BackgroundThe cblC defect is a rare inborn error of intracellular cobalamin metabolism. Biochemical hallmarks are elevated homocysteine and low methionine in plasma accompanied by methylmalonic aciduria. Due to the heterogeneous clinical picture, patients with the late-onset form of the disease (onset >12 months) come to the attention of diverse medical specialists, e.g. paediatricians, neurologists, nephrologists, psychiatrists or haematologists. The report reviews the published clinical data and adds three new cases to raise awareness for this severe but often treatable disease.MethodsThe Pubmed and the Cochrane databases were searched for clinical reports on cblC patients and three unreported cases are presented to illustrate the clinical spectrum.ResultsReports on 58 cases (30 females, 22 males, 6¿=¿no information) and the three new cases underlined the clinical heterogeneity of the disease. Time between first symptoms and diagnosis ranged from three months to more than 20 years. Haemolytic uraemic syndrome and pulmonary hypertension were main presenting symptoms in preschool children. In older children / adolescents, psychiatric symptoms, cognitive impairment, ataxia and myelopathy were frequently observed while thromboembolic events and glomerulopathies were almost exclusively seen in adults. Brain atrophy, white matter lesions and myelopathy were frequently encountered. The majority of patients showed marked biochemical and clinical response to treatment with parenteral hydroxocobalamin combined with oral betaine, folate, carnitine and rarely methionine. The course was less favourable in late treated or untreated patients.ConclusionsThe late-onset cblC defect is a rare disease and unfortunately, diagnosis is often delayed. Raising awareness for this disorder can significantly improve patients¿ outcome and perspective by timely initiation of targeted treatment. Newborn screening (NBS) for the cblC defect might be of benefit especially for late-onset patients since treatment seems efficient when initiated before irreversible organ damage. In general, inborn errors of metabolisms should be considered in unexplained medical cases at any age, especially in patients with multisystemic disease. More specifically, total homocysteine in plasma and methylmalonic acid in urine / plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.
Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of?~?1: 50,000 and PA of?~?1:100'000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity.
This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient.
Both glycogen storage disease type Ia (GSD Ia) and tyrosinemia type I (TYR I) are inherited metabolic disorders that can be complicated by formation of liver adenomas in juvenile/young adult age and/or development of hepatocellular carcinoma. We describe the first application of stereotactic radiofrequency ablation (SRFA) in focal lesions in three patients with inherited metabolic disorders affecting the liver.
Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ? 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.
Early sudden unexpected death in infancy (ESUDI) is a rare cause of death occurring in newborns during the first hours of life. Our aim was to find additional data for the identification of risk factors and establishment of prevention strategies.
This is the first investigation of MMPs in children with febrile seizures. In a prospective, cross sectional study, serum levels of matrix metalloproteinases (MMP8/9), tissue inhibitor of metalloproteinases (TIMP1/2), of children with FS (n=13), children with febrile infection (FI, n=13) and children with unprovoked generalized seizures (US, n=11) were compared. Neither provoked nor unprovoked seizures in FS and US seem to elevate levels of MMPs or TIMPs, whereas in case of febrile infection blood level of MMP8 was significant elevated. Seizures in general might have no influence on this distinctive inflammatory process or even might have suppressive impact.
Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited.
Propionic acidaemia (PA) is an inborn error of intermediary metabolism caused by deficiency of propionyl-CoA carboxylase. The metabolic block leads to a profound failure of central metabolic pathways, including the urea and the citric acid cycles. This review will focus on changes in amino acid metabolism in this inborn disorder of metabolism. The first noted disturbance of amino acid metabolism was hyperglycinaemia, which is detectable in nearly all PA patients. Additionally, hyperlysinaemia is a common observation. In contrast, concentrations of branched chain amino acids, especially of isoleucine, are frequently reported as decreased. These non-proportional changes of branched-chain amino acids (BCAAs) compared with aromatic amino acids are also reflected by the Fischers ratio (concentration ratio of BCAAs to aromatic amino acids), which is decreased in PA patients. As restricted dietary intake of valine and isoleucine as precursors of propionyl-CoA is part of the standard treatment in PA, decreased plasma concentrations of BCAAs may be a side effect of treatment. The concentration changes of the nitrogen scavenger glutamine have to be interpreted in the light of ammonia levels. In contrast to other hyperammonaemic syndromes, in PA plasma glutamine concentrations do not increase in hyperammonaemia, whereas CSF glutamine concentrations are elevated. Despite lactic acidaemia in PA patients, hyperalaninaemia is only rarely reported. The mechanisms underlying the observed changes in amino acid metabolism have not yet been elucidated, but most of the changes can be at least partly interpreted as consequence of disturbance of anaplerosis.
The objective of this study was to investigate which attentional components are of predictive utility in differentiating children with attention-deficit-hyperactivity disorder, combined type (ADHD-C) from their peers without ADHD.
The mitochondrial phospholipid cardiolipin plays an important role in cellular metabolism as exemplified by its involvement in mitochondrial energy production and apoptosis. Following its biosynthesis, cardiolipin is actively remodeled to achieve its final acyl composition. An important cardiolipin remodeling enzyme is tafazzin, of which several mRNA splice variants exist. Mutations in the tafazzin gene cause the X-linked recessive disorder Barth syndrome. In addition to providing an overview of the current knowledge in literature about tafazzin, we present novel experimental data and use this to discuss the functional role of the different tafazzin variants in cardiolipin metabolism in relation to Barth syndrome. We developed and performed specific quantitative PCR analyses of different tafazzin mRNA splice variants in 16 human tissues and correlated this with the tissue cardiolipin profile. In BTHS fibroblasts we showed that mutations in the tafazzin gene affected both the level and distribution of tafazzin mRNA variants. Transient expression of selected human tafazzin variants in BTHS fibroblasts showed for the first time in a human cell system that tafazzin lacking exon5 indeed functions in cardiolipin remodeling.
The objective of the study is to analyze plasma amino acid concentrations in propionic acidemia (PA) for the purpose of elucidating possible correlations between propionyl-CoA carboxylase deficiency and distinct amino acid behavior. Plasma concentrations of 19 amino acids were measured in 240 random samples from 11 patients (6 families) with enzymatically and/or genetically proven propionic acidemia (sampling period, January 2001-December 2007). They were compared with reference values from the literature and correlated with age using the Pearson correlation coefficient test. Decreased plasma concentrations were observed for glutamine, histidine, threonine, valine, isoleucine, leucine, phenylalanine and arginine. Levels of glycine, alanine and aspartate were elevated, while values of serine, asparagine, ornithine and glutamate were normal. For lysine, proline and methionine a clear association was not possible. Significant correlations with age were observed for 13 amino acids (positive correlation: asparagine, glutamine, proline, alanine, histidine, threonine, methionine, arginine; negative correlation: leucine, phenylalanine, ornithine, glutamate and aspartate). This study gives new insight over long-term changes in plasma amino acid concentrations and may provide options for future therapies (e.g., substitution of anaplerotic substances) in PA patients.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is an autosomal recessive mitochondriopathy caused by loss-of-function mutations in the thymidine phosphorylase gene. The disease leads to premature death and is characterized by gastrointestinal dysmotility and cachexia, external ophthalmoplegia, a sensorimotor neuropathy, and leukoencephalopathy. Bone marrow transplantation (BMT) is the only potentially curative treatment that can achieve a sustained biochemical correction of the metabolic imbalances.We report a 23-year-old male homozygous for the c.866A > C, p.Glu289Ala mutation of the TYMP gene, who presented with fatty liver and cachexia. Laboratory examinations were unremarkable except for increased transaminase activities. Grade II fibrosis and steatosis was found in an initial and a follow-up liver biopsy 4 years later. Myeloablative conditioning and BMT was performed 10 years after initial presentation due to the progressive weight loss and polyneuropathy. Pre-transplant liver staging was normal except for an elevated transient elastography of 31.6 kPa. Severe ascites developed after transplantation and liver function deteriorated progressively to liver failure. Despite engraftment on day +15, the patient died on day +18 from liver failure. Autopsy revealed micronodular liver cirrhosis, and postmortem diagnosis of acute-on-chronic liver failure was done.This case illustrates the difficulties and importance of diagnosing liver cirrhosis in MNGIE. Before BMT, patients must be carefully evaluated by transient elastography, liver biopsy, or assessment of hepatic venous pressure gradient. In patients with liver cirrhosis, further studies should evaluate if liver transplantation may be an alternative to BMT. Considerable amounts of thymidine phosphorylase are expressed in liver tissue which may prevent accumulation of toxic metabolites.
Herein, we describe a case of a now 28-month-old boy who presented at the age of 17 months with four episodes of recurrent vomiting and somnolence during a period of four months with increasing severity. A comprehensive clinical and metabolic evaluation revealed normal blood pH and blood glucose, normal cerebral computed tomography and electroencephalogram but an elevated plasma ammonia concentration, which raised the suspicion of a urea cycle disorder. The combination of elevated urinary orotic acid and plasma glutamine with normal citrulline suggested the diagnosis of ornithine transcarbamylase (OTC) deficiency, which was confirmed by molecular genetic testing revealing the novel hemizygous mutation c.535C > T (p.Leu179Phe) of the OTC gene. After restitution of anabolism by administration of parenteral glucose, substitution of citrulline and detoxification of ammonia with sodium benzoate, the patient recovered rapidly and is in a stable metabolic and neurological state since then. This case underlines that the diagnosis of a urea cycle defect should be considered in the differential diagnosis of recurrent idiopathic vomiting in combination with unexplained neurological symptoms also beyond the neonatal period due to the possibility of mild or atypical late-onset presentation (e.g. OTC deficiency in hemizygous males).
Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.
Progressive myoclonic epilepsy (PME) is a heterogeneous group of epilepsies characterized by myoclonus, seizures and progressive neurological symptoms. The index patient was a 6-year old boy showing early-onset therapy resistant PME and severe developmental delay. Genome-wide linkage analysis identified several candidate regions. The potassium channel tetramerization domain containing 7 gene (KCTD7) in the 7q11.21 linkage region emerged as a suitable candidate. Sequence analysis revealed a novel homozygous missense mutation (p.R94W) in a highly conserved segment of exon 2. This is the second family with PME caused by KCTD7 mutations, hence KCTD7 mutations might be a recurrent cause of PME.
Phenylketonuria (PKU, MIM 261600) is an autosomal recessive disorder caused by mutations of the phenylalanine hydroxylase gene (PAH, GenBank U49897.1, RefSeq NM_000277). To date more than 560 variants of the PAH gene have been identified. In Europe there is regional distribution of specific mutations. Due to recent progress in chaperone therapy, the prevalence of BH4-responsive alleles gained therapeutic importance. Here we report the mutational spectrum of PAH deficiency in 147 unrelated Austrian families. Overall mutation detection rate was 98.6 %. There was a total of 62 disease-causing mutations, including five novel mutations IVS4 + 6T>A, p.H290Y, IVS8-2A>G, p.A322V and p.I421S. The five most prevalent mutations found in patients were p.R408W, IVS12 + 1G>A, p.R261Q, p.R158Q and IVS2 + 5G>C. Neonatal phenylalanine levels before treatment were available in 114/147 patients. Prediction of BH4-responsiveness in patients with full genotypes was exclusively made according to published data. Among the 133 patients needing dietary treatment, 28.4 % are expected to be BH4 "non-responsive", 4.5 % are highly likely BH4-responsive, 35.8 % are probably BH4-responsive while no interpretation was possible for 31.3 %. The mutation data reflect the population history of Austria and provide information on the likely proportion of Austrian PKU patients that may benefit from BH4-therapy.
Citrullinemia is a urea cycle disorder caused by deficiency of argininosuccinate synthetase. Late onset forms can remain undiscovered until a decompensation that can resemble encephalitis. Herein, we report a 14-year old patient with suspected encephalitis with fluctuating episodes of confusion. EEG mainly showed bilateral slowing with some spikes plus spike waves; and was interpreted as suspicious for encephalitis. Brain MRI was normal. Leukocytes in CSF were slightly elevated. Treatment for a CNS infectious disease was begun. Symptoms did not resolve and there were several episodes of confusion, so a repeat lumbar puncture was performed according to a standardized protocol including an amino acid profile. An elevation of citrulline in CSF was found, which ultimately led to the diagnosis of a late onset citrullinemia. The establishment of this diagnosis will protect the patient from the sequelae of unrecognized and thus untreated episodes of hyperammonemia. Thus, following a standardized lumbar puncture protocol can be essential to detect patients with otherwise unrecognized underlying metabolic disorders that are not suspected because of clinical symptoms. In addition, it is important to stress that an ammonia concentration should be determined in any patient with neurological signs like confusion.
We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.
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