Showing papers in "Journal of Inherited Metabolic Disease in 2009"

Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.

Abstract: Published data on treatment of fatty acid oxidation defects are scarce. Treatment recommendations have been developed on the basis of observations in 75 patients with long-chain fatty acid oxidation defects from 18 metabolic centres in Central Europe. Recommendations are based on expert practice and are suggested to be the basis for further multicentre prospective studies and the development of approved treatment guidelines. Considering that disease complications and prognosis differ between different disorders of long-chain fatty acid oxidation and also depend on the severity of the underlying enzyme deficiency, treatment recommendations have to be disease-specific and depend on individual disease severity. Disorders of the mitochondrial trifunctional protein are associated with the most severe clinical picture and require a strict fat-reduced and fat-modified (medium-chain triglyceride-supplemented) diet. Many patients still suffer acute life-threatening events or long-term neuropathic symptoms despite adequate treatment, and newborn screening has not significantly changed the prognosis for these severe phenotypes. Very long-chain acyl-CoA dehydrogenase deficiency recognized in neonatal screening, in contrast, frequently has a less severe disease course and dietary restrictions in many patients may be loosened. On the basis of the collected data, recommendations are given with regard to the fat and carbohydrate content of the diet, the maximal length of fasting periods and the use of l-carnitine in long-chain fatty acid oxidation defects.

Clinical and molecular features of mitochondrial DNA depletion syndromes.

Abstract: Mitochondrial DNA depletion syndromes (MDSs) form a group of autosomal recessive disorders characterized by profoundly decreased mitochondrial DNA copy numbers in affected tissues. Three main clinical presentations are known: myopathic, encephalomyopathic and hepatocerebral. The first is associated with mutations in thymidine kinase 2 (TK2) and p53-induced ribonucleotide reductase B subunit (RRM2B); the second with mutations in succinate synthase A (SUCLA2) and B (SUCLG1); the third with mutations in Twinkle (PEO1), pol-γA (POLG1), deoxyguanosine kinase (DGUOK) and MPV17 (MPV17). In this work, we review the MDS-associated phenotypes and present our own experience of 32 MDS patients, with the aim of defining the mutation frequency of the known genes, the clinical spectrum of the diseases, and the genotype–phenotype correlations. Five of our patients carried previously unreported mutations in one of the eight MDS genes.

The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines

Abstract: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A (α-Gal A), with consequent accumulation of its major glycosphingolipid substrate, globotriaosylceramide (GL-3). Over 500 Fabry mutations have been reported; approximately 60% are missense. The iminosugar 1-deoxygalactonojirimycin (DGJ, migalastat hydrochloride, AT1001) is a pharmacological chaperone that selectively binds α-Gal A, increasing physical stability, lysosomal trafficking, and cellular activity. To identify DGJ-responsive mutant forms of α-Gal A, the effect of DGJ incubation on α-Gal A levels was assessed in cultured lymphoblasts from males with Fabry disease representing 75 different missense mutations, one insertion, and one splice-site mutation. Baseline α-Gal A levels ranged from 0 to 52% of normal. Increases in α-Gal A levels (1.5- to 28-fold) after continuous DGJ incubation for 5 days were seen for 49 different missense mutant forms with varying EC50 values (820 nmol/L to >1 mmol/L). Amino acid substitutions in responsive forms were located throughout both structural domains of the enzyme. Half of the missense mutant forms associated with classic (early-onset) Fabry disease and a majority (90%) associated with later-onset Fabry disease were responsive. In cultured fibroblasts from males with Fabry disease, the responses to DGJ were comparable to those of lymphoblasts with the same mutation. Importantly, elevated GL-3 levels in responsive Fabry fibroblasts were reduced after DGJ incubation, indicating that increased mutant α-Gal A levels can reduce accumulated substrate. These data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations.

Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop.

Abstract: At present, long-chain fatty acid oxidation (FAO) defects are diagnosed in a number of countries by newborn screening using tandem mass spectrometry. In the majority of cases, affected newborns are asymptomatic at time of diagnosis and acute clinical presentations can be avoided by early preventive measures. Because evidence-based studies on management of long-chain FAO defects are lacking, we carried out a retrospective analysis of 75 patients from 18 metabolic centres in Germany, Switzerland, Austria and the Netherlands with special regard to treatment and disease outcome. Dietary treatment is effective in many patients and can prevent acute metabolic derangements and prevent or reverse severe long-term complications such as cardiomyopathy. However, 38% of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency had intermittent muscle weakness and pain despite adhering to therapy. Seventy-six per cent of patients with disorders of the mitochondrial trifunctional protein (TFP)-complex including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, had long-term myopathic symptoms. Of these, 21% had irreversible peripheral neuropathy and 43% had retinopathy. The main principle of treatment was a fat-reduced and fat-modified diet. Fat restriction differed among patients with different enzyme defects and was strictest in disorders of the TFP-complex. Patients with a medium-chain fat-based diet received supplementation of essential long-chain fatty acids. l-Carnitine was supplemented in about half of the patients, but in none of the patients with VLCAD deficiency identified by newborn screening. In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects.

Disorders of biopterin metabolism

Abstract: Defects in the metabolism or regeneration of tetrahydrobiopterin (BH4) were initially discovered in patients with hyperphenylalaninaemia who had progressive neurological deterioration despite optimal metabolic control (malignant hyperphenylalaninaemia). BH4 is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH4 deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH4 synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin-4α-carbinolamine dehydratase. Only the latter of these conditions is relatively benign and is associated with transient hyperphenylalaninaemia. All these conditions can be identified in newborns by an elevated phenylalanine, with the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain. Diagnosis relies on the measurement of pterin metabolites in urine, dihydropteridine reductase in blood spots, neurotransmitters and pterins in the CSF and on the demonstration of reduced enzyme activity (red blood cells or fibroblasts) or causative mutations in the relative genes. The outcome of BH4 deficiency is no longer malignant if therapy is promptly initiated to reduce plasma phenylalanine levels and replace missing neurotransmitters. This is accomplished by a special diet and/or BH4 supplements and administration of l-dopa, carbidopa, 5-hydroxytryptophan, and, in certain cases, a MAO-B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH4 deficiency treated since the newborn period have reached adult age with good outcome.

Pathogenic cascades in lysosomal disease—Why so complex?

Abstract: Lysosomal disease represents a large group of more than 50 clinically recognized conditions resulting from inborn errors of metabolism affecting the organelle known as the lysosome. The lysosome is an integral part of the larger endosomal/lysosomal system, and is closely allied with the ubiquitin–proteosomal and autophagosomal systems, which together comprise essential cell machinery for substrate degradation and recycling, homeostatic control, and signalling. More than two-thirds of lysosomal diseases affect the brain, with neurons appearing particularly vulnerable to lysosomal compromise and showing diverse consequences ranging from specific axonal and dendritic abnormalities to neuron death. While failure of lysosomal function characteristically leads to lysosomal storage, new studies argue that lysosomal diseases may also be appropriately viewed as ‘states of deficiency’ rather than simply overabundance (storage). Interference with signalling events and salvage processing normally controlled by the endosomal/lysosomal system may represent key mechanisms accounting for the inherent complexity of lysosomal disorders. Analysis of lysosomal disease pathogenesis provides a unique window through which to observe the importance of the greater lysosomal system for normal cell health.

Mortality and cause of death in mucopolysaccharidosis type II—a historical review based on data from the Hunter Outcome Survey (HOS)

Abstract: Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

l-2-Hydroxyglutaric aciduria, a disorder of metabolite repair

Abstract: The neurometabolic disorder L: -2-hydroxyglutaric aciduria is caused by mutations in a gene present on chromosome 14q22.1 and encoding L: -2-hydroxyglutarate dehydrogenase. This FAD-linked mitochondrial enzyme catalyses the irreversible conversion of L: -2-hydroxyglutarate to alpha-ketoglutarate. The formation of L: -2-hydroxyglutarate results from a side-activity of mitochondrial L: -malate dehydrogenase, the enzyme that interconverts oxaloacetate and L: -malate, but which also catalyses, very slowly, the NADH-dependent conversion of alpha-ketoglutarate to L: -2-hydroxyglutarate. L: -2-Hydroxyglutarate has no known physiological function in eukaryotes and most prokaryotes. Its accumulation is toxic to the mammalian brain, causing a leukoencephalopathy and increasing the susceptibility to develop tumours. L: -2-Hydroxyglutaric aciduria appears to be the first disease of 'metabolite repair'.

Brain Dysfunction in Phenylketonuria: Is Phenylalanine Toxicity the Only Possible Cause?

Abstract: In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture The result is an almost normal outcome, although some neuropsychological disturbances remain The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation Phenylalanine was found to interfere with different cerebral enzyme systems However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain

Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up

Abstract: Aromatic l-amino acid decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded. To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients’ charts. Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some. AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.

Management of neuronopathic Gaucher disease: revised recommendations.

Abstract: The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease

Organelle dynamics and dysfunction: A closer link between peroxisomes and mitochondria

Abstract: Mitochondria and peroxisomes are ubiquitous subcellular organelles, which fulfil an indispensable role in the cellular metabolism of higher eukaryotes. Moreover, they are highly dynamic and display large plasticity. There is growing evidence now that both organelles exhibit a closer interrelationship than previously appreciated. This connection includes metabolic cooperations and cross-talk, a novel putative mitochondria-to-peroxisome vesicular trafficking pathway, as well as an overlap in key components of their fission machinery. Thus, peroxisomal alterations in metabolism, biogenesis, dynamics and proliferation can potentially influence mitochondrial functions, and vice versa. In this review, we present the latest progress in the emerging field of peroxisomal and mitochondrial interrelationship with a particular emphasis on organelle dynamics and its implication in diseases.

Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men

Abstract: Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS–742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS–742, form the framework for human trials.

Nutritional management of PKU with glycomacropeptide from cheese whey

Abstract: Individuals with phenylketonuria (PKU) must follow a lifelong low-phenylalanine (Phe) diet to prevent neurological impairment Compliance with the low-Phe diet is often poor owing to restriction in natural foods and the requirement for consumption of a Phe-free amino acid formula or medical food Glycomacropeptide (GMP), a natural protein produced during cheese-making, is uniquely suited to a low-Phe diet because when isolated from cheese whey it contains minimal Phe (25-5 mg Phe/g protein) This paper reviews progress in evaluating the safety, acceptability and efficacy of GMP in the nutritional management of PKU A variety of foods and beverages can be made with GMP to improve the taste, variety and convenience of the PKU diet Sensory studies in individuals with PKU demonstrate that GMP foods are acceptable alternatives to amino acid medical foods Studies in the PKU mouse model demonstrate that GMP supplemented with limiting indispensable amino acids provides a nutritionally adequate source of protein and improves the metabolic phenotype by reducing concentrations of Phe in plasma and brain A case report in an adult with classical PKU who followed the GMP diet for 10 weeks at home indicates safety, acceptability of GMP food products, a 13-14% reduction in blood Phe levels (p<005) and improved distribution of dietary protein throughout the day compared with the amino acid diet In summary, food products made with GMP that is supplemented with limiting indispensable amino acids provide a palatable alternative source of protein that may improve dietary compliance and metabolic control of PKU

Metabolic programming: Role of nutrition in the immediate postnatal life

Abstract: Although genes and dietary habits are generally implicated in the aetiology of the prevailing obesity epidemic, the steep increase in the incidence of obesity within a relatively short span of time suggests that other contributing factors may be at play. The role of nutritional experience during the very early periods of life is increasingly being recognized as contributing to growth and metabolic changes in later life. Epidemiological data and studies from animal models have established a strong correlation between an aberrant intrauterine environment and adult-onset disorders in offspring. The nutritional experience in the immediate postnatal life is another independent factor contributing to the development of metabolic diseases in adulthood. Although studies on the small-litter rat model have shown that overnourishment during the suckling period results in adult-onset metabolic disorders, our studies have shown that a change in the quality of calories-specifically, increased carbohydrate intake by newborn rat pups in the immediate postnatal period-results in chronic hyperinsulinaemia and adult-onset obesity. Several functional alterations in islets and in the hypothalamic energy homeostatic mechanism appear to support this phenotype. Remarkably, female rats that underwent the high-carbohydrate dietary modification as neonates spontaneously transmitted the obesity phenotype to their offspring, thus establishing a vicious generational effect. The high-carbohydrate diet-fed rat model has particular relevance in the context of the current human infant feeding practices: reduction in breast feeding and increase in formula feeding for infants, accompanied by early introduction of carbohydrate-enriched baby foods.

Inborn errors of purine and pyrimidine metabolism.

Abstract: Genetic disorders of purine and pyrimidine (PP) metabolism are under-reported and infrequently mentioned in the general literature, as well as in reviews dedicated to other inborn errors of metabolism. Owing to limited awareness, relatively recent recognition, as well as considerable phenotypic variation, these disorders may often be misdiagnosed or remain undiagnosed. Disorders that arise as a result of dysfunction in PP metabolism represent some of the most challenging diagnostic problems in medicine. In addition to their low prevalence rates, they also present with extremely variable signs and symptoms. They may affect any system in a variety of manners, and often mimic other, more recognizable disorders. The diagnostic problem is compounded by the fact that some biochemically affected patients are symptom-free. Rapidly evolving laboratory techniques such as high-performance liquid chromatography coupled to tandem mass spectrometry are now well established as the preferred method for detection for these defects, but currently the most important step in diagnosis consists of suspecting the disorder. Diagnosis is vital because genetic counselling can be provided and, in some cases, specific treatment can be offered that may slow or even reverse clinical symptoms. If undiagnosed, these disorders can be devastating to patients and their families, resulting in early death or institutionalization for the rest of patient’s life. This article describes the current state of knowledge about inborn errors of purine and pyrimidine metabolism, focusing on the varying clinical presentations, the laboratory findings and discusses indications for selective screening for these disorders.

Effect of BH4 supplementation on phenylalanine tolerance

Abstract: Background: Tetrahydrobiopterin (BH4) is a potential new orphan drug for the treatment of some patients with phenylketonuria (PKU), mostly mild forms. Numerous studies have confirmed this finding and BH4-responsiveness may be predicted to some extent from the corresponding genotype.

Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters

Abstract: Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria

Abstract: Background The value of genotyping to identify tetrahydrobiopterin-responsive (BH4-responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate.

Sleep-related breathing in children with mucopolysaccharidosis.

Abstract: Background: The mucopolysaccharidoses (MPSs), a group of genetic lysosomal storage disorders, are associated with significant morbidity. Secondarily to specific associated anatomical abnormalities, MPS is associated with sleep disordered breathing (SDB), specifically obstructive sleep apnoea (OSA) that may confer additional morbidity. Few studies have examined SDB in children with MPS using full polysomnography (PSG) and thus the exact prevalence and severity of SDB is unknown. Further, successful treatments for SDB in this population have not been explored. Objectives: This study evaluated both SDB and the efficacy of treatments offered to children with MPS using PSG data. Patients and methods: A retrospective chart review was conducted on all children with MPS and a history of suspected OSA who were referred to the Hospital for Sick Children, Toronto. Both baseline and follow up treatment PSG data were analysed. PSG data recorded included obstructive apnoea-hypopnoea index (OAHI) and central apnoea index (CAI). Results: Fourteen patients (10 male) underwent a baseline PSG. Three of 14 children on ERT were excluded from the main analyses. The median (range) baseline parameters of the population (n = 11) were recorded. The age was 5.2 years (0.8–17.8) and the body mass index (BMI) was 19.9 (13.7–22.2). The OAHI was 6.6 (0.0–54.8); the CAI was 0.6 (0.0–2.6). Seven of 11 (64%) had evidence for OSA and 3/7 children were classified as having severe OSA (OAHI > 10). Of these, 5/7 children underwent treatment for OSA with 3/5 children showing a significant reduction in their OAHI. Further, the 2 patients on ERT therapy with OSA were also both successfully treated. Conclusions: Children with MPS have a high prevalence of significant OSA and thus should be carefully screened for OSA using full polysomnography and treated accordingly.

Inherited disorders in the conversion of methionine to homocysteine.

Abstract: During the last decade much important new information relating to the metabolic pathway from methionine to homocysteine has been gained. Interest has been stimulated by the discovery of two novel disorders, glycine N-methyltransferase deficiency and S-adenosylhomocysteine hydrolase deficiency. Another disorder in this pathway, methionine adenosyltransferase deficiency, has been increasingly detected, thanks to the expansion of newborn screening programmes by tandem mass spectrometry technology. These significant steps allow important insight into the pathogenesis of these three disorders, as well as into the mechanisms of damage to various organs (liver, brain, muscle) and point to the relevance of these disorders for crucial biological processes such as methylation, transsulfuration or carcinogenesis in mammals, the pathogenesis of numerous pathological conditions, in particular those associated with hyperhomocysteinaemia, the action and possible toxicity of some drugs or consequences of nutritional variations. This review summarizes current knowledge of three inherited disorders in this metabolic pathway and draws attention to their much broader significance for human health and understanding of important biological processes.

Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet

Abstract: Glycogen storage disease type III (GSD III) is caused by a deficiency in debranching enzyme, which leads to an accumulation of abnormal glycogen called limit dextrin in affected tissues. Muscle and liver involvement is present in GSD type IIIa, while the defect is limited to the liver only in GSD type IIIb. Besides skeletal muscle involvement, a cardiomyopathy resembling idiopathic hypertrophic cardiomyopathy is seen. Management consists of maintaining normoglycaemia by supplementation with cornstarch therapy and/or protein. While studies are lacking regarding the best treatment for skeletal muscle disease, a high-protein diet was previously reported to be beneficial. No cases of improvement in cardiomyopathy have been reported. Our patient presented in infancy with hypoglycaemia and hepatomegaly. His prescribed management consisted of cornstarch supplementation and a high-protein diet providing 20% of his total energy needs. At 16 years of age, he developed a severe cardiomyopathy with a left ventricular mass index of 209 g/m2. The cardiomyopathy remained stable on a protein intake of 20–25% of total energy. At age 22 years, the diet was changed to increase his protein intake to 30% of total energy and minimize his cornstarch therapy to only what was required to maintain normoglycaemia. Dramatic improvement in the cardiomyopathy occurred. Over one year, his left ventricular mass index decreased from 159.7 g/m2 to 78 g/m2 (normal 50–86 g/m2) and the creatine kinase levels decreased from 455 U/L to 282 U/L. Avoidance of overtreatment with carbohydrate and a high-protein diet can reverse and may prevent cardiomyopathy.

PKU-What is daily practice in various centres in Europe?

Abstract: Since the start of the European Society of Phenylketonuria and Allied Disorders Treated as Phenylketonuria (ESPKU) in 1987, an increasing number of parental organizations of member countries have joined. Treatment varies widely within Europe. A survey among professionals was done to determine goals and practice. In 2005, a questionnaire was sent to professionals of member countries, addressing diagnostic and treatment procedures, numbers of patients necessary for a PKU centre, guidelines followed, numbers of patients treated and professionals involved in care, target phenylalanine concentrations, amount of protein prescribed, frequency of monitoring and clinical visits, need for follow-up of various clinical and biochemical data, the importance of various abnormalities, and definition of (non)compliance. Seventeen centres of 12 countries answered. Professionals of 13 countries could not be reached or did not respond. Differences in care were observed in many issues of care including target phenylalanine concentrations. Only few issues had general consensus. Not all countries were really active at ESPKU level. In the active countries, a professional could not always be contacted. Responses show that PKU care varies largely between European countries. Notwithstanding the large diversity on many issues of day-to-day care and therapeutic targets, results showed increasing consensus on some issues. The most important outcome of this questionnaire might be that the Scientific Advisory Committee of the ESPKU initiated meetings for professionals of different backgrounds taking care of PKU patients besides the already existing programme for parents, patients and delegates. Discussion among these professionals may improve quality of care.

Hydroxocobalamin dose escalation improves metabolic control in cblC

Abstract: Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 μmol/L; normal range <0.27 μmol/L), a 55% reduction of tHcy (112 to 50 μmol/L; normal range: 0–13 μmol/L) and a greater than twofold increase in methionine (17 to 36 μmol/L; normal range: 7–47 μmol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.

Mental retardation and inborn errors of metabolism.

Abstract: In countries where clinical phenylketonuria is detected by newborn screening inborn errors of metabolism are rare causes of isolated mental retardation. There is no international agreement about what type of metabolic tests must be applied in patients with unspecific mental retardation. However, and although infrequent, there are a number of inborn errors of metabolism that can present in this way. Because of the high recurrence risk and the possibility of specific therapies, guidelines need to be developed and adapted to different populations. The application of a universal protocol may result in a low diagnostic performance in individual ethnic populations. Consideration of associated signs (extraneurological manifestations, psychiatric signs, autistic traits, cerebellar dysfunction, epilepsy or dysmorphic traits) greatly improves the diagnostic fulfilment.

Pathophysiology of fatty acid oxidation disorders

Abstract: Mitochondrial fatty acid oxidation represents an important pathway for energy generation during periods of increased energy demand such as fasting, febrile illness and muscular exertion. In liver, the primary end products of the pathway are ketone bodies, which are released into the circulation and provide energy to tissues that are not able to oxidize fatty acids such as brain. Other tissues, such as cardiac and skeletal muscle are capable of direct utilization of the fatty acids as sources of energy. This article provides an overview of the pathogenesis of fatty acid oxidation disorders. It describes the different tissue involvement with the disease processes and correlates disease phenotype with the nature of the genetic defect for the known disorders of the pathway.

Epilepsy and inborn errors of metabolism in children

Abstract: Epilepsy is a frequent symptom in inborn errors of metabolism, with virtually no specific seizure types or EEG signatures. It is most important to look quickly for those few inborn errors of metabolism in which specific therapies such as supplementation of cofactors or diets can make all the difference. If these investigations remain negative, epilepsy has to be treated with conventional antiepileptic drugs. Still, epilepsy is a potentially treatable symptom of many inborn errors of metabolism, and optimal treatment is of great importance for patients and their families.

Adult presentations of medium-chain acyl-CoA dehydrogenase deficiency (MCADD).

Abstract: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of mitochondrial fatty acid oxidation which is usually diagnosed in infancy or through neonatal screening. In the absence of population screening, adults with undiagnosed MCADD can be expected. This review discusses 14 cases that were identified during adulthood. The mortality of infantile patients is approximately 25% whereas in this adult case series it was shown it to be 50% in acutely presenting patients and 29% in total. Therefore, undiagnosed individuals are at risk of sudden fatal metabolic decompensation with high mortality. This review illustrates the need to consider the possibility of a fatty acid oxidation defect in an adult who presents with unexplained sudden clinical deterioration, particularly if precipitated by fasting or alcohol consumption. A history of unexplained sibling death may also raise the index of suspicion. There also needs to be appropriate clinical support for those patients identified clinically or as a result of family studies (sibling or parent).

Inborn errors of metabolism and motor disturbances in children.

Abstract: Motor disturbances are very common in paediatric neurology. Often families can be reassured that these are just variants of normal development. However, abnormal movements can also be the hallmark of severe brain dysfunction of different and complex origins. This review concentrates on motor disturbances as frequent and important symptoms of inborn errors of metabolism. A structured diagnostic approach is developed taking into account age-dependent physiological developments and pathophysiological responses of gross and fine motor functions. A series of investigations are presented with the primary aim of early diagnosis of treatable conditions. The correct recognition and differentiation of movement disorders (ataxia, rigid akinetic syndrome (‘parkinsonism’), dystonia, athetosis, tremor, and others), spasticity, and neuromuscular disorders, requires profound neurological expertise. A high level of suspicion and close interaction between paediatric neurologists and specialists in inborn errors of metabolism are indispensable to effectively and timely identify patients in whom motor disturbances are the presenting and/or main symptom of an inborn error.

Large neutral amino acids supplementation in phenylketonuric patients

Abstract: Phenylketonuria is an inborn error of amino acid metabolism that results in severe mental retardation if not treated early and appropriately. The traditional treatment, consisting of a low-phenylalanine diet, is usually difficult to maintain throughout adolescence and adulthood, resulting in undesirable levels of blood phenylalanine and consequent neurotoxicity. The neurotoxicity of phenylalanine is enhanced by its transport mechanism across the blood-brain barrier, which has the highest affinity for phenylalanine compared with the other large neutral amino acids that share the same carrier. The supplementation of large neutral amino acids in phenylketonuric patients has been showing interesting results. Plasma phenylalanine levels can be reduced, which may guarantee important metabolic and clinical benefits to these patients. Although long-term studies are needed to determine the efficacy and safety of large neutral amino acids supplements, the present state of knowledge seems to recommend their prescription to all phenylketonuric adult patients who are non-compliant with the low-phenylalanine diet.