Expanding the genetic and clinical spectrum of SLC25A42-associated disorders and testing of pantothenic acid to improve CoA level in vitro.

encodes the mitochondrial coenzyme A (CoA) transporter localized at the inner mitochondrial membrane. SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, and encephalopathy. Twenty-one patients have been described so far.

Enteric-Coated Cysteamine Bitartrate in Cystinosis Patients.

Cystinosis is a severe inherited metabolic storage disease caused by the lysosomal accumulation of cystine. Lifelong therapy with the drug cysteamine bitartrate is necessary. Cysteamine cleaves intralysosomal cystine, and thereafter, it can exit from the organelle.

A comparison of immediate release and delayed release cysteamine in 17 patients with nephropathic cystinosis.

Background: Nephropathic cystinosis is a rare and severe metabolic disease leading to an accumulation of cystine in lysosomes which especially harms kidney function. A lifelong therapy with the aminothiol cysteamine can delay the development of end-stage renal disease and the necessity of kidney transplantation. The purpose of our study was to compare the effectiveness of immediate-release and delayed-release cysteamine on cystine and cysteamine levels as well as assessing the onset of adverse effects.

Mannose supplementation in PMM2-CDG.

In this response to the letter by Witters et al., we refer to the authors' arguments regarding spontaneous enhancement of glycosylation and the claim, that mannose has no place in the treatment of PMM2-CDG. Our paper "Dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG)" has shown that further investigation of mannose in PMM2-CDG is worthwhile alongside other treatment options and should not be dismissed off-hand without the willingness to prove or disprove it in controlled prospective clinical trials.

Hypertransaminasemia and liver fibrosis associated with haptoglobin retention and anhaptoglobinemia in a paediatric patient.

Cryptogenic elevation of transaminases in childhood can in a few instances be linked to rare hereditary causes. In this paper, a 7-year old girl is reported who was diagnosed with elevated transaminases of unknown origin since infancy. A liver biopsy showed bridging fibrosis, pale eosinophilic intracytoplasmic hepatocellular inclusions and enlarged endoplasmic reticulum cisternae in the hepatocytes.

Translational balancing questioned: Unaltered glycosylation during disulfiram treatment in mannosyl-oligosaccharide alpha-1,2-mannnosidase-congenital disorders of glycosylation (MAN1B1-CDG).

MAN1B1-CDG is a multisystem disorder caused by mutations in , encoding the endoplasmic reticulum mannosyl-oligosaccharide alpha-1,2-mannnosidase. A defect leads to dysfunction within the degradation of misfolded glycoproteins. We present two additional patients with MAN1B1-CDG and a resulting defect in endoplasmic reticulum-associated protein degradation.

L-Fucose treatment of FUT8-CDG.

FUT8-CDG is a severe multisystem disorder caused by mutations in , encoding the α-1,6-fucosyltransferase. We report on dizygotic twins with FUT8-CDG presenting with dysmorphisms, failure to thrive, and respiratory abnormalities. Due to the severe phenotype, oral L-fucose supplementation was started.

Incidental diagnosis of leukocyte adhesion deficiency type II following ABO typing.

Individuals with the Bombay phenotype (Oh) in the ABO blood group system do not express the H, A, and B antigens but have no clinical symptoms. Bombay phenotype with clinical symptoms has been described in leukocyte adhesion deficiency type II (LAD II), a fucosylation disorder caused by mutations in SLC35C1. Only few LAD II patients have been described so far.

Dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG).

Background: PMM2-CDG (CDG-Ia) is the most frequent N-glycosylation disorder. While supplying mannose to PMM2-deficient fibroblasts corrects the altered N-glycosylation in vitro, short term therapeutic approaches with mannose supplementation in PMM2-CDG patients have been unsuccessful. Mannose found no further mention in the design of a potential therapy for PMM2-CDG in the past years, as it applies to be ineffective.

Mannose phosphate isomerase deficiency-congenital disorder of glycosylation (MPI-CDG) with cerebral venous sinus thrombosis as first and only presenting symptom: A rare but treatable cause of thrombophilia.

Mannose phosphate isomerase deficiency-congenital disorder of glycosylation (MPI-CDG; formerly named CDG type 1b) is characterized by the clinical triad of hepatopathy, protein-losing enteropathy, and hyperinsulinemic hypoglycemia in combination with coagulation disorder (thrombophilia, depletion of antithrombin, proteins C and S, factor XI). In the majority of patients, MPI-CDG manifests during early infancy or childhood. Here, we present a 15-year-old female patient with unremarkable medical history suffering from acute cerebral venous sinus thrombosis necessitating interventional thrombectomy and neurosurgical decompression.

SLC37A4-CDG: Mislocalization of the glucose-6-phosphate transporter to the Golgi causes a new congenital disorder of glycosylation.

Loss-of-function of the glucose-6-phosphate transporter is caused by biallelic mutations in SLC37A4 and leads to glycogen storage disease Ib. Here we describe a second disease caused by a single dominant mutation in the same gene. The mutation abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal.

N-glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency.

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 transferrin.

Cystinosis: Therapy adherence and metabolic monitoring in patients treated with immediate-release cysteamine.

Background: Cystinosis is a metabolic disease caused by intracellular accumulation of cystine within lysosomes. Development of symptoms can be delayed significantly by a life-long therapy with cysteamine, a drug that enters the lysosome and reacts with cystine thereby enabling its export from the organelle.

Methods: During a period of 16 years, blood samples of 330 cystinosis patients were analyzed to investigate therapeutic adherence and metabolic control in patients treated with immediate-release cysteamine.

SOD1 deficiency: a novel syndrome distinct from amyotrophic lateral sclerosis.

Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis.

Transient N-glycosylation abnormalities likely due to a de novo loss-of-function mutation in the delta subunit of coat protein I.

Accurate glycosylation of proteins is essential for their function and their intracellular transport. Numerous diseases have been described, where either glycosylation or intracellular transport of proteins is impaired. Coat protein I (COPI) is involved in anterograde and retrograde transport of proteins between endoplasmic reticulum and Golgi, where glycosylation takes place, but no association of defective COPI proteins and glycosylation defects has been described so far.

Transferrin glycosylation analysis from dried blood spot cards and capillary blood samples.

Background: Congenital disorders of glycosylation (CDG) are a growing group of inherited diseases causing manifold symptoms. Routine diagnostic procedures are high performance liquid chromatography (HPLC) or isoelectric focusing (IEF) of serum transferrin.

Methods: We introduce a modified method to screen for glycosylation abnormalities from dried blood spot (DBS) samples based on isoelectric focusing.

Correction to: Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol.

In the original publication, the text in Table 2 stated 'Hypersensitivity to the active substance, to Ferinject, or to any of its excipients'.

Effect of a Sodium and Calcium DL--Hydroxybutyrate Salt in Healthy Adults.

Background: Ketone body therapy and supplementation are of high interest for several medical and nutritional fields. The intake of ketone bodies is often discussed in relation to rare metabolic diseases, such as multiple acyl-CoA dehydrogenase deficiency (MADD), that have no alternatives for treatment. Case reports showed positive results of therapy using ketone bodies.

QIL1-dependent assembly of MICOS complex-lethal mutation in C19ORF70 resulting in liver disease and severe neurological retardation.

Seven subunits of the mitochondrial contact site and cristae junction (CJ) organizing system (MICOS) in humans have been recently described in function and structure. QIL1 (also named MIC13) is a small complex that is crucial for the maintenance and assembling of MICOS. A novel mutation of an essential splice site in the C19orf70 gene encoding QIL1 induces severe mitochondrial encephalopathy, hepatopathy and lactate acidosis consistent with psychomotor retardation.

Intravenous Ferric Carboxymaltose in Patients with Type 2 Diabetes Mellitus and Iron Deficiency: CLEVER Trial Study Design and Protocol.

Introduction: HbA1c is the gold standard for glycemic control in pre-diabetes and diabetes. However, its validity has been questioned, especially in the presence of imbalanced iron homeostasis. The CLEVER trial aims to evaluate the relationship between iron deficiency and HbA1c (a biomarker for the diagnosis and therapeutic monitoring of type 2 diabetes) in a randomized, placebo-controlled, multicenter clinical trial.

Limitations of galactose therapy in phosphoglucomutase 1 deficiency.

Introduction: Phosphoglucomutase 1 deficiency (PGM1 deficiency) has been identified as both, glycogenosis and congenital disorder of glycosylation (CDG). The phenotype includes hepatopathy, myopathy, oropharyngeal malformations, heart disease and growth retardation. Oral galactose supplementation at a dosage of 1 g per kg body weight per day is regarded as the therapy of choice.

SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy.

PurposeSLC39A8 deficiency is a severe inborn error of metabolism that is caused by impaired function of manganese metabolism in humans. Mutations in SLC39A8 lead to impaired function of the manganese transporter ZIP8 and thus manganese deficiency. Due to the important role of Mn as a cofactor for a variety of enzymes, the resulting phenotype is complex and severe.

A novel mutation in PIGW causes glycosylphosphatidylinositol deficiency without hyperphosphatasia.

In recent years, many mutations have been identified that affect the biosynthesis of the glycosylphosphatidylinositol anchor, a biomolecule that attaches surface molecules to cell membranes. Here, we present two second-degree cousins with unexplained patterns of seizures. Next-generation sequencing identified the homozygous c.

SLC39A8 Deficiency: A Disorder of Manganese Transport and Glycosylation.

SLC39A8 is a membrane transporter responsible for manganese uptake into the cell. Via whole-exome sequencing, we studied a child that presented with cranial asymmetry, severe infantile spasms with hypsarrhythmia, and dysproportionate dwarfism. Analysis of transferrin glycosylation revealed severe dysglycosylation corresponding to a type II congenital disorder of glycosylation (CDG) and the blood manganese levels were below the detection limit.

It Is Not Always Alcohol Abuse--A Transferrin Variant Impairing the CDT Test.

Aims: Elevated Carbohydrate-deficient transferrin (CDT) levels are used as a biomarker in order to screen for chronic alcohol abuse. Transferrin (Tf) variants can impair methods to measure elevated CDT levels such as high-performance liquid chromatography (HPLC). We present a Tf variant affecting the second glycosylation site of Tf and the complications it causes in diagnosing alcoholism.