1/13. Pontocerebellar hypoplasia associated with respiratory-chain defects.Pontocerebellar hypoplasias are congenital disorders of brain morphogenesis which include such diverse etiologies as carbohydrate-deficient glycoprotein syndrome type 1, cerebromuscular dystrophies (walker-warburg syndrome, Fukuyama syndrome, muscle-eye-brain disease) and at least two types of autosomal recessive neurodegenerations known as pontocerebellar hypoplasia type I and II. Pontocerebellar hypoplasia type 1 is a lethal phenotype and clinical features include congenital contractures, respiratory insufficiency, central and peripheral motor dysfunction and spinal anterior horn degeneration. Type 2 is characterized by progressive microcephaly, extrapyramidal dyskinesia and normal spinal cord findings. In this paper, we describe a girl, born at 33 weeks of gestation, presenting with respiratory insufficiency and multiple contractures. MRI scan of the brain demonstrated pontocerebellar hypoplasia and cortical and diffuse periventricular white matter abnormalities. Postmortem examination showed pontocerebellar hypoplasia with extensive gliosis of the periventricular white matter and of the basal ganglia with normal spinal cord findings. histology of skeletal muscle was normal. Biochemical analysis demonstrated multiple deficiencies of respiratory chain enzymes in skin fibroblasts. This case demonstrates a lethal phenotype of pontocerebellar hypoplasia without spinal cord abnormalities associated with a respiratory-chain disorder. The diagnostic workup in a patient whose brain image shows pontocerebellar hypoplasia should include a search for respiratory-chain impairment.- - - - - - - - - - ranking = 1keywords = congenital disorder (Clic here for more details about this article) |
2/13. Lectin analyses of glycoprotein hormones in patients with congenital disorders of glycosylation.OBJECTIVE: The congenital disorders of glycosylation (CDGs) are progressive multisystemic disorders characterized by a heterogeneous deficiency of the carbohydrate moieties in various structural and circulating glycoproteins, representing a natural model for glycoprotein hormone studies. Here, we studied the carbohydrate moiety of circulating glycoprotein hormones in four patients with a clinical suspicion of CDGs. methods: The diagnosis of CDG-I was confirmed in two out of the four cases by transferrin isoelectrofocusing (IEF) and/or carbohydrate-deficient transferrin (CDT) test. The carbohydrate moiety of serum endocrine-related glycoproteins was investigated by means of ricin (immunopurified thyrotropin (TSH)) and concanavalin a (Con-A) (TSH, follicle-stimulating hormone, alpha-subunit and thyroglobulin) lectin affinity chromatography measurement. RESULTS: CDT concentrations were very high in the two patients with CDG-I and moderately enhanced in the remaining two. In the two CDG-I patients, ricin analysis of immunopurified TSH showed a severe impairment of lectin binding, both before and after neuroaminidase treatment, indicating a nearly complete lack of terminal sialic acid and galactose residues. In these two cases, Con-A analysis showed a significant prevalence of firmly bound isoforms with poorly processed carbohydrate chains. In the remaining two cases with unknown CDG classification, TSH binding pattern to ricin was modestly affected and Con-A analysis showed the prevalence of weakly bound glycoprotein isoforms. CONCLUSIONS: The results of ricin analyses in all four patients were consistent with the CDT test and/or serum transferrin IEF. The severe alteration of TSH binding pattern to ricin seems to be characteristic of CDG-I. Nevertheless, TSH biological properties are not severely altered, as normal thyroid function was found in both cases.- - - - - - - - - - ranking = 5keywords = congenital disorder (Clic here for more details about this article) |
3/13. Carbohydrate structures of haptoglobin in sera of healthy people and a patient with congenital disorder of glycosylation.Haptoglobin is one of acute phase glycoproteins often used as markers in glycopathology studies. In this work the oligosaccharide structures of haptoglobin from 'healthy' subjects have been studied in detail, taking into consideration the possible dependence of glycosylation on the phenotype. About 75% of charged haptoglobin glycans were of biantennary complex structure, and some of them lacked one terminal sialic acid molecule. Triantennary structures made up almost 25% of the charged glycans pool, and highly branched tetrasialylated oligosaccharides did not exceed 1%. The main difference between haptoglobin derived from the sample of pooled 44 sera and from the 2-2 phenotype individual concerned the relative content of trisialylated oligosaccharide with one 2-3 linked sialic acid residue. The oligosaccharide profile of haptoglobin derived from serum of a patient suffering from congenital disorder of glycosylation was compared to 'healthy' controls. It was shown, that four main glycans are identical in patient and 'normal' haptoglobins. Some alterations were found in the relative content of mono-, bi-, and trisialylated glycans as well as in the appearance of some tracely abundant oligosaccharides in haptoglobin of the patient with congenital disorder of glycosylation.- - - - - - - - - - ranking = 6keywords = congenital disorder (Clic here for more details about this article) |
4/13. Congenital disorder of glycosylation type Ia: benign clinical course in a new genetic variant.The congenital disorders of glycosylation (CDG) are autosomal recessive disorders of N-glycans processing. Several different subtypes have been identified in recent years. Cerebellar atrophy is a characteristic finding in subtype Ia. We report clinical, imaging and genetic findings in a patient with a particularly benign clinical course, who had a normal CT at the age of 9 months and a new, previously undescribed, combination of mutations of the PMM gene locus on chromosome 16p13 (647,691). The 691 mutation has been described only in severe cases so far. This could indicate that genotype-phenotype correlation is lower than expected.- - - - - - - - - - ranking = 1keywords = congenital disorder (Clic here for more details about this article) |
5/13. Abnormal glycosylation of red cell membrane band 3 in the congenital disorder of glycosylation Ig.A description is provided of the clinical presentation in an infant of the recently described congenital disorder of glycosylation type Ig, and the changes affecting glycosylation of red cell membrane band 3, the anion exchanger. It has been shown that the condition stems from a homozygous mutation within the human ortholog of yeast ALG12 gene, which encodes a dolichol-P-mannose:Man7GlcNAc2-PP-dolichol alpha,1-6 mannosyltransferase of the endoplasmic reticulum. The clinical phenotype included prominent central and peripheral manifestations in the CNS. Although the infant studied had no anemia, band 3 abnormally separated into two fractions upon electrophoresis. The chemical composition of the glycans of both fractions was analyzed in detail. The fraction with low electrophoretic mobility was moderately hypoglycosylated (by 27%) and its mannose content was normal. The fraction with high electrophoretic mobility was deeply carbohydrate deficient (by 64%) and had 1 mol mannose in excess but only three residues of N-acetylglucosamine. glycophorin A was hypoglycosylated with respect to O-linked glycans. glycosphingolipids of red cells were normal. We suggest that the incomplete biosynthesis of the N-linked glycan of band 3 was largely caused by the persistence of the 3-linked mannose residue on the 6-mannose arm of the trimannosyl moiety of the glycoprotein. It is remarkable that the changes recorded in band 3 have no clinical consequences. Band 3 alteration might serve as an additional indicator (some serum N-glycoproteins of hepatic origin are also indicative) of the congenital disorder of glycosylation type Ig.- - - - - - - - - - ranking = 6keywords = congenital disorder (Clic here for more details about this article) |
6/13. Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.The congenital disorders of glycosylation (CDG) are characterized by defects in N-linked glycan biosynthesis that result from mutations in genes encoding proteins directly involved in the glycosylation pathway. Here we describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a subunit of the conserved oligomeric Golgi (COG) complex. The mutation impairs integrity of the COG complex and alters Golgi trafficking, resulting in disruption of multiple glycosylation pathways. These cases represent a new type of CDG in which the molecular defect lies in a protein that affects the trafficking and function of the glycosylation machinery.- - - - - - - - - - ranking = 5keywords = congenital disorder (Clic here for more details about this article) |
7/13. CDG-Id caused by homozygosity for an ALG3 mutation due to segmental maternal isodisomy UPD3(q21.3-qter).We report on a patient with a congenital disorder of glycosylation type Id (CDG-Id) caused by a homozygous mutation in the ALG3 gene, which results from a de novo mutation in combination with a segmental maternal uniparental isodisomy (UPD). The patient presented with severe psychomotor delay, primary microcephaly, and opticus atrophy, compatible with a severe form of CDG. isoelectric focusing of transferrin showed a type I pattern and lipid-linked oligosaccharide analysis showed an accumulation of dol-PP-GlcNAc2Man5 in patient's fibroblasts suggesting a defect in the ALG3 gene. A homozygous ALG3 missense mutation p.R266C (c.796C > T) was identified. Further evaluation revealed that neither the mother nor the father were carrier of the p.R266C mutation. Marker analysis revealed a segmental maternal isodisomy for the chromosomal region 3q21.3-3qter. UPD for this region has not been described before. More important, the combination of UPD with a de novo mutation is an exceptional coincidence and an extraordinary observation.- - - - - - - - - - ranking = 1keywords = congenital disorder (Clic here for more details about this article) |
8/13. Congenital disorder of glycosylation Ic due to a de novo deletion and an hALG-6 mutation.We describe a new cause of congenital disorder of glycosylation-Ic (CDG-Ic) in a young girl with a rather mild CDG phenotype. Her cells accumulated lipid-linked oligosaccharides lacking three glucose residues, and sequencing of the ALG6 gene showed what initially appeared to be a homozygous novel point mutation (338G>A). However, haplotype analysis showed that the patient does not carry any paternal dna markers extending 33kb in the telomeric direction from the ALG6 region, and microsatellite analysis extended the abnormal region to at least 2.5Mb. We used high-resolution karyotyping to confirm a deletion (10-12Mb) [del(1)(p31.2p32.3)] and found no structural abnormalities in the father, suggesting a de novo event. Our findings extend the causes of CDG to larger dna deletions and identify the first Japanese CDG-Ic mutation.- - - - - - - - - - ranking = 1keywords = congenital disorder (Clic here for more details about this article) |
9/13. Congenital disorder of glycosylation type Ia in a 6-year-old girl with a mild intellectual phenotype: two novel PMM2 mutations.We report two novel mutations in the PMM2 gene in a girl with congenital disorder of gylcosylation type Ia (CDG Ia) and a mild intellectual phenotype.- - - - - - - - - - ranking = 1keywords = congenital disorder (Clic here for more details about this article) |
10/13. High myopia and congenital myopathy with partial pachygyria in cutis laxa syndrome.PURPOSE: Several types of inborn errors of the O-glycan biosynthesis are known, leading to clinically very distinct phenotypes. Children with O-mannosyl glycan biosynthesis defects commonly present as a severe form of congenital muscular dystrophy with decreased alpha-dystroglycan staining, congenital eye anomalies, and brain migration defects. Alpha-dystroglycan is an O-mannosylated glycoprotein with additional mucin type O-glycans. methods: Based on overlapping clinical features with O-mannosyl glycan defects, especially with muscle-eye-brain disease, the authors performed a muscle biopsy in a child with severe congenital hypotonia, high myopia, partial pachygyria, mental retardation, cutis laxa, and an inborn error affecting the biosynthesis of both mucin type O-glycans and N-linked glycans. RESULTS: The histology showed no signs of muscle dystrophy, but a mild myopathy with slight increase in the muscle fiber diameter variability and type I fiber predominance. No significant decrease in the alpha-dystroglycan staining was detected; therefore, in spite of the phenotypic similarities the authors could not confirm the role of abnormal dystroglycan in the etiology of the muscle weakness and the developmental anomalies. CONCLUSIONS: High myopia, muscle weakness, and cortical neuronal migration abnormalities are common in disorders of O-mannosylation and also observed in the authors' patient. However, compared to the severe generalized defect observed in mannosyl glycan defects, in this child the cerebral white matter and cerebellum were spared, and no muscle dystrophy could be confirmed. This is the first description of high myopia in cutis laxa syndrome in combination with congenital disorders of glycosylation.- - - - - - - - - - ranking = 1keywords = congenital disorder (Clic here for more details about this article) |
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