1 (GA-1) is a rare but treatable inherited disease caused by deficiency of glutaryl-CoA dehydrogenase activity due to GCDH gene mutations. In this study, we report 24 symptomatic GA-1 Brazilian patients, and present their clinical, biochemical, and molecular findings. Patients were diagnosed by high levels of glutaric and/or 3-hydroxyglutaric and glutarylcarnitine. Diagnosis was confirmed by genetic analysis. Most patients had the early-onset severe form of the disease and the main features were neurological deterioration, seizures and dystonia, usually following an episode of metabolic decompensation. Despite the early symptomatology, diagnosis took a long time for most patients. We identified 13 variants in the GCDH gene, four of them were novel: c.91 + 5G > A, c.167T > G, c.257C > T, and c.10A > T. The most common mutation was c.1204C > T (p.R402W). Surprisingly, the second most frequent mutation was the new mutation c.91 + 5G > A (IVS1 ds G-A + 5). Our results allowed a complete characterization of the GA-1 Brazilian patients. Besides, they expand the mutational spectrum of GA-1, with the description of four new mutations. This work reinforces the importance of awareness of GA-1 among doctors in order to allow early diagnosis and treatment in countries like Brazil where the disease has not been included in newborn screening programs.

Novel LRPPRC compound heterozygous mutation in a child with early-onset Leigh syndrome French-Canadian type: case report of an Italian patient

BackgroundMitochondrial diseases, also known as oxidative phosphorylation (OXPHOS) disorders, with a prevalence rate of 1:5000, are the most frequent inherited metabolic diseases. Leigh Syndrome French Canadian type (LSFC), is caused by mutations in the nuclear gene (2p16) leucine-rich pentatricopeptide repeat-containing (LRPPRC). It is an autosomal recessive neurogenetic OXPHOS disorder, phenotypically distinct from other types of Leigh syndrome, with a carrier frequency up to 1:23 and an incidence of 1:2063 in the Saguenay-Lac-St Jean region of Quebec. Recently, LSFC has also been reported outside the French-Canadian population.Patient presentationWe report a male Italian (Sicilian) child, born preterm at 28 + 6/7 weeks gestation, carrying a novel LRPPRC compound heterozygous mutation, with facial dysmorphisms, neonatal hypotonia, non-epileptic paroxysmal motor phenomena, and absent sucking-swallowing-breathing coordination requiring, at 4.5 months, a percutaneous endoscopic gastrostomy tube placement. At 5 months brain Magnetic Resonance Imaging showed diffuse cortical atrophy, hypoplasia of corpus callosum, cerebellar vermis hypoplasia, and unfolded hippocampi. Both auditory and visual evoked potentials were pathological. In the following months Video EEG confirmed the persistence of sporadic non epileptic motor phenomena. No episode of metabolic decompensation, acidosis or ketosis, frequently observed in LSFC has been reported. Actually, aged 14 months corrected age for prematurity, the child shows a severe global developmental delay. Metabolic investigations and array Comparative Genomic Hybridization (aCGH) results were normal. Whole-genome sequencing (WGS) found a compound heterozygous mutation in the LRPPRC gene, c.1921–7A > G and c.2056A > G (p.Ile686Val), splicing-site and missense variants, inherited from the mother and the father, respectively.ConclusionsWe first characterized the clinical and molecular features of a novel LRPPRC variant in a male Sicilian child with early onset encephalopathy and psychomotor impairment. Our patient showed a phenotype characterized by a severe neurodevelopmental delay and absence of metabolic decompensation attributable to a probable residual enzymatic activity. LRPPRC is a rare cause of metabolic encephalopathy outside of Québec. Our patient adds to and broaden the spectrum of LSFC phenotypes. WGS analysis is a pivotal genetic test and should be performed in infants and children with hypotonia and developmental delay in whom metabolic investigations and aCGH are normal.

Plasma methylcitric acid and its correlations with other disease biomarkers: The impact in the follow up of patients with propionic and methylmalonic acidemia.

Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second-tier test in newborn screening, but its utility for patients monitoring still needs to be established. We explored the potential contribution of MCA in the long-term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical status, and disease burden in 22 patients, 13 with propionic acidemia (PA) and nine with methylmalonic acidemia (MMA) on standard treatment and/or after transplantation. Samples were collected at scheduled routine controls or during episodes of metabolic decompensation (MD), 10 patients were evaluated after transplantation (six liver, two combined liver and kidney, 2 kidney). MCA levels were higher in PA compared to MMA and its levels were not influenced by the clinical status (MD vs well state). In MMA, MCA was higher in elder patients and, along with fibroblast growth factor 21 (FGF21) and plasma methylmalonic acid, negatively correlated with GFR. In both diseases, MCA correlated with ammonia, glycine, lysine, C3, and the C3/C2, C3/C16 ratios. The disease burden showed a direct correlation with MCA and FGF21, for both diseases. All transplanted patients showed a significant reduction of MCA in comparison to baseline values, with some differences dependent on the type of transplantation. Our study provided new insights in understanding the disease pathophysiology, showing similarities between MCA and FGF21 in predicting disease burden, long-term complications and in evaluating the impact of organ transplantation.

3-Hydroxy-3-Methylglutaric Acid Impairs Redox and Energy Homeostasis, Mitochondrial Dynamics, and Endoplasmic Reticulum-Mitochondria Crosstalk in Rat Brain.

3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a neurometabolic disorder characterized by predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in tissues and biological fluids. Patients often present in the first year of life with metabolic acidosis, non-ketotic hypoglycemia, hypotonia, lethargy, and coma. Since neurological symptoms may be triggered or worsened during episodes of metabolic decompensation, which are characterized by high urinary excretion of organic acids, this study investigated the effects of HMG intracerebroventricular administration on redox homeostasis, citric acid cycle enzyme activities, dynamics (mitochondrial fusion and fission), and endoplasmic reticulum (ER)-mitochondria crosstalk in the brain of neonatal rats euthanized 1 (short term) or 20 days (long term) after injection. HMG induced lipid peroxidation and decreased the activities of glutathione peroxidase (GPx) and citric acid cycle enzymes, suggesting bioenergetic and redox disruption, 1 day after administration. Levels of VDAC1, Grp75, and mitofusin-1, proteins involved in ER-mitochondria crosstalk and mitochondrial fusion, were increased by HMG. Furthermore, HMG diminished synaptophysin levels and tau phosphorylation, and increased active caspase-3 content, indicative of cell damage. Finally, HMG decreased GPx activity and synaptophysin levels, and changed MAPK phosphorylation 20 days after injection, suggesting that long-term toxicity is further induced by this organic acid. Taken together, these data show that HMG induces oxidative stress and disrupts bioenergetics, dynamics, ER-mitochondria communication, and signaling pathways in the brain of rats soon after birth. It may be presumed that these mechanisms underlie the onset and progression of symptoms during decompensation occurring in HL-deficient patients during the neonatal period.

Acute lysine overload provokes marked striatum injury involving oxidative stress signaling pathways in glutaryl-CoA dehydrogenase deficient mice

Glutaric acidemia type I (GA I) is a neurometabolic disorder of lysine (Lys) catabolism caused by glutaryl-CoA dehydrogenase (GCDH) deficiency. Patients are susceptible to develop acute striatum degeneration during catabolic stress situations whose underlying mechanisms are not fully established. Thus, in the present work we investigated the effects of a single intrastriatal Lys administration (1.5–4 μmol) to 30-day-old wild type (WT) and GCDH deficient (Gcdh−/−) mice on brain morphology, neuronal injury, astrocyte reactivity and myelin structure, as well as signaling pathways of redox homeostasis. We observed a marked vacuolation/edema in striatum and at higher doses also in cerebral cortex of Gcdh−/−, but not of WT mice. Lys also provoked a reduction of NeuN and synaptophysin, as well as an increase of astrocytic GFAP, in the striatum of Gcdh−/− mice, indicating neuronal loss and astrocyte reactivity. Furthermore, we verified an increase of Nrf2 and NF-κB expression in the nuclear fraction, and a decrease of heme oxygenase-1 (HO-1) content in the striatum of Lys-injected Gcdh−/− mice, implying disruption of redox homeostasis. Finally, it was found that Lys provoked alterations of myelin structure reflected by decreased myelin basic protein (MBP) in the cerebral cortex of Gcdh−/− mice. Taken together, the present data demonstrate neuronal loss, gliosis, altered redox homeostasis and demyelination caused by acute Lys overload in brain of Gcdh−/− mice, supporting the hypothesis that increased brain concentrations of glutaric and 3-hydroxyglutaric acids formed from Lys may be responsible for the acute brain degeneration observed in GA I patients during episodes of metabolic decompensation.