Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Complete loss of N-glycosylation is lethal in both yeast and mammals. Substantial deficiencies in some rate-limiting biosynthetic steps cause human congenital disorders of glycosylation (CDG). Patients have a range of clinical problems including variable degrees of mental retardation, liver dysfunction, and intestinal disorders. Over 60 mutations in phosphomannomutase (encoded by PMM2) diminish activity and cause CDG-Ia. The severe mutation R141H in PMM2 is lethal when homozygous, but heterozygous in about 1/70 Northern Europeans. Another disorder, CDG-Ic, is caused by mutations in ALG6, an alpha 1,3glucosyl transferase used for lipid-linked precursor synthesis, yet some function-compromising mutations occur at a high frequency in this gene also. Maintenance of seemingly deleterious mutations implies a selective advantage or positive heterosis. One possible explanation for this is that production of infective viruses such as hepatitis virus B and C, or others that rely heavily on host N-glycosylation, is substantially inhibited when only a tiny fraction of their coat proteins is misglycosylated. In contrast, this reduced glycosylation does not affect the host. Prevalent functional mutations in rate-limiting glycosylation steps could provide some resistance to viral infections, but the cost of this insurance is CDG. A balanced glycosylation level attempts to accommodate these competing agendas. By assessing the occurrence of a series of N-glycosylation-compromising alleles in multi-genic diseases, it may be possible to determine whether impaired glycosylation is a risk factor or a major determinant underlying their pathology.
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PMID:Balancing N-linked glycosylation to avoid disease. 1153 Feb 12

Congenital disorder of glycosylation Ia (CDG-Ia) is a metabolic disease with a broad spectrum of clinical signs, including recently described mild phenotypes. Our aim was to describe the clinical presentation and follow-up of eight CDG-Ia patients highlighting atypical features and aspects of evolution of the disease. CDG diagnosis was confirmed by enzymatic analysis of phosphomannomutase (PMM2) and molecular studies of the PMM2 gene. Four neonates presented with cerebral haemorrhage (1), failure to thrive (2) and non-immune hydrops (1) and a fatal course to death (2); pathological examination of the brain in one case revealed olivopontocerebellar atrophy of prenatal origin. During infancy failure to thrive, coagulopathy and hepatopathy were the most significant causes of morbidity, but these disappeared after the first years of life in most patients. Three patients are currently in their 20s; they present mental retardation and severe motor impairment but no acute decompensations were noticed after the first decade of life. They do not present spinal or thoracic deformities otherwise observed in patients from northern countries. A 10-year-old patient who manifested gastrointestinal dysfunction in early childhood showed normal neurodevelopment. Mutation analysis of the PMM2 gene showed great variability, with all patients being compound heterozygous for two different mutations. Long-term evolution in our patients indicates that CDG-Ia is a stable systemic and neurological condition after the first decade of life. The diverse phenotypes and atypical manifestations in our series may be due to their genetic heterogeneity.
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PMID:Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations. 1894 42

Congenital disorder of glycosylation-Ia (CDG-Ia, also known as PMM2-CDG) is caused by mutations in the gene that encodes phosphomannomutase 2 (PMM2, EC 5.4.2.8) leading to a multisystemic disease with severe psychomotor and mental retardation. In a hypomorphic Pmm2 mouse model, we were able to overcome embryonic lethality by feeding mannose to pregnant dams. The results underline the essential role of glycosylation in embryonic development and may open new treatment options for this disease.
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PMID:Successful prenatal mannose treatment for congenital disorder of glycosylation-Ia in mice. 2215 80

Congenital disorders of glycosylation (CDG) are genetic diseases due to defects in the synthesis or the attachment of the glycan moiety of glycoproteins and glycolipids. They can be divided into four groups: disorders of protein N-glycosylation, disorders of protein O-glycosylation, disorders of lipid glycosylation, and disorders of other glycosylation pathways and of multiple glycosylation pathways. Of the more than 40 reported CDG, some 80% are neurological or have an important neurological component. By far the most common neurological CDG is phosphomannomutase 2 deficiency. Isoelectrofocusing of serum transferrin, the most widely used screening test, picks up only CDG associated with sialic acid deficiency of N-linked glycans. Predominant neurological signs and symptoms are psychomotor retardation, epilepsy, hypotonia, hyporeflexia, strabismus, retinitis pigmentosa, polyneuropathy, myopathy, and cerebellar hypotrophy/hypoplasia. All known neurological CDG have an autosomal recessive inheritance except for IAP-CDG, an X-linked pure mental retardation syndrome. No curative or effective treatment is available for neurological CDG. Since at least 1% of the genome is involved in glycosylation, it is likely that the large majority of CDG is yet to be discovered. In 2008, a novel nomenclature was introduced using the gene symbol followed by -CDG, e.g., CDG-Ia becomes PMM2-CDG. CDG should be looked for in any unexplained neurological syndrome.
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PMID:Congenital disorders of glycosylation. 2362 97