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.

First Japanese Case of Carnitine Palmitoyltransferase II Deficiency with the Homozygous Point Mutation S113L.

Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inherited disorder related to recurrent episodes of rhabdomyolysis. The adult myopathic form of CPT II deficiency is relatively benign and difficult to diagnose. The point mutation S113L in CPT2 is very common in Caucasian patients, whereas F383Y is the most common mutation among Japanese patients. We herein present a case of CPT II deficiency in a Japanese patient homozygous for the missense mutation S113L. The patient showed a decreased frequency of rhabdomyolysis recurrence after the administration of a diet containing medium-chain triglyceride oil and supplementation with carnitine and bezafibrate.

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.

[Novel nutritional management regimen for very long-chain acyl-CoA dehydrogenase deficiency].

We report a novel regimen of nutritional management in 22-year-old woman with myopathic form of very-long-chain acyl-CoA dehydrogenase deficiency. This regimen is based on avoidance of fasting by frequent intake of carbohydrates and substitution of medium chain triglyceride for long- and very long-chain fatty acids. Oral intake of medium amount of long-chain fatty acid (300 kcal daily) was allowed, to facilitate compliance and to escape pigmentary retinopathy. After this nutritional management and lifestyle guidance about prevention of fatigue and starvation, the patient was free from severe rhabdomyolysis for more than three years, which had forced her to hospital management nine times in seven years.

Carnitine palmitoyltransferase II deficiency: successful anaplerotic diet therapy.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. METHODS: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. RESULTS: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. CONCLUSIONS: The triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency.

Glycaemic and insulinaemic response of quarter horses to concentrates high in fat and low in soluble carbohydrates.

REASONS FOR PERFORMING STUDY: Quarter Horses are particularly susceptible to polysaccharide storage myopathy (PSSM). Nutritional therapy and possibly prophylaxis includes fat-supplemented diets whilst starch supply should be kept to a minimum. OBJECTIVES: To investigate the glycaemic and insulinaemic response of clinically normal Quarter Horses to concentrates high in fat and low in starch. METHODS: Twelve Quarter Horses were studied. The precondition for inclusion in the study population was that the horses had not shown clinical signs of myopathy. The Quarter Horses were fed according to a 4 x 4 Latin square design haylage plus isocaloric concentrates based on barley and oats as control (CO), sugar beet pulp, grass meal and soybean oil (SB), rice bran and grass meal (RB) and rice bran, grass meal, sugar beet pulp and soybean oil (CP), each over 2 weeks after 1 week of adaptation. At the end of each period, 1 kg of concentrate was fed and blood sampled 0, 30, 60, 90, 120, 180, 240, and 300 min post prandial (ppr.). Creatine kinase (CK; 0 min ppr. only), glucose and insulin were analysed. Glycaemic and insulinaemic index was calculated from each concentrates area under the curve (AUC) relative to CO. RESULTS: Rice bran containing concentrates were partially refused at the beginning of the trial periods. CK activity, and glucose and insulin patterns (ppr. mean, peak, AUC, index) were highest with CO (P<0.05). The correlation between glucose and insulin (P<0.001) ranged from r = 0.570 (CO) to r = 0.364 (RB). Basal CK was highly correlated (P<0.001) to the mean ppr. plasma glucose. CONCLUSION: Rice bran, sugar beet pulp, grass meal and soybean oil are suitable to include in concentrates that induce low glycaemic and insulinaemic response. Its acceptance seems to be a question of habituation. Although the mechanism is not completely understood, glucose patterns and basal CK activity are highly positively correlated. Both were affected by the type of concentrate used. POTENTIAL RELEVANCE: Results support the suggestion that low-starch and high-fat feeding may be helpful not only in the nutrition of affected horses, but also to prevent future PSSM associated discomfort in particularly susceptible horses.

The effect of varying dietary starch and fat content on serum creatine kinase activity and substrate availability in equine polysaccharide storage myopathy.

The effect of dietary starch and fat content on serum creatine kinase (CK) activity and substrate availability was evaluated in 4 mares of Quarter Horse-related breeds with polysaccharide storage myopathy (PSSM). Four isocaloric diets ranging in digestible energy (DE) from 21.2% (diet A), 14.8% (B), 8.4% (C), to 3.9% (D) for starch, and 7.2% DE (diet A), 9.9% (B), to 12.7% DE (diet C and D) for fat were fed for 6-week periods (4 weeks with exercise) using a 4 X 4 Latin square design. Postprandial glucose and insulin responses were measured, and 4 hours postexercise, serum CK activity, glucose, insulin, free fatty acids (FFA), and beta-hydroxybutyrate (beta-HBA) were analyzed. Glycogen, glucose-6-phosphate, citrate synthase, 3-hydroxy-acyl-CoA dehydrogenase, lactate dehydrogenase as well as abnormal polysaccharide and lipid content were measured in middle gluteal muscle samples. Postprandial insulin and glucose response was higher for diet A versus D. Log CK activity was higher with diets A, B, and C versus D. Daily insulin was higher and FFA lower on diet A versus B, C, and D, whereas glucose varied only slightly with diet. Muscle oxidative capacity and lipid stores were low in PSSM horses and muscle glycogen and abnormal polysaccharide content high on both diets A and D. Individual variation occurred in the response of PSSM horses to diets differing in starch and fat content. However, for those horses with clinical manifestations of PSSM, a diet with <5% DE starch and >12% DE fat can reduce exertional rhabdomyolysis, potentially by increasing availability of FFA for muscle metabolism.

Four cases of equine polysaccharide storage myopathy in the United Kingdom.

This paper describes four cases of equine polysaccharide storage myopathy which were confirmed by histological examination of muscle biopsy specimens. The horses were of mixed breeding, with warmblood and thoroughbred dominating. They all had recurrent episodes of rhabdomyolysis, indicated by clinical signs and increased plasma levels of muscle enzymes. They were managed conservatively and have continued athletic careers despite their disease.

A case of severe hyperlipidemia caused by long-term tube feedings.

A 77-year-old woman with type II diabetes mellitus was admitted to our hospital in August/ 1995 with severe hyperlipidemia. She had taken feedings through a nasogastric tube with 1000 ml (1000 kcal) of Ensureliquid daily since 1993 because of the muscle weakness after rhabdomyolysis. Her serum total cholesterol was 515 mg/dl and triglyceride was 3378 mg/dl despite administration of 10 mg of simvastatin daily. After substitution of a standard diet starting August 21, we found significant decreases of total cholesterol from 725 mg/dl to 194 mg/dl and triglyceride from 4680 mg/dl to 550 mg/dl within 37 days. We also found a severe decrease in her serum total carnitine level of 22 micromol/l (normal range 45-91 micromol/l) before changing the diet, suggesting secondary carnitine deficiency. Severe hyperlipidemia was reversed by changing the carnitine deficient diet (Ensureliquid) to a carnitine-containing diet. We suggested that the development of hyperlipidemia was related to the carnitine deficiency.

Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride.

The current dietary treatment of long-chain fatty acid oxidation defects (high carbohydrate with medium-even-chain triglycerides and reduced amounts of long-chain fats) fails, in many cases, to prevent cardiomyopathy, rhabdomyolysis, and muscle weakness. We hypothesized that the apparent defect in energy production results from a depletion of the catalytic intermediates of the citric acid cycle via leakage through cell membranes (cataplerosis). We further hypothesized that replacing dietary medium-even-chain fatty acids (precursors of acetyl-CoA) by medium-odd-chain fatty acids (precursors of acetyl-CoA and anaplerotic propionyl-CoA) would restore energy production and improve cardiac and skeletal muscle function. We fed subjects with long-chain defects a controlled diet in which the fat component was switched from medium-even-chain triglycerides to triheptanoin. In three patients with very-long-chain acyl-CoA dehydrogenase deficiency, this treatment led rapidly to clinical improvement that included the permanent disappearance of chronic cardiomyopathy, rhabdomyolysis, and muscle weakness (for more than 2 years in one child), and of rhabdomyolysis and weakness in the others. There was no evidence of propionyl overload in these patients. The treatment has been well tolerated for up to 26 months and opens new avenues for the management of patients with mitochondrial fat oxidation disorders.

Dietary control of exertional rhabdomyolysis in horses.

OBJECTIVE: To determine whether feeding a low-carbohydrate, high-fat diet would decrease severity of exercise-induced muscle injury in horses with exertional rhabdomyolysis. ANIMALS: 19 horses with a history of exertional rhabdomyolysis. DESIGN: Case series. PROCEDURE: Specimens of the semitendinosus or semimembranosus muscle were obtained for histologic examination, and serum creatine kinase (CK) and aspartate transaminase (AST) activities 4 hours after exercise were determined. Horses were then fed a low-carbohydrate, high-fat diet, and serum CK and AST activities 4 hours after exercise were reevaluated at approximately monthly intervals for 3 to 6 months. RESULTS: Serum CK and AST activities 4 hours after exercise were high before any change in diet. All 19 horses had evidence of chronic myopathic change and abnormal glycogen accumulation in muscle biopsy specimens; 11 horses also had evidence of complex polysaccharide accumulation. Adaptation to diet change required approximately 3 to 6 months. Sixteen horses did not have any episodes of exertional rhabdomyolysis after 3 to 6 months of diet change, and 3 horses had mild episodes of exertional rhabdomyolysis following either a reduction in dietary fat intake or restriction in exercise. Postexercise serum CK and AST activities 3 to 6 months after the change in diet were significantly less than initial values. CLINICAL IMPLICATIONS: Results indicated that exertional rhabdomyolysis may be a result of abnormal carbohydrate metabolism in some horses. Feeding a diet with low carbohydrate and high fat content may reduce severity of exercise-induced injury in some horses with exertional rhabdomyolysis.