Response letter
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 27, 2018 Category: Internal Medicine Source Type: research

Letter to the Editors: Concerning “Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia” by Lee et al.
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 25, 2018 Category: Internal Medicine Source Type: research

View from inside
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 24, 2018 Category: Internal Medicine Source Type: research

The diagnostic challenge in very-long chain acyl-CoA dehydrogenase deficiency (VLCADD)
In this study, we show the outcome of enzyme testing in lymphocytes a s a confirmatory tool in newborns identified by screening, and the correlation with molecular sequencing of theACADVL gene. From April 2013 to March 2017, in 403 individuals with characteristic acylcarnitine profiles indicative of VLCADD, palmitoyl-CoA oxidation was measured followed by molecular genetic analysis in most of the patients with residual activity (RA)50%, one-third of the individuals (125/403) displayed a RA of 30 –50% and 69/403 individuals showed a residual activity of 0–30%. Sequencing of theACADVL gene revealed that all indiv...
Source: Journal of Inherited Metabolic Disease - September 7, 2018 Category: Internal Medicine Source Type: research

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry
ConclusionTreatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 3, 2018 Category: Internal Medicine Source Type: research

Oral Presentations
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Mucolipidosis type III, a series of adult patients
ConclusionsSevere skeletal abnormalities, resulting from abnormal bone development and severe progressive osteoarthritis, are the hallmark of MLIII, necessitating surgical orthopaedic interventions early in life. Future therapies for this disease should focus on improving cartilage and bone quality, preventing skeletal complications and improving mobility. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Organic acidurias in adults: late complications and management
AbstractOrganic acidurias (synonym, organic acid disorders, OADs) are a heterogenous group of inherited metabolic diseases delineated with the implementation of gas chromatography/mass spectrometry in metabolic laboratories starting in the 1960s and 1970s. Biochemically, OADs are characterized by accumulation of mono-, di- and/or tricarboxylic acids ( “organic acids”) and corresponding coenzyme A, carnitine and/or glycine esters, some of which are considered toxic at high concentrations. Clinically, disease onset is variable, however, affected individuals may already present during the newborn period with life-...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Treatment with chenodeoxycholic acid in cerebrotendinous xanthomatosis: clinical, neurophysiological, and quantitative brain structural outcomes
ConclusionCDCA may reverse the pathophysiological process in patients with CTX, especially if treatment is initiated early in the disease process. Besides tendon xanthoma, this study stresses the need to consider plasma cholestanol measurement in any patient with infantile chronic diarrhea and/or jaundice, juvenile cataract, learning disability and/or autism spectrum disorder, pyramidal signs, cerebellar syndrome or peripheral neuropathy. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Intrafamilial oocyte donation in classic galactosemia: ethical and societal aspects
This study aimed to provide guidance in aspects to con sider based on the views of different groups involved in the oocyte donation process. A qualitative study using in-depth semi-structured interviews with>  50 participants (patients, family members, and healthcare providers) was conducted. From these interviews, themes of concern emerged, which are illustrated and reviewed: (1) family relations, (2) medical impact, (3) patients’ cognitive level, (4) agreements to be made in advance and organization of counseling, (5) disclosure to the child, and (6) need for follow-up. We conclude that discussing and carry...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Hepatocellular carcinoma in Gaucher disease: an international case series
AbstractGaucher disease (GD) is associated with an increased risk for malignancies. Next to hematological malignancies, the development of solid tumors in several organs has been described. The liver is one of the major storage sites involved in GD pathogenesis, and is also affected by liver-specific complications. In this case series, we describe 16 GD type 1 (GD1) patients from eight different referral centers around the world who developed hepatocellular carcinoma (HCC). Potential factors contributing to the increased HCC risk in GD patients are studied. Eleven patients had undergone a splenectomy in the past. Liver cir...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Oxygen in mitochondrial disease: can there be too much of a good thing?
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Risks and benefits of oxygen therapy
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

The phenotype of adult versus pediatric patients with inborn errors of metabolism
AbstractUntil recently, inborn errors of metabolism (IEM) were considered a pediatric specialty, as emphasized by the term “inborn,” and the concept of adult onset IEM has only very recently reached the adult medical community. Still, an increasing number of adult onset IEM have now been recognized, as new metabolomics and molecular diagnostic techniques have become available. Here, we discuss possible mechanisms un derlying phenotypic variability in adult versus children with IEM. Specifically, phenotypic severity and age of onset are expected to be modulated by differences in residual protein activity possibl...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

A SEPSECS mutation in a 23-year-old woman with microcephaly and progressive cerebellar ataxia
AbstractMutations in theSEPSECS gene are associated with pontocerebellar hypoplasia type 2D. Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare autosomal recessive neurodegenerative disorders, mainly affecting pons and cerebellum. Patients have severe motor and cognitive impairments and often die during infancy. Here, we report a 23-year-old woman with slowly progressive cerebellar ataxia and cognitive impairment, in whom a homozygous missense mutation in theSEPSECS gene (c.1321G>A; p.Gly441Arg) was identified with whole exome sequencing. Our findings underline that defects in selenoprotein synthesis can ...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult –onset type II citrullinemia
We present the therapy for six CTLN2 patients. All the patients’ general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia leve l, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at A...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months
This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvem ents in relevant disease clinical measures. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome
ConclusionsWe cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity.ClinicalTrials.gov Identifier: NCT00947960. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Presentation, progression, and predictors of ovarian insufficiency in classic galactosemia
AbstractClassic galactosemia (CG) is an inherited metabolic disorder that affects about 1 in 50,000 live births in the United States and many other countries. With the benefit of early detection by newborn screening and rapid dietary restriction of galactose, generally achieved by removing dairy from the diet, most affected infants are spared the acute and potentially lethal symptoms of disease. Despite early detection and life-long dietary intervention, however, most patients grow to experience a constellation of long-term complications that include premature ovarian insufficiency in the vast majority of girls and young w...
Source: Journal of Inherited Metabolic Disease - September 1, 2018 Category: Internal Medicine Source Type: research

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease
ConclusionsChildren withPOLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 30, 2018 Category: Internal Medicine Source Type: research

Fibroblast growth factor 21 as a biomarker for long-term complications in organic acidemias
ConclusionThis study demonstrates the potential role of FGF-21 as a biomarker for long-term complications in classical organic acidemias, attributed to mitochondrial dysfunction. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 29, 2018 Category: Internal Medicine Source Type: research

Molecular genetics of a cohort of 635 cases of phenylketonuria in a consanguineous population
AbstractPhenylketonuria (PKU) is an inborn error of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH) gene, characterized by intellectual deficit and neuropsychiatric complications in untreated patients with estimated frequency of about one in 10,000 to 15,000 live births.PAH deficiency can be detected by neonatal screening in nearly all cases with hyperphenylalaninemia on a heel prick blood spot. Molecular testing of thePAH gene can then be performed in affected family members. Herein, we report molecular study of 635 patients genetically diagnosed with PKU from all ethnicities in Iran. The ...
Source: Journal of Inherited Metabolic Disease - August 29, 2018 Category: Internal Medicine Source Type: research

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study
In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 28, 2018 Category: Internal Medicine Source Type: research

Clinical effectiveness of enzyme replacement therapy with galsulfase in mucopolysaccharidosis type VI treatment: systematic review
ConclusionThis review provided a broader panoramic view of the outcomes related to mucopolysaccharidosis type VI. Regardless of the inherent limitations of observational studies, the outcomes indicate that the enzyme replacement therapy has a positive effect on most of the outcomes associated to the disease. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 22, 2018 Category: Internal Medicine Source Type: research

Setting the stage for a role of the postsynaptic proteome in inherited neurometabolic disorders
AbstractNeurotransmitter diseases are a well-defined group of metabolic conditions caused, in most instances, by genes specifically expressed in the presynaptic button. Better understanding of presynaptic molecular physiology, both in normal and pathological conditions, should help develop therapeutical strategies. The clinical relevance of the presynapse in inherited metabolic disorders is in glaring contrast with that of the postsynaptic component, which so far does not seem to play a relevant role in these disorders. This is somewhat surprising, as postsynaptic proteins are known to be involved in many nervous system di...
Source: Journal of Inherited Metabolic Disease - August 21, 2018 Category: Internal Medicine Source Type: research

Allogeneic haematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy
AbstractThe adult cerebral form of X-linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic haematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73  ± 11%), eight with stable cognition and seven of them with stable motor function (estimated eve...
Source: Journal of Inherited Metabolic Disease - August 21, 2018 Category: Internal Medicine Source Type: research

Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model
AbstractIntroductionMenkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood –brain barrier in MD model mice.MethodsWild type and MD model mice were pretreated with disulfiram for 30  min before oral administration of64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assesse...
Source: Journal of Inherited Metabolic Disease - August 21, 2018 Category: Internal Medicine Source Type: research

Index of Authors
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 20, 2018 Category: Internal Medicine Source Type: research

Oral Presentations
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 20, 2018 Category: Internal Medicine Source Type: research

Craniosynostosis affects the majority of mucopolysaccharidosis patients and can contribute to increased intracranial pressure
ConclusionsCraniosynostosis occurs in the majority of MPS patients. Since the clinical consequences can be severe and surgical intervention is possible, skull growth and signs and symptoms of increased ICP should be monitored in both neuronopathic and non-neuronopathic patients with MPS. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - August 6, 2018 Category: Internal Medicine Source Type: research

Improvement in bone marrow infiltration in patients with type I Gaucher disease treated with taliglucerase alfa
AbstractPreliminary data suggest a positive effect of taliglucerase alfa on the bone marrow infiltration of Gaucher cells. In this investigator-initiated study, we report the impact of taliglucerase alfa on the bone marrow fat fraction (FF) in 26 patients assessed by quantitative chemical shift imaging (QCSI). Of 15 treatment-na ïve patients (median age 48 [range 24–68] years), eight had baseline FF ≤ 0.3, six of those with a FF ≤ 0.23 (‘bone at risk’). All significantly improved from a median baseline FF of 0.24 (0.15–0.32) to 1st year FF of 0.37 (0.25–0...
Source: Journal of Inherited Metabolic Disease - July 31, 2018 Category: Internal Medicine Source Type: research

Correction to: Medical and financial burden of acute intermittent porphyria
Due to a typesetting error the wrong figure 2 was used. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 27, 2018 Category: Internal Medicine Source Type: research

The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy
This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence o f approximately 1:64,352 live births. This report provides a comprehensive overview of knownALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newb...
Source: Journal of Inherited Metabolic Disease - July 24, 2018 Category: Internal Medicine Source Type: research

Long-term complications of glycogen storage disease type Ia in the canine model treated with gene replacement therapy
ConclusionsHere, we show that the canine GSD Ia model demonstrates similar long-term complications as GSD Ia patients in spite of gene replacement therapy. Further development of gene therapy is needed to develop a more effective treatment to prevent long-term complications of GSD Ia. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 24, 2018 Category: Internal Medicine Source Type: research

Correction to: Manifesting heterozygotes in McArdle disease: a myth or a reality-role of statins
Unfortunately the name of one of the authors was spelled incorrectly in the published original article. The correct name is Alejandro Santos-Lozano. The original article got updated. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 20, 2018 Category: Internal Medicine Source Type: research

Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop
AbstractAlthough there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in child...
Source: Journal of Inherited Metabolic Disease - July 19, 2018 Category: Internal Medicine Source Type: research

Presynaptic disorders: a clinical and pathophysiological approach focused on the synaptic vesicle
AbstractThe aim of this report is to present a tentative clinical and pathophysiological approach to diseases affecting the neuronal presynaptic terminal, with a major focus on synaptic vesicles (SVs). Diseases are classified depending on which step of the neurobiology of the SV is predominantly affected: (1) biogenesis of vesicle precursors in the neuronal soma; (2) transport along the axon; (3) vesicle cycle at the presynaptic terminal (exocytosis –endocytosis cycle, with the main purpose of neurotransmitter release). Given that SVs have been defined as individual organelles, we highlight the link between the biolo...
Source: Journal of Inherited Metabolic Disease - July 18, 2018 Category: Internal Medicine Source Type: research

Synaptic metabolism: a new approach to inborn errors of neurotransmission
AbstractTo date, inborn errors of neurotransmitters have been defined based on the classic concept of inborn error of metabolism (IEM), and they include defects in synthesis, catabolism, and transport pathways. However, the omics era is bringing insights into new diseases and is leading to an extended definition of IEM including new categories and mechanisms. Neurotransmission takes place at the synapse, the most specialized tight junction in the brain. The concept of “synaptic metabolism” would point to the specific chemical composition and metabolic functions of the synapse. Based on these specialized functio...
Source: Journal of Inherited Metabolic Disease - July 16, 2018 Category: Internal Medicine Source Type: research

Cellular neurometabolism: a tentative to connect cell biology and metabolism in neurology
AbstractIt has become increasingly evident that inborn errors of metabolism (IEMs) are particularly prevalent as diseases of the nervous system and that a broader, more inclusive definition of IEM is necessary. In fact, as long as biochemistry is involved, any kind of monogenic disease can become an IEM. This new, extended definition includes new categories and mechanisms, and as a general trend will go beyond a single biochemical pathway and/or organelle, and will appear as a connection of multiple crossroads in a system biology approach.From one side, a simplified and updated classification of IEM is presented that mixes...
Source: Journal of Inherited Metabolic Disease - July 16, 2018 Category: Internal Medicine Source Type: research

Transcranial electrical stimulation (tES) mechanisms and its effects on cortical excitability and connectivity
AbstractIn this review, we describe transcranial electrical stimulation (tES) techniques currently being used in neuroscientific research, including transcranial direct  current (tDCS), alternating current (tACS) and random noise (tRNS) stimulation techniques. We explain how these techniques are used and summarise the proposed mechanisms of action for each technique. We continue by describing how each method has been used to alter endogenous neuronal oscillations and connectivity between brain regions, and we conclude by highlighting the varying effects of stimulation and discussing the future direction of these stimu...
Source: Journal of Inherited Metabolic Disease - July 13, 2018 Category: Internal Medicine Source Type: research

Results from a 78-week, single-arm, open-label Phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD)
AbstractLong-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78  weeks at a target dose of 25–35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitaliza...
Source: Journal of Inherited Metabolic Disease - July 9, 2018 Category: Internal Medicine Source Type: research

Induced pluripotent stem cells (iPSCs) as model to study inherited defects of neurotransmission in inborn errors of metabolism
AbstractThe ability to reprogram somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human disease. Especially for the modeling of rare human monogenetic diseases with limited numbers of patients available worldwide and limited access to the mostly affected tissues, iPSCs have become an invaluable tool. To study rare diseases affecting neurotransmitter biosynthesis and neurotransmission, stem cell models carrying patient-specific mutations have become highly important as most of the cell types present in the human brain and the central nervous system (CNS), including motoneurons, ...
Source: Journal of Inherited Metabolic Disease - July 6, 2018 Category: Internal Medicine Source Type: research

The efficacy of intracerebroventricular idursulfase-beta enzyme replacement therapy in mucopolysaccharidosis II murine model: heparan sulfate in cerebrospinal fluid as a clinical biomarker of neuropathology
We examined the efficacy of intracerebroventricular (ICV) enzyme replacement therapy (ERT) of idursulfase-beta (IDS- β) and evaluated the usefulness of HS as a biomarker for neuropathology in MPS II mice. We first examined the efficacy of three different doses (3, 10, and 30 μg) of single ICV injections of IDS-β in MPS II mice. After the single-injection study, its long-term efficacy was elucidated with 30 μ g of IDS-β ICV injections repeated every 4 weeks for 24 weeks. The efficacy was assessed by the HS content in the cerebrospinal fluid (CSF) and the brain of the animals along wi...
Source: Journal of Inherited Metabolic Disease - July 5, 2018 Category: Internal Medicine Source Type: research