PMM2-CDG

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.

1. 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.

2. 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.

3. 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.