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

Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders —a successful strategy for clinical research of rare diseases
ConclusionsCombined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilising differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 4, 2018 Category: Internal Medicine Source Type: research

Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience
In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 4, 2018 Category: Internal Medicine Source Type: research

Development and characterization of an inducible mouse model for glycogen storage disease type Ib
ConclusionsTM-induced inactivation of G6PT in these mice leads to a phenotype which mimics that of human GSD1b patients. The conditional mice we have generated represent an excellent tool to study the tissue-specific role of theG6PT gene and the mechanism of long-term complications in GSD1b. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 2, 2018 Category: Internal Medicine Source Type: research

View from inside
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - July 2, 2018 Category: Internal Medicine Source Type: research

A new opportunity: metabolism and neuropsychiatric disorders
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - June 28, 2018 Category: Internal Medicine Source Type: research

Manifesting heterozygotes in McArdle disease: a myth or a reality —role of statins
AbstractMcArdle disease is an autosomal recessive condition caused by deficiency of thePYGM gene-encoded muscle isoform of glycogen phosphorylase. Some cases of “manifesting” heterozygotes or carriers (i.e., patients who show some McArdle-like symptoms or signs despite being carriers of only one mutatedPYGM allele) have been reported in the literature but there is controversy, with misdiagnosis being a possibility. The purpose of our study was to determine if there are actually “manifesting” heterozygotes of McArdle disease and, if existing, whether statin treatment can trigger such condition. Eight...
Source: Journal of Inherited Metabolic Disease - June 20, 2018 Category: Internal Medicine Source Type: research

Long-term evaluation of urinary copper excretion and non-caeruloplasmin associated copper in Wilson disease patients under medical treatment
ConclusionDue to their variability, urinary copper excretion rates and serum copper concentrations are less than ideal parameters by which to monitor the benefit of a copper-reducing therapy. Urinary copper excretion rates seem to be more suitable than non-caeruloplasmin associated copper concentrations for this purpose. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - June 20, 2018 Category: Internal Medicine Source Type: research

Newborn screening for homocystinurias: recent recommendations versus current practice
ConclusionsDue to the favourable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, e.g. birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - June 15, 2018 Category: Internal Medicine Source Type: research

Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms
AbstractMovement disorders comprise a group of heterogeneous diseases with often complex clinical phenotypes. Overlapping symptoms and a lack of diagnostic biomarkers may hamper making a definitive diagnosis. Next-generation sequencing techniques have substantially contributed to unraveling genetic etiologies underlying movement disorders and thereby improved diagnoses. Defects in dopaminergic signaling in postsynaptic striatal medium spiny neurons are emerging as a pathogenic mechanism in a number of newly identified hyperkinetic movement disorders. Several of the causative genes encode components of the cAMP pathway, a c...
Source: Journal of Inherited Metabolic Disease - June 13, 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 - June 8, 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 - June 6, 2018 Category: Internal Medicine Source Type: research

The effectiveness of enzyme replacement therapy for juvenile-onset Pompe disease: a systematic review
ConclusionsInterpretation of the findings was hindered by the lack of good quality evidence. The available data suggests that some JOPD patients may benefit in the short term from ERT through improved muscle strength and a reduced need for assisted ventilation. A focus by clinicians on improved and more consistent evidence collection, and use of study designs tailored to rare conditions, would provide more definitive results. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - June 5, 2018 Category: Internal Medicine Source Type: research

Influence of implementing a protocol for an intravenously administered ammonia scavenger on the management of acute hyperammonemia in a pediatric intensive care unit
AbstractThe purpose of the study was to evaluate the influence of establishing a protocol for the use of combined sodium benzoate and sodium phenylacetate (SBSP) (Ammonul ®) to treat acute hyperammonemia. This was a retrospective, single-center study in a 24-bed medical and surgical pediatric intensive care unit (PICU) in a tertiary care teaching maternal–child hospital in Canada. Inclusion criteria were age
Source: Journal of Inherited Metabolic Disease - June 5, 2018 Category: Internal Medicine Source Type: research

Polycystic kidney features of the renal pathology in glycogen storage disease type I: possible evolution to renal neoplasia
AbstractGlycogen storage disease type I (GSDI) is a rare genetic pathology characterized by glucose-6 phosphatase (G6Pase) deficiency, translating in hypoglycemia during short fasts. Besides metabolic perturbations, GSDI patients develop long-term complications, especially chronic kidney disease (CKD). In GSDI patients, CKD is characterized by an accumulation of glycogen and lipids in kidneys, leading to a gradual decline in renal function. At a molecular level, the activation of the renin-angiotensin system is responsible for the development of renal fibrosis, eventually leading to renal failure. The same CKD phenotype wa...
Source: Journal of Inherited Metabolic Disease - June 4, 2018 Category: Internal Medicine Source Type: research

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases
AbstractAmino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis ofl-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor ofl-glycine andd-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instanc...
Source: Journal of Inherited Metabolic Disease - June 4, 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 - June 4, 2018 Category: Internal Medicine Source Type: research

Characteristics and outcomes of patients with formiminoglutamic aciduria detected through newborn screening
ConclusionsThese data suggest that the majority of individuals with FTCD deficiency detected by newborn screening are asymptomatic. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - June 4, 2018 Category: Internal Medicine Source Type: research

Inhibiting PNP for the therapy of hyperuricemia in Lesch-Nyhan disease: preliminary in vitro studies with analogues of immucillin-G
We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - June 4, 2018 Category: Internal Medicine Source Type: research

Lipids and synaptic functions
AbstractSynaptic functions have long been thought to be driven by proteins, especially the SNARE complex, contrasting with a relatively passive role for lipids constituting cell membranes. It is now clear that not only lipids, i.e. glycerophospholipids, sphingolipids and sterols, play a determinant role in the dynamics of synaptic membranes but they also actively contribute to the endocytosis and exocytosis of synaptic vesicles in conjunction with synaptic proteins. On the other hand, a growing number of inborn errors of metabolism affecting the nervous system have been related to defects in the synthesis and remodelling o...
Source: Journal of Inherited Metabolic Disease - June 4, 2018 Category: Internal Medicine Source Type: research

Combined malonic and methylmalonic aciduria due to ACSF3 mutations: benign clinical course in an unselected cohort
AbstractBackgroundThe clinical significance of combined malonic and methylmalonic aciduria due to ACSF3 deficiency (CMAMMA) is controversial. In most publications, affected patients were identified during the investigation of various complaints.MethodsUsing a cross-sectional multicenter retrospective natural history study, we describe the course of all known CMAMMA individuals in the province of Quebec.ResultsWe identified 25 CMAMMA patients (6  months to 30 years old) with a favorable outcome regardless of treatment. All but one came to clinical attention through the Provincial Neonatal Urine Screening Program (...
Source: Journal of Inherited Metabolic Disease - June 1, 2018 Category: Internal Medicine Source Type: research

Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial
ConclusionsThese findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 30, 2018 Category: Internal Medicine Source Type: research

Role of continuous glucose monitoring in the management of glycogen storage disorders
This study revealed that in addition to overnight hypoglycemia, CGMS can uncover previously undetected, subclinical, low glucose levels during daytime hours. Additionally, the CGMS detected daytime and overnight hyperglycemia, an often overlooked concern in liver GSDs. The CGMS with concurrent dietary adjustments made by a metabolic dietitian improved metabolic parameters and stabilized blood glucose levels. The CGMS was found to be a safe, effective, an d reliable method for optimizing treatment in patients with GSD I, III, and IX. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 25, 2018 Category: Internal Medicine Source Type: research

Long-term safety and efficacy of AAV gene therapy in the canine model of glycogen storage disease type Ia
ConclusionrAAV-GPE-hG6PC treatment in GSD-Ia dogs was found to be safe and efficacious. GSD-Ia is an attractive target for human gene therapy since it is a monogenic disorder with limited tissue involvement. Blood glucose and lactate monitoring can be used to assess effectiveness and as a biomarker of success. GSD-Ia can also serve as a model for other hepatic monogenic disorders. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 25, 2018 Category: Internal Medicine Source Type: research

Inborn errors of coenzyme A metabolism and neurodegeneration
AbstractTwo inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the fir...
Source: Journal of Inherited Metabolic Disease - May 16, 2018 Category: Internal Medicine Source Type: research

The cholic acid extension study in Zellweger spectrum disorders: results and implications for therapy
ConclusionsAlthough CA treatment did lead to reduced levels of toxic C27-bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21  months of treatment. We discuss the implications for CA therapy in ZSD based on these results. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 15, 2018 Category: Internal Medicine Source Type: research

Evaluation of plasma biomarkers of inflammation in patients with maple syrup urine disease
In conclusion, our findings in plasma of patients with MSUD suggest that inflammation may play an important role in the pathogenesis of MSUD, although this process is not directly associated with BCAA blood levels. Ov erall, data reported here are consistent with the working hypothesis that inflammation may be involved in the pathophysiological mechanism underlying the brain damage observed in MSUD patients. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 8, 2018 Category: Internal Medicine Source Type: research

Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia
AbstractGlycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase- α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unc lear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD+-dependent deacetylase that can deacetylate and ac...
Source: Journal of Inherited Metabolic Disease - May 8, 2018 Category: Internal Medicine Source Type: research

Acknowledgement to Referees
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 7, 2018 Category: Internal Medicine Source Type: research

In memoriam
(Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 7, 2018 Category: Internal Medicine Source Type: research

Comprehensive long-term efficacy and safety of recombinant human alpha-mannosidase (velmanase alfa) treatment in patients with alpha-mannosidosis
AbstractIntroductionLong-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM).MethodsPatient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after com pletion of the trials were invited to participate in a comprehensive evaluation v...
Source: Journal of Inherited Metabolic Disease - May 3, 2018 Category: Internal Medicine Source Type: research

Patterns, evolution, and severity of striatal injury in insidious- versus acute-onset glutaric aciduria type 1
ConclusionsInsidious-onset type GA1 is characterized by dorsolateral putaminal lesions, less severe dystonia, and an asymptomatic latency phase, despite already existing lesions. Initially normal MRI during the first months and deviations from guideline-recommended treatment in a large proportion of insidious-onset patients substantiate the protective effect of neonatally initiated treatment. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 2, 2018 Category: Internal Medicine Source Type: research

Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: update of 34 patients
AbstractBackgroundTransaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype –genotype correlation.MethodsWe performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations o...
Source: Journal of Inherited Metabolic Disease - May 2, 2018 Category: Internal Medicine Source Type: research

Integration of genomics and metabolomics for prioritization of rare disease variants: a 2018 literature review
AbstractMany inborn errors of metabolism (IEMs) are amenable to treatment; therefore, early diagnosis and treatment is imperative. Despite recent advances, the genetic basis of many metabolic phenotypes remains unknown. For discovery purposes, whole exome sequencing (WES) variant prioritization coupled with clinical and bioinformatics expertise is the primary method used to identify novel disease-causing variants; however, causation is often difficult to establish due to the number of plausible variants. Integrated analysis of untargeted metabolomics (UM) and WES or whole genome sequencing (WGS) data is a promising systema...
Source: Journal of Inherited Metabolic Disease - May 2, 2018 Category: Internal Medicine Source Type: research

Severe ichthyosis in MPDU1-CDG
We report on an infant with severe ichthyosis caused by MPDU1 mutations. The case illustrates that skin manifestations are an important feature of CDG syndromes. Therefore, metabolic investigations should be included in the workup of infantile ichthyosis disorders. (Source: Journal of Inherited Metabolic Disease)
Source: Journal of Inherited Metabolic Disease - May 2, 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 - May 2, 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 - April 27, 2018 Category: Internal Medicine Source Type: research