A 5-year-old boy was brought into his primary care clinic by his mother, who expressed concern about her son’s increasing impulsiveness, aggression, and difficulty staying on task at preschool and at home. The child’s medical history was unremarkable, and he was taking no medications. The family history was negative for hepatic or metabolic disease and positive for attention deficit-hyperactivity disorder (ADHD; father).
The child’s growth was normal. His physical exam was remarkable for a liver edge 1 cm below his costal margin. No Kayser-Fleischer rings were present.
Screening included a complete metabolic panel. Notable results included an alanine aminotransferase (ALT) level of 208 U/dL (normal range, < 30 U/dL), an aspartate transaminase (AST) level of 125 U/dL (normal range, 10-34 U/dL), and an alkaline phosphatase (ALP) of 470 U/dL (normal range, 93-309 U/dL). Subsequent repeat laboratory testing confirmed these elevations (ALT, 248 U/dL; AST, 137 U/dL; ALP, 462 U/dL). Ceruloplasmin levels were low (11 mg/dL; normal range, 18-35 mg/dL), and 24-hour urinary copper was not obtainable. Prothrombin/partial thromboplastin time, ammonia, lactate, total and direct bilirubin, and gamma-glutamyltransferase levels were normal.
Further evaluation included abdominal ultrasound and brain magnetic resonance imaging, both of which yielded normal results. Testing for Epstein-Barr virus; cytomegalovirus; hepatitis A, B, and C titers; and antinuclear, anti-smooth muscle, and anti–liver-kidney microsomal antibodies was negative.
The patient’s low ceruloplasmin prompted referral to Pediatric Gastroenterology for consultation and liver biopsy due to concern for Wilson disease. Biopsy results were consistent with, and quantitative liver copper confirmatory for, this diagnosis (FIGURE).
Genetic testing for mutations in the ATP7B gene was performed on the patient, his mother, and his siblings (his father was unavailable). The patient, his mother, and his sister were all positive for His1069Gln mutation; only the patient was positive for a 3990_3993 del mutation (his half-brother was negative for both mutations). The presence of 2 different mutant alleles for the ATP7B gene, one on each chromosome—the common substitution mutation, His1069Gln, in exon 14 and a 3990_3993 del TTAT mutation in exon 19—qualified the patient as a compound heterozygote.
The 3990_3993 del TTAT mutation—which to our knowledge has not been previously reported—produced a translational frame shift and premature stop codon. As others have pointed out, frame shift and missense mutations produce a more severe phenotype.1
Continue to: Further testing was prompted...