Congenital Myotonic Dystrophy with Combined Heterozygous ATP8B1/ABCB4 Mutation Leading to Progressive Cholestasis and Liver Failure

**Background:** Myotonic dystrophy (MyoD) is an autosomal dominant multisystem disorder caused by CTG trinucleotide repeat expansion in the DMPK gene. Congenital MyoD is the most severe form, presenting at birth with respiratory distress, hypotonia, and feeding difficulties. While MyoD affects multiple systems, primary hepatic disease is not commonly associated. This case describes a child with congenital MyoD who developed progressive familial intrahepatic cholestasis (PFIC)-like liver disease and underwent successful liver transplantation (LT).

**Methods:** This is a single case report of a newborn with congenital MyoD, diagnosed by confirmed expansion in the DMPK gene in both patient and mother. The child was delivered at 34 weeks gestation due to reduced fetal movement. Postnatally, the infant had respiratory distress, hypotonia, and required parenteral nutrition (PN) from day 1 until 6 months due to GI dysmotility and feed intolerance. At 2 months, conjugated hyperbilirubinemia developed with pigmented stool and normal hepatobiliary ultrasound. Screening for other causes of neonatal cholestasis was normal. At 6 months, enteral autonomy was achieved and PN discontinued, but liver dysfunction progressed. Serum bilirubin peaked at 471 µmol/L, ALT 431 U/L, AST 648 U/L, with low/normal GGT (<50 U/L). Liver biopsy at 10 months showed cholestasis with canalicular bile plugs, hepatocyte rosetting, and ballooning. Immunostaining showed absent GGT expression in most lobules with positive bile salt export pump and MRP2. Electron microscopy did not show Byler bile. Targeted DNA sequencing with a 24-gene cholestasis panel revealed heterozygous mutations in ATP8B1 (2855G>A[p.R952Q]) and ABCB4 (1954A>G[R652G]), associated with PFIC type-1 and type-3 respectively. No mutations were found in other low-GGT cholestasis genes.

**Key Results:** The child developed decompensated liver disease and underwent LT at 4 years 9 months. Explanted liver histology showed severe cholestasis and established cirrhosis. No anesthetic complications occurred. At 7 years post-LT, the patient was well with normal liver biochemistry (bilirubin 25 µmol/L, AST 31 U/L, ALT 27 U/L, albumin 39 g/L, normal coagulation). The child was ambulating, independent in daily activities, and required no feeding or respiratory support except for right-ankle contracture.

**Clinical Implications:** This case demonstrates an uncommon association between congenital MyoD and progressive cholestatic liver disease. The etiology appears multifactorial: (1) possible subclinical hepatic dysfunction from MyoD itself, (2) combined heterozygous mutations in ATP8B1 and ABCB4 genes leading to a PFIC-like phenotype, and (3) intestinal failure-associated liver disease (IFALD) from prolonged PN. The heterozygous ATP8B1 mutation (2855G>A[p.R952Q]) has been described in benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy, while the ABCB4 mutation (1954A>G[R652G]) is pathogenic for PFIC type-3. The low GGT and immunohistochemistry findings supported PFIC1, but genetic testing showed only heterozygous mutations, suggesting that even single-allele mutations or combined heterozygosity in two PFIC genes can produce a PFIC-like phenotype. Successful LT in this patient, without cardiorespiratory involvement, indicates that LT is a viable option for selected MyoD patients with progressive liver disease, provided careful anesthetic management per specific recommendations for MyoD.