Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the CTNS gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra-renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease-modifying treatment. We aimed

McArdle disease is caused by recessive mutations in PYGM gene. The condition is considered to cause a “pure” muscle phenotype with symptoms including exercise intolerance, inability to perform isometric activities, contracture, and acute rhabdomyolysis leading to acute renal failure. This is a retrospective observational study aiming to describe phenotypic and genotypic features of a large cohort of

Wilson's disease (WD), a rare genetic disorder responsible for copper accumulation in the body, is fatal if left untreated. Although there are effective treatments, adherence to treatment tends to be low. We evaluated the medication adherence of 139 patients using the Morisky scale. Adherence was correlated with age at diagnosis and at inclusion in the study, the form of the disease, the treatment

In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal

Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor

Fucosylation is essential for intercellular and intracellular recognition, cell-cell interaction, fertilization, and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG, and the only recently described GFUS-CDG. This review summarizes the clinical findings of

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by α-L-iduronidase deficiency. Patients present with a broad spectrum of disease severity ranging from the most severe phenotype (Hurler) with devastating neurocognitive decline, bone disease and early death to intermediate (Hurler-Scheie) and more attenuated (Scheie) phenotypes, with a normal life expectancy. The most

Subdural hematoma (SDH) was initially reported in 20-30% of patients with glutaric aciduria type 1 (GA1). A recent retrospective study found SDH in 4% of patients, but not in patients identified by newborn screening (NBS).

In the following article,1 the following mutation printed in Table 1 and Figure 1 was incorrect: c.646G > A, p.Ala261Pro (Table 1) and c.646G > A, p.Ala216Pro (Figure 1). The correct mutation in Table 1 (Patient 1 and 2) for CYP27A1 mutation allele 1 and in Figure 1 should have read: c.646G > C, p. Ala216 Pro. The authors apologise for the errors. REFERENCE [1] Stelten BML, Bonnot O, Huidekoper HH

Energy-demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of

Deficiency of the transacylase tafazzin due to loss of function variants in the X-chromosomal TAZ gene causes Barth syndrome (BTHS) with severe neonatal or infantile cardiomyopathy, neutropenia, myopathy, and short stature. The condition is characterized by drastic changes in the composition of cardiolipins, a mitochondria-specific class of phospholipids. Studies examining the impact of tafazzin (TAFAZZIN)

1 BACKGROUND Molybdenum cofactor deficiency (MoCD) type A is a very rare, fatal, autosomal recessive disease with an estimated U.S. prevalence of approximately 50 patients, primarily under 10 years of age. It is caused by pathogenic variants in the MOCS1 gene that lead to deficiency of cyclic pyranopterin monophosphate (cPMP), an intermediate in the biosynthetic pathway of molybdenum cofactor (MoCo)

Wilson disease (WD) is a rare genetic condition that results from a build-up of copper in the body. It requires life-long treatment and is mainly characterized by hepatic and neurological features. Copper accumulation has been reported to be related to the occurrence of heart disease, although little is known regarding this association. We have conducted a systematic review of the literature to document

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials

Barth syndrome is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, and neutropenia, caused by deleterious variants in TAFAZZIN. This gene encodes a phospholipid-lysophospholipid transacylase that is required for the remodeling of the mitochondrial phospholipid cardiolipin (CL). Biochemically, individuals with Barth syndrome have a deficiency of mature CL and accumulation of

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, however, these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations

Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic

Barth Syndrome is a rare X-linked disorder caused by pathogenic variants in the gene TAFAZZIN, which encodes for an enzyme involved in the remodeling of cardiolipin, a phospholipid primarily localized to the inner mitochondrial membrane. Barth Syndrome is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities, among other features. In this review, we will discuss

Mutation of the gene Tafazzin (TAZ) causes Barth syndrome, an X-linked disorder characterized by cardiomyopathy, skeletal muscle weakness, and neutropenia. TAZ is an acyltransferase that catalyzes the remodeling of cardiolipin, the signature phospholipid of the inner mitochondrial membrane. Here, we review the major model systems that have been established to study the role of cardiolipin remodeling

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry

A 53-year-old man was addressed to the orthopedic clinic for a knee replacement surgery. The patient complained of pain in several joints starting at age 30, mostly affecting the lumbar spine. Over several years, he developed non-inflammatory arthritis of the hips and knees, leading to the indication of total replacement of the right knee joint. Upon opening of the joint capsule, the surgeon was startled

The field of inborn errors of metabolism has become highly dynamic in recent years. Advances in metabolic and genetic methods lead to a faster and more reliable diagnosis even for extremely rare conditions. It is therefore all the more important that the future generation of metabolic professionals receive early support and the best possible training. The “Young Metabolic Society (Junge Stoffwechselmedizin

Acute intermittent porphyria (AIP) is a rare genetic metabolic disease caused by a specific enzyme dysfunction in the hepatic heme biosynthesis pathway. Besides the obvious clinical relevance of a disease in which patients are at risk of acute life-threatening neurovisceral attacks, the study of this disorder is of particular interest because it can provide straightforward proof-of-concept for new

Over the last few years, various inborn disorders have been reported in the malate aspartate shuttle (MAS). The MAS consists of four metabolic enzymes and two transporters, one of them having two isoforms that are expressed in different tissues. Together they form a biochemical pathway that shuttles electrons from the cytosol into mitochondria, as the inner mitochondrial membrane is impermeable to

It is with deep sadness that we inform you of the passing of a great paediatrician Professor Barbara M. Cabalska - a pioneer of neonatal screening and organizer of the care system for patients suffering from phenylketonuria and other rare diseases in Poland. During World War II, teenage Barbara fought to defend Warsaw during the Warsaw Uprising (1944) as a nurse for the legendary underground organization

Urea cycle disorders (UCDs) are inherited metabolic diseases causing hyperammonemia by defects in urea cycle enzymes or transporters. Liver transplantation (LT) currently is the only curative treatment option until novel therapies become available. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to investigate the effect of LT in patients with UCDs in Japan.

3-Hydroxyisobutyric acid (3HiB) is an intermediate in the degradation of the branched-chain amino acid valine. Disorders in valine degradation can lead to 3HiB accumulation and its excretion in the urine. This article describes the first two patients with a new metabolic disorder, 3-hydroxyisobutyrate dehydrogenase (HIBADH) deficiency, its phenotype and its treatment with a low-valine diet. The detected

Mucopolysaccharidoses type I (MPS I) is an inherited metabolic disease characterized by a malfunction of the α-l-iduronidase (IDUA) enzyme leading to the storage of glycosaminoglycans in the lysosomes. This disease has longtime been studied as a therapeutic target for those studying gene therapy and many studies have been done using various vectors to deliver the IDUA gene for corrective treatment

Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in-depth analysis of the phenotypic spectrum of MVA

The loss-of-function variants of the human asparagine synthetase (ASNS) gene cause asparagine synthetase deficiency (ASNSD). Diagnosis of ASNSD requires genetic tests because a specific biochemical diagnostic for ASNSD is not available. There are a few reports describing the functional evaluation of ASNS variants. Therefore, in vitro methods are needed to evaluate the detected variants in patients

The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised

Phosphoglucomutase 1 (PGM1) catalyzes the interconversion of glucose-6-phosphate to glucose-1-phosphate and is a key enzyme of glycolysis, glycogenesis, and glycogenolysis. PGM1 deficiency (OMIM: 614921) was initially defined as a glycogen storage disorder (type XIV), and later re-classified as a PGM1-congenital disorder of glycosylation (PGM1-CDG). Serum transferrin (Tf) glycan isoform analysis by

OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X-linked OTC gene. Phenotype-genotype correlations are well understood in males but still poorly known in females. Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation, and OTC gene sequencing to genetic counseling in heterozygous

Urea cycle disorders (UCD) are rare diseases that usually affect neonates or young children. During decompensations, hyperammonemia is neurotoxic, leading to severe symptoms and even coma and death if not treated rapidly. The aim was to describe a cohort of patients with adult onset of UCDs in a multicentric, retrospective and descriptive study of French adult patients with a diagnosis after 16 years

1 BACKGROUND Patients diagnosed with LC‐FAOD are unable to utilize long‐chain fats obtained from diet or catabolism to create TCA cycle substrates (also called anaplerotic substrates). Specifically, this group of autosomal recessive disorders is caused by pathogenic defects in the nuclear genes that encode the mitochondrial enzymes necessary for the creation of anaplerotic substrates. The enzymes transport

Louis Isaac Woolf, PhD, Professor Emeritus, Department of Psychiatry, University of British Columbia (b London, UK, April 24, 1919, q 1943 University College London, d February 7, 2021, Vancouver, Canada). Professor Louis Woolf died aged 101 from a heart condition on Sunday February 7, 2021 in Vancouver, British Columbia. He is best known for his pioneering work developing his concept of a dietary

Ethylmalonic acid (EMA) is a major and potentially cytotoxic metabolite associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency, a condition whose status as a disease is uncertain. Unexplained high EMA is observed in some individuals with complex neurological symptoms, who carry the SCAD gene (ACADS) variants, c.625G>A and c.511C>T. The variants have a high allele frequency in the general

Mitochondrial myopathies (MM) are caused by mutations that typically affect genes involved in oxidative phosphorylation. Main symptoms are exercise intolerance and fatigue. Currently, there is no specific treatment for MM. Resveratrol (RSV) is a nutritional supplement that in preclinical studies has been shown to stimulate mitochondrial function. We hypothesized that RSV could improve exercise capacity

Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized

Citrin deficiency develops in different symptomatic periods from the neonatal period to adulthood. Some infantile patients are diagnosed by newborn mass screening or symptoms of neonatal intrahepatic cholestasis caused by citrin deficiency, some patients in childhood may develop hepatopathy or dyslipidemia as failure to thrive and dyslipidemia caused by citrin deficiency, and some adults are diagnosed

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time-to-event analyses were performed to assess time to major disease-related milestones in different subgroups

Glutamyl-tRNA synthetase 2 (encoded by EARS2) is a mitochondrial aminoacyl-tRNA synthetase required to translate the 13 subunits of the electron transport chain encoded by the mitochondrial DNA. Pathogenic EARS2 variants cause combined oxidative phosphorylation deficiency, subtype 12 (COXPD12), an autosomal recessive disorder involving lactic acidosis, intellectual disability, and other features of

X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy. Despite intensive research in recent years, it remains unclear, what drives the different clinical disease courses. Due to this missing pathophysiological link, therapy for the childhood cerebral disease course of X-ALD (CCALD) remains symptomatic; the allogenic hematopoietic stem cell transplantation or hematopoietic stem-cell

Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking. This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders

The current diagnostic work-up of inborn errors of metabolism (IEM) is rapidly moving toward integrative analytical approaches. We aimed to develop an innovative, targeted urine metabolomics (TUM) screening procedure to accelerate the diagnosis of patients with IEM. Urinary samples, spiked with three stable isotope-labeled internal standards, were analyzed for 258 diagnostic metabolites with an ultra-high

Urea cycle disorders (UCDs) are inherited metabolic disorders with impaired nitrogen detoxification caused by defects in urea cycle enzymes. They often manifest with hyperammonemic attacks resulting in significant morbidity or death. We performed a nationwide questionnaire-based study between January 2000 and March 2018 to document all UCDs in Japan, including diagnoses, treatments, and outcomes. A

Continuous glucose monitoring (CGM) systems have great potential for real-time assessment of glycemic variation in patients with hepatic glycogen storage disease (GSD). However, detailed descriptions and in-depth analysis of CGM data from hepatic GSD patients during interventions are scarce. This is a retrospective in-depth analysis of CGM parameters, acquired in a continuous, real-time fashion describing

For the last three decades, enzyme replacement therapy (ERT) for Gaucher disease (GD) has been available. We aimed to evaluate the effect of ERT on the pregnancy and obstetric outcome in a unique group of multiparous women with type 1 GD (GD1) who had pregnancies with and without ERT. The Gaucher Unit database (1987-2019) was searched for multiparous women who had pregnancies before and after the institution

This Mitochondrial Medicine special issue of the Journal of Inherited Metabolic Disease includes a mini‐symposium of articles based on platform presentations at the 4th International Conference on Mitochondrial Medicine hosted by The Wellcome Trust at Hinxton Hall on the Genome Campus in Cambridge, UK, from 11 to 13 December 2019. The guest editors of this issue include the three organizers of this

Pathogenic variants in ALG13 (ALG13 UDP-N-acetylglucosaminyltransferase subunit) cause an X-linked congenital disorder of glycosylation (ALG13-CDG) where individuals have variable clinical phenotypes that include developmental delay, intellectual disability, infantile spasms, and epileptic encephalopathy. Girls with a recurrent de novo c.3013C>T; p.(Asn107Ser) variant have normal transferrin glycosylation

Classic galactosemia (CG) is a rare inborn error of metabolism that results from profound deficiency of galactose-1-P uridylyltransferase (GALT). Despite early detection and rapid and lifelong dietary restriction of galactose, which is the current standard of care, most patients grow to experience a broad range of complications that can include motor difficulties. The goal of this study was to characterize