JAEKEN SYNDROME
CDG1A
phosphomannomutase 2 deficiency
CDG Ia
CDGIa
Congenital disorder of glycosylation type Ia
Congenital disorder of glycosylation type 1a
Carbohydrate deficient glycoprotein syndrome type Ia
CDG-Ia
CARBOHYDRATE-DEFICIENT GLYCOPROTEIN SYNDROME, TYPE Ia, FORMERLY
CDG syndrome type Ia
Congenital disorder of glycosylation with epilepsy as a major feature
-Rare genetic disease
-Rare neurologic disease
Congenital disorder of glycosylation with hepatic involvement
-Rare genetic disease
-Rare hepatic disease
Congenital disorder of glycosylation with skin involvement
-Rare genetic disease
-Rare skin disease
Disorder of protein N-glycosylation
-Rare genetic disease
Non-X-linked congenital disorder of glycosylation with intellectual disability as a major feature
-Rare genetic disease
-Rare neurologic disease
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, ... 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. - Genetic Heterogeneity of Congenital Disorder of Glycosylation Type I Multiple forms of CDG type I have been identified; see CDG1B (602579) through CDG1X (615597).
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 ... 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. - 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.
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 ... 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. - 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 Knapp 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.
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 ... 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 Arabic) 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.
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) ... 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.
PMM2-CDG (CDG-Ia) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides. The presentation of this disorder is highly variable; therefore, the diagnosis should be considered in a child with developmental delay and hypotonia in combination with any of the following findings:...
DiagnosisClinical DiagnosisPMM2-CDG (CDG-Ia) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides. The presentation of this disorder is highly variable; therefore, the diagnosis should be considered in a child with developmental delay and hypotonia in combination with any of the following findings:Failure to thriveHepatic dysfunction (elevated transaminases)Coagulopathy with low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein SHypothyroidism, hypogonadismEsotropiaPericardial effusionAbnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistencySeizuresStroke-like episodesOsteopenia, scoliosisCerebellar hypoplasia/atrophy and small brain stem [Aronica et al 2005]The diagnosis of PMM2-CDG (CDG-Ia) should be considered in adolescents or adults with suggestive histories and any of the following findings:Cerebellar dysfunction (ataxia, dysarthria, dysmetria)Non-progressive cognitive impairmentStroke-like episodesPeripheral neuropathy with or without muscle wastingAbsent puberty in females, small testes in malesRetinitis pigmentosaProgressive scoliosis with truncal shorteningJoint contracturesThe diagnosis of PMM2-CDG (CDG-Ia) should also be considered in a fetus with non-immune hydrops fetalis [van de Kamp et al 2007, Léticée et al 2010].Neuroimaging. An enlarged cisterna magna and superior cerebellar cistern is observed in late infancy to early childhood. Occasionally, both infratentorial and supratentorial changes compatible with atrophy are present. Dandy-Walker malformations and small white matter cysts have been reported [Peters et al 2002].Myelination varies from normal to delayed or insufficient [Holzbach et al 1995].Serial CTs performed on three children with PMM2-CDG (CDG-Ia) revealed that enlargement of the spaces between the folia of the cerebellar hemispheres, especially from the anterior to the posterior aspect, as well as atrophy of the anterior vermis, seemed to progress until around age five years [Akaboshi et al 1995]. Progression of cerebellar atrophy on MRI after age five years is variable. After age nine years, progression of the cerebellar atrophy was not evident. Development of the supratentorial structures was normal.TestingPMM2-CDG (CDG-Ia) is caused by deficiency of phosphomannomutase (PMM) enzyme activity resulting in the defective synthesis of N-linked oligosaccharides, sugars linked together in a specific pattern and attached to proteins and lipids (N-linked glycans link to the amide group of asparagine via an N-acetylglucosamine residue) [Jaeken & Matthijs 2001, Grunewald et al 2002].Analysis of serum transferrin glycoforms (also called "transferrin isoforms analysis" or "carbohydrate-deficient transferrin analysis"). The diagnostic test for PMM2-CDG (CDG-Ia) is isoelectric focusing (IEF) or other isoform analysis (i.e., performed by capillary electrophoresis, GC/MS, CE-ESI-MS, MALDI-MS) to determine the number of sialylated N-linked oligosaccharide residues linked to serum transferrin [Jaeken & Carchon 2001, Marklová & Albahri 2007, Sanz-Nebot et al 2007]. Results of such testing may reveal the following:Normal transferrin isoform pattern. Two biantennary glycans linked to asparagine with four sialic acid residuesType I transferrin isoform pattern. Decreased tetrasialotransferrin and increased asialotransferrin and disialotransferrin. The pattern indicates defects in the earliest synthetic steps of the N-linked oligosaccharide synthetic pathway.Type II transferrin isoform pattern. Increased trisialotransferrins and/or monosialotransferrins. The pattern indicates defects in the later parts of the N-linked glycan pathway.Note: (1) The diagnostic validity of analysis of serum transferrin glycoforms before age three weeks is controversial [Clayton et al 1992, Stibler & Skovby 1994]. (2)The use of Guthrie cards with whole blood samples is not suggested; however, the use of Guthrie cards with blotted serum yields accurate results [Carchon et al 2006]. (3) Individuals with the clinical diagnosis of PMM2-CDG (CDG-Ia) and biochemical diagnosis of PMM enzyme deficiency with normal transferrin glycosylation have been reported [Fletcher et al 2000, Marquardt & Denecke 2003, Hann et al 2006]. (4) The possibility that an abnormal transferrin glycoform analysis is the result of a transferrin protein variant can be confirmed with a glycoform analysis of a serum sample from the parents.Phosphomannomutase (PMM) enzyme activity. In individuals presenting with a severe/classic clinical picture of PMM2-CDG (CDG-Ia), PMM enzyme activity in fibroblasts and leukocytes is typically 0% to 10% of normal [Van Schaftingen & Jaeken 1995, Carchon et al 1999, Jaeken & Carchon 2001]. Molecular Genetic TestingGene. PMM2 is the only gene associated with (PMM2-CDG (CDG-Ia).Clinical testingSequence analysisIn individuals with enzymatically proven PMM2-CDG (CDG-Ia), the mutation detection rate in PMM2 is as high as 100%.The p.Arg141His mutation is found in the compound heterozygous state in approximately 40% of individuals; it is never found in the homozygous state.The mutation p.Phe119Leu is frequently found in northern Europe, where the genotype [p.Arg141His]+[p.Phe119Leu] makes up approximately 72% of all mutations [Jaeken & Matthijs 2001].The mutations p.Val231Met and p.Pro113Leu are common all over Europe.Deletion/duplication analysis to detect the 28-kb deletion which includes exon 8 [Schollen et al 2007] and other novel exonic or whole-deletionsTable 1. Summary of Molecular Genetic Testing Used in PMM2-CDG (CDG-Ia)View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTwo MutationsOne MutationPMM2Sequence analysisSequence variants 295%98%ClinicalDeletion / duplication analysis 3Exonic or whole-gene deletionsUnknownUnknown1. Individuals with enzymatically confirmed diagnosis [G Matthijs, personal communication]2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirmation of the diagnosis in a proband requires molecular genetic testing (sequence analysis followed by deletion/duplication analysis if one or both mutations are not identified) following the finding of a type I transferrin isoform pattern.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in PMM2.
The typical clinical course of PMM2-CDG (CDG-Ia) has been divided into an infantile multisystem stage, late-infantile and childhood ataxia-intellectual disability stage, and adult stable disability stage. Recent reports have widened the phenotypic spectrum to include hydrops fetalis at the severe end [van de Kamp et al 2007] and a mild neurologic phenotype in adults with multisystemic involvement at the mild end [Barone et al 2007, Coman et al 2007, Grünewald 2009]....
Natural HistoryThe typical clinical course of PMM2-CDG (CDG-Ia) has been divided into an infantile multisystem stage, late-infantile and childhood ataxia-intellectual disability stage, and adult stable disability stage. Recent reports have widened the phenotypic spectrum to include hydrops fetalis at the severe end [van de Kamp et al 2007] and a mild neurologic phenotype in adults with multisystemic involvement at the mild end [Barone et al 2007, Coman et al 2007, Grünewald 2009].Infantile multisystem stage. Historically, PMM2-CDG (CDG-Ia) was characterized by cerebellar hypoplasia, facial dysmorphism, psychomotor retardation, and abnormal subcutaneous fat distribution; however, the clinical phenotype continues to broaden.Infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, and diarrhea may cause severe failure to thrive. Growth is significantly impaired [Kjaergaard et al 2002]. Although distinctive facies (high nasal bridge and prominent jaw) and large ears have been reported in the northern European population, these features have not been emphasized in reports of US individuals [Krasnewich & Gahl 1997, Enns et al 2002]. An unusual distribution of subcutaneous fat over the buttocks and the suprapubic region may be observed. In girls, the labia majora are involved as well. Inverted nipples are common.In one large study, two distinct clinical presentations were observed [de Lonlay et al 2001]:A purely neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia early on, and neuropathy and retinitis pigmentosa in the first or second decade. This form was not fatal.A neurologic-multivisceral form in which manifestations occur early in life. All organs with the exception of the lungs can be involved. Hepatic fibrosis and renal hyperechogenicity are consistent. Some infants have hepatopathy, pericardial effusion, nephrotic syndrome, renal cysts, and multiorgan failure. Approximately 20% of the infants die within the first year of life from failure to thrive, hypoalbuminemia, and aspiration pneumonia in what is called the "infantile catastrophic phase" characterized by intractable hypoalbuminemia, anasarca, and respiratory distress [de Lonlay et al 2001, Marquardt & Denecke 2003]. Strabismus and cerebellar hypoplasia are occasionally absent.Note: The relatively specific findings of PMM2-CDG (CDG-Ia) including dysmorphic features, inverted nipples, and abnormal fat pads are occasionally absent.Congenital cardiac anomalies, hypertrophic cardiomyopathy with transient myocardial ischemia, or cardiac effusions have been reported but are rare [Kristiansson et al 1998, Marquardt et al 2002, Romano et al 2009]. Pericardial effusions are typically without clinical sequelae and usually disappear in a year or two; however, persistent pericardial effusions have been seen in a few more medically involved cases, and have resulted in death in one case [Truin et al 2008] Liver function measurements begin to rise in the first year of life. Transaminases (AST and ALT) in young children may be in the range of 1000 to 1500 without clinical sequelae. Typically, the ALT and AST return to normal by age three to five years in children with PMM2-CDG (CDG-Ia) and remain normal throughout their lives with occasional mild elevations during intercurrent illnesses. These children do not need a liver biopsy unless warranted by additional clinical evidence. Liver biopsy can demonstrate lamellar inclusions in macrophages and in hepatocyte lysosomes but not in Kupffer cell lysosomes [Jaeken & Matthijs 2001].In general, children with PMM2-CDG (CDG-Ia) are chemically euthyroid [Miller & Freeze 2003].Seizures, which are usually responsive to antiepileptic drugs, may occur as early as the second or third year.Renal ultrasound examinations in eight infants and children with PMM2-CDG (CDG-Ia) showed no changes in the two with the neurologic form and increased cortical echogenicity and/or small pyramids that may or may not have been hyperechoic in the six with the multivisceral form [Hertz-Pannier et al 2006]. Nephrotic syndrome is rare but has been reported [Grünewald 2009]. Siblings with PMM2-CDG (CDG-Ia) have been reported with immunologic dysfunction/diminished chemotaxis of neutrophils and poor immune response to vaccinations [Blank et al 2006].One child with PMM2-CDG (CDG-Ia) and a skeletal dysplasia, characterized by flattening of all vertebrae (platyspondyly), had severe spinal cord compression at the level of the craniocervical junction [Schade van Westrum et al 2006].Osteopenia, seen both on x-ray and documented by densitometry is common and remains throughout life.Late-infantile and childhood ataxia-intellectual disability stage occurs between ages three and ten years. Children have a more static course characterized by hypotonia and ataxia. Language and motor development are severely delayed and walking without support is rarely achieved [Jaeken & Matthijs 2001]. IQ ranges from 40 to 70. As the spectrum of PMM2-CDG (CDG-Ia) expands, individuals with borderline and even normal development have been described [Barone et al 2007, Giurgea et al 2005, Pancho et al 2005]. The children usually are extroverted and cheerful. Seizures may occur; they are usually responsive to antiepileptic drugs.In this stage and in adulthood, affected individuals may have stroke-like episodes or transient unilateral loss of function sometimes associated with fever, seizure, dehydration, or trauma. Recovery may occur over a few weeks to several months. Persistent neurologic deficits after a stroke-like episode occasionally occur but are rare. The etiology of these stroke-like episodes has not been fully elucidated. In one patient, MRI imaging demonstrated different findings after two such episodes, the first an ischemic process and the second edema with subsequent focal necrosis [Ishikawa et al 2009]. A progressive peripheral neuropathy may begin in this age range.Retinitis pigmentosa, myopia [Jensen et al 2003], cataract [Morava et al 2009], joint contractures, and skeletal deformities may also occur.Adult stable disability stage. Adults with PMM2-CDG (CDG-Ia) typically demonstrate stable rather than progressive intellectual disability and variable peripheral neuropathy. Progression of thoracic and spinal deformities can result in severe kyphoscoliosis.Previously undiagnosed adults are now being recognized because of multisystem involvement and cerebellar ataxia [Schoffer et al 2006, Barone et al 2007]. Additionally the mild end of the adult phenotypic spectrum has expanded to include normal cognitive abilities; in three affected sibs, all had multisystem involvement, one with significant cognitive impairment and two with normal cognition [Stibler et al 1994, Jaeken & Matthijs 2001, Coman et al 2007, Krasnewich et al 2007].Women lack secondary sexual development as a result of hypogonadotrophic hypogonadism [De Zegher & Jaeken 1995, Kristiansson et al 1995, Miller & Freeze 2003]. In some females, laparoscopy and ultrasound examination have revealed absent ovaries. Males virilize normally at puberty but may exhibit decreased testicular volume.Other endocrine dysfunction includes hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and hyperinsulinemic hypoglycemia [Miller & Freeze 2003, Shanti et al 2009]. Glycosylation and resultant function of IGFBP3 and an acid-labile subunit (ALS) in the IGF pathway is impaired in CDG [Miller et al 2009].Coagulopathy with decreased serum concentrations of factors IV, IX, and XI, antithrombin III, protein C, and protein S may be present. Deep venous thrombosis in adults has been reported [Krasnewich et al 2007].Renal microcysts may be identified on renal ultrasound examination but renal function is typically preserved throughout adulthood [Strom et al 1993].Pathophysiology. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids, incorrect synthesis of these compounds results in multisystemic clinical manifestations [Varki 1993, Freeze 2006].
Lack of correlation between genotype and phenotype in PMM2-CDG (CDG-Ia) has been reported [Erlandson et al 2001, Jaeken & Matthijs 2001, Westphal et al 2001]. In general, individuals with all genotypes show the basic signs of the disorder; i.e., developmental delay, cerebellar atrophy, peripheral neuropathy, stroke-like episodes or comatose episodes, epilepsy, retinal pigmentary degeneration, strabismus, skeletal abnormalities, and hepatopathy. However, the extent of the non-neurologic findings varies depending on the genotype:...
Genotype-Phenotype CorrelationsLack of correlation between genotype and phenotype in PMM2-CDG (CDG-Ia) has been reported [Erlandson et al 2001, Jaeken & Matthijs 2001, Westphal et al 2001]. In general, individuals with all genotypes show the basic signs of the disorder; i.e., developmental delay, cerebellar atrophy, peripheral neuropathy, stroke-like episodes or comatose episodes, epilepsy, retinal pigmentary degeneration, strabismus, skeletal abnormalities, and hepatopathy. However, the extent of the non-neurologic findings varies depending on the genotype:C-terminal mutations, including p.His218Leu, p.Thr237Met, and p.Cys241Ser, may be associated with a milder phenotype [Matthijs et al 1999, Tayebi et al 2002].The phenotypic spectrum of the [p.Arg141His]+[p.Phe119Leu] genotype, the most prevalent genotype in PMM2-CDG (CDG-Ia), was studied in Scandinavia [Kjaergaard et al 2001]. Individuals with the [p.Arg141His]+[p.Phe119Leu] genotype probably represent the severe end of the clinical spectrum of CDG-1a. Presentation was uniformly early with severe feeding problems, severe failure to thrive, severe hypotonia, developmental delay obvious before age six months, and hepatic dysfunction. Asymptomatic pericardial effusions were common in the first year of life. The functional outcome in ambulation and speech was variable.A severe phenotype presenting with a high mortality rate was observed with the [p.Asp188Gly]+[p.Arg141His] genotype: in the study by Matthijs et al [1998], four of five children with this genotype died before age two years. The remaining child, aged ten years, was severely affected.de Lonlay et al [2001] reported several compound heterozygous genotypes (including [p.Arg141His]+[ p.Thr226Ser], [p.Arg141His]+[p.Ile132Thr], and [p.Arg141His]+[p.Glu139Lys]) that appear to be associated with a milder phenotype termed the "neurologic form" without pericardial effusions, coagulation defects, or nutritional disturbances. Some individuals are able to walk independently.The p.Val231Met mutation is associated with high early mortality and severe multi-organ insufficiency.Homozygosity or compound heterozygosity for severe mutations with virtually no residual activity, such as p.Arg141His, is likely incompatible with life [Matthijs et al 2000].
Any child with evidence of coagulopathy, hepatopathy, elevated TSH, or cerebellar hypoplasia and the triad of hypotonia, developmental delay, and failure to thrive should be evaluated for PMM2-CDG (CDG-Ia)...
Differential DiagnosisAny child with evidence of coagulopathy, hepatopathy, elevated TSH, or cerebellar hypoplasia and the triad of hypotonia, developmental delay, and failure to thrive should be evaluated for PMM2-CDG (CDG-Ia)Other genetic disorders to consider in the differential diagnosisPrader-Willi syndromeCongenital muscular dystrophies including Fukuyama congenital muscular dystrophy (FCMD) caused by mutations in FCMD, muscle-eye-brain (MEB) disease caused by mutations in POMGNT1 [Yoshida et al 2001, Martin & Freeze 2003] and Walker-Warburg syndrome, caused by mutations in POMT1 (see Congenital Muscular Dystrophies Overview)Congenital myopathies (e.g., X-linked myotubular myopathy, multiminicore myopathy)Many metabolic and genetic disorders that present in infancy share at least some of the clinical features of CDG-1a. The following metabolic disorders are in the differential diagnosis of hypotonia, developmental delay, and failure to thrive:Mitochondrial disorders (see Mitochondrial Disorders Overview)Peroxisome biogenesis disorders, Zellweger syndrome spectrumUrea cycle defects (see Urea Cycle Disorders Overview)Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with PMM2-CDG (CDG-Ia) the following evaluations are recommended [Jaeken & Carchon 2001, Jaeken & Matthijs 2001, Grunewald et al 2002, Kjaergaard et al 2002, Miller & Freeze 2003, Grünewald 2009]:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with PMM2-CDG (CDG-Ia) the following evaluations are recommended [Jaeken & Carchon 2001, Jaeken & Matthijs 2001, Grunewald et al 2002, Kjaergaard et al 2002, Miller & Freeze 2003, Grünewald 2009]:Liver function testsMeasurement of serum albumin concentrationThyroid function tests to evaluate for decreased thyroid binding globulin, elevated serum concentration of TSH, and low serum concentration of free T4Coagulation studies including protein C, protein S, antithrombin III, and factor IXUrinalysis to evaluate for proteinuriaMeasurement of serum concentration of gonadotropins in adolescent and adult women to look for evidence of hypogonadotrophic hypogonadismEchocardiogram to evaluate for pericardial effusionsRenal ultrasound examination to evaluate for microcystsFormal ophthalmologic evaluation since ocular anomalies are frequent and can involve both the structural components (development of the lens and retina) as well as ocular mobility and intraocular pressure [Morava et al 2009]Treatment of ManifestationsFailure to thrive. Infants and children can be nourished with any type of formula for maximal caloric intake. They can tolerate carbohydrates, fats, and protein. Early in life, children may do better on elemental formulas. Their feeding may be advanced based on their oral motor function. Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve.Oral motor dysfunction with persistent vomiting. Thickening of feeds, maintenance of an upright position after eating, and antacids can help children who experience gastroesophageal reflux and/or persistent vomiting. Consultation with a gastroenterologist and nutritionist is often necessary. Children with a gastrostomy tube should be encouraged to eat by mouth if the risk of aspiration is low. Continued speech therapy and oral motor therapy aid transition to oral feeds and encourage speech when the child is developmentally ready.Developmental delay. Occupational therapy, physical therapy, and speech therapy should be instituted. As the developmental gap widens between children with PMM2-CDG (CDG-Ia) and their unaffected peers, parents need continued counseling and support."Infantile catastrophic phase." Very rarely, infants may have a complicated early course presenting with infection or seizure, hypoalbuminemia with third spacing that may progress to anasarca. Some children are responsive to aggressive albumin replacement with lasix, others may have a more refractory course. Symptomatic treatment in a pediatric tertiary care center is recommended. Parents should also be advised that some infants with PMM2-CDG (CDG-Ia) never experience a hospital visit while others may require frequent hospitalizations.Strabismus. Intervention by a pediatric ophthalmologist early in life is important to preserve vision through glasses, patching, or surgery.Hypothyroidism. Thyroid function tests are frequently abnormal in children with PMM2-CDG (CDG-Ia). However, free thyroxine analyzed by equilibrium dialysis, the most accurate method, has been reported as normal in seven individuals with PMM2-CDG (CDG-Ia). Diagnosis of hypothyroidism and L-thyroxine supplementation should be reserved for those children and adults with elevated TSH and low free thyroxine measured by equilibrium dialysis.Stroke-like episodes. Supportive therapy includes hydration by IV if necessary and physical therapy during the recovery period.Coagulopathy. Low levels of coagulation factors, both pro- and anti-coagulant, rarely cause clinical problems in daily activities but must be acknowledged if an individual with PMM2-CDG (CDG-Ia) undergoes surgery. Consultation with a hematologist (to document the coagulation status and factor levels) and discussion with the surgeon are important. When necessary, infusion of fresh frozen plasma corrects the factor deficiency and clinical bleeding. The potential for imbalance of the level of both pro- and anti-coagulant factors may lead to either bleeding or thrombosis. Care givers, especially of older affected individuals, should be taught the signs of deep venous thrombosis.Osteopenia. While present from infancy there does not appear to be a significant increased risk of fracture. Should fracture occur, management should follow standards of medical care.Additional management issues of adults with PMM2-CDG (CDG-Ia)Orthopedic issues—thorax shortening, scoliosis/kyphosis. Management involves appropriate orthopedic and physical medicine management, well-supported wheel chairs, appropriate transfer devices for the home, and physical therapy. Occasionally, surgical treatment of spinal curvature is warranted.Deep venous thrombosis (DVT). DVT has been reported in two adults with PMM2-CDG (CDG-Ia). Rapid diagnosis and treatment of DVT are essential to minimize the risk of pulmonary emboli; sedentary affected adults and children are at increased risk for DVT. Independent living issues. Young adults with PMM2-CDG (CDG-Ia) and their parents need to address issues of independent living. Aggressive education throughout the school years in functional life skills and/or vocational training helps the transition when schooling is completed. Independence in self care and the activities of daily living should be encouraged. Support and resources for parents of a disabled adult are an important part of management.Prevention of Secondary ComplicationsBecause infants with PMM2-CDG (CDG-Ia) have less physiologic reserve than their peers, parents should have a low threshold for evaluation by a physician for prolonged fever, vomiting, or diarrhea. Aggressive intervention with antipyretics, antibiotics if warranted, and hydration may prevent the morbidity associated with the "infantile catastrophic phase."Although only one case of skeletal dysplasia in PMM2-CDG (CDG-Ia) has been reported, plain spine films assessing cervical spine anomalies may be useful [Schade van Westrum et al 2006].SurveillanceAnnualAssessment by a physician with attention to overall health and referral for speech therapy, occupational therapy, and physical therapyEye examinationLiver function tests, thyroid panel, protein C, protein S, factor IX, and antithrombin IIIOtherPeriodic assessment of bleeding and clotting parameters by a hematologistFollow-up with an orthopedist when scoliosis becomes evidentAgents/Circumstances to AvoidAcetaminophen and other agents metabolized by the liver should be used with caution.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. PMM2-CDG (CDG-Ia): Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPMM216p13.2Phosphomannomutase 2PMM2 homepage - Mendelian genesPMM2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for PMM2-CDG (CDG-Ia) (View All in OMIM) View in own window 212065CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia; CDG1A 601785PHOSPHOMANNOMUTASE 2; PMM2Normal allelic variants. PMM2 is 51.49 kb with eight exons and codes for a transcript length of 2290 bp. Northern blot analysis shows the highest expression of PMM2 in the pancreas and liver with weak expression in brain, in contrast to PMM1, which is highly expressed in brain. A processed pseudogene, PMM2P1, has been identified on chromosome 18 [Schollen et al 1998].Pathologic allelic variants. See Table 2. Approximately 90 mutations are listed in the Euroglycan Mutation Database (www.euroglycanet.org) [de Lonlay et al 2001, Jaeken & Matthijs 2001, Westphal et al 2001]. These data are collated from six research and diagnostic laboratories [Matthijs et al 2000]. There are numerous missense/nonsense mutations, as well as some nucleotide substitutions, small deletions, small insertion/deletions, and one report of a complex rearrangement. Recently, splice site variants, truncating mutations, and intronic branch site mutations have also been reported [Vuillaumier-Barrot et al 2006, Schollen et al 2007].The p.Arg141His mutation is the most common; p.Phe119Leu is the second most common. Kjaergaard et al [1998] reported that these two mutations together accounted for 88% of all mutations in the Danish population.Table 2. Selected PMM2 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencec.338C>T p.Pro113LeuNM_000303.2 NP_000294.1c.357C>Ap.Phe119Leuc.395T>Cp.Ile132Thrc.415 G>Ap.Glu139Lysc.422G>Ap.Arg141Hisc.563A>Gp.Asp188Glyc.653A>Tp.His218Leuc.677C>Gp.Thr226Serc.691G>Ap.Val231Metc.710C>Tp.Thr237Metc.722G>Cp.Cys241SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. The product of PMM2 is a 246-amino acid protein with an approximate molecular weight of 28.1 kd. Phosphomannomutase 2 is an enzyme required for the synthesis of GDP-mannose specifically involved in the conversion of mannose-6-phosphate to mannose-1-phosphate, which is then transformed to GDP-mannose, a precursor of mannose for the biosynthesis of N-glycoproteins.Abnormal gene product. The abnormal phosphomannomutase 2 protein causes hypoglycosylation by lowering the intracellular mannose-1-phosphate pool, producing dysfunctional proteins leading to deficient synthesis of GDP-mannose and incorrect N-linked oligosaccharide synthesis.