Alternative titles; symbols
SNOMEDCT: 277893002, 459063003; ORPHA: 79318; DO: 0080552;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.2 | Congenital disorder of glycosylation, type Ia | 212065 | Autosomal recessive | 3 | PMM2 | 601785 |
A number sign (#) is used with this entry because congenital disorder of glycosylation type Ia (CDG Ia, CDG1A) is caused by homozygous or compound heterozygous mutation in the gene encoding phosphomannomutase-2 (PMM2; 601785) on chromosome 16p13.
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs (see, e.g., CDG2A, 212066) refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. CDG1A is the most common form of CDG and was the first to be characterized at the molecular level (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002).
Matthijs et al. (1997) noted that Jaeken syndrome (CDG1A) is a genetic multisystem disorder characterized by defective glycosylation of glycoconjugates. It usually presents as a severe disorder in the neonatal period. There is a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced psychomotor retardation, as well as peripheral neuropathy, cerebellar hypoplasia, and retinitis pigmentosa. Patients show a peculiar distribution of subcutaneous fat, nipple retraction, and hypogonadism. There is a 20% lethality in the first year of life due to severe infections, liver insufficiency, or cardiomyopathy.
Marques-da-Silva et al. (2017) noted that CDG1A is the most prevalent form of CDG, with more than 700 patients reported worldwide.
Genetic Heterogeneity of Congenital Disorder of Glycosylation Type I
Multiple forms of CDG type I have been identified; see CDG1B (602579) through CDG1Y (300934) and CDG1AA (617082) through CDG1CC (see 301031).
A congenital disorder of deglycosylation (CDDG; 615273), formerly designated CDG1V, is caused by mutation in the NGLY1 gene (610661).
A disorder formerly designated CDG1Z has been classified as a form of developmental and epileptic encephalopathy (DEE50; 616457).
CDG type Ia was first described in an abstract by Jaeken et al. (1980). In a complete report, Jaeken et al. (1984) described Belgian identical twin sisters with a disorder characterized by psychomotor retardation suggestive of a demyelinating disease and multiple serum glycoprotein abnormalities. Serum and CSF transferrin (TF; 190000) were found to be deficient in sialic acid.
Jaeken et al. (1987) described 4 girls, including the monozygotic twins described earlier, from 3 unrelated families who had a neurologic syndrome characterized by severe psychomotor retardation with generalized hypotonia, hyporeflexia, and trunk ataxia. Growth was retarded, but 2 were moderately obese. All 4 had almond-shaped eyes and alternating internal strabismus. Two had fusiform phalanges of the fingers, prominent labia majora, and symmetric fat accumulations as well as lipodystrophy of the buttocks, which seemed to disappear with age. Biochemical analysis and isoelectric focusing showed a decrease of several serum glycoproteins, and total serum glycoproteins were deficient in sialic acid, galactose, and N-acetylglucosamine. Serum activity of N-acetylglucosaminyltransferase was reduced to 37% of normal, but Jaeken et al. (1987) suggested that since a mixture of isoenzymes from various sources was being measured, the 37% reduction might represent a more profound deficiency of 1 isoenzyme. Among the parents, only the fathers showed some biochemical abnormalities: partial thyroxine-binding globulin (TBG; 314200) deficiency, hypocholesterolemia, and a 10% deficiency of sialic acid, galactose, and N-acetylglucosamine in total serum glycoproteins. Jaeken et al. (1987) thus initially considered that the affected girls might be homozygous for a mutant gene coding for an N-acetylglucosaminyltransferase, possibly on the X chromosome.
Jaeken and Stibler (1989) described the disorder as a neurologic syndrome with cerebellar hypoplasia and peripheral demyelination associated with abnormalities of multiple secretory glycoproteins. All serum glycoproteins were reported as partially deficient in sialic acid, galactose, and N-acetylglucosamine, suggesting a deficiency of N-acetylglucosaminyltransferase.
Kristiansson et al. (1989) reported 7 Swedish children with what the authors termed 'disialotransferrin developmental deficiency syndrome.' There were 3 pairs of sibs and 1 sporadic case. All 7 patients had mental retardation, were prone to acute cerebral dysfunction during catabolic states, and developed abnormal lower neuron, cerebellar, and retinal functions in later childhood. They had a characteristic external appearance with decreased subcutaneous tissue. Biochemical studies showed abnormal sialic acid transferrin patterns in serum and CSF.
Buist and Powell (1991) reported 2 sisters, aged 14 and 16 years, whom they had followed for 13 years. Both presented in infancy with developmental delay, hypotonia, wandering eye movements, strabismus, and failure to thrive. One child had pseudolipomas over each gluteus medius and the other had similar fatty tissue causing enlarged labia majora. The characteristic fat pads disappeared in childhood. Isoelectric focusing of transferrin showed marked decrease of the tetrasialo fraction and increase in the di- and asialo fractions. The findings suggested a generalized defect in sialylation of serum glycoproteins.
Eeg-Olofsson and Wahlstrom (1991) reported that 20 Swedish patients with the carbohydrate-deficient glycoprotein syndrome came from 13 families, all from the southern part of the country. The oldest patient with CDG was a woman born in 1942, and the youngest, a girl born in 1988. Eight Swedish families had 2 sibs with CDG. Two concordantly affected monozygotic twin-pairs were known. In 20 CDG families, if correction was made for the ascertainment bias by exclusion of the index patient in each family, the number of affected sibs and healthy sibs agreed satisfactorily with the recessive hypothesis.
Harrison et al. (1992) studied a 24-month-old girl whose clinical findings of hypotonia, delayed development, cerebellar hypoplasia, and metabolic crises were consistent with the clinical diagnosis of CDG. They also studied a brother and sister, aged 21 and 19 years, respectively, with this disorder. High-resolution 2-dimensional polyacrylamide gel electrophoresis (2DE) and silver staining yielded a potentially pathognomonic profile of multiple serum protein anomalies in CDG. Both parents had normal serum protein 2DE patterns.
Petersen et al. (1993) reported on the first 5 of 8 patients with CDG diagnosed in Denmark from 1989 until the end of 1991. Three were male and 2 were a pair of male-female twins. All 5 children were seen during their first year of life with failure to thrive, feeding difficulties, psychomotor retardation, hypotonia, esotropia, inverted nipples, lipodystrophy, pericardial effusion, and hepatic dysfunction. Steatosis was observed in liver biopsy specimens, and cerebellar hypoplasia was present on computed tomography.
Ohno et al. (1992) described 3 affected Japanese children from 2 families. The clinical picture was that of a multisystem disorder characterized by mental retardation, nonprogressive ataxia, polyneuropathy, hepatopathy during infancy, and growth retardation. Studies of serum transferrin by isoelectric focusing demonstrated increases in disialotransferrin and asialotransferrin. Removal of sialic acid with neuraminidase demonstrated the same transferrin phenotypes as in the parents. Similarly, carbohydrate-deficient fractions of serum alpha-1-antitrypsin (PI; 107400) were detected.
Harrison (1993) identified 9 patients with CDG, including 1 from a nonconsanguineous Puerto Rican family and another from a nonconsanguineous Chinese family.
In a review, Hagberg et al. (1993) stated that CDG I had been diagnosed in 45 Scandinavian patients and presented different clinical phenotypic features of the syndrome according to period of life. During infancy, internal organ symptoms predominate and some may be life-threatening. In later childhood and adolescence, static mental deficiency, cerebellar ataxia, slowly progressive lower limb neuropathy, pigmentary retinal degeneration, and secondary skeletal deformities are the most prominent findings. Hagberg et al. (1993) summarized the features of CDG IIa and compared them with those of CDG I.
Drouin-Garraud et al. (2001) also noted that clinical findings of CDG Ia tend to change with age. During infancy, patients present with severe neurologic involvement with hypotonia, failure to thrive, roving eye movements, and developmental delay. There is often cerebellar and brainstem atrophy as well as hepatic and cardiac manifestations. Children with CDG Ia have a relatively static clinical course, with ataxia as the predominant sign. Musculoskeletal complications, such as kyphoscoliosis and muscular atrophy, appear in late childhood. Adults commonly manifest endocrine dysfunctions, such as hypogonadism and insulin resistance.
De Lonlay et al. (2001) reported the clinical, biologic, and molecular analysis of 26 patients with CDG I including 20 CDG Ia, 2 CDG Ib, 1 CDG Ic, and 3 CDG Ix patients detected by Western blotting and isoelectric focusing of serum transferrin. Based on clinical features, de Lonlay et al. (2001) concluded that CDG Ia could be split into 2 subtypes: a neurologic form with psychomotor retardation, strabismus, cerebellar hypoplasia, and retinitis pigmentosa, and a multivisceral form with neurologic and extraneurologic manifestations including liver, cardiac, renal, or gastrointestinal involvement. Inverted nipples, cerebellar hypoplasia, and abnormal subcutaneous fat distribution were not present in all cases.
Drouin-Garraud et al. (2001) identified a French family in which 3 sibs with CDG Ia displayed an unusual presentation remarkable for both the neurologic presentation and the dissociation between intermediate PMM2 activity in fibroblasts and a decreased PMM2 activity in leukocytes. Their report showed that the diagnosis of CDG Ia must be considered in patients with nonregressive early-onset encephalopathy with cerebellar atrophy, and that intermediate values of PMM2 activity in fibroblasts do not exclude the diagnosis.
Coman et al. (2008) reviewed the skeletal manifestations of congenital disorders of glycosylation, which they suggested may be underrecognized.
Martinez-Monseny et al. (2019) compared the clinical features of 31 patients with CDG Ia, who ranged in age from 4 to 19 years, with those of 26 age, sex, and ethnicity-matched controls. Dysmorphic features, which were categorized as major if the prevalence of the feature was 50% higher in patients compared to controls, included strabismus, upslanting palpebral fissures, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum, and joint laxity. The average number of major dysmorphic features exhibited by each patient was 4.4. Among dysmorphic features that change with increasing age, retrognathia and anteverted nares were more common in younger patients and prominent jaw and prominent nose were more common in older patients. The presence of 3 major dysmorphic features (inverted nipples, strabismus, and lipodystrophy) significantly correlated to the patient score on the International Cooperative Ataxia Rating Scale and to the Nijmegen Paediatric CDG Rating Scale and was inversely correlated with the midsagittal vermis relative diameter on MRI.
Ligezka et al. (2021) described clinical features in 24 patients with CDG Ia. The patients ranged in age from 1 to 70 years, with an average age of 13 years. Twenty-three of the patients had severe developmental disability and cerebellar ataxia, 19 had hypotonia, 14 had neuropathy, 23 had impaired mobility, 8 had a movement disorder, and 22 had impaired communication skills. Other features included seizures in 10 patients, visual impairment in 10, hearing loss in 5, spasticity in 5, coagulation abnormalities in 15, endocrine disturbances in 10, and liver involvement in 10.
Neonatal-Onset CDG Ia
The most severe form of CDG Ia has a neonatal onset. Agamanolis et al. (1986) reported 2 sibs with olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. Cerebellar degeneration progressed rapidly during the first year of life and both children died from intercurrent infections and surgical complications. The authors suggested a metabolic defect. Harding et al. (1988) reported a similar case of neonatal onset with biochemical abnormalities and other systemic involvement. Horslen et al. (1991) reported 2 brothers with neonatal onset of olivopontocerebellare degeneration, failure to thrive, hypotonia, liver disease, and visual inattention. Microcystic renal changes were observed at autopsy. The patients also had abnormalities in serum transferrin, and Horslen et al. (1991) concluded that the disorder was a severe manifestation of CDG.
Clayton et al. (1992) described their seventh patient with neonatal-onset CDG in whom the disorder was established by electrophoresis with immunofixation of serum transferrin, which showed a reduced amount of tetrasialotransferrin, an increased amount of disialotransferrin, and the presence of asialotransferrin. A new feature was severe hypertrophic cardiomyopathy. Respiratory distress and a murmur with episodes of arterial oxygen desaturation had brought the neonate to cardiologic assessment. After initial spontaneous improvement he presented at 9 weeks with severe manifestations of the cardiomyopathy. Chang et al. (1993) reported the case of an 8-month-old male infant who presented in the neonatal period with failure to thrive, bilateral pleural and pericardial effusions, and hepatic insufficiency and showed at autopsy olivopontocerebellar atrophy, micronodular cirrhosis, and renal tubular microcysts.
In a neonate with neurologic abnormalities and congenital nephrotic syndrome of diffuse mesangial sclerosis type, van der Knaap et al. (1996) found diagnostic evidence of CDG I. However, there was no evidence of pontocerebellar atrophy by imaging or at autopsy. They concluded that CDG I should be considered in patients with congenital nephrotic syndrome and that absence of pontocerebellar atrophy did not exclude the diagnosis.
From a review of the literature, Altassan et al. (2018) found that of 933 patients with CDG1A, 55 were reported to have renal involvement. Cystic kidneys were reported in 19, increased renal echogenicity in 23, and enlarged kidney size in 7. Twenty-one patients had proteinuria, described as tubular in 16. Nephrotic-range proteinuria was reported in 6 individuals, with data available for 4, all of whom presented in infancy. Most of the renal findings were reported in the early infantile form of the disorder.
Stromland et al. (1990) found all 10 of the children with this syndrome who were examined had ocular involvement. Esotropia and deficient abduction was found in all 10 patients. Seven children had retinitis pigmentosa, which was verified by an ERG in 3. One patient had retinal signs suggestive of retinitis pigmentosa.
Andreasson et al. (1991) reported the findings in full-field ERGs in 5 patients with CDG. Only 2 of them showed fundus changes typical for retinitis pigmentosa, whereas abnormal ERGs were seen in all. There was no recordable rod response; however, a delay in the cone b-wave implicit time was noted. All patients had nyctalopia. The observations suggested that patients with CDG have a progressive tapetoretinal degenerative disorder of the retinitis pigmentosa type with defined alterations in the ERG.
Martinsson et al. (1994) pictured a 16-year-old patient who showed short stature, prominent jaw, mild anterior chest deformity, and muscle atrophy of the lower limbs. He was unable to stand and walk without support because of peripheral neuropathy and cerebellar ataxia.
Fiumara et al. (1994, 1996) suggested that a familial Dandy-Walker variant (220200) may occur as a feature of the CDG.
De Koning et al. (1998) observed 2 sibs with CDG and nonimmune hydrops fetalis.
Patients with CDG Ia have a thrombotic tendency, whereas a patient with CDG IIa, described by Van Geet et al. (2001), had an increased bleeding tendency. This prompted Van Geet et al. (2001) to investigate whether abnormally glycosylated platelet membrane glycoproteins are involved in the hemostatic complications of both CDG groups. Van Geet et al. (2001) observed abnormal glycosylation of platelet glycoproteins in CDG Ia causing enhanced onset of platelet interactions, leading to thrombotic tendency. Reduced GP Ib (231200)-mediated platelet reactivity with vessel wall components in the CDG IIa patient under flow conditions provided a basis for his bleeding tendency.
Bohles et al. (2001) reported a male infant who presented with persistent hyperinsulinemic hypoglycemia responding to diazoxide treatment. However, this therapy was discontinued because of seizures as a consequence of disturbed water and electrolyte balance. Glucose homeostasis could only be maintained by subtotal pancreatectomy, which was performed at 3.75 years of age. The patient subsequently developed a severe thrombosis, whereupon a congenital disorder of glycosylation was suspected. An abnormal isoelectric focusing pattern of transferring was found and a diagnosis of CDG Ia was confirmed by enzymatic and molecular genetic analysis. The patient had internal strabismus and inverted nipples with an MRI scan demonstrating hypoplasia of the cerebellar vermis and of both cerebral hemispheres. Molecular analysis identified compound heterozygosity for 2 mutations in the PMM2 gene (601785.0001; 601785.0018). Fibroblast phosphomannomutase activity was less than 5% of normal.
Silengo et al. (2003) described hair abnormalities in 3 patients with CDG type I, 1 with CDG Ia and 2 with an unclassified form of the disorder. The hair was sparse and coarse textured, lacked luster, and was slow growing. It showed enhanced fragility with the microscopic findings of trichorrhexis nodosa and pili torti. Silengo et al. (2003) postulated that the underlying cause of the hair anomaly in CDG I was an abnormality of membrane glycoprotein expression during differentiation of epidermis and adnexes.
Coman et al. (2008) described a female infant with mutation-positive CDG1A who died at 3 weeks of age due to cardiac tamponade and who had a skeletal phenotype reminiscent of a type II collagenopathy. Skeletal survey revealed short long bones with 'dumbbell' metaphyseal expansions, generalized epiphyseal ossification delay, ovoid and anteriorly beaked vertebral bodies, hypoplastic cervical vertebrae, 13 rib pairs, hypoplastic pubic bones, and bullet-shaped short tubular bones. Coman et al. (2008) stated that the radiographic skeletal appearance was consistent with a primary skeletal dysplasia, most similar to Kniest dysplasia (156550) or spondyloepiphyseal dysplasia congenita (183900). In addition, MRI of the cervical spine showed elevation of the posterior arch of C1 with the occipital bone and significant spinal canal stenosis at the craniocervical junction due to a bone spur.
In a cohort of 43 patients with CDG Ia, Cechova et al. (2021) identified 10 patients with low cortisol levels and 1 patient with cortisol levels at the lower limit of normal; 2 of the patients had low ACTH levels and 9 had normal ACTH levels, which was suggestive of secondary adrenal insufficiency. Two of the patients had confirmed central adrenal insufficiency and received hydrocortisone replacement therapy or steroid stress dosing during illness. Of the remaining 9 patients, 3 had a normal cortisol response to low-dose ACTH stimulation testing and 1 had a subnormal peak cortisol. The other 5 patients did not undergo ACTH stimulation testing.
The characteristic biochemical abnormality of CDG was discovered serendipitously by Stibler and Jaeken (1990) in the isoelectric focusing of serum transferrin, a test originally devised to screen for alcohol abuse in normal adults (Stibler et al., 1978). Serum transferrin from affected individuals showed a consistent increase of isotransferrins with higher isoelectric points than normal. Carbohydrate determinations in purified transferrin showed deficiencies of sialic acid, galactose, and N-acetylglucosamine. The results suggested that either 2 or all of the normally 4 terminal trisaccharides in transferrin were missing, suggesting a defect in synthesis or catabolism.
Wada et al. (1992) determined the structure of serum transferrin in CDG type I and showed that it was disialylated, missing either of 2 N-linked sugar chains, suggestive of a metabolic error in the early steps of protein glycosylation.
Because coagulation factors and inhibitors are glycoproteins, Van Geet and Jaeken (1993) performed a systematic study of these factors and inhibitors in 9 patients with CDG. All showed a decreased activity of factor XI (F11; 264900) and of the coagulation inhibitors antithrombin III (AT3; 107300) and protein C (PROC; 612283). In 5 of 7 patients older than 1 year, there was also a less pronounced decrease of protein S (PROS1; 176880) and of heparin cofactor II (HCF2; 142360). The authors suggested that this combined coagulation inhibitor deficiency may explain the stroke-like episodes occurring in children with this disorder.
Van Schaftingen and Jaeken (1995) reported that the activity of phosphomannomutase, the enzyme that converts mannose 6-phosphate to mannose 1-phosphate, was markedly deficient (10% or less of control activity) in fibroblasts, liver, and/or leukocytes of 6 patients with CDG I. This was the first report of phosphomannomutase deficiency in higher organisms. Other enzymes involved in the conversion of glucose to mannose 1-phosphate had normal activities. Phosphomannomutase activity was normal in fibroblasts of 2 patients with CDG IIa (212066). Since this enzyme provides the mannose 1-phosphate required for the initial step of protein glycosylation, Van Schaftingen and Jaeken (1995) concluded that phosphomannomutase deficiency is a major cause of CDG I.
Sala et al. (2002) investigated the possible relationship between lipid and protein glycosylation to determine if a compensatory mechanism was present. CDG Ia fibroblasts had higher levels of glycosphingolipids (GSLs) compared to normal fibroblasts and a diminished biosynthesis of cellular glycoproteins in metabolic studies with radioactive precursor sugars including galactose and N-acetylmannosamine. CDG Ia fibroblasts also had increased GSL biosynthesis with radiolabeled sphingosine and lactosylceramide and slowed degradation of GSLs. Using normal and CHO fibroblasts labeled with radioactive galactose in the presence or absence of dMM (an inhibitor of N-glycan maturation), Sala et al. (2002) found an inverse relationship between glycoprotein expression and GSL content. The authors concluded that the increase in GSLs may help to preserve the overall equilibrium of the outer layer of the plasma membrane.
Ligezka et al. (2021) described biochemical features in urine in 24 patients with CDG Ia. Urine sorbitol was elevated in 74% of patients and urine mannitol was elevated in 61% of patients. Urine sorbitol levels were higher in patients with moderate neuropathy compared to no neuropathy. Urine mannitol and sorbitol levels were elevated in patients with mild liver disease. Urine sorbitol levels positively correlated to a severe rating on the Nijmegen pediatric CDG rating scale (NPCRS).
Heyne and Weidinger (1992) reported 3 cases. Analyses of the glycoprotein alpha-1-antitrypsin showed an abnormal cathodic isoform which represented almost half of the total amount of alpha-1-antitrypsin. The authors suggested the use of this marker glycoprotein as a diagnostic tool and suggested that diseases due to inborn errors of N-glycan synthesis be referred to as 'glycanoses.'
Skovby (1993) emphasized the diagnostic usefulness of the finding of inverted nipples at birth in CDG Ia. This sign in floppy infants with poor weight gain, strabismus, abnormal distribution of subcutaneous fat, and cerebellar hypoplasia can suggest the diagnosis which is confirmed by demonstration of carbohydrate-deficient transferrin in serum.
Schollen et al. (2004) concluded that the recurrence risk for CDG Ia is close to 1 in 3 rather than 1 in 4 as expected of an autosomal recessive, indicating transmission ratio distortion. In 92 independent pregnancies among couples at risk for CDG Ia, genotyping in the context of prenatal diagnosis demonstrated that the percentage of affected fetuses (34%; 31/92, p = 0.039) was higher than expected based on Mendel's second law. The transmission ratio distortion might explain the relatively high carrier frequency of the R141H mutation in the PMM2 gene (601785.0001). The authors suggested that the drive of the mutated alleles may relate to a reproductive advantage at the stage of gametogenesis, fertilization, implantation, or embryogenesis, rather than to resistance to environmental factors during infant or adult life.
Martinez-Monseny et al. (2019) trained the Face2Gene facial recognition technology to identify individuals with CDG Ia based on photographs of 31 patients. After training, Face2Gene was able to correctly identify CDG Ia based on the facial photographs of the 31 patients. When 41 photographs of new patients with a confirmed diagnosis of CDG Ia were added, CDG Ia appeared as one of the top 10 syndrome matches offered by this technology.
Prenatal Diagnosis
Bjursell et al. (1998) proposed the combined use of mutation analysis and linkage analysis with polymorphic markers as diagnostic tools for Scandinavian CDG I families requesting prenatal diagnosis. Using this strategy, they had successfully performed 15 prenatal diagnoses for CDG Ia to the time of report.
The typical side chains (or 'antennae') of complex-type N-linked oligosaccharides on most normal human serum glycoproteins arise from the processing and remodeling of mannose-containing structures and are therefore the net product of multiple exoglycosidases and glycosyltransferases. Based on a partial decrease in total GlcNAc transferase activity in serum, abnormalities were postulated of one or more of the specific GlcNAc transferases responsible for the initial extension of the antennae of N-linked oligosaccharides. Powell et al. (1994) studied both serum glycoproteins and oligosaccharides derived from fibroblasts of individuals with CDG type I. Several experiments failed to show a specific defect in the processing of N-linked oligosaccharides, but instead suggested a defect in the synthesis and transfer of the dolichol lipid-linked precursor itself, with reduced levels of mannose incorporation into both the precursor and nascent glycoproteins. As protein synthesis itself was not affected, the net result was a relative underglycosylation of glycoproteins in the CDG samples relative to controls. In some CDG patients, the lipid-linked oligosaccharide was abnormally small. Powell et al. (1994) concluded that at least in some patients, CDG is not due to a defect in processing of N-linked oligosaccharides, but rather to defective synthesis and transfer of nascent dolichol-linked oligosaccharide precursors.
Panneerselvam and Freeze (1996) showed that 4 CDG fibroblast cell lines had 2 glycosylation abnormalities: incorporation of labeled mannose into proteins was reduced 3- to 10-fold below normal and the size of the lipid-linked oligosaccharide precursor was much smaller than in controls. Addition of exogenous mannose, but not glucose, to these CDG cells corrected both abnormalities. The correction was not permanent, and the defects immediately reappeared when mannose was removed. Although they did not identify the primary defect in CDG, Panneerselvam and Freeze (1996) suggested that their studies showed that intracellular mannose is limited and that some patients may benefit from including mannose in their regular diets.
Barone et al. (2008) reported 2 adult Sicilian brothers with CDG Ia confirmed by genetic analysis (601785.0001; 601785.0003). Clinical features in both patients included early-onset cerebellar atrophy, mental impairment, pigmentary retinopathy, and dysmorphic features. The younger brother, patient 2, was more severely affected and had additional features, including abnormal subcutaneous fat distribution, inverted nipples, genu valgum and flat and inverted feet. He also had more severely affected motor-adaptive functions and communication ability and lower full-scale IQ compared to his older brother. MALDI-TOF mass spectrometry of serum transferrin and alpha-1-antitrypsin showed more pronounced glycosylation defects in the younger brother. Barone et al. (2008) concluded that there is a correlation between absence of N-glycosylation and clinical expression, and that glycoproteomic analysis may reveal differences in CDGIa patients with different disease severity.
Ligezka et al. (2021) treated a patient with CDG Ia with epalrestat for 12 months on a compassionate use protocol. Liver elastography, antithrombin III levels, and INR remained normal throughout treatment. The patient's international cooperative ataxia rating scale (ICARS) score improved within 12 months of treatment and the patient's body mass index and appetite improved. The level of transferrin glycosylation improved after 6 months of therapy and urine sorbitol and mannitol levels nearly normalized. Ligezka et al. (2021) also treated fibroblasts from 6 patients with CDG Ia with epalrestat and demonstrated an improved global glycosylation profile.
Martinsson et al. (1994) performed linkage analysis in 25 CDG I pedigrees using highly polymorphic microsatellite markers and detected linkage with markers on chromosome 16p. The lod score was above 8 (theta = 0.00) for several markers in that region. Recombination events in some pedigrees indicated that the CDG1 locus was located in a 13-cM interval between D16S406 and D16S500. No heterogeneity could be detected in the European families studied. The positions of the cytogenetically localized flanking markers suggested that the CDG1 locus was on 16p13.3-p13.12.
Matthijs et al. (1996) analyzed a series of polymorphic markers on 16p13 in 17 families with CDG1 and confirmed linkage to the region between D16S406 and D16S500. The telomeric border of the candidate region was placed proximal to D16S406 by crossovers observed in 2 families. In 1 family with 2 affected sibs, the disease was not linked to 16p. Matthijs et al. (1996) stated that genetic heterogeneity had not previously been reported for CDG I and they noted implications for prenatal diagnosis. Allelic associations suggested to them that the disease locus was close to D16S414/D16S497.
Bjursell et al. (1997) studied 44 CDG I families from 9 countries using markers from the 16p13 region. One specific haplotype was found to be markedly overrepresented in CDG I patients from a geographically distinct region in Scandinavia: western parts of Sweden, southern parts of Norway, and eastern Denmark. Their analyses of the extent of the common haplotype in these families indicated a refined region for the CDG1 gene and indicated strong linkage disequilibrium with selected markers, thus narrowing the assignment to less than 1 Mb of DNA and less than 1 cM in the very distal part of the CDG1 region previously defined by Martinsson et al. (1994).
The transmission pattern of CDG Ia in the families reported by Matthijs et al. (1997) and Imtiaz et al. (2000) was consistent with autosomal recessive inheritance.
In 16 CDG I patients from different geographic origins and with a documented phosphomannomutase deficiency, Matthijs et al. (1997) found 11 different missense mutations in the PMM2 gene (see, e.g., 601785.0001-601785.0004). Additional mutations, including point mutations, deletions, intronic mutations and exon-skipping mutations were reported by others, including Carchon et al. (1999), Matthijs et al. (1999), and Vuillaumier-Barrot et al. (1999).
Imtiaz et al. (2000) reported the U.K. experience with CDG type Ia. Eighteen patients from 14 families had been diagnosed with CDG type I on the basis of their clinical symptoms and/or abnormal electrophoretic patterns of serum transferrin. Eleven of the 16 infants died before the age of 2 years. Patients from 12 families had a typical type I transferrin profile, but one had a variant profile and another, who had many clinical features of CDG type I, had a normal profile. Eleven of the patients from 10 families with a typical type I profile had deficiency of PMM, but there was no correlation between residual enzyme activity and severity of disease. All these patients were compound heterozygotes for mutations in the PMM2 gene, with 7 of 10 families having the common arg141-to-his (601785.0001) mutation. Imtiaz et al. (2000) identified 8 different mutations in the PMM2 gene, including 3 novel ones. There was no correlation between genotype and phenotype, although the sibs had similar phenotypes. Three patients, including the one with the normal transferrin profile, did not have a deficiency of phosphomannomutase or phosphomannose isomerase.
Neumann et al. (2003) identified homozygosity for an N216I mutation (601785.0002) in the PMM2 gene in a 16-month-old boy with postnatal macrosomia, unusual eyebrows, and typical biochemical findings on isoelectric focusing of serum transferrin and reduced phosphomannomutase activity in leukocytes and cultured fibroblasts. The child did not have inverted nipples or abnormal fat pads. Neumann et al. (2003) suggested that the homozygous mutation could have a specific CDG Ia phenotype correlation.
Van de Kamp et al. (2007) reported 2 unrelated male and female infants who presented with nonimmune hydrops fetalis and were later diagnosed with CDG Ia. Both patients were compound heterozygotes for the common, relatively mild F119L mutation (601785.0006), as well as a more severe mutation (a frameshift and another missense mutation, respectively). Van de Kamp et al. (2007) suggested that the presence of 1 severe mutation may be required for the development of hydrops fetalis, and that CDG Ia should be considered in the differential diagnosis of nonimmune hydrops fetalis.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family 8307998, they identified a homozygous missense mutation in the PMM2 gene (601785.0023) in 3 sibs with mild intellectual disability, thin upper lip, flat nasal bridge, and strabismus, who were diagnosed with glycosylation disorder CDG Ia (212065). The parents, who were first cousins, were carriers, and they had 5 healthy children.
In 31 patients with CDG Ia, who ranged in age from 4 to 19 years, Martinez-Monseny et al. (2019) identified 30 mutations in the PMM2 gene. Parents of the patients were confirmed to be carriers. The severity of the homozygous mutations, which were found in 3 patients, was categorized based on potential protein alteration effects and prior published in vitro studies of residual enzymatic activity. The severity of the potential protein impacts of compound heterozygous mutations were classified as mild, moderate, or severe based on the combined protein alteration effects and residual enzymatic activity of each mutation. The distribution of patients based on potential protein alterations of their molecular findings included 1 severe, 17 moderate, 1 mild, and 11 unknown (due to lack of information about the pathogenicity of at least 1 pathogenic variant). No genotype/phenotype correlations were identified.
Kane et al. (2016) noted that very few individuals with CDGs have homozygous mutations compared to compound heterozygous mutations. It had been proposed that homozygous mutations are either lethal or result in subclinical phenotypes, and that a genotype conveying residual catalytic activity is necessary for survival. By analysis of DNA from cultured fibroblasts of 8 patients with variable CDGs who had compound heterozygous mutations of PMM2, MOGS (601336), MPI (154550), ALG3 (608750), ALG12 (607144), DPAGT1 (191350), and ALG1 (605907), Kane et al. (2016) found that many of the somatic cells had genotypes that included wildtype alleles. These findings suggested that mitotic recombination can generate wildtype alleles in somatic cells, which may contribute to the survival and the variable expressivity seen in individuals with compound heterozygous CDGs. The findings also provided an explanation for prior observations of a reduced frequency of homozygous mutations.
Skovby (1993) stated that cases of CDG Ia had been observed in many parts of the world, including Iran and Japan, but that about half of the cases known worldwide were Scandinavian.
Bjursell et al. (1998) showed that the specific haplotype in CDG I patients from western Scandinavia is associated with the 357C-A mutation in the PMM2 gene (601785.0010).
Briones et al. (2002) presented their experience with a diagnosis of CDG Ia in 26 Spanish patients from 19 families. Patients in all but 1 of the families were compound heterozygous for mutations in the PMM2 gene. Eighteen different mutations were detected. In contrast to other series in which the R141H (601785.0001) mutation represents 43 to 53% of the alleles, only 9 of 36 (25%) of the alleles had this mutation. The common European F119L (601785.0006) mutation was not identified in any of the Spanish patients, but the V44A (601785.0020) and D65Y (601785.0005) mutations probably originated in the Iberian peninsula, as they have only been reported in Portuguese and Latin-American patients. Probably because of this genetic heterogeneity, Spanish patients showed very diverse phenotypes that are, in general, milder than in other series.
CDGs were formerly referred to as 'carbohydrate-deficient glycoprotein syndromes' (Marquardt and Denecke, 2003; Grunewald et al., 2002). Conventionally, untyped and unclassified cases of CDG are labeled CDG-x (see 212067) until they are characterized at the molecular level. Orlean (2000) discussed the revised nomenclature for CDGs proposed by the participants at the First International Workshop on CDGs in Leuven, Belgium, in November 1999.
Jaeken (1990) favored autosomal recessive inheritance, although he had not completely abandoned the possibility of X-linked inheritance. Some have referred to the condition as the 'desialotransferrin developmental deficiency syndrome' (Kristiansson et al., 1989), but this is a misnomer since the serum protein abnormality is not limited to sialic acid or to transferrin (Jaeken, 1990).
Schneider et al. (2012) generated transgenic mice with homozygous or compound heterozygous hypomorphic Pmm2 alleles: R137H, which is analogous to human R141H (601785.0001), and F118L, which is predicted to lead to mild loss of enzyme activity. Homozygous R137H and compound heterozygous R137H/F118L mice were embryonic lethal. Homozygosity for R137H was associated with no residual enzymatic activity, whereas R137H/F118L mice had about 11% residual activity. Homozygous F118L mice were clinically similar to wildtype, with 38 to 42% residual PMM2 activity, which was sufficient to prevent pathologic consequences. Compound heterozygous R137H/F118L embryos showed very poor intrauterine growth with extensive degradation of multiple organs and evidence of hypoglycosylation of glycoproteins. Treatment of heterozygous F118L females with oral mannose in water beginning 1 week prior to mating resulted in a 2-fold increase of serum mannose concentrations and rescued the embryonic lethality of compound heterozygous R137H/F118L offspring, who survived beyond weaning. Compound heterozygous offspring under treatment showed organ development and glycosylation comparable to wildtype mice, indicating mannose-mediated normalization of glycosylation. The phenotypic rescue remained apparent even after 4-month maintenance of the offspring on normal water. The results revealed an essential role for proper glycosylation during embryogenesis and suggested that mannose administration to at-risk mothers may reduce the phenotype of offspring.
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