NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

PMM2-CDG (CDG-Ia)

Synonyms: CDG1a, Congenital Disorder of Glycosylation Type 1a, Phosphomannomutase 2 Deficiency

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: October 29, 2015.

Summary

Clinical characteristics.

PMM2-CDG (CDG-Ia) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three types: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three types notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in sibs.

  • In the infantile multisystem type, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, failure to thrive, and impaired growth are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life.
  • The late-infantile and childhood ataxia-intellectual disability type, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities.
  • In the adult stable disability type, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk for deep venous thrombosis is present.

Diagnosis/testing.

The diagnosis of PMM2-CDG (CDG-Ia) is established in a proband with type I transferrin isoform pattern and either identification of biallelic pathogenic variants in PMM2 on molecular genetic testing or low levels of phosphomannomutase (PMM) enzyme activity if results of molecular genetic testing are uncertain.

Management.

Treatment of manifestations: Maximal caloric intake including use of a nasogastric tube or gastrostomy tube; anti-gastroesophageal reflux measures; occupational therapy, physical therapy, and speech therapy for developmental delay; hydration and physical therapy for stroke-like episodes; orthopedic intervention for scoliosis; rehabilitation medicine services including wheelchairs, transfer devices, and physical therapy as needed.

Prevention of secondary complications: Attention to coagulation status before surgery because of increased risk of bleeding and/or deep venous thrombosis. Education about risks and symptoms of deep venous thrombosis.

Agents/circumstances to avoid: Cautious use of acetaminophen and other agents metabolized by the liver.

Genetic counseling.

PMM2-CDG (CDG-Ia) is inherited in an autosomal recessive manner. 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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both PMM2 pathogenic variants in the family have been identified.

Diagnosis

PMM2-CDG (CDG-Ia) is the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides.

Suggestive Findings

PMM2-CDG (CDG-Ia) should be suspected in a child, adolescent or adult, or fetus with the following findings.

In a Child

In a child with developmental delay and hypotonia in combination with any of the following clinical and laboratory findings:

  • Clinical findings
    • Failure to thrive
    • 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] and characteristic findings on brain MRI (see Clinical Description)
  • Laboratory findings
    • Hepatic dysfunction (elevated transaminases)
    • Coagulopathy with low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
    • Type I transferrin isoform pattern on analysis of serum transferrin glycoforms (also called "transferrin isoforms analysis" or "carbohydrate-deficient transferrin analysis"). The analysis, based on isoform analysis (by isoelectric focusing (IEF) or other methods (capillary electrophoresis, GC/MS, CE-ESI-MS, MALDI-MS), determines 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 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, Hahn 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 or by a neuraminidase treatment followed by IEF and ESI-TOF MS [Park et al 2014, Zühlsdorf et al 2015]. (5) In adults with milder forms of PMM2-CDG (CDG-Ia), serum transferrin glycoforms can be mildly abnormal or near normal [Wolthuis et al 2014].

In an Adolescent or Adult

An adolescent or adult with any of the following clinical and laboratory findings:

  • Clinical findings
    • Cerebellar dysfunction (ataxia, dysarthria, dysmetria) and characteristic findings on brain MRI (see Clinical Description)
    • Non-progressive cognitive impairment
    • Seizures
    • 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
  • Laboratory findings. Type I transferrin isoform pattern on analysis of serum transferrin glycoforms (see In a Child, Laboratory findings, Type I transferrin isoform pattern)

In a Fetus

A fetus with non-immune hydrops fetalis [van de Kamp et al 2007, Léticée et al 2010]

Establishing the Diagnosis

The diagnosis of PMM2-CDG (CDG-Ia) is established in a proband with type I transferrin isoform pattern and identification of either biallelic pathogenic variants in PMM2 on molecular genetic testing (see Table 1) or low levels of phosphomannomutase (PMM) enzyme activity if results of molecular genetic testing are uncertain.

Molecular testing approaches can include single-gene testing, a multigene panel, and more comprehensive genomic testing.

Single-gene testing. Sequence analysis of PMM2 is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Note: Three pathogenic variants are common in individuals of European ancestry and may be included on carrier screening panels:

A multigene panel that includes PMM2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes PMM2) fails to confirm a diagnosis in an individual with features of PMM2-CDG (CDG-Ia).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in PMM2-CDG (CDG-Ia)

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method 3
PMM2Sequence analysis 4~100% 5
Gene-targeted deletion/duplication analysis 6Unknown 7
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Individuals with either an abnormal transferrin isoform pattern on analysis of serum transferrin glycoforms or enzymatically confirmed phosphomannomutase 2 deficiency [Jaeken et al 2014] (full text)

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

A 28-kb deletion that includes exon 8 as well as other novel exon or whole-deletions has been reported [Schollen et al 2007].

Phosphomannomutase 2 (PMM2) enzyme activity. In individuals presenting with a severe/classic clinical picture of PMM2-CDG (CDG-Ia), PMM2 enzyme activity in fibroblasts and leukocytes is typically 0% to 10% of normal [Van Schaftingen & Jaeken 1995, Carchon et al 1999, Jaeken & Carchon 2001]. If measurement of enzyme activity is used to verify the diagnosis, use of leukocytes is preferable given that intermediate enzyme activity values (including values in the normal range) in fibroblasts have been reported [Grünewald 2009].

Clinical Characteristics

Clinical Description

The typical clinical course of PMM2-CDG (CDG-Ia) has been divided into an infantile multisystem type, late-infantile and childhood ataxia-intellectual disability type, and adult stable disability type. 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 multisystem involvement at the mild end [Barone et al 2007, Coman et al 2007, Grünewald 2009].

Infantile Multisystem Type

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 and vomiting 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 affected individuals in the US [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 affected 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 may disappear with age and are occasionally absent in milder cases [Funke et al 2013].

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 individual [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]. Note that measurement of thyroid binding globulin (TBG) may be low and thyroid stimulating hormone (TSH) may be transiently high. Free T4 should also be measured, as clinically relevant hypothyroidism in PMM2-CDG (CDG-Ia) is rare [Mohamed et al 2012].

Seizures, which are usually responsive to antiepileptic drugs, are common. In one study of 23 affected individuals who had seizures, the mean age of the first seizure was 17 months (range: 3-53 months) [Pérez-Dueñas et al 2009].

Renal ultrasound examination 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 [Sinha et al 2009].

Sibs 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 on x-ray and also documented by densitometry, is common and remains throughout life.

Lymphatic edema due to abnormal lymphatic vessel development has been described [Verstegen et al 2012]. Note that this differs from the generalized edema resulting from hypoalbuminemia.

Late-Infantile and Childhood Ataxia-Intellectual Disability Type

Late-infantile and childhood ataxia-intellectual disability type occurs between ages three and ten years. Children have a more static course characterized by hypotonia and ataxia. Language and motor development are delayed and walking without support is rarely achieved [Jaeken & Matthijs 2001]. IQ typically ranges from 40 to 70. As the spectrum of PMM2-CDG (CDG-Ia) expands, individuals with borderline and even normal development have been described [Giurgea et al 2005, Pancho et al 2005, Barone et al 2007]. The children usually are extroverted and cheerful. Seizures may occur; they are usually responsive to antiepileptic drugs.

In this type 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 person, brain MRI demonstrated different findings after two such episodes, the first an ischemic process and the second edema with subsequent focal necrosis [Ishikawa et al 2009].

Intracranial hemorrhage, while not common, has been described [Stefanits et al 2014].

A progressive peripheral neuropathy may begin in this age range.

Retinitis pigmentosa due to a progressive photoreceptor degeneration [Thompson et al 2013], myopia [Jensen et al 2003], cataract [Morava et al 2009], joint contractures, and skeletal deformities may also occur.

Adult Stable Disability Type

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. Osteopenia and osteoporosis are common in adults [Monin et al 2014].

Previously undiagnosed individuals are now being identified as adults 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; of 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 hypogonadotropic 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 are 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 [Strøm et al 1993].

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, appeared 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, cerebellar atrophy did not appear to progress. Development of the supratentorial structures was normal.

Pathophysiology

PMM2-CDG (CDG-Ia) is caused by deficiency of phosphomannomutase 2 (PMM2) 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]. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids, incorrect synthesis of these compounds results in multisystem clinical manifestations [Varki 1993, Freeze 2006].

See Figure 1.

Figure 1. . N-linked glycans are synthesized by adding individual charged sugars in a specific order to the growing multi-sugar structure, or oligosaccharide.

Figure 1.

N-linked glycans are synthesized by adding individual charged sugars in a specific order to the growing multi-sugar structure, or oligosaccharide. The enzyme PMM2 is required for synthesis of one of these charged sugars, mannose-1-phosphate (man-1-P) (more...)

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 pathogenic variants, 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-Ia. 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, age 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 pathogenic variant p.Val231Met is associated with high early mortality and severe multi-organ insufficiency.
  • Homozygosity or compound heterozygosity for pathogenic variants with virtually no residual activity (e.g., p.Arg141His) is likely incompatible with life [Matthijs et al 2000].
  • The pathogenic variant p.Leu32Arg, which is particularly frequent in Italy, is associated with a milder phenotype with preserved ambulation and mild cognitive impairment despite cerebellar hypoplasia on brain MRI [Barone et al 2015].
  • A relatively common mild ALG6 variant (p.Phe304Ser) in combination with confirmed PMM2-CDG (CDG-Ia) may exacerbate the clinical severity in PMM2-CDG (CDG-Ia); however, this information cannot currently be used to predict clinical outcome [Westphal et al 2002, Bortot et al 2013].

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].

PMM2-CDG was previously referred to as CDGS1a; carbohydrate-deficient glycoprotein syndrome, type 1a; and Jaeken syndrome.

Prevalence

PMM2-CDG (CDG-Ia) is the most common form of congenital disorders of glycosylation. The prevalence could be as high as 1:20,000 [Jaeken & Matthijs 2001].

The expected carrier frequency for a PMM2 pathogenic variant in the Danish population is 1:60 to 1:79 [Matthijs et al 2000].

Differential Diagnosis

Any child with evidence of coagulopathy, hepatopathy, elevated thyroid stimulating hormone (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 diagnosis

Many metabolic and genetic disorders that present in infancy share at least some of the clinical features of PMM2-CDG (CDG-Ia). The following metabolic disorders are in the differential diagnosis of hypotonia, developmental delay, and failure to thrive:

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 hypogonadotropic 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, Thompson et al 2013]
  • Consultation with a clinical geneticist and/or genetic counselor with inclusion in a multidisciplinary team if needed

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 and 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 wheelchairs, 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 individual with 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
  • Monitoring for osteopenia/osteoporosis and counseling about the risk of fractures
  • 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.

Evaluation 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 in the US and www.ClinicalTrialsRegister.eu in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 an affected child are obligate heterozygotes (i.e., carriers of one PMM2 pathogenic variant).
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

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].
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

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

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PMM2 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the PMM2 pathogenic variants 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 heterozygotes (i.e., carriers of one PMM2 pathogenic variant).

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

High a priori risk. Once the PMM2 pathogenic variants have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis for PMM2-CDG (CDG-Ia) are possible.

Low a priori risk. PMM2-CDG (CDG-Ia) molecular testing should be considered in non-immune hydrops fetalis [van de Kamp et al 2007].

Note: 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
PMM216p13​.2Phosphomannomutase 2PMM2 databasePMM2PMM2

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PMM2-CDG (CDG-Ia) (View All in OMIM)

212065CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia; CDG1A
601785PHOSPHOMANNOMUTASE 2; PMM2

Gene structure. 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]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 2. More than 100 pathogenic variants have been reported, including missense, nonsense, and frameshift variants, splicing defects, and complete loss of exon 8 due to a deletion mediated by an Alu retrotransposition [Haeuptle & Hennet 2009, Pérez et al 2011, Jaeken et al 2014].

The p.Arg141His pathogenic variant is the most common in northern European populations; p.Phe119Leu is the second most common. Kjaergaard et al [1998] reported that these two pathogenic variants together accounted for 88% of all pathogenic variants in the Danish population.

Table 2.

Selected PMM2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequence
c.95T>Gp.Leu32ArgNM_000303​.2
NP_000294​.1
c.338C>Tp.Pro113Leu
c.357C>Ap.Phe119Leu
c.395T>Cp.Ile132Thr
c.415G>Ap.Glu139Lys
c.422G>Ap.Arg141His
c.563A>Gp.Asp188Gly
c.653A>Tp.His218Leu
c.677C>Gp.Thr226Ser
c.691G>Ap.Val231Met
c.710C>Tp.Thr237Met
c.722G>Cp.Cys241Ser

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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.

References

Literature Cited

  • Akaboshi S, Ohno K, Takeshita K. Neuroradiological findings in the carbohydrate-deficient glycoprotein syndrome. Neuroradiology. 1995;37:491–5. [PubMed: 7477867]
  • 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]
  • Barone R, Carrozzi M, Parini R, Battini R, Martinelli D, Elia M, Spada M, Lilliu F, Ciana G, Burlina A, Leuzzi V, Leoni M, Sturiale L, Matthijs G, Jaeken J, Di Rocco M, Garozzo D, Fiumara A. A nationwide survey of PMM2-CDG in Italy: high frequency of a mild neurological variant associated with the L32R mutation. J Neurol. 2015;262:154–64. [PubMed: 25355454]
  • 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]
  • 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]
  • Bortot B, Cosentini D, Faletra F, Biffi S, De Martino E, Carrozzi M, Severini GM. PMM2-CDG: phenotype and genotype in four affected family members. Gene. 2013;531:506–9. [PubMed: 23988505]
  • 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]
  • Carchon HA, Nsibu Ndosimao C, Van Aerschot S, Jaeken J. Use of serum on guthrie cards in screening for congenital disorders of glycosylation. Clin Chem. 2006;52:774–5. [PubMed: 16595835]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • Freeze HH. Genetic defects in the human glycome. Nat Rev Genet. 2006;7:537–51. [PubMed: 16755287]
  • Funke S, Gardeitchik T, Kouwenberg D, Mohamed M, Wortmann SB, Korsch E, Adamowicz M, Al-Gazali L, Wevers RA, Horvath A, Lefeber DJ, Morava E. Perinatal and early infantile symptoms in congenital disorders of glycosylation. Am J Med Genet A. 2013;161A:578–84. [PubMed: 23401092]
  • 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]
  • Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta. 2009;1792:827–34. [PubMed: 19272306]
  • Grunewald S, Matthijs G, Jaeken J. Congenital disorders of glycosylation: a review. Pediatr Res. 2002;52:618–24. [PubMed: 12409504]
  • Haeuptle MA, Hennet T. Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Hum Mutat. 2009;30:1628–41. [PubMed: 19862844]
  • Hahn 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]
  • 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]
  • 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]
  • 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]
  • Jaeken J, Carchon H. Congenital disorders of glycosylation: the rapidly growing tip of the iceberg. Curr Opin Neurol. 2001;14:811–5. [PubMed: 11723393]
  • Jaeken J, Matthijs G. Congenital disorders of glycosylation. Annu Rev Genomics Hum Genet. 2001;2:129–51. [PubMed: 11701646]
  • Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta. 2009;1792:825–6. [PMC free article: PMC3917312] [PubMed: 19765534]
  • Jaeken J, Lefeber D, Matthijs G. Clinical utility gene card for: Phosphomannomutase 2 deficiency. Eur J Hum Genet. 2014;22(8) [PMC free article: PMC4350603] [PubMed: 24424124]
  • 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]
  • 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]
  • 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]
  • 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]
  • Krasnewich D, Gahl WA. Carbohydrate-deficient glycoprotein syndrome. Adv Pediatr. 1997;44:109–40. [PubMed: 9265969]
  • 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]
  • 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]
  • 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]
  • 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]
  • Marklová E, Albahri Z. Screening and diagnosis of congenital disorders of glycosylation. Clin Chim Acta. 2007;385:6–20. [PubMed: 17716641]
  • 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]
  • 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]
  • Martin PT, Freeze HH. Glycobiology of neuromuscular disorders. Glycobiology. 2003;13:67R–75R. [PubMed: 12736200]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • Mohamed M, Theodore M, Claahsen-van der Grinten H, van Herwaarden AE, Huijben K, van Dongen L, Kouwenberg D, Lefeber DJ, Wevers RA, Morava E. Thyroid function in PMM2-CDG: diagnostic approach and proposed management. Mol Genet Metab. 2012;105:681–3. [PubMed: 22386715]
  • Monin ML, Mignot C, De Lonlay P, Héron B, Masurel A, Mathieu-Dramard M, Lenaerts C, Thauvin C, Gérard M, Roze E, Jacquette A, Charles P, de Baracé C, Drouin-Garraud V, Khau Van Kien P, Cormier-Daire V, Mayer M, Ogier H, Brice A, Seta N, Héron D. 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype. Orphanet J Rare Dis. 2014;9:207. [PMC free article: PMC4266234] [PubMed: 25497157]
  • 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]
  • 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]
  • Park JH, Zühlsdorf A, Wada Y, Roll C, Rust S, Du Chesne I, Grüneberg M, Reunert J, Marquardt T. The novel transferrin E592A variant impairs the diagnostics of congenital disorders of glycosylation. Clin Chim Acta. 2014;436:135–9. [PubMed: 24875750]
  • Pérez B, Briones P, Quelhas D, Artuch R, Vega AI, Quintana E, Gort L, Ecay MJ, Matthijs G, Ugarte M, Pérez-Cerdá C. The molecular landscape of phosphomannose mutase deficiency in Iberian peninsula: identification of 15 population-specific mutations. JIMD Rep. 2011;1:117–23. [PMC free article: PMC3509825] [PubMed: 23430838]
  • Pérez-Dueñas B, García-Cazorla A, Pineda M, Poo P, Campistol J, Cusí V, Schollen E, Matthijs G, Grunewald S, Briones P, Pérez-Cerdá C, Artuch R, Vilaseca MA. Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations. Eur J Paediatr Neurol. 2009;13:444–51. [PubMed: 18948042]
  • 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]
  • 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]
  • 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]
  • Schade van Westrum SM, Nederkoorn PJ, Schuurman PR, Vulsma T, Duran M, Poll-The BT. Skeletal dysplasia and myelopathy in congenital disorder of glycosylation type IA. J Pediatr. 2006;148:115–7. [PubMed: 16423609]
  • 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]
  • 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]
  • 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]
  • 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]
  • Sinha MD, Horsfield C, Komaromy D, Booth CJ, Champion MP. Congenital disorders of glycosylation: a rare cause of nephrotic syndrome. Nephrol Dial Transplant. 2009;24:2591–4. [PubMed: 19474279]
  • 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;32 Suppl 1:S241–51. [PubMed: 19396570]
  • Stefanits H, Konstantopoulou V, Kuess M, Milenkovic I, Matula C. Initial diagnosis of the congenital disorder of glycosylation PMM2-CDG (CDG1a) in a 4-year-old girl after neurosurgical intervention for cerebral hemorrhage. J Neurosurg Pediatr. 2014;14:546–9. [PubMed: 25192236]
  • Stibler H, Skovby F. Failure to diagnose carbohydrate-deficient glycoprotein syndrome prenatally. Pediatr Neurol. 1994;11:71. [PubMed: 7527215]
  • 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]
  • Strøm EH, Stromme P, Westvik J, Pedersen SJ. Renal cysts in the carbohydrate-deficient glycoprotein syndrome. Pediatr Nephrol. 1993;7:253–5. [PubMed: 8518092]
  • 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]
  • Thompson DA, Lyons RJ, Russell-Eggitt I, Liasis A, Jägle H, Grünewald S. Retinal characteristics of the congenital disorder of glycosylation PMM2-CDG. J Inherit Metab Dis. 2013;36:1039–47. [PubMed: 23430200]
  • 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]
  • van de Kamp JM, Lefeber DJ, Ruijter GJ, Steggerda SJ, den Hollander NS, Willems SM, Matthijs G, Poorthuis BJ, Wevers RA. Congenital disorders of glycosylation type Ia presenting with hydrops fetalis. J Med Genet. 2007;44:277–80. [PMC free article: PMC2598051] [PubMed: 17158594]
  • 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]
  • Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology. 1993;3:97–130. [PubMed: 8490246]
  • Verstegen RH, Theodore M, van de Klerk H, Morava E. Lymphatic edema in congenital disorders of glycosylation. JIMD Rep. 2012;4:113–6. [PMC free article: PMC3509901] [PubMed: 23430905]
  • 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]
  • Westphal V, Kjaergaard S, Schollen E, Martens K, Grunewald S, Schwartz M, Matthijs G, Freeze HH. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum Mol Genet. 2002;11:599–604. [PubMed: 11875054]
  • Wolthuis DF, Janssen MC, Cassiman D, Lefeber DJ, Morava E. Defining the phenotype and diagnostic considerations in adults with congenital disorders of N-linked glycosylation. Expert Rev Mol Diagn. 2014;14:217–24. [PubMed: 24524732]
  • 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]
  • Zühlsdorf A, Park JH, Wada Y, Rust S, Reunert J, DuChesne I, Grüneberg M, Marquardt T. Transferrin variants: pitfalls in the diagnostics of congenital disorders of glycosylation. Clin Biochem. 2015;48:11–13. [PubMed: 25305627]

Suggested Reading

  • Jaeken J, Matthijs G, Carchon H, Van Schaftingen E. Defects of N-glycan synthesis. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 74. McGraw-Hill.

Chapter Notes

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 subsequently 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 1999 and 1997 respectively. She is currently a medical director for genetic diseases with Sanofi Genzyme.

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

  • 29 October 2015 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1110PMID: 20301289

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...