Diseases of glycosylation beyond classical congenital disorders of glycosylation.

BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

Congenital disorders of glycosylation (CDG): it's (nearly) all in it!

Congenital disorders of glycosylation (CDG) is a booming class of metabolic diseases. Its number has increased nearly fourfold (to 45) since 2003, the year of the Komrower lecture, entitled 'Congenital disorders of glycosylation CDG): It's all in it!'. This paper presents an overview of recently discovered CDG and CDG phenotypes, of a diagnostic approach, of (the lack of) treatment, of CDG genetics, of a novel CDG nomenclature and classification, and of some future directions in the CDG field.

On the nomenclature of congenital disorders of glycosylation (CDG).

A new nomenclature of CDG is proposed because the current one is too complex for clinicians and provides no added value.

Mass spectrometry for congenital disorders of glycosylation, CDG.

Congenital disorders of glycosylation (CDG) constitute a group of diseases affecting N-linked glycosylation pathways. The classical type of CDG, now called CDG-I, results from deficiencies in the early glycosylation pathway for biosynthesis of lipid-linked oligosaccharide and its transfer to proteins in endoplasmic reticulum, while the CDG-II diseases are caused by defects in the subsequent processing steps. Mass spectrometry (MS) produced a milestone in CDG research, by localizing the CDG-I defect to the early glycosylation pathway in 1992. Currently, MS of transferrin, either by electrospray ionization or matrix-assisted laser desorption/ionization, plays the central role in laboratory screening of CDG-I. On the other hand, the glycopeptide analysis recently developed for site-specific glycans of glycoproteins allows detailed glycan analysis in a high throughput manner and will solve problems in CDG-II diagnosis. These techniques will facilitate studying CDG, a field now expanding to O-linked glycosylation and to acquired as well as inherited conditions that can affect protein glycosylation.

Sporadic and familial glut1ds Italian patients: A wide clinical variability.

PURPOSE: GLUT1 deficiency syndrome is a treatable neurological disorder characterized by developmental delay, movement disorders and epilepsy. It is caused by mutations in the SLC2A1 gene inherited as an autosomal dominant trait with complete penetrance, even if most detected SCL2A1 mutations are de novo. Our aim is to present a wide series of Italian patients to highlight the differences among subjects with de novo mutations and those with familial transmission. METHODS: We present clinical and genetic features in a series of 22 GLUT1DS Italian patients. Our patients were classified in two different groups: familial cases including GLUT1DS patients with genetically confirmed affected relatives and sporadic cases with detection of SLC2A1 de novo mutation. RESULTS: We found remarkable differences in the severity of the clinical picture regarding the type of genetic inheritance (sporadic versus familial): sporadic patients were characterized by an earlier epilepsy-onset and higher degree of intellectual disability. No significant differences were found in terms of type of movement disorder, whilst Paroxysmal Exertion-induced Dyskinesia (PED) is confirmed to be the most characteristic movement disorder type in GLUT1DS. In familial cases the clinical manifestation of the disease was particularly variable and heterogeneous, also including asymptomatic patients or those with minimal-symptoms. CONCLUSION: The finding of a "mild" phenotype in familial GLUT1DS gives rise to several questions: the real incidence of the disease, treatment option with ketogenic diet in adult patients and genetic counseling.

Increased alpha3-fucosylation of alpha(1)-acid glycoprotein in patients with congenital disorder of glycosylation type IA (CDG-Ia).

Increased fucosylation of the type (sialyl) Lewis(x) was detected on the acute-phase plasma protein alpha(1)-acid glycoprotein (AGP) in patients with the congenital disorder of glycosylation type IA. This is remarkable, because in these patients the biosynthesis of guanosine 5'-diphosphate (GDP)-D-mannose is strongly decreased, and GDP-D-mannose is the direct precursor for GDP-L-fucose, the substrate for fucosyltransferases. The concomitantly occurring increased branching of the glycans of AGP and the increased fucosyltransferase activity in plasma suggest that a chronic hepatic inflammatory reaction has induced the increase in fucosylation.

The malabsorption of commonly occurring mono and disaccharides: levels of investigation and differential diagnoses.

BACKGROUND: Adverse food reactions (AFR) have has recently attracted increased attention from the media and are now more commonly reported by patients. Its classification, diagnostic evaluation, and treatment are complex and present a considerable challenge in clinical practice. Non-immune-mediated types of food intolerance have a cumulative prevalence of 30% to 40%, while true (immune-mediated) food allergies affect only 2% to 5% of the German population. METHOD: We selectively searched the literature for pertinent publications on carbohydrate malabsorption, with special attention to published guidelines and position papers. RESULTS: Carbohydrate intolerance can be the result of a rare, systemic metabolic defect (e.g., fructose intolerance, with a prevalence of 1 in 25,000 persons) or of gastrointestinal carbohydrate malabsorption. The malabsorption of simple carbohydrates is the most common type of non-immune-mediated food intolerance, affecting 20% to 30% of the European population. This condition is caused either by deficient digestion of lactose or by malabsorption of fructose and/or sorbitol. Half of all cases of gastrointestinal carbohydrate intolerance have nonspecific manifestations, with a differential diagnosis including irritable bowel syndrome, intolerance reactions, chronic infections, bacterial overgrowth, drug side effects, and other diseases. The diagnostic evaluation includes a nutritional history, an H2 breath test, ultrasonography, endoscopy, and stool culture. CONCLUSION: The goals of treatment for carbohydrate malabsorption are to eliminate the intake of the responsible carbohydrate substance or reduce it to a tolerable amount and to assure the physiological nutritional composition of the patient's diet. In parallel with these goals, the patient should receive extensive information about the condition, and any underlying disease should be adequately treated.

Genetic syndromes of severe insulin resistance.

Insulin resistance is among the most prevalent endocrine derangements in the world, and it is closely associated with major diseases of global reach including diabetes mellitus, atherosclerosis, nonalcoholic fatty liver disease, and ovulatory dysfunction. It is most commonly found in those with obesity but may also occur in an unusually severe form in rare patients with monogenic defects. Such patients may loosely be grouped into those with primary disorders of insulin signaling and those with defects in adipose tissue development or function (lipodystrophy). The severe insulin resistance of both subgroups puts patients at risk of accelerated complications and poses severe challenges in clinical management. However, the clinical disorders produced by different genetic defects are often biochemically and clinically distinct and are associated with distinct risks of complications. This means that optimal management of affected patients should take into account the specific natural history of each condition. In clinical practice, they are often underdiagnosed, however, with low rates of identification of the underlying genetic defect, a problem compounded by confusing and overlapping nomenclature and classification. We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology.

[Genetic disorders of N-acetylneuraminic acid metabolism: sialurias and sialidoses]. / Les maladies génétiques du métabolisme de l'acide N-acétylneuraminique: sialuries et sialidoses.

Sialuria and sialidosis represent the two known types of genetic errors of sialic acid metabolism. Sialuria type I (or "massive Sialuria") remains a very rare disease, characterized by the daily excretion of 10 g of N-acetylneuraminic acid. Although the primary defect has not been established, the absence of a feedback inhibition of the anabolic reactions is probably involved in the massive production of free sialic acid. Sialuria type II (Salla disease) and type III are lysosomal storage diseases and the patients have shown to have a 10 to 15 fold increase in the amount of free sialic acid in urine. These sialurias probably involve a defect in translocation of sialic acid from lysosomes to the site of biosynthesis. The sialidase deficiency has been found to be responsible of a number of storage diseases previously unclassified or described as "lipomucopolysaccharidosis" or "mucolipidosis I". The sialidase deficiency, or Sialidosis, is characterized by and increased urinary excretion of sialyloligosaccharides and storage of sialylated compounds. A third type of genetic error, the combined beta-galactosidase-sialidase deficiency, is due to the genetic deficiency of a 32 KD "protective protein" which is part of the complex formed between multimeric beta-galactosidase and sialidase.

Mannosidosis in two brothers: prolonged survival in the severe phenotype.

Two cases of mannosidosis are reported in brothers, one aged 41 years at death, the other aged 40 years and still alive. These patients are the oldest reported in the literature. Prolonged survival has previously been associated with the milder Type II phenotype. In addition to the characteristic clinical and radiological features of mannosidosis, both had severe joint destruction, which may be related to abnormal lysosomal enzymes in cartilage. The activity of acidic alpha-mannosidase was markedly reduced in plasma, leucocytes and fibroblasts, and the altered kinetic and physical properties are described.

Congenital disorders of glycosylation: a booming chapter of pediatrics.

PURPOSE OF REVIEW: The detection and identification of new congenital disorders of glycosylation continues at a rapid pace. Sine June 2003, four new congenital disorders of glycosylation have been reported, making a total of 20 diseases (on average nearly 1 disease per year since the first report in 1980; 12 of these congenital disorders of glycosylation were identified in the past 6 years). RECENT FINDINGS: Three of these newly discovered CDG are caused by defects in early steps of dolichol-linked oligosaccharide biosynthesis. Affected patients have a neurologic or a multisystem disease. The fourth new CDG is a completely new CDG type caused by a defect in an endoplasmic reticulum-Golgi shuttle protein carrying multiple glycosyltransferases and nucleotide-sugar transporters. SUMMARY: Disorders of nearly all organs and systems have been reported and continue to be reported in congenital disorders of glycosylation. Therefore, it is strongly recommended that congenital disorders of glycosylation be considered in any child with an unexplained clinical syndrome.

Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II.

The carbohydrate deficient glycoprotein (CDG) syndromes are a family of genetic multisystemic disorders with severe nervous system involvement. This report is on a child with a CDG syndrome that differs from the classical picture but is very similar to a patient reported in 1991. Both these patients are therefore designated CDG syndrome type II. Compared with type I patients they have a more severe psychomotor retardation but no peripheral neuropathy nor cerebellar hypoplasia. The serum transferrin isoform pattern obtained by isoelectric focusing showed disialotransferrin as the major fraction. The serum disialotransferrin, studied in the present patient, contained two moles of truncated monoantennary Sialyl-Gal-GlcNAc-Man(alpha 1-->3)[Man(alpha 1-->6)]Man(beta 1-->4)GlcNAc (beta 1-->4)GlcNAc-Asn per mole of transferrin. A profoundly deficient activity of the Golgi enzyme N-acetylglucosaminyltransferase II (EC 2.4.1.143) was demonstrated in fibroblasts.