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Glycosylation is essential for the normal functioning of many proteins, lipids, and other organic molecules. Disrupted or defective glycosylation results in both physiological and biochemical consequences. Congenital disorders of glycosylation is a group of diseases related to defects in the synthesis and attachment of glycans to proteins and lipids. Protein glycosylation may be either N-linked or O-linked. N-glycosylation includes both assembly and processing of the lipid-linked oligosaccharide. Assembly begins in the cytosol and continues in the endoplasmic reticulum (ER). Processing begins with the trimming of the glycoprotein intermediate in the ER and is completed after further modification in the Golgi. Currently 16 N-glycosylation defects have been described; 14 are related to assembly (CDG-I) and 2 are related to processing (CDG-II). O-glycosylation consists only of assembly and occurs primarily in the Golgi. Further processing does not occur in O- glycosylation. Eight O-glycosylation defects have been identified. In addition to specific N- and O- glycosylation of proteins, glycosphingolipid defects and glycosylphosphatidylinositol (GPI)-anchor glycosylation defects have been identified as well as disorders that involve combined N- and O-glycosylation defects. An astonishingly broad clinical spectrum has been described; however, psychomotor retardation, dysmorphia, failure to thrive, ataxia, vision problems, coagulopathies and laboratory abnormalities are frequently seen in CDG patients.
Many of the most common forms of CDG may be recognizable by transferrin isoelectrofocusing (TIEF). TIEF of normal serum transferrin reveals that transferring consists primarily of tetrasialotransferrin; cathodal shifts occur in both type I and type II CDG. The type I pattern is characterized by increased disialotransferrin and asialotransferrin and decreased tetrasialostransferrin; the type II pattern is characterized by an increase in the triasialtransferrin and/or monosialotransferrin. Although the most common forms are detectable using this method, it is not possible to identify all forms of CDG through TIEF.
The largest group of patients have a type I TIEF pattern associated with N-glycosylation defects. Phosphomannomutase (PMM) 2 deficiency (PMM2-CDG) is the most common CDG, with a type I pattern. It affects over 700 patients (1). Laboratory investigations show increased serum transaminases, hypoalbuminemia, hypocholesterolemia, and tubular proteinuria. Decreased PMM2 activity in leukocytes or fibroblasts confirms the PMM2-CDG diagnosis. The clinical spectrum is broad; all patients have nervous system involvement and variable multi-organ involvement. Psychomotor retardation, strabismus, hypotonia, ataxia, and hyporeflexia are common neurological symptoms. Other clinical symptoms include failture to thrive, dysmorphia, hepatomegaly, hypogonadism, and occasionally cardiomyopathy and other cardiac problems.
Phosphomannose-isomerase (MPI) deficiency (MPI-CDG) presents with biochemical abnormalities similar to those of PMM2-CDG. This disease has little neurological involvement and is primarily a hepatic-intestinal disorder. Symptoms include vomiting, protein-losing enteropathy, recurrent thromboses, liver disease and hypoglycemia symptoms. MPI-CDG is treatable with mannose therapy, making it exceptional from most other CDG subtypes.
ALG6-CDG is the second most common form of CDG. Symptoms include hypotonia, strabismus, seizures and some psychomotor retardation, though there is generally less psychomotor retardation than in PMM2-CDG. Less dysmorphia is reported; cerebellar hypoplasia and retinitis pigmentosa are also less common.
When no known mutation is found, the patient is said to have CDG-X. The subsequent approach to solving the unknown CDG type is TIEF, followed by blood enzyme studies for PMM2 and PMI. If a type II TIEF pattern is found, Apo C III studies are performed. If a type I TIEF pattern is found, LLO analysis is performed in fibroblasts. If these follow up tests fail to yield a diagnosis, a genetic approach is used in the case of a classical phenotype or consanguinity. The largest subset of unsolved patients are those exhibiting the type 2 pattern.
Since first being described over 30 years ago, the CDG disease family has expanded to include 45 distinct disorders. In past five years alone, 16 new subtypes have been identified, many of which arise from newly discovered defects in multiple glycosylation pathways and in other pathways. This article highlights the important recent advances in the field of CDG , including a summary of the updated nomenclature, a review of the research months that has deepened our understanding of existing types and an introduction to newly discovered CDG types.
Recently, CDG nomenclature was changed to reflect the increasing diversity of glycosylation defect subtypes. As an increasing amount of CDG types were been identified, the prevailing opinion in the field was to move away from alphabetical categorization based on the chronology of discovery in favor of a more specific, biology-based nomenclature, using the involved gene (2). Additionally, these newly identified defects include defects of other pathways including lipid glycosylation which did not fit into the existing nomenclature, thus necessitating a change in the classification system(2). The new nomenclature, proposed in the end of 2009, uses the symbol of the involved gene followed by the common ââ‚¬"CDG ending (3).
Recent Updates in CDG
Recent research continues to elucidate and expand the clinical spectrum of previously described CDG subtypes.
Though dilated cardiomyopathy (CMP) in CDG has been reported on in the past, recent reports have highlighted its association with a number of CDG subtypes. In 2010, the first report of dilated CMP in a patient with ALG6-CDG was published (4), expanding the ALG6 clinical phenotype. Additional recent literature has also shed light on CMP in CDG. A case of late-onset dilated CMP described in an 11-year old female with an still unknown CDG is remarkable, because according to previous literature, CMP in CDG patients generally presents in the first two years of life(5).
Skeletal abnormalities including skeletal dysplasia and brachytelephalangy were also recently reported in an ALG6-CDG patient (6). Skeletal abnormalities included a large, open fontanel, shortening of the terminal phalanx of the thumb and brachytelephalangy of fingers 2-5, brachydactyly of the feet, uneven humerus ossification and mild metaphyseal flaring of the lower extremity long bones. The authors suggest that the compound heterozygous mutation in ALG6 found in the patient is responsible for the multiple skeletal malformations. Skeletal abnormalities in the CDG disease family were previously reviewed. The spectrum of skeletal abnormalities in CDG is exceedingly broad. Though less frequently reported in the literature, skeletal abnormalities are present in many CDG types and the broadly observed skeletal abnormalities suggests that glycosylation is essential for the proper functioning of proteins involved in the development and cartilage and bone (7).
Further genetic research has deepened our understanding of the mechanisms resulting in glycosylation defects. ATP6V0A2-CDG, a defect found in a subset of patients with autosomal recessive cutis laxa type II (wrinkly skin syndrome)and is a combined defect in N- and O-glycosylation was described in 2005. Clinical features consistently found in these patients include cutis laxa, microcephaly, a large anterior fontanel, dysmorphic features (high forehead, downslanting palpebral fissures, midfacial hypoplasia), motor developmental delay, hypotonia, eye anomalies (strabismus, myopia), and joint laxity. Less frequent features are seizures, urogenital anomalies, and cobblestone-like brain dysgenesis. Histology of the skin reveals shortened and fragmented elastic fibers. Skin symptoms appear to improve with age(8). Although the cutis laxa phenotype had been described earlier in relation to CDG, recently a ATP6V0A2 mutation coding for the a2 subunit of the V-type H+ ATPase, has been found to lead to a glycosylation defect(9).
ADD Loss of function mutations (hucthagowden, 2009)
Existing Therapy and Updates
Currently only three CDG types are treatable. MPI-CDG may be treated with high dose oral mannose with general improvement in symptoms, though, liver improvement is variable depending on disease severity at time of treatment. Patients with SLC35C1-CDG, a deficiency in the GDP-fucose transporter, have variable responses to fucose treatment. Success relies on the type of mutation present. Dysmorphy and neurological symptoms are intractable, but the common infections with hyperleukocytosis may be successfully treated with fucose. Also, intractable absence seizures generally characteristic of PIGM-CDG may be controlled with butyrate, which increases PIGM transcription(10, 11).
Newly Identified Congenital Disorders of Glycosylation
Since 2009, 8 new defects have been identified. Many are characterized by abnormal TIEF; others have a clear syndromic presentation, are recognizable through specific blood analyses, or are identified using a genetic approach.
Defects in protein N-glycosylation
RFT1-CDG has been reported in six families of diverse ethnic origin. Severe neurological symptoms were described in all patients, with developmental retardation, sensorineural deafness, hypotonia, epilepsy, poor to absent visual contact, feeding problems, and failure to thrive. Other variable clinical features include microcephaly, respiratory problems, venous thromboses, cerebral atrophy, and dysmorphic features (12, 13)RFT1-CDG appears to be the first CDG with deafness as a consistent feature(13).
ALG11-CDG has been reported in the literature in two siblings of Turkish descent (14)(include jaekenââ‚¬â„¢s Belgian example from (10))Feeding problems, recurrent vomiting, hypotonia, epilepsy, and deafness were reported in these patients. One of the reported patients also had dysmorphism, psychomotor retardation, and died at 2 years of age.
Defects in GPI-anchor glycosylation
PIGV-CDG, a defect in the GPI anchor biosynthesis pathway, has been indentified in a group of patients with hyperphosphatasia mental retardation syndrome (Mabry syndrome). Clinical characteristics include dysmorphic facial features (hypertelorism, long palpebral fissures, broad nasal ridge and tip, thin upper lip, and downturned mouth corners), brachytelephelangy, hypotonia and epilepsy in addition to elevated serum alkaline phosphatases(15).
Defects of multiple glycosylation and other pathways
SRD5A3-CDG is a defect in dolichol phosphate synthesis. Patients show a cerebello-opthalmo-cutaneous syndrome which consists of cerebellar atrophy/vermis malformations, skin abnormalities (ichthyosis, erythroderma, dry skin) and eye abnormalities (coloboma, cataract, glaucoma, nystagmus, optic atrophy)(16).
SEC23B-CDG is known as congenital dyserythropoeitic anemia type II (CDAII). It is the most frequently seen genetic anemia, and is characterized by ineffective erythropoiesis, hemolysis, morphological abnormalities in erythroblasts, and hypoglycosylation of red blood cell (RBC) membrane proteins. Clinically, variable splenomegaly, mild to moderate anemia, jaundice, and iron overload due to increased RBC turnover caused by ineffective erythropoiesis and peripheral hemolysis. Iron overload has been related to complications such as liver cirrhosis and cardiac failure, generally in the third decade of life(17).
COG NEEDS AN INTRODUCTION:
COG appears to play a role in a number of Golgi-associated glycosylation enzymes.
As of yet, six conserved oligomeric Golgi (COG) defects have been described. The disorders range from the mild to the very severe which are often associated with early lethality. COG1, COG7, and COG8 have been recently joined by COG4, COG5, and COG6. COG4-CDG also has a mild clinical phenotype, with patients displaying mild psychomotor retardation, mild dysmorphia, and epilepsy (18).The clinical picture of the one reported patient with COG5-CDG is yet milder than other known COG disorders and includes a global developmental delay with moderate mental retardation, truncal ataxia, hypotonia, cerebellar and brain stem atrophy, and normal routine laboratory findings. In COG5-CDG, only terminal sialyation is affected, resulting in minor profile changes in TIEF(19). COG6-CDG is characterized by a severe clinical picture including, focal seizures, vomiting, intracranial bleeding resulting in loss of consciousness, and early death in the index patient (patient died due to brain edema at 5 weeks of age). Cholestasis resulting in vitamin K deficiency was discovered, and partially explained the intracranial bleedings. Biochemical analyses revealed mildly elevated lactate, aspartate aminotransferase and creatine kinase, and normal albumin(20).