Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L‐threo‐3,4‐dihydroxyphenylserine (L‐DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world‐wide reported patients with DBH‐deficiency, and to present detailed new data on long‐term follow‐up of a relatively large Dutch

Primary mitochondrial disorders (PMDs) are challenging due to overall poor outcomes, no proven treatments, and a history of failed clinical trials, leading to a critical need to design future trials that can prove efficacy of an intervention. Selection of outcome measures for PMDs is complicated by extreme clinical, biochemical and genetic heterogeneity; PMDs are effectively a collection of nearly

Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell‐and gene‐based therapies have become available. Inherent to the rare nature of the single conditions, generating

Mitochondrial diseases (MDs) are occasionally difficult to diagnose. Growth differentiation factor 15 (GDF15) has been reported as a biomarker useful for not only diagnosing MDs, but also evaluating disease severity and therapeutic efficacy. To enable the measurement of serum GDF15 concentrations at medical institutions, we developed a new latex‐enhanced turbidimetric immunoassay (LTIA) as an automated

Mitochondria share extensive evolutionary conservation across nearly all living species. This homology allows robust insights to be gained into pathophysiologic mechanisms and therapeutic targets for the heterogeneous class of primary mitochondrial diseases through the study of diverse in vitro cellular and in vivo animal models. Dramatic advances in genetic technologies, ranging from RNA interference

This study provides a general overview on liver and/or kidney transplantation in patients with an amino and organic acid‐related disorder (AOA) with the aim to investigate patient characteristics and global outcome in Europe. This study was an initiative of the E‐IMD and the AOA subnetwork of MetabERN.

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17)

Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile‐onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease‐modifying therapy has yet been

1 THE BLISSFUL BEGINNING My first child Dylan was born in October 2012, it was an incredible feeling to finally be a Dad. I recall telling a friend it felt like I was walking on clouds. I promised myself and my son that I would try to be the best Dad in the world. A few days after the birth my wife Michelle and I took him home feeling like the world was at our feet. The first 18 months of Dylan's life

Acute intoxication‐type inborn errors of metabolism (IT‐IEM) such as urea cycle disorders and non‐acute IT‐IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and – in acute diseases – metabolic decompensations nevertheless. Research on the subjective burden of IT‐IEM remains sparse. Studies with

TANGO2 variants result in a complex disease phenotype consisting of recurrent crisis‐induced rhabdomyolysis, encephalopathy, seizures, lactic acidosis, hypoglycemia, and cardiac arrhythmias. Although first described in a fruit fly model as a protein necessary for some aspect of Golgi function and organization, its role in the cell at a fundamental level has not been addressed. Such studies are necessary

The aim of this study was to compare the value of serum biomarkers, fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), with histological analysis of muscle in the diagnosis of mitochondrial disease. We collected 194 serum samples from patients with a suspected or known mitochondrial disease. Biomarkers were analyzed blinded using enzyme‐labeled immunosorbent assay. Clinical

In a joint collaboration between the Journal of Inherited Metabolic Disorders and Neuropathology and Applied Neurobiology, we have drawn together a special, free‐to‐access, online collection of 12 articles from both journals, published in the past few years, which could interest the readers of both journals. We have chosen a number of intriguing case demonstrations, as well as showcasing neurologic

Routine screening of all newborns for inherited disorders began in the 1960s after the American microbiologist Robert Guthrie, MD, PhD, developed a simple test to identify neonates with phenylketonuria.1 Neonates who tested positive could receive treatment before they became symptomatic. Since then, newborn screening (NBS) has become the standard approach to screening populations for several rare disorders

Classic galactosemia (CG) is a rare metabolic disorder that results from profound deficiency of galactose‐1‐P uridylyltransferase (GALT). Despite early detection by newborn screening and rapid and lifelong dietary restriction of galactose, which is the current standard of care, most patients grow to experience a broad constellation of long‐term complications. The mechanisms underlying these complications

Long‐term outcome is postulated to be different in isolated methylmalonic aciduria caused by mutations in the MMAA gene (cblA type) compared with methylmalonyl‐CoA mutase deficiency (mut), but case definition was previously difficult.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1‐CDG. PGM1‐CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia

Sulfite oxidase (SO) deficiency is a disorder caused either by isolated deficiency of SO or by defects in the synthesis of its molybdenum cofactor. It is characterized biochemically by tissue sulfite accumulation. Patients present with seizures, progressive neurological damage, and basal ganglia abnormalities, the pathogenesis of which is not fully established. Treatment is supportive and largely ineffective

Long‐chain fatty acid oxidation disorders (LC‐FAOD) are autosomal recessive conditions that impair conversion of long‐chain fatty acids into energy, leading to significant clinical symptoms. Triheptanoin is a highly purified, 7‐carbon chain triglyceride approved in the United States as a source of calories and fatty acids for treatment of pediatric and adult patients with molecularly confirmed LC‐FAOD

Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8‐CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of N‐glycosylation is the analysis of serum

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone‐ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients

Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease‐modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial

(+)‐Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)‐EPI in pediatric subjects with Friedreich's ataxia (FRDA).

Citrin deficiency is a hereditary disorder caused by SLC25A13 mutations and manifests as neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult‐onset type II citrullinemia (CTLN2). Citrin is a component of the malate‐aspartate nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, an essential shuttle for hepatic glycolysis. Hepatic glycolysis and the

Methylcitric acid (MCA) analysis has been mainly utilized for the diagnosis of propionate disorders or as a second‐tier test in newborn screening, but its utility for patients monitoring still needs to be established. We explored the potential contribution of MCA in the long‐term management of organic acidurias. We prospectively evaluated plasma MCA and its relationship with disease biomarkers, clinical

Galactosemia is a rare, treatable hereditary disorder of carbohydrate metabolism. We investigated the etiology of decreased GALT enzyme activity in a cohort of newborns referred by the Florida Newborn Screening Program with no detectable GALT variants in diagnostic molecular tests. Six affected individuals from four families with Guatemalan heritage were included. GALT enzyme activity ranged from 20%

Multiple sulfatase deficiency (MSD) is an ultra‐rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine‐generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID

Post‐translational protein modifications derived from metabolic intermediates, such as acyl‐CoAs, have been shown to regulate mitochondrial function. Patients with a genetic defect in the propionyl‐CoA carboxylase (PCC) gene clinically present symptoms related to mitochondrial disorders and are characterised by decreased mitochondrial respiration. Since propionyl‐CoA accumulates in PCC deficient patients

Adult‐onset noncirrhotic hyperammonemia (NCH) is poorly understood and has a high morbidity and mortality. To elucidate the etiology and management of NCH, we performed a retrospective analysis of 23 adults (median age 51) with NCH treated between 2014 and 2020 at two academic medical centers. Hyperammonemia was diagnosed in all cases during the evaluation of altered mental status, with 22% presenting

The neurological phenotype of 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) and short‐chain enoyl‐CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations

Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result

Glycine abundance is modulated in a tissue‐specific manner by use in biosynthetic reactions, catabolism by the glycine cleavage system (GCS), and excretion via glycine conjugation. Dysregulation of glycine metabolism is associated with multiple disorders including epilepsy, developmental delay, and birth defects. Mutation of the GCS component glycine decarboxylase (GLDC) in non‐ketotic hyperglycinemia

Mannose phosphate isomerase MPI‐CDG (formerly CDG‐1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D‐mannose. We retrospectively reviewed long‐term outcomes of patients with MPI‐CDG, all but one of whom were treated with D‐mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D‐mannose treatment. Nine patients were diagnosed

Bikunin (Bkn) isoforms are serum chondroitin sulfate (CS) proteoglycans synthesized by the liver. They include two light forms, that is, the Bkn core protein and the Bkn linked to the CS chain (urinary trypsin inhibitor [UTI]), and two heavy forms, that is, pro‐α‐trypsin inhibitor and inter‐α‐trypsin inhibitor, corresponding to UTI esterified by one or two heavy chains glycoproteins, respectively.

Asparagine‐linked glycosylation 13 homolog (ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in

Anaplerotic odd‐chain fatty acid supplementation has been suggested as an approach to replenish citric acid cycle intermediate (CACi) pools and facilitate adenosine triphosphate (ATP) production in subjects with long‐chain fatty acid oxidation disorders, but the evidence that cellular CACi depletion exists and that repletion occurs following anaplerotic substrate supplementation is limited. We exercised

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively

Classic galactosemia (OMIM# 230400) is an autosomal recessive disorder due to galactose‐1‐phosphate uridyltransferase deficiency. Newborn screening and prompt treatment with a galactose‐free diet prevent the severe consequences of galactosemia, but clinical outcomes remain suboptimal. Five men and five women with classic galactosemia (mean age = 27.2 ± 5.47 years) received comprehensive neurological

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies

Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by acute encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. We investigated the efficacy of substrate reduction through inhibition of 2‐aminoadipic semialdehyde synthase (AASS), an enzyme upstream of the defective glutaryl‐CoA dehydrogenase (GCDH), in a cell line and mouse model

Multiple Sulfatase Deficiency (MSD, MIM#272200) is an ultra‐rare lysosomal storage disorder arising from mutations in the SUMF1 gene, which encodes the formylglycine‐generating enzyme (FGE). FGE is necessary for the activation of sulfatases, a family of enzymes that are involved in the degradation of sulfated substrates such as glycosaminoglycans and sulfolipids. SUMF1 mutations lead to functionally

Genetic therapies based on gene addition have witnessed a variety of clinical successes and the first therapeutic products have been approved for clinical use. Moreover, innovative gene editing techniques are starting to offer new opportunities in which the mutations that underlie genetic diseases can be directly corrected in afflicted somatic cells. The toolboxes underpinning these DNA modifying technologies

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar‐ATPase (V‐ATPase) assembly defects, various degrees of hepatic injury have been described, including end‐stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation.

The aim of this study was to compare the long‐term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross‐reactive immunologic material (CRIM)‐negative, two in the 20 mg

5‐Amino‐4‐imidazolecarboxamide‐ribosiduria (AICA)‐ribosiduria is an exceedingly rare autosomal recessive condition resulting from the disruption of the bifunctional purine biosynthesis protein PURH (ATIC), which catalyzes the last two steps of de novo purine synthesis. It is characterized biochemically by the accumulation of AICA‐riboside in urine. AICA‐ribosiduria had been reported in only one individual

Hearing loss is frequently seen in mucopolysaccharidoses (MPS) patients. Although hematopoietic cell transplantation (HCT) increases overall survival, disease progression is observed in certain tissues. This study describes the course of hearing loss (HL) over time in transplanted MPS patients. Transplanted MPS patients between 2003 and 2018 were included and received yearly audiological evaluation

Our daughter Nina Contreras D'Agosto is a half‐Spanish, half‐Italian 30‐month‐old baby girl. She is also known as Nina, the Von Gierke's Warrior, and she is unique. Not only because she lives with Glycogen Storage Disease (GSD) type 1b—an inherited metabolic condition that affects one out of 1 million people—but also because during her short life, and despite all her health‐related challenges, she

Sjögren‐Larsson syndrome (SLS) is a rare neurometabolic syndrome caused by deficient fatty aldehyde dehydrogenase. Patients exhibit intellectual disability, spastic paraplegia, and ichthyosis. The accumulation of fatty alcohols and fatty aldehydes has been demonstrated in plasma and skin but never in brain. Brain magnetic resonance imaging and spectroscopy studies, however, have shown an abundant lipid

Glycogen storage disease type Ia (GSD‐Ia) is an inherited metabolic disease caused by a deficiency in glucose‐6‐phosphatase‐α (G6Pase‐α or G6PC) which plays a critical role in blood glucose homeostasis by catalyzing the hydrolysis of glucose‐6‐phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients with GSD‐Ia manifest life‐threatening fasting hypoglycemia

At the time of writing, severe Covid‐19 disease has been responsible for 383 000 deaths worldwide (Johns Hopkins data). Most deaths occur in the <10% of infected individuals that develop respiratory failure.1 This is caused by bilateral interstitial pneumonia and acute respiratory distress syndrome and leads to dependence on mechanical ventilation.2 The pathogenesis of the pneumonia is poorly understood

Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability

2‐Oxoglutarate dehydrogenase (OGDH) is a rate‐limiting enzyme in the mitochondrial TCA cycle, encoded by the OGDH gene. α‐Ketoglutarate dehydrogenase (OGDH) deficiency was previously reported in association with developmental delay, hypotonia, and movement disorders and metabolic decompensation, with no genetic data provided. Using whole exome sequencing, we identified two individuals carrying a homozygous