Deoxyguanosine Kinase Deficiency

Excerpt

Clinical characteristics: The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and developmental delay) evident within weeks of birth. Those with isolated liver disease may also have renal involvement, and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms.

Diagnosis/testing: The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic variants in DGUOK on molecular genetic testing.

Management: Treatment of manifestations: Care is best provided by a multidisciplinary team. Feeding therapy and/or gastrostomy tube as needed for feeding issues; developmental and education support. Children with cholestatic liver disease may require formulas with enriched medium-chain triglyceride content and fractional meals with enteral nutrition at night for adequate nutrition. Cornstarch for those with symptomatic hypoglycemia; supplementation with fat-soluble vitamins and essential fatty acids; routine immunizations for affected individuals and household contacts to prevent viral illness. Liver transplantation has been used to treat individuals without neurologic involvement or with minimal neurologic involvement. Treatment of hepatocellular carcinoma per oncologist; social work support and care coordination as needed.

Surveillance: Monitor fasting blood sugar during infancy; neurologic and developmental assessment at each visit; assess weight gain, nutritional status, and serum concentrations of ALT, AST, GGT, bilirubin, albumin, and coagulation profile at each visit; AFP and abdominal ultrasound every three months; urinalysis and urine amino acids at each visit in those with isolated hepatic disease; assess family needs at each visit.

Genetic counseling: DGUOK deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the DGUOK pathogenic variants in the family are known.