Lipidic myopathy with severe cardiomyopathy caused by a generalized carnitine deficiency. Favourable course during carnitine hydrochloride treatment]

The case of a girl who presented with gastrointestinal upsets with nausea, vomiting and occasional hypoglycaemic attacks during childhood is reported. At about 5 years of age generalised muscular weakness with severe amyotrophy, cardiomegaly with a cardiothoracic ratio of 0,63, left ventricular hypertrophy on electrocardiography and left ventricular dilatation with hypokinesis on echocardiography were observed. A few weeks later she developed severe cardiac failure. Muscle biopsy showed muscular dystrophy with lipid infiltration due to carnitine deficiency )serum carnitine 9 nmoles/ml, normal values: 46 +/- 6,9 nmoles/ml; muscle carnitine 0,27 nmoles/mg, normal values: 3,0 +/- 0,79 nmoles/mg fresh frozen weight). She improved rapidly with carnitine chlorhydrate and a diet low in lipids and high in medium chain triglycerides. Regression of muscular symptoms and cardiac failure was observed. After 13 months follow-up with no tonicardiac therapy she is much improved; the signs of heart failure have disappeared, the cardiothoracic ratio is now 0,55 and the electrocardiogramme and echocardiogramme are normal.     

Heterozygotes for plasmalemmal carnitine transporter defect are at increased risk for valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts

Summary One of the mechanisms by which chronic valproic acid (VPA) therapy induces serum and tissue depletion of carnitine in normal controls is through inhibition of plasmalemmal carnitine uptake (Tein et al 1993). To determine the effect of VPA on proven heterozygotes for the plasmalemmal carnitine transporter defect, we studied this system in cultured human skin fibroblasts with reducedV _max for the carnitine transporter usingL-[³H]carnitine. There was en exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations and the relative inhibitory effect was the same for all three carnitine concentrations for a given cell line. Importantly, the lower the maximal velocity of carnitine uptake of the heterozygote, the lower the number of carnitine transporters and the lower the carnitine uptake per given concentration of VPA. The degree of inhibition was also directly proportional to the time of VPA preincubation up to a specific maximal saturation time. The maximal effect of VPA exposure time was reached by 10 days in the control cell line and by 3 days in the two heterozygote lines, probably reflecting earlier saturation. We conclude that patients who are heterozygous for the plasmalemmal carnitine transporter defect are at increased risk for VPA-associated serum and tissue depletion of carnitine through inhibition of plasmalemmal carnitine uptake.     

Medium-chain acyl-CoA dehydrogenase deficiency: Metabolic effects and therapeutic efficacy of long-terml-carnitine supplementation

Summary Medium-chain acyl-CoA dehydrogenase deficiency is a recently described inborn error of metabolism characterized by episodes of coma and hypoketotic hypoglycaemia in response to prolonged fasting. Secondary carnitine deficiency has been documented in these patients as well as the excretion in the urine of medium-chain-length acyl carnitine esters, such as octanoylcarnitine. Based on the potential toxicity of medium-chain fatty acid metabolites and the beneficial responses of patients with other inborn errors of metabolism and secondary carnitine deficiency, oral carnitine has been proposed as treatment for children with medium-chain acyl-CoA dehydrogenase deficiency. We report the results of carefully monitored fasting challenges of an infant with this deficiency both before and after 3 months of oral carnitine therapy. Carnitine supplementation failed to prevent lethargy, vomiting, hypoglycaemia and accumulation of free fatty acids in response to fasting despite normalization of plasma carnitine levels and a marked increase in urinary excretion of acyl-carnitine esters. Potentially toxic medium-chain fatty acids accumulated in the plasma in spite of therapy. Based on this study of one patient, we stress that avoidance of fasting and prompt institution of glucose supplementation in situations when oral intake is interrupted remain the mainstays of therapy for medium-chain acyl-CoA dehydrogenase deficient patients.     

Successful treatment of severe heart failure in an infant with Hurler syndrome

Summary Hurler syndrome (MPS IH) is the most severe form of mucopolysaccharidosis type I. It is caused by deficiency or absence of the enzyme α-l-iduronidase. Cardiac involvement includes cardiomyopathy and valve and coronary pathology. Cardiomyopathy causing symptoms in an infant with MPS IH carries a very poor prognosis. We describe a previously healthy 10-week-old boy who was admitted to hospital critically ill with severe heart failure. Echocardiography on admission showed severe dilatation of the left ventricle and moderate insufficiency of the left-sided cardiac valves. Accumulation of heparan sulfate and dermatan sulfate substrates in the urine and leukocyte analysis confirmed the diagnosis of MPS IH. Enzyme replacement therapy (ERT) with intravenous laronidase at a standard dosage of 100 U/kg weekly was started soon after. This improved the child’s general clinical wellbeing dramatically. His cardiac function improved steadily over a period of months. Stem cell transplantation from cord blood is not available in Norway and he underwent successful transplantation from an unrelated bone marrow donor at the age of 11 months. ERT was stopped four months later. At the age of 26 months his heart function is close to normal and he is currently on no medication. This report highlights three important clinical issues: (1) MPS IH must be considered in infants with cardiomyopathy; (2) early ERT may have a significant impact on short-term outcome in children less than 18 months old with severe cardiomyopathy; (3) our report confirms that patients in poor condition benefit from ERT before stem cell transplantation. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Online citation: JIMD Short Report #080 (2007) Online     

Prospective treatment in carnitine–acylcarnitine translocase deficiency

Summary  Carnitine–acylcarnitine translocase (CACT) deficiency is a rare disorder that results in long-chain fatty acids being unavailable for mitochondrial β-oxidation and ketogenesis. It can present in the neonatal period or infancy with a severe clinical form, typically with convulsions, hypothermia, encephalopathy, cardiomyopathy and liver dysfunction, or with a milder phenotype with episodes of hypoglycaemia and hyperammonaemia during intercurrent illness. Investigations show hypoketonaemia, intermittent dicarboxyluria and hypocarnitinaemia with grossly elevated acylcarnitines. Enzyme assay or DNA analysis confirms the diagnosis. The severe phenotype results in severe disability or death. The less severe phenotype can also cause significant disability secondary to hypoglycaemia and/or hyperammonaemia at presentation. We report the outcome of two siblings with CACT deficiency. The index patient presented at the age of 2 months during a respiratory illness with hypoglycaemia, hyperammonaemia and cardiorespiratory collapse. Acylcarnitine profiles showed decreased free carnitine but striking elevations of long-chain acylcarnitines. Urine organic acids showed dicarboxylic aciduria. Fatty acid oxidation studies showed reduced oleate and myristate oxidation. His acylcarnitine profile normalized after he was started on a medium-chain triglyceride (MCT) low-fat diet and carnitine supplementation. Low CACT activity on enzyme assay confirmed the diagnosis. He has resulting profound developmental delay and epilepsy. The sibling was prospectively treated with a low-fat MCT diet and carnitine supplementation. Acylcarnitine profile at birth also showed elevated long-chain acylcarnitines. Fatty acid oxidation studies confirmed the diagnosis. To date he has normal development and has not had any significant periods of hypoglycaemia or hyperammonaemia. Electronic Supplementary Material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Online citation: JIMD Short Report #053 (2007) Online Competing interests: None declared     

Sympathetic responsiveness and plasma norepinephrine during therapy of chronic congestive heart failure with captopril

The interaction of cardiac function and sympathetic tone in severe chronic heart failure was evaluated in 24 patients by assessing the cardiac index/plasma norepinephrine relationship. Potential changes were assessed during first-dose and long-term captopril therapy including sympathetic responsiveness to the gravitational stress of head-up tilt. Baseline cardiac index and norepinephrine levels demonstrated a significant inverse correlation (r = ?0.640, p < 0.001). Norepinephrine decreased from 803 ± 116 to 635 ± 76 pg/ml following first-dose captopril therapy (p < 0.02), with overall hemodynamic improvement. However significant first-dose correlations were not observed. During long-term therapy, norepinephrine decreased from 694 ± 118 to 457 ± 106 pg/ml, associated with improvement of symptoms and exercise tolerance. The extent of cardiac index increase was matched by norepinephrine reduction, so that their correlation was maintained (r = ?0.540, p < 0.02). First-dose and long-term therapy were associated with improved responsiveness of sympathetic tone to the reduction of cardiac index induced by the gravitational stress of tilt. In summary, sympathetic tone was increased in severe heart failure, correlating inversely with cardiac function. Although there was improvement of cardiac function with first-dose captopril therapy, significant correlations of supine improvement with reduction of sympathetic tone were noted primarily with long-term therapy. Responsiveness of sympathetic tone to the stress of tilt however, was evident during first-dose and long-term therapy.     

Rapid reversal of dilated cardiomyopathy following removal of neuroblastoma.

Reported is a child with dilated cardiomyopathy, in whom medical therapy resulted in a mild improvement of cardiac function. Metabolic studies suggested the presence of a catecholamine-secreting tumour; and an adrenal neuroblastoma was identified and surgically removed. Following surgery, there was progressive and complete normalization of cardiac function. Although very rare, neurogenic tumours may be involved in the development of a dilated cardiomyopathy in the infant and child.     

Prospective treatment in carnitine-acylcarnitine translocase deficiency

Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder that results in long-chain fatty acids being unavailable for mitochondrial beta-oxidation and ketogenesis. It can present in the neonatal period or infancy with a severe clinical form, typically with convulsions, hypothermia, encephalopathy, cardiomyopathy and liver dysfunction, or with a milder phenotype with episodes of hypoglycaemia and hyperammonaemia during intercurrent illness. Investigations show hypoketonaemia, intermittent dicarboxyluria and hypocarnitinaemia with grossly elevated acylcarnitines. Enzyme assay or DNA analysis confirms the diagnosis. The severe phenotype results in severe disability or death. The less severe phenotype can also cause significant disability secondary to hypoglycaemia and/or hyperammonaemia at presentation. We report the outcome of two siblings with CACT deficiency. The index patient presented at the age of 2 months during a respiratory illness with hypoglycaemia, hyperammonaemia and cardiorespiratory collapse. Acylcarnitine profiles showed decreased free carnitine but striking elevations of long-chain acylcarnitines. Urine organic acids showed dicarboxylic aciduria. Fatty acid oxidation studies showed reduced oleate and myristate oxidation. His acylcarnitine profile normalized after he was started on a medium-chain triglyceride (MCT) low-fat diet and carnitine supplementation. Low CACT activity on enzyme assay confirmed the diagnosis. He has resulting profound developmental delay and epilepsy. The sibling was prospectively treated with a low-fat MCT diet and carnitine supplementation. Acylcarnitine profile at birth also showed elevated long-chain acylcarnitines. Fatty acid oxidation studies confirmed the diagnosis. To date he has normal development and has not had any significant periods of hypoglycaemia or hyperammonaemia.     

Pilot studies on the use of 3,5-diiodothyropropionic acid,a thyroid hormone analog,in the treatment of congestive heart failure

After an initial safety study in 7 normal volunteers, a randomized double-blind comparison was made between 3,5-diiodothyropropionic acid (DITPA) and placebo in 19 patients with moderately severe congestive failure. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Systolic cardiac function was unchanged but isovolumetric relaxation time was decreased significantly, suggesting improvement in diastolic function. Total serum cholesterol (p = 0.005) and triglycerides (p = 0.01) also were decreased significantly. DITPA could represent a useful new agent for treatment of congestive heart failure.     

Efficacy of the Acorn Cardiac Support Device in Animals with Heart Failure Secondary to High Rate Pacing

Aim: To utilise an ovine model of tachycardia induced progressive dilated cardiomyopathy and heart failure to investigate the efficacy of passive ventricular constraint with the Acorn cardiac support device as a heart failure treatment. Methods: (a) Moderate heart failure was produced in 16 sheep by pacing for 3 weeks. Half were implanted and half sham implanted with the CSD. Pacing continued at a higher rate for an additional 3 weeks. Cardiac function was assessed by echocardiography and manometry. (b) Moderate heart failure was produced (as above) in 27 sheep, 9 were implanted with CSD, pacing was restarted for 4 weeks, the initial CSD implants were terminated and another 9 animals were CSD implanted (severe heart failure), pacing was restarted in the remaining 18 animals for an additional 4 weeks (total 12 weeks) and then all animals were terminated. Cardiac function was assessed using echocardiography and treadmill exercise testing. Results: (a) After 6 weeks of rapid pacing CSD implant animals had significantly better cardiac function both when compared with pre implant values and with non-implanted animals at termination. (b) CSD implantation at both moderate and severe failure resulted in significant improvements in cardiac function both when compared with pre implant values and with non-implanted animals at termination. When compared to pre implant values the improvement was greatest in severe implant animals. Conclusion: In this ovine model of tachycardia induced progressive heart failure, CSD implantation in either moderate or severe heart failure resulted in improved cardiac function, reduced left ventricular volume and mitral regurgitation both when compared with function at time of implant and with non implanted control animals.     

High incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation

Cardiac scintigraphy has been performed in 60 beta-thalassaemia major patients aged 8-35 years who received regular blood transfusions and subcutaneous desferrioxamine (DFX) chelation. Fifty-seven showed no clinical, radiological or electrocardiographic evidence of heart disease and 3 had clinically apparent cardiac failure. Twenty-two patients (37%) showed severe cardiac functional impairment defined by a resting left ventricular ejection fraction (LVEF) less than 45% and/or a drop of greater than 12% on stress, while 19 were normal and 19 had a mild abnormality. There was no significant correlation between abnormality of LVEF and age, serum ferritin, number of units transfused, dose and duration of subcutaneous DFX therapy, liver disease or sexual maturation. Non-compliant patients (defined as the use of subcutaneous DFX less than 4 times weekly) generally showed worse cardiac function. Repeat study on 17 patients after 6-28 months of better compliance with subcutaneous or intravenous DFX (using an indwelling catheter) showed a significant overall improvement in LVEF associated with a significant drop in serum ferritin. We conclude that cardiac scintigraphy uncovers a high incidence of cardiac functional abnormality in asymptomatic, well-transfused thalassaemia patients, particularly those poorly compliant with chelation. Those with poor LVEF results should be offered intensive chelation therapy to improve cardiac function.     

NORMAL GROWTH AND PUBERTAL DEVELOPMENT DURING BROMOCRIPTINE TREATMENT FOR A PROLACTIN-SECRETING PITUITARY MACROADENOMA

An 11-year-old male presented with a 2-year history of headache and lethargy. Serum PRL was elevated at 14,000 mU/l and computerized tomography showed a pituitary macroadenoma. Visual fields and fundi were normal and the testes showed early pubertal changes. There was normal responsiveness of serum cortisol but absence of GH response to hypoglycaemia. After bromocriptine therapy for 4 months serum PRL had fallen to 90 mU/l and the tumour was not visible on repeat computerized tomography. After 7 months treatment, repeat pituitary function testing showed restoration of GH response to hypoglycaemia. Treatment with bromocriptine was continued and there was spontaneous progression of normal puberty; the serum testosterone continued to rise, and height maintained the 50th centile. Bromocriptine therapy should be considered as initial therapy in the management of prolactinomas in prepubertal patients.     

Precipitation of heart failure following sudden withdrawal of hydralazine.

Sudden withdrawal of oral therapy with hydralazine for reduction of afterload in a patient precipitated severe congestive heart failure. Signs of metabolic encephalopathy evolved due to low cardiac output. Reinstitution of therapy with hydralazine resulted in prompt improvement in cardiac and neurologic status. This case underscores the need for careful follow-up of such patients and argues against sudden withdrawal of vasodilator therapy.     

Familial cardiomyopathy caused by carnitine deficiency

The authors report a familial case of carnitine insufficiency presenting in two out of seven children as a severe, isolated, hypertrophic and hypokinetic cardiomyopathy. The etiology was confirmed by histological study and measurement of carnitine concentrations in the blood and muscle. The evolution was spectacular with specific therapy. Left ventricular hypokinesia regressed completely within 18 months (fractional fibre shortening increased from 10 to 33% and the SCI from 26 to 55% in the more severe of the two cases). Hypertrophy and dilatation decreased significantly. This is a so-called intermediary form of carnitine insufficiency and very unusual because of the isolated cardiac involvement. These cases underline the value of systematic muscle biopsy with measurement of carnitine concentrations in the investigation of all cases of supposed primary cardiomyopathy, especially as a rapid improvement can be obtained by specific replacement therapy.     

The importance of recognizing secondary carnitine deficiency in organic acidaemias: Case report in glutaric acidaemia type II

Summary Secondary carnitine deficiency in a patient with glutaric acidaemia type II, due to deficient ETF-dehydrogenase activity, is described. The patient responded clinically to a pharmacological dose of riboflavin and a restricted protein diet. In the second year of her life she developed more frequent and severe exacerbations during intercurrent infections from which she did not fully recover. Hypotonia and marked ataxia persisted. Plasma carnitine was entirely complexed as acylcarnitine with no free carnitine detected. Retrospective evaluation of several frozen urine specimens obtained since the age of 10 months revealed undetectable free carnitine with elevated acylcarnitine levels. Marked clinical improvement was observed followingL-carnitine supplementation. The hypotonia and ataxia disappeared. The frequency and the severity of the exacerbations were noticeably decreased. The role ofL-carnitine in preventing the accumulation of acyl-CoA compounds in inborn errors of organic acid metabolism is further emphasized by this patient. The necessity to evaluate free carnitine, acylcarnitine and acyl/free ratio in the assessment, follow-up and management of patients with inborn errors of organic acid metabolism is discussed.     

Long-term recovery from unawareness,deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia,following institution of rational,intensive insulin therapy in IDDM

Summary Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on conventional insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n=16), or maintenance of the original conventional therapy (control group, CON, n=5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5±0.05 to 0.045±0.02 episodes/patient-day; HbA_1C increased from 5.83±0.18 to 6.94±0.13% (range in non-diabetic subjects 3.8–5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p<0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.Abbreviations IDDM Insulin-dependent diabetes mellitus - IIT intensive insulin therapy - HU hypoglycaemia unawareness - EXP experimental patient group - CON control group     

Management of mucopolysaccharidosis type IH (Hurler’s syndrome) presenting in infancy with severe dilated cardiomyopathy: a single institution’s experience

Mucopolysaccharidosis type IH (MPSIH) is a lysosomal storage disorder whose untreated course involves progressive multisystem deterioration and death within the first decade of life. Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment modality that improves functional outcome and long-term survival. Optimal outcome requires transplantation early in life and with myeloablative conditioning. Severe cardiomyopathy can be present at diagnosis and may seemingly preclude this approach. We performed a retrospective review of those cases transplanted in Manchester since 2000 that initially presented with established cardiomyopathy, with a view to identifying general management principles. Of 44 MPSIH children transplanted in this period, 6 had displayed moderate or severe cardiomyopathy at presentation; symptomatic cardiac failure was the predominant presenting feature in five of these. Echocardiographic and clinical improvement in cardiac function was observed with extended enzyme replacement therapy (ERT) in all cases, with recovery of fractional shortening to ≥25 % achieved in all patients before coming to transplant (after median 19 weeks ERT). All were transplanted successfully, with good functional and cardiologic outcomes. However, cyclophosphamide conditioning was implicated in acute post-transplant cardiac decompensation in several cases. Our experiences highlight three important messages: (1) A diagnosis of MPSIH should be considered in any infant presenting with unexplained severe cardiac failure; (2) ERT pre-transplant can improve cardiac function sufficiently to permit safe HSCT using myeloablative conditioning; and (3) High dose cyclophosphamide should be avoided in conditioning these patients.     

The role of L-carnitine in the pathogenesis of cardiomegaly in patients with chronic hemodialysis

Many reports have suggested that cardiac dysfunction with cardiomegaly is more often observed in patients with chronic hemodialysis. Moreover, cardiac dysfunction has been thought as one of the most important factors affecting the prognosis of these patients. In this study, in order to clarify the role of l-carnitine in the pathogenesis of cardiomegaly, 33 patients with chronic hemodialysis were studied using the multivariate analysis method. Among the factors which may affect cardiac function, the following 10 variables were examined. 1) age, 2) duration of dialysis, 3) plasma carnitine, 4) serum total cholesterol, 5) serum HDL-cholesterol, 6) triglyceride, 7) systolic blood pressure, 8) diastolic blood pressure, 9) left ventricular voltage on a electrocardiogram at rest and 10) hematocrit. The plasma carnitine levels in these patients were markedly reduced and inversely correlated with the cardiothoracic ratio (CTR) on the chest X-ray films (r = 0.38, p less than 0.05). In principal component analysis, the CTR was closely related to hematocrit and plasma carnitine levels. By multiregression analysis, both hypo-carnitinemia and anemia were independently shown to be important causes of cardiomegaly. Thus, it is suggested that the cardiomegaly in patients with chronic hemodialysis may be improved by supplemental therapy with l-carnitine, even in cases with severe anemia.