Deoxyguanosine kinase deficiency is a rare autosomal recessive mitochondrial DNA depletion syndrome characterized by severe progressive hepatic failure and neurologic involvement in infancy or early childhood. The disease often progresses to end-stage liver disease, necessitating liver transplant in selected patients. We present the anesthetic management of a 17-year-old female patient with end-stage liver disease due to deoxyguanosine kinase deficiency who was scheduled for liver transplant. Liver transplant is currently the only definitive treatment option for hepatic failure associated with deoxyguanosine kinase deficiency, although perioperative morbidity and mortality remain high. Anesthesia management of patients with deoxyguanosine kinase deficiency who undergo liver transplant requires aggressive blood glucose and lactic acidosis monitoring. Comprehensive preoperative assessment, with careful consideration of systemic manifestations and underlying mitochondrial dysfunction, is essential. Successful anesthetic mana-gement requires a multidisciplinary team approach, meticulous perioperative planning, and watchful intraoperative monitoring to optimize outcomes and improve prognosis in this high-risk population.

Primary mitochondrial disorders are a cause of neonatal liver failure. Biallelic pathogenic variants of the gene encoding the mitochondrial localizing enzyme deoxyguanosine kinase (DGUOK) cause hepatocerebral mitochondrial DNA depletion syndrome, leading to acute neonatal liver failure and early mortality. There are currently no effective disease-modifying therapies. In this study, we developed an adeno-associated virus 9 (AAV9) gene therapy approach to treat a mouse model of DGUOK deficiency that recapitulates human disease. We delivered AAV9-hDGUOK intravenously to newborn Dguok knock-out mice and showed that liver dysfunction was prevented in a dose-dependent manner. Unexpectedly for neonatal delivery, durable and long-lasting liver transduction and RNA expression were observed. Liver mitochondrial DNA depletion, deficiencies of oxidative phosphorylation complexes I, III, and IV and liver transaminitis and survival were ameliorated in a dose-dependent manner.

Inborn errors of metabolism (IEMs) are inherited diseases causing significant morbidity and mortality, particularly in childhood. Liver transplantation (LT) can be curative or partially effective for these diseases. LT for IEMs has increased, making IEMs the second most common reason for pediatric LT after biliary atresia. Between 2001 and 2023, 50 pediatric patients with IEMs underwent LT at Başkent University, Ankara Hospital. Data collected retrospectively included diagnosis, gender, age of diagnosis, age of LT, LT indication, donor data, graft type, rejection episodes, post-transplant complications, and clinical findings of the IEMs before and after LT. Treatment methods, follow-up duration, and survival time were also recorded. Of the 332 pediatric LT patients, 50 (15.1%) had IEMs, with three requiring re-transplantations. Diagnoses included glycogen storage diseases (n = 11), tyrosinemia type 1 (n = 10), primary hyperoxaluria (n = 6), urea cycle disorders (n = 6), homozygous familial hypercholesterolemia (n = 4), propionic acidemia (n = 4), deoxyguanosine kinase deficiency (n = 3), maple syrup urine disease (n = 2), methylmalonic acidemia (n = 1), Niemann-Pick disease type B (n = 1), alkaptonuria with unknown neonatal cholestasis (n = 1), and bile acid synthesis disorder (n = 1). The parental consanguinity rate was 74%. Living-related donors provided organs for 48 (90.5%) patients. The mean age at LT was 75.3 ± 8.2 months (range: 5-218), with a follow-up period of 82.1 ± 10.2 months (range:1 day-229 months). Survival rates at 1, 5, 10, and 15 years were 83.7%, 81%, 81%, and 70.9%, respectively. LT is an effective solution for children with IEM causing chronic organ failure and difficult to manage with medical treatment, showing a good long-term prognosis.

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates (P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation.

Although thrombocytopenia is a frequent complication that develops after liver transplantation, immune thrombocytopenia rarely occurs post-transplant. We present an 8-year-old boy who experienced 2 immune thrombocytopenia episodes that occurred 72 and 93 months after liver transplant while the patient was on tacrolimus therapy. The patient, who had primary diagnosis being deoxyguanosine kinase deficiency, received a liver transplant from his father at 1 year of age. Parents were first-degree relatives. In both episodes, the patient was admitted because of diffuse petechial lesions that developed 7 to 14 days after upper respiratory tract infection. Laboratory findings were unremarkable except for low platelet count (13 × 109/L and 6 × 109/L) and increased immature megakaryocytes in the bone marrow. The first episode responded to a mega-level dose of methylprednisolone; platelet count remained stable at >150 × 109/L until immune thrombocytopenia recurred 21 months later. The second episode was resistant to standard treatment modalities, including steroid, intravenous immunoglobulin G, and rituximab administration but responded to eltrombopag (starting at 25 mg/day and gradually increased to 75 mg/day) as a bridging regimen for partial splenic embolization and as maintenance therapy for 45 days. Platelet count has remained normal and stable over 3 years. In our literature review, we found 9 children who developed immune thrombocytopenia after liver transplant. In our patient, with response to eltrombopag as a bridging regimen for partial splenic embolization and maintenance therapy and primary liver pathology showing deoxyguanosine kinase deficiency, the posttransplant period before diagnosis of immune thrombocytopenia was longer than periods reported in the literature. These factors make our case unique. Our case highlights the need for clinicians to be aware of posttransplant immune thrombocytopenia, which can develop despite ongoing immunosuppressive therapy, and to differentiate this entity from other causes of thrombocytopenia.