Deoxyguanosine kinase deficiency: natural history and liver transplant outcome

Abstract

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.

Keywords: DGUOK; deoxyguanosine kinase; liver transplant; mitochondrial DNA; nucleosides.

Graphical abstract

Figure 1

Clinical manifestations of dGk deficient patients. (A) Percentage of patients with muscular, central nervous system, or liver signs/symptoms at age of onset. Data were available for: 85/88 neonatal patients, 49/51 infantile patients, 4/4 pediatric patients and 15/15 adult patients. (B, C) Prevalence of symptoms in different organs or tissues at the disease onset (B) and during the clinical progression (C) expressed as a percentage. Data availability: 160/202 patients for liver symptoms, 181/202 patients for CNS symptoms, 159/202 patients for muscular symptoms. Follow-up data on the clinical course were available in 181/202. CNS: central nervous system.

Figure 2

Kaplan-Meier analysis of dGk deficiency mortality. (A) Survival curve stratified for age at onset (n = 149) and (B) clinical forms (n = 178); (C) Survival curve in dGk deficient patients with or without CNS involvement (n = 172). Survival analysis was assessed by log-rank Mantel-Cox test. Numbers at risk are specified below each panel. When statistically significant, P values are indicated in the figure. CNS: central nervous system.

Figure 3

LTx outcome: (A) Survival curves comparing LTx versus untreated patients (n = 128). (B) Survival curve comparing subgroups of LTx patients presenting or not CNS involvement (n = 26) and (C) specifically with or without nystagmus (n = 24). Survival analysis was assessed by log-rank Mantel-Cox test. Numbers at risk are specified below each panel. When statistically significant, P values are indicated in the figure. CNS, central nervous system; LTx, liver transplant.

Figure 4

DGUOK disease-causing variants: graphical representation of DGUOK gene showing identified pathogenic variants in the coding and splice-site regions (NM_080916.3). Exons are marked in red boxes. Protein changes are colour-coded based on the clinical form.