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.     

Carbohydrate deficient glycoprotein syndrome type I: A cause of cerebellar vermis hypoplasia

Abstract: To report the first case of carbohydrate deficient glycoprotein syndrome Type I (CDG I) that has been identified in Australia and confirmed enzymatically to raise the awareness of paediatricians with regard to CDG I and its manifestations, implications and diagnostic investigations. Clinical and autopsy findings of an infant with CDG I are presented. The diagnosis of CDG I was suggested by the clinical findings and biochemical abnormalities and was confirmed by showing an abnormal transferrin isoform pattern. Subsequent studies showed a reduced level of phosphomannomutase in skin fibroblasts. Carbohydrate-deficient glycoprotein syndrome I is one of the many causes of cerebellar hypoplasia. It is an important disorder to identify because of the prognostic and genetic implications and may be underdiagnosed in Australia.     

Budd-Chiari syndrome associated with coagulation abnormalities in a child with carbohydrate deficient glycoprotein syndrome type Ix

A 6-year-old male patient presented with Budd-Chiari syndrome and glycoprotein abnormalities associated with carbohydrate deficient glycoprotein syndrome type I with yet unidentified molecular defect (type Ix). Budd-Chiari syndrome most likely developed after hepatic venous thrombosis caused by coagulation abnormalities resulting from hypoglycosylation and functional impairment of anticoagulant proteins.     

Cerebellar atrophy: an important feature of carbohydrate deficient glycoprotein syndrome type 1

We report three children, all younger than 2 years of age, presenting with cerebellar atrophy related to carbohydrate-deficient glycoprotein syndrome type 1, an autosomal recessive metabolic disease. One patient had multisystem disease; two others had mental retardation with ataxia. In all cases the cerebellar atrophy was diagnosed on magnetic resonance imaging and, in one case, confirmed by autopsy. The cerebellar atrophy predominantly affected the anterior lobe. Vertical orientation of the tentorium cerebelli from the neonatal period in two cases suggests antenatal onset of the disease. Biological tests confirmed the diagnosis in all cases. Received: 23 February 1998 Accepted: 6 July 1998     

Carbohydrate deficient serum transferrin in a new systemic hereditary syndrome.

Four patients with a new, inherited, complex developmental deficiency syndrome were studied. The syndrome affects the central and peripheral nervous system, and also the retina, liver, bone, adipose tissue, and genital organs. Abnormalities of glycoproteins, glycopeptide hormones, and lipids have been found in serum from these patients, the most pronounced being increased cathodal forms of transferrin. Isoforms of serum transferrin were therefore analysed qualitatively and quantitatively by isoelectric focusing and isocratic anion exchange chromatography, and the carbohydrate composition was determined in transferrin isolated by immune affinity chromatography. All the patients had about tenfold raised serum concentrations of isotransferrins with higher isoelectric points than normal. Similar findings, though less pronounced, were made in all the fathers and in one of the mothers. Half the transferrin in the patients was constantly present in two principal abnormal cathodal forms in approximately equal amounts. Carbohydrate determinations in purified transferrin showed quantitatively similar deficiencies of sialic acid, galactose, and N-acetylglucosamine, the mannose content being normal. The results suggest that either two or all of the normally four terminal trisaccharides in transferrin may be missing. A defect in the synthesis or catabolism, or both, of this trisaccharide, which is common to many secretory glyco-conjugates, is likely. Apart from providing a quantitative diagnostic method, the present findings may serve as a basis for further studies of the metabolic deficiency in this syndrome.     

Normal pubertal development in a female with carbohydrate deficient glycoprotein syndrome

A girl is reported who presented with many of the clinical and biochemical characteristics of type I carbohydrate deficient glycoprotein syndrome. Unusually, however, she experienced a normal pubertal development.     

Successful treatment of carbohydrate deficient glycoprotein syndrome type 1b with oral mannose

An Asian girl presented with failure to thrive, congenital hepatic fibrosis, protein losing enteropathy, and hypoglycaemia. Phosphomannose isomerase activity in skin fibroblasts was reduced. She is homozygous for a mutation, D131N, in the phosphomannose isomerase gene (PM1), consistent with the diagnosis of carbohydrate deficient glycoprotein syndrome type 1b. She responded to oral mannose treatment.     

Successful treatment of carbohydrate deficient glycoprotein syndrome type 1b with oral mannose.

An Asian girl presented with failure to thrive, congenital hepatic fibrosis, protein losing enteropathy, and hypoglycaemia. Phosphomannose isomerase activity in skin fibroblasts was reduced. She is homozygous for a mutation, D131N, in the phosphomannose isomerase gene (PM1), consistent with the diagnosis of carbohydrate deficient glycoprotein syndrome type 1b. She responded to oral mannose treatment.     

Normal pubertal development in a female with carbohydrate deficient glycoprotein syndrome.

A girl is reported who presented with many of the clinical and biochemical characteristics of type I carbohydrate deficient glycoprotein syndrome. Unusually, however, she experienced a normal pubertal development.     

Neurophysiological findings in a case of carbohydrate-deficient glycoprotein (CDG) syndrome type I with phosphomannomutase deficiency.

The carbohydrate-deficient glycoprotein (CDG) syndromes are multisystemic disorders involving the glycosylation pathway. The most common subtype is CDG syndrome type I (CDG I). In most CDG I patients a phosphomannomutase (PMM) deficiency has been recognized as the basic defect. We made a neurophysiological evaluation in an 8-year-old boy affected by CDG I with PMM deficiency. The evaluation included central and peripheral nervous system assessment [electroencephalogram (EEG), multimodal evoked potentials (MEP), somatosensory evoked potentials (SEP), visual evoked potentials (VEP), auditory brainstem response (ABR), electroretinogram (ERG) and motor and sensory nervous conduction velocity (NCV)]. We found a peculiar electrophysiological pattern characterized by slowly and mildly progressive motor NCV reduction; progressive impairment of ERG and VEP; slowing of background activity and sharp waves at the EEGs; late sensorineural abnormality of ABR; decreased amplitude and increased latency of SEP. To our knowledge this is the first report involving the neurophysiological aspects both at onset and during follow-up of a case of CDG I with proven PMM deficiency.     

Diagnosis and nosology of glycanosis CDG ("carbohydrate deficient glycoprotein syndrome")]

BACKGROUND: The "Carbohydrate-deficient glycoprotein syndrome" is a recently discovered inborn error of complex carbohydrate metabolism. The disease involves a number of organ systems and various deficient glycoproteins. An abnormal isoform of serum transferrin is of diagnostic value. METHODS: We analysed the glycoprotein alpha-1-antitrypsin of two affected infants and their clinically healthy parents using high resolution isoelectric focusing technique. Besides normal isoforms of alpha-1-antitrypsin, we found an abnormal cathodic isoform ("CDG-alpha-1-antitrypsin") which represented almost half of the total amount of alpha-1-antitrypsin of the patients. RESULTS: This new marker-glycoprotein suggests a defect of the production of biantennary and of triantennary N-glycans during an early step of their synthesis, resulting in monoantennary N-glycans. Also this marker-glycoprotein seems to be a specific biochemical diagnostic tool for discovering glycanosis CDG (Carbohydrate-deficient glycoprotein syndrome). The mode of inheritance is probably incomplete autosomal dominant. The same genetic defect of N-glycan synthesis may be present in more than one type of the hybrid molecule glycoprotein, and was also found in transferrin, resembling a "genetic back-pack", that might explain the multitude of clinical symptoms. CONCLUSION: In view of these findings, we present novel systematics of those diseases that are due to inborn errors of N-glycan synthesis, and which we suggest to call "glycanoses".     

Continuous mannose infusion in carbohydrate-deficient glycoprotein syndrome type I

The effects on isoelectrofocusing patterns of serum glycoproteins were studied in a patient with CDG syndrome type I and phosphomannomutase deficiency during 3 weeks of continuous intravenous mannose infusion. Doses of 5. 7 g/kg/day led to stable serum mannose levels up to 2. 0 mmol/1 and were well tolerated without signs of liver or renal toxicity. While most of the pathological glycoprotein patterns, including α₁-antitrypsin, typical for CDG syndrome type I remained unchanged, mannose infusion led to a unique change of the isoelectrofocusing pattern of serum sialotransferrins with appearance of two extra bands after 3 weeks of treatment.     

Oto-palato-digital syndrome type II

Two cases with major features of bowed long bones, hypertelorism, mandibular hypoplasia and hand and foot abnormalities with early neonatal death due to respiratory failure are presented. The radiologic and clinical findings are in keeping with oto-palato-digital syndrome type II and differ significantly from other causes of bowed long bones such as campomelic and kyphomelic dysplasias.     

Aldosterone synthase deficiency type II with hypospadias

Aldosterone synthase deficiency (ASD) type II was diagnosed in a 3 week old boy with severe dehydration. Elevated plasma renin activity, low-normal aldosterone, increased levels for 18-OH corticosterone (18-OHB) and 18-OH-deoxycorticosterone were measured. Sequencing revealed a homozygous mutation for c554C > T in exon 3 (p.T185I) (CYP11B2). Hypospadias has so far not been reported in ASD.     

Regional deficiency of secretory IgA in a patient with combined immunodeficiency of the ADA deficient type.

The IgA system in a patient with SCID and ADA deficiency showed heterogeneity. Serum IgA and stool secretory IgA (SIgA) levels were normal, but with altered kappa/lambda and A1/A2 subclass ratios; IgA in saliva and urine was deficient. Amounts of secretory component were normal. Jejunal and rectal biopsies showed prominent lymphonodular hyperplasia, but no cells containing IgA. A normal serum IgA level therefore does not always predict an intact secretory IgA system.     

临床表现为Rett综合征的戊二酸尿症Ⅱ型一例

患儿女,3岁4个月,因“智体力落后2年3个月,反复搓手1年10个月,发作性跌倒5个月”入院。入院前2年3个月（约1岁1月龄时）,父母发现患儿与人缺少交流,动作笨拙,能听懂简单指令,能发音,但无语言表达。1岁3月时会走路后还表现出走路不稳,运动明显退步。1岁6月龄时,出现搓手和双手甩打动作,渐不能持物、取物。不仅仍无语言,而且理解力明显下降。平日表情愉快,甚少哭闹,伴流涎、用嘴呼吸、过度换气、咬牙等表现。2岁11月龄时出现跌倒发作,表现为四肢无力,倒地（没有固定方向）,意识未完全丧失,无面色改变,持续约1min即可缓解,1—2次／d。为进一步诊治,就诊于我院。