Clinical Diagnosis

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:

• Failure to thrive
• Hepatic dysfunction (elevated transaminases)
• Coagulopathy with low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
• Hypothyroidism, hypogonadism
• Esotropia
• Pericardial effusion
• Abnormal subcutaneous fat pattern including increased suprapubic fat pad, skin dimpling, and inverted nipples or subcutaneous fat pads having a toughened, puffy, or uneven consistency
• Seizures
• Stroke-like episodes
• Osteopenia, scoliosis
• Cerebellar 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 impairment
• Stroke-like episodes
• Peripheral neuropathy with or without muscle wasting
• Absent puberty in females, small testes in males
• Retinitis pigmentosa
• Progressive scoliosis with truncal shortening
• Joint contractures

The 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.

Testing

PMM2-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]. Such testing is clinically available.

Results of such testing may reveal the following:

• Normal transferrin isoform pattern. Two biantennary glycans linked to asparagine with four sialic acid residues
• Type 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]. In the US, enzyme testing for PMM2-CDG (CDG-Ia) is available clinically.

Molecular Genetic Testing

Gene. PMM2 is the only gene associated with (PMM2-CDG (CDG-Ia).

Clinical testing

• Sequence analysis
  • In 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-deletions

Table 1. Summary of Molecular Genetic Testing Used in PMM2-CDG (CDG-Ia)

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Two Mutations	One Mutation
PMM2	Sequence analysis	Sequence variants 2	95%	98%	Clinical
	Deletion / duplication analysis 3	Exonic or whole-gene deletions	Unknown	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. 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. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirmation 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in PMM2.

Natural History

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].

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].

Genotype-Phenotype Correlations

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:

• 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].

Nomenclature

In 2009 the nomenclature for all types of CDG was changed to include the official gene symbol (not in italics) followed by “-CDG”. If the type has a known letter name, it follows in parenthesis; thus the new nomenclature for this disorder is PMM2-CDG (CDG-Ia) [Jaeken et al 2009].

Prevalence

PMM2-CDG (CDG-Ia) is the most common form of the congenital disorders of glycosylation reported to date, with more than 700 affected individuals worldwide. The prevalence could be as high as 1:20,000 [Jaeken & Matthijs 2001].

The expected carrier frequency of PMM2 mutations in the Danish population is one in 60 to one in 79 [Matthijs et al 2000].

Evaluations Following Initial Diagnosis

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]:

• Liver function tests
• Measurement of serum albumin concentration
• Thyroid function tests to evaluate for decreased thyroid binding globulin, elevated serum concentration of TSH, and low serum concentration of free T4
• Coagulation studies including protein C, protein S, antithrombin III, and factor IX
• Urinalysis to evaluate for proteinuria
• Measurement of serum concentration of gonadotropins in adolescent and adult women to look for evidence of hypogonadotrophic hypogonadism
• Echocardiogram to evaluate for pericardial effusions
• Renal ultrasound examination to evaluate for microcysts
• Formal 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 Manifestations

Failure 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 Complications

Because 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].

Surveillance

Annual

• Assessment by a physician with attention to overall health and referral for speech therapy, occupational therapy, and physical therapy
• Eye examination
• Liver function tests, thyroid panel, protein C, protein S, factor IX, and antithrombin III

Other

• Periodic assessment of bleeding and clotting parameters by a hematologist
• Follow-up with an orthopedist when scoliosis becomes evident

Agents/Circumstances to Avoid

Acetaminophen and other agents metabolized by the liver should be used with caution.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

PMM2-CDG (CDG-Ia) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of the proband are obligate heterozygotes and therefore each carry one mutant allele.
• Carriers are asymptomatic.

Sibs of a proband

• At conception, the theoretic risks to sibs of an affected individual are a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier. However, based on outcomes of at-risk pregnancies, the risk of having an affected child is closer to 1/3 than to the expected 1/4 [Schollen et al 2004].
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Adults with PMM2-CDG (CDG-Ia) have not been reported to reproduce.

Carrier Detection

Carrier testing for at-risk family members is available on a clinical basis after the PMM2 disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Increased recurrence risk for PMM2-CDG (CDG-Ia). Studies of the outcomes of prenatal testing suggest that the percentage of affected fetuses is higher than predicted by Mendel’s second law. The risk to sibs of a proband is estimated to be closer to 1/3 than to the expected 1/4. This finding of an apparent increased recurrence risk caused by transmission ratio distortion continues to be validated [Schollen et al 2004].

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

High a priori risk. Prenatal diagnosis for pregnancies at increased risk for PMM2-CDG (CDG-Ia) is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both PMM2 disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Low a priori risk. PMM2-CDG (CDG-Ia) should be considered in non-immune hydrops fetalis. Transferrin isoform analysis on fetal serum is an unreliable diagnostic test. PMM enzyme activity may also be falsely low in poor-growing amniocytes or chorionic villi. Molecular genetic testing for PMM2 mutations can be considered [van de Kamp et al 2007].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Akaboshi S, Ohno K, Takeshita K. Neuroradiological findings in the carbohydrate-deficient glycoprotein syndrome. Neuroradiology. 1995;37:491–5. [PubMed: 7477867]
2. Aronica E, van Kempen AA, van der Heide M, Poll-The BT, van Slooten HJ, Troost D, Rozemuller-Kwakkel JM. Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. Acta Neuropathol (Berl). 2005;109:433–42. [PubMed: 15714316]
3. Barone R, Sturiale L, Fiumara A, Uziel G, Garozzo D, Jaeken J. Borderline mental development in a congenital disorder of glycosylation (CDG) type Ia patient with multisystemic involvement (intermediate phenotype). J Inherit Metab Dis. 2007;30:107. [PubMed: 17186415]
4. Blank C, Smith L, Hammer D, Fehrenbach M, DeLisser H, Perez E, Sullivan K. Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia). J Inherit Metab Dis. 2006;29:592. [PubMed: 16826448]
5. Carchon H, Nsibu Ndosimao C, Van Aerschot S, Jaeken J. Use of serum on guthrie cards in screening for congenital disorders of glycosylation. Clinical Chemistry. 2006;52:774–5. [PubMed: 16595835]
6. Carchon H, Van Schaftingen E, Matthijs G, Jaeken J. Carbohydrate-deficient glycoprotein syndrome type IA (phosphomannomutase-deficiency). Biochim Biophys Acta. 1999;1455:155–65. [PubMed: 10571009]
7. Clayton PT, Winchester BG, Keir G. Hypertrophic obstructive cardiomyopathy in a neonate with the carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis. 1992;15:857–61. [PubMed: 1293380]
8. Coman D, McGill J, MacDonald R, Morris D, Klingberg S, Jaeken J, Appleton D. Congenital disorder of glycosylation type 1a: Three siblings with a mild neurological phenotype. J Clin Neurosci. 2007;14:668–72. [PubMed: 17451957]
9. de Lonlay P, Seta N, Barrot S, Chabrol B, Drouin V, Gabriel BM, Journel H, Kretz M, Laurent J, Le Merrer M, Leroy A, Pedespan D, Sarda P, Villeneuve N, Schmitz J, van Schaftingen E, Matthijs G, Jaeken J, Korner C, Munnich A, Saudubray JM, Cormier-Daire V. A broad spectrum of clinical presentations in congenital disorders of glycosylation I: a series of 26 cases. J Med Genet. 2001;38:14–9. [PMC free article: PMC1734729] [PubMed: 11134235]
10. De Zegher F, Jaeken J. Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence. Pediatr Res. 1995;37:395–401. [PubMed: 7596677]
11. Enns GM, Steiner RD, Buist N, Cowan C, Leppig KA, McCracken MF, Westphal V, Freeze HH, O'Brien JF, Jaeken J, Matthijs G, Behera S, Hudgins L. Clinical and molecular features of congenital disorder of glycosylation in patients with type 1 sialotransferrin pattern and diverse ethnic origins. J Pediatr. 2002;141:695–700. [PubMed: 12410200]
12. Erlandson A, Bjursell C, Stibler H, Kristiansson B, Wahlstrom J, Martinsson T. Scandinavian CDG-Ia patients: genotype/phenotype correlation and geographic origin of founder mutations. Hum Genet. 2001;108:359–67. [PubMed: 11409861]
13. Fletcher JM, Matthijs G, Jaeken J, Van Schaftingen E, Nelson PV. Carbohydrate-deficient glycoprotein syndrome: beyond the screen. J Inherit Metab Dis. 2000;23:396–8. [PubMed: 10896303]
14. Freeze H. Genetic defects in the human glycome. Nature Reviews-Genetics. 2006;7:537–48. [PubMed: 16755287]
15. Giurgea I, Michel A, Le Merrer M, Seta N, de Lonlay P. Underdiagnosis of mild congenital disorders of glycosylation type Ia. Pediatr Neurol. 2005;32:121–3. [PubMed: 15664773]
16. Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: a review. Pediatr Res. 2002;52:618–24. [PubMed: 12409504]
17. Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta. 2009;1792:827–34. [PubMed: 19272306]
18. Hann SH, Minnich SJ, O’Brien JF. Stabilization of hypoglycosylation in a patient with congenital disorder of glycosylation type Ia. J Inherit Metab Dis. 2006;29:235–7. [PubMed: 16601903]
19. Hertz-Pannier L, Dechaux M, Sinico M, Emond S, Cormier-Daire V, Saudubray JM, Brunelle F, Niaudet P, Seta N, de Lonlay P. Congenital disorders of glycosylation type I: a rare but new cause of hyperechoic kidneys in infants and children due to early microcystic changes. Pediatr Radiol. 2006;36:108–14. [PubMed: 16328327]
20. Holzbach U, Hanefeld F, Helms G, Hanicke W, Frahm J. Localized proton magnetic resonance spectroscopy of cerebral abnormalities in children with carbohydrate-deficient glycoprotein syndrome. Acta Paediatr. 1995;84:781–6. [PubMed: 7549297]
21. Ishikawa N, Tajima G, Ono H, Kobayashi M. Different neuroradiological findings during two stroke-like episodes in a patient with congenital disorder of glycosylation type Ia. Brain Dev. 2009;31:240–3. [PubMed: 18485644]
22. Jaeken J, Carchon H. Congenital disorders of glycosylation: the rapidly growing tip of the iceberg. Curr Opin Neurol. 2001;14:811–5. [PubMed: 11723393]
23. Jaeken J, Matthijs G. Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet. 2001;2:129–51. [PubMed: 11701646]
24. Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta. 2009;1792:825–6. [PubMed: 19765534]
25. Jensen H, Kjaergaard S, Klie F, Moller HU. Ophthalmic manifestations of congenital disorder of glycosylation type 1a. Ophthalmic Genet. 2003;24:81–8. [PubMed: 12789572]
26. Kjaergaard S, Muller J, Skovby F. Prepubertal growth in congenital disorder of glycosylation type Ia (CDG-Ia). Arch Dis Child. 2002;87:324–7. [PMC free article: PMC1763046] [PubMed: 12244009]
27. Kjaergaard S, Schwartz M, Skovby F. Congenital disorder of glycosylation type Ia (CDG-Ia): phenotypic spectrum of the R141H/F119L genotype. Arch Dis Child. 2001;85:236–9. [PMC free article: PMC1718926] [PubMed: 11517108]
28. Kjaergaard S, Skovby F, Schwartz M. Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1. Eur J Hum Genet. 1998;6:331–6. [PubMed: 9781039]
29. Krasnewich D, Gahl WA. Carbohydrate-deficient glycoprotein syndrome. Adv Pediatr. 1997;44:109–40. [PubMed: 9265969]
30. Krasnewich D, O’Brien K, Sparks S. Clinical features in adults with congenital disorders of glycosylation type Ia (CDG-Ia). Am J Med Genet. 2007;145C:302–6. [PubMed: 17639595]
31. Kristiansson B, Stibler H, Conradi N, Eriksson BO, Ryd W. The heart and pericardial effusions in CDGS-I (carbohydrate-deficient glycoprotein syndrome type I). J Inherit Metab Dis. 1998;21:112–24. [PubMed: 9584262]
32. Kristiansson B, Stibler H, Wide L. Gonadal function and glycoprotein hormones in the carbohydrate-deficient glycoprotein (CDG) syndrome. Acta Paediatr. 1995;84:655–9. [PubMed: 7670249]
33. Léticée N, Bessières-Grattagliano B, Dupré T, Vuillaumier-Barrot S, de Lonlay P, Razavi F, El Khartoufi N, Ville Y, Vekemans M, Bouvier R, Seta N, Attié-Bitach T. Should PMM2-deficiency (CDG-Ia) be searched in every case of unexplained hydrops fetalis? Mol Genet Metab. 2010;101:253–7. [PubMed: 20638314]
34. Marklová E, Albahri Z. Screening and diagnosis of congenital disorders of glycosylation. Clin Chim Acta. 2007;385:6–20. [PubMed: 17716641]
35. Marquardt T, Denecke J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr. 2003;162:359–79. [PubMed: 12756558]
36. Marquardt T, Hulskamp G, Gehrmann J, Debus V, Harms E, Kehl HG. Severe transient myocardial ischaemia caused by hypertrophic cardiomyopathy in a patient with congenital disorder of glycosylation type Ia. Eur J Pediatr. 2002;161:524–7. [PubMed: 12297897]
37. Martin P, Freeze H. Glycobiology of neuromuscular disorders. Glycobiology. 2003;13:67R–75R. [PubMed: 12736200]
38. Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imtiaz F, Kjaergaard S, Martinsson T, Schwartz M, Seta N, Vuillaumier-Barrot S, Westphal V, Winchester B. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat. 2000;16:386–94. [PubMed: 11058895]
39. Matthijs G, Schollen E, Heykants L, Grunewald S. Phosphomannomutase deficiency: the molecular basis of the classical Jaeken syndrome (CDGS type Ia). Mol Genet Metab. 1999;68:220–6. [PubMed: 10527672]
40. Matthijs G, Schollen E, Van Schaftingen E, Cassiman JJ, Jaeken J. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. Am J Hum Genet. 1998;62:542–50. [PMC free article: PMC1376957] [PubMed: 9497260]
41. Miller BS, Freeze HH. New disorders in carbohydrate metabolism: congenital disorders of glycosylation and their impact on the endocrine system. Rev Endocr Metab Disord. 2003;4:103–13. [PubMed: 12618564]
42. Miller BS, Khosravi MJ, Patterson MC, Conover CA. IGF system in children with congenital disorders of glycosylation. Clin Endocrinol (Oxf). 2009;70:892–7. [PubMed: 19207313]
43. Morava E, Wosik HN, Sykut-Cegielska J, Adamowicz M, Guillard M, Wevers RA, Lefeber DJ, Cruysberg JR. Ophthalmological abnormalities in children with congenital disorders of glycosylation type I. Br J Ophthalmol. 2009;93:350–4. [PubMed: 19019927]
44. Pancho C, Garcia-Cazorla A, Varea V, Artuch R, Ferrer I, Vilaseca MA, Briones P, Campistol J. Congenital disorder of glycosylation type Ia revealed by hypertransaminasemia and failure to thrive in a young boy with normal development. J Pediatr Gastroenterol Nutr. 2005;40:230–2. [PubMed: 15699704]
45. Peters V, Penzien JM, Reiter G, Korner C, Hackler R, Assmann B, Fang J, Schaefer JR, Hoffmann GF, Heidemann PH. Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy. Neuropediatrics. 2002;33:27–32. [PubMed: 11930273]
46. Romano S, Bajolle F, Valayannopoulos V, Lyonnet S, Colomb V, de Baracé C, Vouhe P, Pouard P, Vuillaumier-Barrot S, Dupré T, de Keyzer Y, Sidi D, Seta N, Bonnet D, de Lonlay P. Conotruncal heart defects in three patients with congenital disorder of glycosylation type Ia (CDG Ia). J Med Genet. 2009;46:287–8. [PubMed: 19357119]
47. Sanz-Nebot V, Balaguer E, Benavente F, Neusub C, Barbosa J. Characterization of transferrin glycoforms in human serum by CE-UV and CE-ESI-MS. Electrophoresis. 2007;28:1949–57. [PubMed: 17523137]
48. Schade van Westrum S, Nederkoorn P, Schuurman R P, Vulsma T, Duran M, Poll-The B T. Skeletal dysplasia and myelopathy in congenital disorder of glycosylation type IA. J Pediatr. 2006;148:115–7. [PubMed: 16423609]
49. Schoffer KL, O'Sullivan JD, McGill J. Congenital disorder of glycosylation type Ia presenting as early-onset cerebellar ataxia in an adult. Mov Disord. 2006;21:869–72. [PubMed: 16482534]
50. Schollen E, Keldermans L, Foulquier F, Briones P, Chabas A, Sanchez-Valverde F, Adamowicz M, Pronicka E, Wevers R, Matthijs G. Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. Mol Genet Metab. 2007;90:408–13. [PubMed: 17307006]
51. Schollen E, Kjaergaard S, Martinsson T, Vuillaumier-Barrot S, Dunoe M, Keldermans L, Seta N, Matthijs G. Increased recurrence risk in congenital disorders of glycosylation type Ia (CDG-Ia) due to a transmission ratio distortion. J Med Genet. 2004;41:877–80. [PMC free article: PMC1735620] [PubMed: 15520415]
52. Schollen E, Pardon E, Heykants L, Renard J, Doggett NA, Callen DF, Cassiman JJ, Matthijs G. Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. Hum Mol Genet. 1998;7:157–64. [PubMed: 9425221]
53. Shanti B, Silink M, Bhattacharya K, Howard NJ, Carpenter K, Fietz M, Clayton P, Christodoulou J. Congenital disorder of glycosylation type Ia: Heterogeneity I the clinical presentation from multivisceral failure to hyperinsulinaemic hypoglycaemia as leading symptoms in three infants with phosphomannomutase deficiency. J Inherit Metab Dis. 2009 [PubMed: 19396570]
54. Stibler H, Skovby F. Failure to diagnose carbohydrate-deficient glycoprotein syndrome prenatally. Pediatr Neurol. 1994;11:71. [PubMed: 7527215]
55. Stibler H, Blennow G, Kristiansson B, Lindehammer H, Hagberg B. Carbohydrate-deficient glycoprotein syndrome: clinical expression in adults with a new metabolic disease. J Neurol Neurosurg Psychiatry. 1994;57:552–6. [PMC free article: PMC1072913] [PubMed: 8201322]
56. Strom EH, Stromme P, Westvik J, Pedersen SJ. Renal cysts in the carbohydrate-deficient glycoprotein syndrome. Pediatr Nephrol. 1993;7:253–5. [PubMed: 8518092]
57. Tayebi N, Andrews DQ, Park JK, Orvisky E, McReynolds J, Sidransky E, Krasnewich DM. A deletion-insertion mutation in the phosphomannomutase 2 gene in an African American patient with congenital disorders of glycosylation-Ia. Am J Med Genet. 2002;108:241–6. [PubMed: 11891694]
58. Truin G, Mailys G, Lefeber DJ, Sykut-Cegielska J, Adamowicz M, Hoppenreijs E, Sengers RCA, Wevers RA, Morava E. Pericardial and abdominal fluid accumulation in congenital disorder of glycosylation type Ia. Mol Genet Metab. 2008;94:481–4. [PubMed: 18571450]
59. van de Kamp J, Lefeber D, Ruijter G, Steggerda S, den Hollander N, Willems S, Matthijs G, Poorthuis B, Wevers R. Congenital disorders of glycosylation type Ia presenting with hydrops fetalis. J Med Genet. 2007;44:277–80. [PMC free article: PMC2598051] [PubMed: 17158594]
60. Van Schaftingen E, Jaeken J. Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett. 1995;377:318–20. [PubMed: 8549746]
61. Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology. 1993;3:97–130. [PubMed: 8490246]
62. Vuillaumier-Barrot S, Le Bizec C, De Lonlay P, Madinier-Chappat N, Barnier A, Dupre T, Durand G, Seta N. PMM2 intronic branch-site mutations in CDG-Ia. Mol Genet Metab. 2006;87:337–40. [PubMed: 16376131]
63. Westphal V, Enns GM, McCracken MF, Freeze HH. Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry. Mol Genet Metab. 2001;73:71–6. [PubMed: 11350185]
64. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell. 2001;1:717–24. [PubMed: 11709191]

Suggested Reading

1. Jaeken J, Matthijs G, Carchon H, Van Schaftingen E. Defects of N-glycan synthesis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 74. New York: McGraw-Hill. Available at www​.ommbid.com. Accessed 4-13-11.

Author Notes

Susan Sparks is a board-certified pediatrician, clinical geneticist, and clinical biochemical geneticist. After completion of her genetics and biochemical genetics fellowship at the National Institutes of Health, she joined the faculty at Children’s National Medical Center in Washington, DC, and is currently on the faculty at Levine Children’s Hospital at Carolinas Medical Center in Charlotte, NC. She received her MD and PhD in molecular biology and pharmacology from the Chicago Medical School in 1997 and 1999 respectively. She has a strong research interest in glycosylation defects including congenital disorders of glycosylation and congenital muscular dystrophies.

Donna Krasnewich is a board-certified clinical biochemical geneticist and pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan, and received her MD and PhD in pharmacology in 1986. After completing her fellowship in genetics at the National Institutes of Health (NIH), she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH where she saw children with developmental delay and congenital disorders of glycosylation. In 2009 she moved to the National Institute of General Medical Sciences where she is a Program Director in the Division of Genetics.

Revision History

• 21 April 2011 (me) Comprehensive update posted live
• 8 July 2008 (me) Comprehensive update posted live
• 15 August 2005 (me) Review posted to live Web site
• 27 February 2004 (dk) Original submission