Alpers-Huttenlocher syndrome (AHS), which first received attention from Alpers in 1931 [1] and was further described with its hepatic manifestation by Huttenlocher et al. [2] and Harding [3], is a rare mitochondrial disease characterized by its classic triad of refractory seizures, psychomotor regression, and hepatopathy [3]. In 1999, Naviaux et al. [4] established the biochemical and enzymatic relevance of polymerase gamma (POLG) in AHS with their description of mitochondrial DNA depletion and reduced POLG activity. In most cases, the first manifestation of AHS is a neurodevelopmental delay or intractable seizures, but it has been reported that in some rare cases its first manifestation is hepatic [5]. Hepatic failure is most commonly presented in the preterminal stage regardless of valproate exposure, and many patients die due to either hepatic failure or neurological deterioration [56].

Our team investigated a 10-month-old patient with AHS whose first manifestation was hepatic failure he received liver transplantation and later developed epilepsy and psychomotor regression. His prognosis was sufficiently good to be discharged from hospital with neurodevelopmental improvement.

A 10-month-old male patient was admitted for persistent hepatitis and jaundice. He did not have any perinatal, familial, or past history except that he had received treatment for bronchitis in another hospital two weeks prior to admission. His aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were elevated upon his admission for bronchitis, and reactive hepatitis was suspected because of his intact liver function and clinical history. However, he eventually developed impending hepatic failure, and was referred to the hepatology department. The initial laboratory finding suggested acute liver failure with AST and ALT levels of 194 IU/L and 69 IU/L, total and direct bilirubin of 7.4 mg/dL and 6.3 mg/dL, ammonia of 57 µg/dL, and gamma-glutamyl transpeptidase of 101 IU/L, respectively. His initial blood gas analysis test, with normal pH of 7.40 and bicarbonate of 25.8 mmol/L, was not suggestive of definite metabolic acidosis, although the lacate level was slightly elevated to 2.4 mmol/L. Numerous evaluations such as viral, autoimmune, endocrinologic, and genetic studies for ATP7B and ABCB11 were performed that all turned out normal, and there were no remarkable findings in his imaging study. The lactate-to-pyruvate ratio was 82.5, and plasma amino acid assay suggested the possibility of lactic acidosis. Therefore, the whole exome sequencing (WES) analysis was sent out for further evaluation. Meanwhile, his mental status became drowsy with hyperammonemia, and he received a living donor liver transplantation at admission day 24. The pathologist confirmed cirrhosis with marked fatty change, cholestasis, ballooning degeneration and marked ductular proliferation, favoring metabolic disease (Fig. 1). The liver transplantation was successful, and he was discharged home with normal neurological function. One month later, he was readmitted to the neurology department for eye blinking and myoclonus on the right side of his face. Electroencephalogram (EEG) was performed, which determined left periodic lateralized epileptiform discharges, and brain magnetic resonance imaging (MRI) showed multifocal diffusion restriction areas in the left insula, deep gray matter and bilateral perirolandic area, suggesting metabolic disorder (Fig. 2). A combination therapy of six antiepileptic drugs did not improve his continuous myoclonic seizures, and other symptoms such as psychomotor regression, nystagmus, swallowing difficulty and frequent central apnea subsequently occurred. WES revealed the known compound heterozygous mutation of the POLG gene (p.Arg807His and p.Arg627Trp), confirming AHS (Table 1). The EEG pattern evolved to a generalized slow spike and waves with generalized paroxysmal fast activities in the left hemisphere, and follow-up MRI showed diffuse cerebral atrophy, especially on the left posterior quadrant. Valproate was discontinued immediately, and a mitochondrial cocktail therapy comprised of thiamine, coenzyme Q10 (CoQ10), and L-carnitine was started. After four months of this cocktail therapy, the number of apnea events had reduced and nystagmus and motor function had slightly improved. The feeding problem was resolved after the gastrostomy, and he could tolerate enteral feeding without reflux. Recently, he was able to intake some feeding per oral. He was discharged home after one year of hospitalization.

AHS is a mitochondrial disease caused by autosomal recessive POLG mutation [5]. POLG is the DNA polymerase in mitochondria that is responsible for mitochondrial DNA replication and repair in the mitochondria of eukaryotic cells [7]. Ultimately, a significant amount of mitochondrial DNA depletion is noted when mutation occurs in POLG which leads to dysfunction in multiple organs such as the brain and liver [7]. The first manifestation usually starts with seizures or psychomotor regression. Liver involvement was rarely reported as the first manifestation, and it is mostly associated with preterminal disease stage [5]. There is no available treatment with which the clinical course of the disease can be modified, and patients with this disease die within four years of the onset of features [5]. Therefore, liver transplantation is said to be contraindicated in the disease due to the poor prognosis even after the successful transplantation [56]. The treatment of this disease is focused on symptomatic treatment for the control of seizures, ventilation disorders, or nutritional issues [5]. Valproate is usually contraindicated in AHS since it can accelerate the dysfunction of mitochondria, leading to liver failure [6]. In our case, although the patient had already undergone liver transplantation, we decided to discontinue valproate since it did not seem to be essential for controlling his seizures. Cocktail therapy including vitamins and CoQ10 can be considered as a treatment option in mitochondrial disease by enhancing the mitochondrial function [8].

In the literature review, this was the first report of AHS presenting its first manifestation as liver failure [5]. The patient's neurological function was normal even after liver transplantation, and he was discharged to home and began to develop epilepsia partialis continua one month after liver transplantation. A cocktail therapy for mitochondrial disease was started after the diagnosis of POLG mutation, and it seemed to stabilize our patient's organ function even though we could not stop his partial seizures. We could presume that his organic dysfunction and clinical symptoms became more severe than the degree of his DNA depletion, which resulted in the positive prognosis of his clinical symptoms with CoQ10 and vitamin support.

AHS is one of the most severe phenotypes of POLG mutation and is a fatal disease for which there is no available treatment that modifies its clinical course. However, we want to make the point that liver transplantation can be considered as a treatment option if the disease's course is stable, especially when presenting at a late age. Moreover, in a patient with liver failure of unknown etiology, investigation including genetic study should always be considered when there are signs of metabolic disorders.