Neurophthalmological Findings in Deoxyguanosine Kinase Deficiency: A Poor Outcome Predictor
We would like to share our experience during the clinical follow-up of a patient with deoxyguanosine kinase (DGUOK) deficiency, a rare hepatocerebral mitochondrial DNA (mtDNA) depletion syndrome. Deficiency of DGUOK impairs the mitochondrial nucleotide synthesis. It is associated with a reduction in mtDNA copy number, leading to insufficient production of key subunits of mitochondrial respiratory chain complexes, and ultimately to insufficient energy production. DGUOK deficiency presents in variable phenotypes, ranging from isolated hepatic disease to multisystemic disease. Patients with neonatal onset are usually affected by multiorgan disease including liver and neurological manifestations. DGUOK deficiency may also present later in infancy or childhood as isolated hepatic disease. This form is associated with less severe prognosis and can benefit from liver transplantation.   
Our female patient was born at term with a birth weight of 1,890 g (<3th percentile) to consanguineous parents of Pakistani ancestry. Pregnancy was complicated by intrauterine growth restriction. At the age of 12 hours, she developed recurrent hypoglycemia. At 24 hours of life, she presented hepatic failure with coagulopathy refractory to intravenous vitamin K (prothrombine time 4.09 international normalized ratio), persistent hypoglycemia (glucose 23–35 mg/dL), and lactic acidemia (pH 7.18, HCO3 10.3 mEq/L, base excess −22, and lactate 18 mmol/L). She had normal aspartate aminotransferase and alanine aminotransferase, elevated gamma glutamyl transpeptidase (1,450 U/L), high-ferritin level (971 ng/mL), and elevated α-fetoprotein level (88,846 ng/mL). She required regular fresh frozen plasma transfusion. Brain magnetic resonance imaging showed a structurally normal brain, but magnetic resonance spectroscopy revealed a lactate peak.
Mitochondrial disease was suspected, and the diagnosis was confirmed by next generation sequencing panel for hepatocerebral forms of mtDNA depletion syndromes. Sequence analysis of the DGUOK gene revealed known homozygous pathogenic c.352C > T (p.Arg118Cys) mutation.
Patient showed rapidly progressively neurological and ophthalmological findings. At 1 month of life, she was noted to have mild hypotonia and normal visual function with stable fixation and without abnormal ocular movements. At 2 months of age, she could not fix her gaze and exhibited jerky pursuits with striking oscillating eye movements without clear nystagmus ([Fig. 1] and [Video 1]). At 3 months of age, she was noted to have profound hypotonia, absent fixation with pursuit difficult to evoke, and disconjugated eye movements with upbeating nystagmus ([Video 1]).
Showing disconjugated and multidirectional eye movements at 3 months of age.
Liver transplantation was initially considered, but it was not feasible due to the patient's low weight. The liver disease progressed despite supportive care and liver transplantation was ultimately not considered as a treatment choice due to the onset of neurological signs and symptoms. The patient died at 3 months of age of end-stage liver failure.
Mitochondrial DNA depletion syndromes (OMIM 251880) are a genetically and clinically heterogeneous group of autosomal recessive diseases characterized by reduction in mtDNA copy number in different tissues. The main clinical presentations of mtDNA depletion include myopathic, encephalomyopathic, and hepatocerebral forms. DGUOK deficiency is the commonest type of mtDNA depletion syndrome associated with a hepatocerebral phenotype. Mutations in DGUOK gene can cause variable phenotypes, ranging from isolated liver disease to multisystemic disorders.    Patients with severe forms usually have hepatic disease and neurologic dysfunction evident within weeks after birth.
Neurological involvement is characterized by hypotonia, delayed milestones, and prominent ocular movement disturbances, including oscillating and dysconjugated eye movements and rotary, pendular, or multidirectional nystagmus.  Nevertheless, there is no data regarding the timing of presentation of ocular movement disturbances in these patients.
Our report represents the first description of evolution of neuroophthalmological damage in a patient with a severe form of DGUOK deficiency supported by video documentation.
There has been extensive discussion in the literature about the role of liver transplantation in patients with DGUOK deficiency. Evidence currently indicate that liver transplantation is futile in the presence of neurological signs and/or symptoms, as transplantation provides no survival benefit in such patients.
Neuroophthalmological features should be a part of patient assessment to evaluate eligibility for liver transplantation in patients with DGUOK deficiency. Among the neurological features, nystagmus is considered as a predictor of poor outcome despite liver transplantation.
Our case described the stage progression of neurophtalmological features, also before the onset of nystagmus, providing a clinical help for the pretransplantation evaluation of patients with DGUOK deficiency.
Received: 20 September 2020
Accepted: 28 October 2020
18 December 2020 (online)
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