Cardiometabolic risk factor clustering in patients with deficient branched‐chain amino acid catabolism: A case‐control study

AbstractClassical organic acidemias (OAs) result from defective mitochondrial catabolism of branched‐chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case‐control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31P/1H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome‐like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA

Aspects of Newborn Screening in Isovaleric Acidemia

Isovaleric acidemia (IVA), an inborn error of leucine catabolism, is caused by mutations in the isovaleryl-CoA dehydrogenase (IVD) gene, resulting in the accumulation of derivatives of isovaleryl-CoA including isovaleryl (C5)-carnitine, the marker metabolite used for newborn screening (NBS). The inclusion of IVA in NBS programs in many countries has broadened knowledge of the variability of the condition, whereas prior to NBS, two distinct clinical phenotypes were known, an “acute neonatal” and a “chronic intermittent” form. An additional biochemically mild and potentially asymptomatic form of IVA and its association with a common missense mutation, c.932C>T (p.A282V), was discovered in subjects identified through NBS. Deficiency of short/branched chain specific acyl-CoA dehydrogenase (2-methylbutyryl-CoA dehydrogenase), a defect of isoleucine degradation whose clinical significance remains unclear, also results in elevated C5-carnitine, and may therefore be detected by NBS for IVA. Treatment strategies for the long-term management of symptomatic IVA comprise the prevention of catabolism, dietary restriction of natural protein or leucine intake, and supplementation with l-carnitine and/or l-glycine. Recommendations on how to counsel and manage individuals with the mild phenotype detected by NBS are required

Disease control via intensified lipoprotein apheresis in three siblings with familial hypercholesterolemia

BACKGROUND: Familial hypercholesterolemia (FH), the prevalent monogenic form of hypercholesterolemia, carries the risk of premature coronary heart disease. Lipoprotein-apheresis is established in children with severe dyslipidemia. We present 3 siblings with a negative/negative residual low density lipoprotein (LDL) receptor mutation (p.Trp577Arg), unresponsive to drug treatment. OBJECTIVE: Intensified lipoprotein-apheresis is well tolerated and results in permanently low lipid values without harming the health-related quality of life in children. METHODS: Three homozygous FH siblings, aged 7-13 years, had been treated with statins and ezetimibe for 12 months but still showed highly elevated low-density lipoprotein cholesterol (LDL-C) plasma concentrations. They were started on double-filtration plasmapheresis that was subsequently intensified according to plasma lipid levels. RESULTS: Each lipoprotein apheresis session reduced LDL-C concentration by 66% to 70%. Treated plasma volume was doubled after 6 months due to a sustained rebound of LDL-C between sessions. However, the rebound remained unchanged. Only an increase in frequency of sessions to every 3 to 4 days resulted in acceptable pre-treatment LDL-C concentrations (Cmax). Neither cessation of statins nor reduction of plasma exchange volume to 1.5 fold in follow-up influenced Cmax. Intensified therapy did not harm health-related quality of life as assessed by PedsQL and was well tolerated. CONCLUSIONS: In pediatric FH patients unresponsive to drug treatment, intensified lipoprotein apheresis can normalize plasma lipid levels. Apparently, treatment frequency rather than volume has greater influence on its efficacy. The potential burden of intensified therapy to daily life has to be regarded. Serum lipid levels in FH should be normalized to minimize cardiovascular risk. (C) 2016 National Lipid Association. All rights reserved

Living with intoxication-type inborn errors of metabolism: a qualitative analysis of interviews with paediatric patients and their parents

INTRODUCTION Progress in diagnosis and treatment of patients with intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders, organic acidurias or maple syrup urine disease is resulting in a growing number of long-term survivors. Consequently, health-related quality of life (HrQoL) of patients is increasingly regarded as a meaningful outcome parameter. To develop the first validated, disease-specific HrQoL questionnaire for IT-IEM, patients and parents were interviewed as content experts to identify major physical and psychosocial constraints and resources. METHODS Focus group interviews with 19 paediatric IT-IEM patients and 26 parents were conducted in four metabolic centres in Austria, Germany and Switzerland. Disease-specific HrQoL categories were established by qualitative content analysis. RESULTS Fourteen disease-specific topics related to the three well-established generic HrQoL dimensions of physical, mental and social functioning were derived from the interview transcripts. Both patients and parents perceived dietary restrictions and social stigmatisation as major burdens. Dietary restrictions and emotional burdens were more important for young (<8 years) patients, whereas cognition, fatigue and social issues were more relevant to older patients (≥8 years). Treatment-related topics had a significant effect on social and emotional HrQoL. DISCUSSION By exploring patients' and parents' perspectives, 14 HrQoL categories were identified. These new categories will allow the development of a disease-specific, standardised questionnaire to assess HrQoL in paediatric IT-IEM patients. Age-appropriate information on the disease and psychosocial support targeted to patients' individual burdens are essential to the delivery of personalised care that takes account of physical, mental and social dimensions of HrQoL

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency

BACKGROUND: Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology. METHODS: Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site. RESULTS: Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome. CONCLUSION: Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused bymutations in theHMGCL gene. In order to obtain a comprehensive view on this disease,we have collected clinical and biochemical data aswell as information onHMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive developmentwhile the remainder showed psychomotor deficits.We identified seven novel HMGCLmutations. In agreementwith previous reports, no clear genotypephenotype correlation could be found. This is the largest cohort ofHMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important