Impact of Newborn Screening and Early Dietary Management on Clinical Outcome of Patients with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and Medium Chain Acyl-CoA Dehydrogenase Deficiency-A Retrospective Nationwide Study.

Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD/MTPD) and medium chain acyl-CoA dehydrogenase deficiency (MCADD) were included in the expanded neonatal screening program (ENBS) in Czechia in 2009, allowing for the presymptomatic diagnosis and nutritional management of these patients. The aim of our study was to assess the nationwide impact of ENBS on clinical outcome. This retrospective study analysed acute events and chronic complications and their severity in pre-ENBS and post-ENBS cohorts. In total, 28 children (12 before, 16 after ENBS) were diagnosed with LCHADD/MTPD (incidence 0.8/100,000 before and 1.2/100,000 after ENBS). In the subgroup detected by ENBS, a significantly longer interval from birth to first acute encephalopathy was observed. In addition, improvement in neuropathy and cardiomyopathy (although statistically non-significant) was demonstrated in the post-ENBS subgroup. In the MCADD cohort, we included 69 patients (15 before, 54 after ENBS). The estimated incidence rose from 0.7/100,000 before to 4.3/100,000 after ENBS. We confirmed a significant decrease in the number of episodes of acute encephalopathy and lower proportion of intellectual disability after ENBS (p < 0.0001). The genotype-phenotype correlations suggest a new association between homozygosity for the c.1528C > G variant and more severe heart involvement in LCHADD patients.

Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with CPT2D, VLCADD and LCHADD/TFPD.

BACKGROUND: The plasma acylcarnitine profile is frequently used as a biochemical assessment for follow-up in diagnosed patients with fatty acid oxidation disorders (FAODs). Disease specific acylcarnitine species are elevated during metabolic decompensation but there is clinical and biochemical heterogeneity among patients and limited data on the utility of an acylcarnitine profile for routine clinical monitoring. METHODS: We evaluated plasma acylcarnitine profiles from 30 diagnosed patients with long-chain FAODs (carnitine palmitoyltransferase-2 (CPT2), very long-chain acyl-CoA dehydrogenase (VLCAD), and long-chain 3-hydroxy acyl-CoA dehydrogenase or mitochondrial trifunctional protein (LCHAD/TFP) deficiencies) collected after an overnight fast, after feeding a controlled low-fat diet, and before and after moderate exercise. Our purpose was to describe the variability in this biomarker and how various physiologic states effect the acylcarnitine concentrations in circulation. RESULTS: Disease specific acylcarnitine species were higher after an overnight fast and decreased by approximately 60% two hours after a controlled breakfast meal. Moderate-intensity exercise increased the acylcarnitine species but it varied by diagnosis. When analyzed for a genotype/phenotype correlation, the presence of the common LCHADD mutation (c.1528G > C) was associated with higher levels of 3-hydroxyacylcarnitines than in patients with other mutations. CONCLUSIONS: We found that feeding consistently suppressed and that moderate intensity exercise increased disease specific acylcarnitine species, but the response to exercise was highly variable across subjects and diagnoses. The clinical utility of routine plasma acylcarnitine analysis for outpatient treatment monitoring remains questionable; however, if acylcarnitine profiles are measured in the clinical setting, standardized procedures are required for sample collection to be of value.

Energy exchangers with LCT as a precision method for diet control in LCHADD.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare genetic disease. The LCHADD treatment is mainly based on special diet. In this diet, energy from long-chain triglycerides (LCT) cannot exceed 10%, however energy intake from the consumption of medium-chain triglycerides (MCTs) should increase. The daily intake of energy should be compatible with energy requirements and treatment should involve frequent meals including during the night to avoid periods of fasting. In fact, there are no recommendations for total content of LCT in all of the allowed food in the LCHADD diet. The aim of the study was to present a new method of diet composition in LCHADD with the use of blocks based on energy exchangers with calculated LCT content. In the study, the diet schema was shown for calculating the energy requirements and LCT content in the LCHADD diet. How to create the diet was also shown, based on a food pyramid developed for patients with LCHADD. The blocks will make it possible, in a quick and simple way, to create a balanced diet which provides adequate energy value, essential nutrients and LCT content. This method can be used by doctors and dietitians who specialize in treating rare metabolic diseases. It can also be used by patients and their families for accurate menu planning with limited LCT content.

Most patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency develop pathological or subnormal retinal function.

AIM: There have been few studies on long-term electroretinographic findings in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). This study correlated long-term electroretinographic findings with age, metabolic control and clinical symptoms. METHODS: We examined 12 Swedish patients with LCHADD. Visual acuity testing, fundus examinations, optical coherence tomography and electroretinography were performed. The results were correlated to age, the levels of 3-hydroxyacylcarnitine and acylcarnitine and clinical metabolic control. RESULTS: Blindness or moderate visual impairment was found in two patients. Retinal pigmentation, atrophy and fibrosis were present in 11, seven and one of the patients, respectively, and optical coherence tomography showed retinal thinning in three of the six patients examined. Electroretinography was performed on 11 of the 12 patients. It was pathological, with reduced rod and cone responses, in five patients, subnormal in four and was related to poor clinical metabolic control and severe neonatal symptoms. Repeated electroretinographies revealed reduced function with increasing age. CONCLUSION: More than 80% of the LCHADD patients developed pathological or subnormal retinal function. This was more pronounced in patients with neonatal symptoms, but ameliorated by strict dietary treatment. Annual ophthalmological follow-ups, with electroretinography every second or third year, are recommended.

Peripheral neuropathy in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency - A follow-up EMG study of 12 patients.

BACKGROUND: The neonatal screening and early start of the dietary therapy have improved the outcome of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD). The acute symptoms of LCHADD are hypoketotic hypoglycemia, failure to thrive, hepatopathy and rhabdomyolysis. Long term complications are retinopathy and neuropathy. Speculated etiology of these long term complications are the accumulation and toxicity of hydroxylacylcarnitines and long-chain fatty acid metabolites or deficiency of essential fatty acids. AIMS: To study the possible development of polyneuropathy in LCHADD patients with current dietary regimen. METHODS: Development of polyneuropathy in 12 LCHADD patients with the homozygous common mutation c.G1528C was evaluated with electroneurography (ENG) studies. The ENG was done 1-12 times to each patient, between the ages of 3 and 40 years. Clinical data of the patients were collected from the patient records. RESULTS: The first sign of polyneuropathy was detected between the ages of 6-12 years, the first abnormality being reduction of the sensory amplitudes of the sural nerves. With time, progression was detected by abnormalities in sensory responses extending to upper limbs, as well as abnormalities in motor responses in lower limbs. Altogether, eight of the patients had polyneuropathy, despite good compliancy of the diet. CONCLUSIONS: This study is the first to report the evolution of polyneuropathy with clinical neurophysiological methods in a relative large LCHADD patient group. Despite early start, and good compliance of the therapy, 6/10 of the younger patients developed neuropathy. However, in most patients the polyneuropathy was less severe than previously described.

Earlier diagnosis and strict diets improve the survival rate and clinical course of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

AIM: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a severe metabolic disease that, without treatment, often leads to premature death or serious handicap. The aim of this study was to evaluate the clinical course of LCHADD with the homozygous 1528G>C (E510Q) mutation when patients underwent strict dietary treatment. METHODS: From 1997 to 2010, 16 patients with LCHADD were diagnosed in Finland. They were followed up, and data were prospectively collected as they emerged. Clinical data before diagnosis were retrospectively collected from hospital records. This cohort was compared with an earlier cohort of patients diagnosed from 1976 to 1996. RESULTS: The disease presented from birth to five months of age with failure to thrive, hypotonia, hepatomegaly, metabolic acidosis, cardiomyopathy and hypoketotic hypoglycaemia. In this cohort, the therapeutic delay was 0-30 days and the survival rate at the end of the study was 62.5% compared with 10-year survival rate of 14.3% for the earlier cohort. The survivors were in good overall condition, but some of them had developed mild retinopathy or mild neuropathy. CONCLUSION: Earlier diagnosis and stricter dietary regimes improved the survival rates and clinical course of patients with LCHADD in Finland. However, improvements in therapy are still needed to prevent the development of long-term complications, such as retinopathy and neuropathy.

Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with Long-Chain 3-Hydroxy Acyl CoA Dehydrogenase Deficiency (LCHADD).

BACKGROUND: LCHADD is a long-fatty acid oxidation disorder with immediate symptoms and long-term complications. We evaluated data on clinical status, biochemical parameters, therapeutic regimens and outcome of Austrian LCHADD patients. STUDY DESIGN: Clinical and outcome data including history, diagnosis, short- and long-term manifestations, growth, psychomotor development, hospitalizations, therapy of 14 Austrian patients with LCHADD were evaluated. Biochemically, we evaluated creatine kinase (CK) and acyl carnitine profiles. RESULTS: All LCHADD patients are homozygous for the common mutation. Three are siblings. Diagnosis was first established biochemically. Nine/14 (64%) were prematures, with IRDS occurring in six. In nine (64%), diagnosis was established through newborn screening, the remaining five (36%) were diagnosed clinically. Four pregnancies were complicated by HELLP syndrome, one by preeclampsia. In two, intrauterine growth retardation and placental insufficiency were reported. Five were diagnosed with hepatopathy at some point, seven with cardiomyopathy and eight with retinopathy, clinically relevant only in one patient. Polyneuropathy is only present in one. Three patients have a PEG, one is regularly fed via NG-tube. Growth is normal in all, as well as psychomotor development, except for two extremely premature girls. In 11 patients, 165 episodes with elevated creatine kinase concentrations were observed with 6-31 (median 14) per patient; three have shown no elevated CK concentrations. Median total carnitine on therapy was 19 µmol/l (range 11-61). For 14 patients, there have been 181 hospitalizations (median 9 per patient), comprising 1337 in-patient-days. All centres adhere to treatment with a fat-defined diet; patients have between 15% and 40% of their energy intake from fat (median 29%), out of which between 20% and 80% are medium-chain triglycerides (MCT) (median 62%). Four patients have been treated with heptanoate (C7). CONCLUSION: Our data show LCHADD outcome can be favourable. Growth and psychomotor development is normal, except in two prematures. Frequency of CK measurements decreases with age, correlating with a decreasing number of hospitalizations. About 50% develop complications affecting different organ systems. There is no relevant difference between the patients treated in the respective centers. Concluding from single case reports, anaplerotic therapy with heptanoate should be further evaluated.

Increased and early lipolysis in children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency during fast.

Children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) have a defect in the degradation of long-chain fatty acids and are at risk of hypoketotic hypoglycemia and insufficient energy production as well as accumulation of toxic fatty acid intermediates. Knowledge on substrate metabolism in children with LCHAD deficiency during fasting is limited. Treatment guidelines differ between centers, both as far as length of fasting periods and need for night feeds are concerned. To increase the understanding of fasting intolerance and improve treatment recommendations, children with LCHAD deficiency were investigated with stable isotope technique, microdialysis, and indirect calometry, in order to assess lipolysis and glucose production during 6 h of fasting. We found an early and increased lipolysis and accumulation of long chain acylcarnitines after 4 h of fasting, albeit no patients developed hypoglycemia. The rate of glycerol production, reflecting lipolysis, averaged 7.7 ± 1.6 µmol/kg/min, which is higher compared to that of peers. The rate of glucose production was normal for age; 19.6 ± 3.4 µmol/kg/min (3.5 ± 0.6 mg/kg/min). Resting energy expenditure was also normal, even though the respiratory quotient was increased indicating mainly glucose oxidation. The results show that lipolysis and accumulation of long chain acylcarnitines occurs before hypoglycemia in fasting children with LCHAD, which may indicate more limited fasting tolerance than previously suggested.

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet.

Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2-3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention.

[Mitochondrial beta-oxidation defects]. / Defekter i mitokondriell fettsyrenedbrytning.

BACKGROUND: Mitochondrial beta-oxidation of fatty acids is an important source of energy for the cells, especially during fasting. Since 1973 several inherited defects in beta-oxidation have been described. Defects in mitochondrial beta-oxidation are one of the largest groups of inborn errors of metabolism. MATERIAL AND METHODS: This review article is based on the experience of the authors and on literature studies. The authors' experience is from laboratory diagnostics and clinical experience in the departments of medical biochemistry and peadiatrics at our hospital. RESULTS AND INTERPRETATION: Beta-oxidation defects are potentially fatal disorders. Symptoms are usually seen during fasting, e.g. during childhood infections. Organs which preferably oxidize fatty acids or ketone bodies are especially vulnerable. Often, but not always, the patients have hypoketotic hypoglycaemia. In addition one can see affection of the liver, heart, muscular and nervous systems. The diseases can manifest both in childhood and adulthood and are often less severe in adulthood. The main principles of symptomatic treatment are avoidance of fasting and regular intake of a low-fat, high-carbohydrate diet. The diagnosis can be difficult to establish, especially in asymptomatic phases.

Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency.

BACKGROUND: Primary coenzyme Q(10) (CoQ(10)) deficiency is rare. The encephalomyopathic form, described in few families, is characterized by exercise intolerance, recurrent myoglobinuria, developmental delay, ataxia, and seizures. OBJECTIVE: To report a rare manifestation of CoQ(10) deficiency with isolated mitochondrial myopathy without central nervous system involvement. METHODS: The patient was evaluated for progressive muscle weakness. Comprehensive clinical evaluation and muscle biopsy were performed for histopathologic analysis and mitochondrial DNA and respiratory chain enzyme studies. The patient began taking 150 mg/d of a CoQ(10) supplement. RESULTS: The elevated creatine kinase and lactate levels with abnormal urine organic acid and acylcarnitine profiles in this patient suggested a mitochondrial disorder. Skeletal muscle histochemical evaluation revealed ragged red fibers, and respiratory chain enzyme analyses showed partial reductions in complex I, I + III, and II + III activities with greater than 200% of normal citrate synthase activity. The CoQ(10) concentration in skeletal muscle was 46% of the normal reference mean. The in vitro addition of 50 micromol/L of coenzyme Q(1) to the succinate cytochrome-c reductase assay of the patient's skeletal muscle whole homogenate increased the succinate cytochrome-c reductase activity 8-fold compared with 2.8-fold in the normal control homogenates. Follow-up of the patient in 6 months demonstrated significant clinical improvement with normalization of creatine kinase and lactate levels. CONCLUSIONS: The absence of central nervous system involvement and recurrent myoglobinuria expands the clinical phenotype of this treatable mitochondrial disorder. The complete recovery of myopathy with exogenous CoQ(10) supplementation observed in this patient highlights the importance of early identification and treatment of this genetic disorder.

Clinical and molecular heterogeneity in very-long-chain acyl-coenzyme A dehydrogenase deficiency.

Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency is an increasingly recognized defect of mitochondrial fatty acid beta-oxidation manifesting with episodes of metabolic decompensation or isolated recurrent myoglobinuria. In this report the clinical, biochemical, and molecular studies in a series of five patients (four Italian and one Spanish) with this disorder are discussed. Biochemical studies included the determination of fibroblast substrate oxidation rates and enzyme activity and Western blot analysis of VLCAD protein. Molecular analysis was performed by sequencing the VLCAD gene from the genomic DNA. Clinical features were within the spectrum previously reported. Four patients presented in infancy or childhood with episodes of severe metabolic decompensation and dicarboxylic aciduria. Two exhibited cardiomyopathy. The fifth patient presented with isolated recurrent rhabdomyolysis, with no cardiomyopathy or dicarboxylic aciduria. In all patients a significant loss of VLCAD activity associated with a marked reduction of VLCAD protein levels occurred. Molecular analysis disclosed one novel missense mutation (Cys437Tyr) and four previously reported mutations, including two missense substitutions (Phe418Leu and Arg419Trp), a single amino acid deletion (Lys258del), and one splice site mutation (IVS8-C(-2)), which was present in all four Italian patients. All patients exhibited compound heterozygosity. The phenotypic variability and the high genotypic heterogeneity of this hereditary metabolic disorder is reported.

[Treatment of mitochondrial diseases]. / Tratamiento de las enfermedades mitocondriales.

Until gene therapy is perfected, developed should reaching for a curative treatment of mitochondrial diseases in a next future, the present management of these metabolic disorders is directed to obtain the optimum energetic efficiency of dysfunctional mitochondria. Among other general measures the patient must avoid fever, exhausting exercise and drugs that inhibit mitochondrial metabolism. Dietetic restrictions are more useful in lipidic disorders, such as fatty acid oxidation or carnitine cycle defects, in which diets free of long chain and very long chain fatty acids are recommended. Pharmacological therapy should always be attempted, since some patients may experience a beneficial response. In respiratory chain deficits, coenzyme Q is the most widely used drug, although in the only double blind placebo-controlled study performed, results were contradictory. In isolated cases, vitamins K3, B2, C and E have been useful. Exogenous carnitine treatment may improve symptoms (sometimes dramatically) in patients with primary or secondary carnitine deficit. Dichloroacetate administration has a mild benefit in some cases of Leigh disease due to pyruvate dehydrogenase deficiency. Finally, sustained aerobic exercise may ameliorate symptoms of exercise intolerance due to mitochondrial dysfunction.

[Treatment of mitochondrial diseases in childhood and adolescence]. / Tratamiento de las enfermedades mitocondriales durante la infancia y adolescencia.

The advances made in recent years in understanding this large group of disorders has led to the development of ways of approaching their treatment, although in most cases it is neither definitive nor curative. In this article we review current aspects of the treatment of defects: of substrate transport, substrate use, the Krebs cycle, the mitochondrial respiratory chain and oxidation-phosphorylation coupling. We conclude with comments on possible future treatment.