PMM2-CDG (CDG-Ia)

Other Names: CDG 1A; CDG1A; Jaeken syndrome; Carbohydrate-deficient glycoprotein syndrome type 1A; Phosphomannomutase 2 deficiency; Carbohydrate-deficient glycoprotein syndrome type 1A (formerly); Congenital disorder of glycosylation, type Ia ; CDG syndrome type Ia; CDG-Ia; Carbohydrate deficient glycoprotein syndrome type Ia; Congenital disorder of glycosylation type 1a; Congenital disorder of glycosylation type Ia; PMM2-CDG

Congenital disorder of glycosylation type Ia (CDG-Ia) is an inherited condition that affects many parts of the body. The type and severity of problems associated with CDG-Ia vary widely among affected individuals, sometimes even among members of the same family.

Epidemiology

More than 800 individuals with PMM2-CDG have been identified worldwide.

Cause

PMM2-CDG is caused by mutations in the PMM2 gene. This gene provides instructions for making an enzyme called phosphomannomutase 2 (PMM2). The PMM2 enzyme is involved in a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. Glycosylation modifies proteins so they can perform a wider variety of functions. Mutations in the PMM2 gene lead to the production of an abnormal PMM2 enzyme with reduced activity. Without a properly functioning PMM2 enzyme, glycosylation cannot proceed normally. As a result, incorrect oligosaccharides are produced and attached to proteins. The wide variety of signs and symptoms in PMM2-CDG are likely due to the production of abnormally glycosylated proteins in many organs and tissues.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Individuals with PMM2-CDG typically develop signs and symptoms of the condition during infancy. Affected infants may have weak muscle tone (hypotonia), retracted (inverted) nipples, an abnormal distribution of fat, eyes that do not look in the same direction (strabismus), developmental delay, and a failure to gain weight and grow at the expected rate (failure to thrive).

Infants with PMM2-CDG also frequently have an underdeveloped cerebellum, which is the part of the brain that coordinates movement. Distinctive facial features are sometimes present in affected individuals, including a high forehead, a triangular face, large ears, and a thin upper lip. Children with PMM2-CDG may also have elevated liver function test results, seizures, fluid around the heart (pericardial effusion), and blood clotting disorders. About 20 percent of affected infants do not survive the first year of life due to multiple organ failure.

The most severe cases of PMM2-CDG are characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Most babies with hydrops fetalis are stillborn or die soon after birth.

People with PMM2-CDG who survive infancy may have moderate intellectual disability, and some are unable to walk independently. Affected individuals may also experience stroke-like episodes that involve an extreme lack of energy (lethargy) and temporary paralysis. Recovery from these episodes usually occurs over a period of a few weeks to several months.

During adolescence or adulthood, individuals with PMM2-CDG have reduced sensation and weakness in their arms and legs (peripheral neuropathy), an abnormal curvature of the spine (kyphoscoliosis), impaired muscle coordination (ataxia), and joint deformities (contractures).

Some affected individuals have an eye disorder called retinitis pigmentosa that causes vision loss. Females with PMM2-CDG have hypergonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, females with PMM2-CDG do not go through puberty. Affected males experience normal puberty but often have small testes.

Diagnosis

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.

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

• Prader-Willi syndrome
• Congenital muscular dystrophies including Fukuyama congenital muscular dystrophy (FCMD) caused by mutation of FKTN, muscle-eye-brain (MEB) disease caused by mutation of POMGNT1 , and Walker-Warburg syndrome, caused by mutation of POMT1
• Congenital myopathies

Treatment

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.

NIH genetic and rare disease info

• NIH info on PMM2-CDG (CDG-Ia)

PMM2-CDG (CDG-Ia) is a rare disease.

PMM2-CDG (CDG-Ia) Resources
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