Clinical characteristics.

PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs.

• In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding issues, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life.
• The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages 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, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities.
• In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased.

Diagnosis/testing.

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

Management.

Treatment of manifestations: Symptomatic treatment for severe infantile phase in a pediatric tertiary care center. Optimal routine care in infants and children should maximize caloric intake including: use of a nasogastric tube or gastrostomy tube, anti-gastroesophageal reflux measures, speech and oral motor therapy to aid transition to oral feeds. Standard treatment for seizures; occupational therapy, physical therapy, and speech therapy for developmental delay. In all affected individuals care should include standard treatment of ocular and vision issues and cardiac issues; treatment of bleeding disorders and/or coagulopathy per hematologist with consultation with surgeon prior to surgeries; hydration for stroke-like episodes with physical therapy, occupational therapy, and speech therapy during the recovery period; standard management of deep venous thrombosis (DVT) with education regarding risk of DVT; treatment of hypothyroidism, hypoglycemia, and other endocrinopathies per endocrinologist. Multicystic kidneys are managed conservatively; standard treatments for other renal issues; counseling regarding avoidance of fracture; orthopedic intervention for scoliosis; rehabilitation medicine services including wheelchairs, transfer devices, physical therapy, and educational adaptation as needed; management of immune dysfunction per immunologist; education for life skills, vocational training, independent self-care, and activities of daily living; parental support for long-term care planning.

Surveillance: At each visit assess growth, nutritional status, safety of oral intake, seizures, and developmental progress; ophthalmology evaluations every one to two years; cardiology assessment as needed; annual AST, ALT, and albumin until normalization; liver ultrasound every three to five years; measure TSH, free T4, and glucose every one to two years; assess gonadal function at pubertal age as recommended by endocrinologist; blood pressure, urine dipstick for proteinuria, and serum creatinine every one to two years or as needed; assessment for osteopenia every one to two years; orthopedic assessment if scoliosis becomes evident; complete blood count and differential every one to two years; annual assessment of bleeding and clotting parameters by a hematologist including prothrombin time, protein C, protein S, antithrombin III, factor IX, and factor XI.

Agents/circumstances to avoid: Cautious use of acetaminophen and other agents metabolized by the liver if significant liver insufficiency is present.

Genetic counseling.

PMM2-CDG 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 testing for a pregnancy at increased risk are possible if both PMM2 pathogenic variants in the family have been identified.

Suggestive Findings

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

In a child. Developmental delay and hypotonia in combination with any of the following:

• Clinical findings
  • Faltering growth
  • 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
  • Recurrent infections with concerns about immunologic dysfunction and vaccine non-responsiveness
  • Osteopenia, scoliosis
  • Cerebellar hypoplasia/atrophy and small brain stem and additional characteristic findings on brain MRI (See Clinical Description.)
• Laboratory findings
  • Hepatic dysfunction (elevated transaminases)
  • Coagulopathy with abnormal prothrombin time, low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
  • Occasional hypoglycemia seen in infants, with some due to hyperinsulinemia
  • Possible hypothyroidism reflected by elevated TSH; however, thyroxine levels, performed by equilibrium dialysis, are the most reliable marker for thyroid function.
  • Osteopenia frequently with normal calcium, magnesium, and phosphate levels
  • Proteinuria and aminoaciduria with elevated creatinine reported in some individuals

In an adolescent or adult. Any of the following:

• 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 or atypical secondary sexual development in females, small testes in males
  • Retinitis pigmentosa and myopia
  • Progressive scoliosis with truncal shortening
  • Joint contractures
• Laboratory findings
  • Elevated liver function tests (transaminases)
  • Low serum concentration of factors IX and XI, antithrombin III, protein C, and/or protein S
  • Gonadal dysfunction in most but not all adult females with varying levels of FSH, LH, and estradiol. Most males have normal pubescence but may have low testosterone and sex hormone-binding globulin.

In a fetus. Nonimmune hydrops fetalis [van de Kamp et al 2007, Léticée et al 2010]

Establishing the Diagnosis

The diagnosis of PMM2-CDG is established in a proband with suggestive findings and most often a type I transferrin isoform pattern and either biallelic pathogenic (or likely pathogenic) variants in PMM2 identified on molecular genetic testing (see Table 1) or (if results of molecular genetic testing are uncertain) low levels of phosphomannomutase 2 (PMM2) enzyme activity.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic PMM2 variants of uncertain significance (or of one known PMM2 pathogenic variant and one PMM2 variant of uncertain significance) does not establish or rule out the diagnosis.

Diagnostic 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 historically by isoelectric focusing (IEF) or other currently used methods (capillary electrophoresis, GC/MS, CE-ESI-MS, MALDI-MS), determines the number and structure of sialylated N-linked oligosaccharide residues linked to serum transferrin [Marklová & Albahri 2007, Sanz-Nebot et al 2007].

Possible results of such testing include:

• Normal transferrin isoform pattern. Two biantennary glycans linked to asparagine with four sialic acid residues
• Type I transferrin isoform pattern. Decreased tetra-sialotransferrin and increased asialo-transferrin and di-sialotransferrin. The pattern indicates defects in the earliest synthetic steps of the N-linked oligosaccharide synthetic pathway.
• Type II transferrin isoform pattern. Increased tri-sialotransferrins and/or mono-sialotransferrins. The pattern indicates defects in the later parts of the N-linked glycan pathway.

Note: (1) There are significant concerns about the diagnostic validity of analysis of serum transferrin glycoforms before age three weeks [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 clinical features of PMM2-CDG, PMM2 enzyme deficiency, and a normal transferrin isoform pattern have been reported [Hahn et al 2006]. (4) Historically the possibility that an abnormal transferrin glycoform analysis is due to PMM2-CDG can be confirmed with a glycoform analysis of a serum sample from the parents or by a neuraminidase treatment followed by IEF and electrospray ionization time-of-flight mass spectrometry (ESI-TOF MS) [Park et al 2014, Zühlsdorf et al 2015]. (5) In adults with milder forms of PMM2-CDG, serum transferrin glycoforms can be mildly abnormal or near normal [Wolthuis et al 2014]. (6) Type I transferrin isoform patterns can also be seen in individuals with untreated galactosemia or fructosemia, liver disease, severe infections, and chronic inflammatory disease.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with neurologic and/or multiorgan dysfunction are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Some features of PMM2-CDG are usually present in infancy, but may be too subtle to recognize and thus not come to medical attention. The clinical course varies by severity and includes the following typical presentations and stages: hydrops fetalis at the severe end, infantile multisystem presentation, late-infantile and childhood ataxia–intellectual disability stage, and an adult stable disability stage [Schiff et al 2017, Altassan et al 2019].

Pathophysiology

PMM2-CDG 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 embryologic developmental differences and postnatal 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. Phosphomannomutase 2 (PMM2) is required for synthesis of one of these charged sugars, mannose-1-phosphate (more...)

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been proposed, although recognition that there is significant phenotypic variability even with the same genotype is prudent.

• 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, was studied in Scandinavia [Kjaergaard et al 2001]. Individuals presented with severe feeding issues, severe failure to thrive, severe hypotonia, developmental delay 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. 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].
• 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 appeared to be associated with a milder phenotype without pericardial effusions, coagulation defects, or nutritional disturbances. Some individuals were able to walk independently.
• 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].

Modifiers. A relatively common mild ALG6 variant (p.Phe304Ser) in combination with biallelic PMM2 pathogenic variants may exacerbate the clinical severity in PMM2-CDG; 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 italicized) 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 [Jaeken et al 2009].

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

Prevalence

PMM2-CDG 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].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PMM2-CDG, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended [Grünewald 2009, Schiff et al 2017, Altassan et al 2019].

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

Newborns at risk should have molecular testing for the familial PMM2 pathogenic variants.

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 EU Clinical Trials Register 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.

Mode of Inheritance

PMM2-CDG is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are typically heterozygotes (i.e., carriers of one PMM2 pathogenic variant).
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a PMM2 variant. If carrier testing detects the variant in only one parent:
  • And the child appears to have homozygous PMM2 pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy for chromosome 16. (Uniparental isodisomy was reported in a proband with PMM2-CDG [Vaes et al 2020].)
  • And the child has compound heterozygous PMM2 pathogenic variants, the child may theoretically have one inherited variant and one de novo pathogenic variant. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a PMM2 pathogenic variant, the theoretic risks to sibs of an affected individual at conception 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]. (See Related Genetic Counseling Issues, Increased recurrence risk for PMM2-CDG.)
• If the proband has PMM2-CDG as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for a PMM2 pathogenic variant, the theoretic risks to sibs of an affected individual at conception are a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier. (The risk to the sibs of being affected with PMM2-CDG is not increased over that of the general population.)
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Adults with PMM2-CDG are not known 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 Detection

Carrier testing for at-risk relatives requires prior identification of the PMM2 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Increased recurrence risk for PMM2-CDG. 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 and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

High a priori risk. Once the PMM2 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for PMM2-CDG are possible.

Low a priori risk. PMM2 molecular testing should be considered in nonimmune hydrops fetalis [van de Kamp et al 2007].

Note: Transferrin isoform analysis on fetal serum is an unreliable diagnostic test. PMM2 enzyme activity may also be falsely low in poorly growing amniocytes or chorionic villi.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PMM2 encodes phosphomannomutase 2 (PMM2), an enzyme specifically involved in the conversion of mannose-6-phosphate to mannose-1-phosphate, which is then further converted to GDP-mannose. GDP-mannose is the activated mannose used in the biosynthesis of N-linked glycoproteins.

Deficient PMM2 causes hypoglycosylation by lowering the intracellular mannose-1-phosphate pool, leading to deficiency of GDP-mannose, and thus deficient lipid-linked oligosaccharide synthesis. With deficiency of lipid-linked oligosaccharides, glycosylation of proteins at the asparagine residue becomes deficient, leading to dysfunction of these underglycosylated proteins.

Mechanism of disease causation. Loss of function

PMM2-specific laboratory technical considerations. A processed pseudogene, PMM2P1, has been identified on chromosome 18 [Schollen et al 1998].

Author Notes

Christina Lam is a board-certified clinical geneticist and medical biochemical geneticist. After completion of her pediatrics and genetics residency at UCLA and her medical biochemical genetics and clinical research fellowship at the National Institutes of Health, she joined the faculty at the University of Washington in Seattle, Washington, practicing medical biochemical genetics mostly at Seattle Children's Hospital. She received her MD from the David Geffen School of Medicine at UCLA in 2007. She is currently an Assistant Professor of Pediatrics at the University of Washington.

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.

Acknowledgments

Our thanks to all the individuals with CDG and their families, who have shared their important stories with us. In addition, we are grateful to medical teams who have cared for individuals with CDG and added critical information to our knowledge base. Lastly, we appreciate the CDG advocacy group CDG Care for their empathic support over the years of families, children, and adults affected by CDG.

Author History

Christina Lam, MD (2021-present)
Susan E Sparks, MD, PhD; Sanofi Genzyme (2005-2021)
Donna M Krasnewich, MD, PhD (2005-present)

Revision History

• 20 May 2021 (sw) Comprehensive update posted live
• 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 live
• 27 February 2004 (dk) Original submission

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