Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

INTRODUCTION Mitochondrial DNA (mtDNA) is inherited maternally and codes for a mitochondrion's ribosomal proteins, tRNAs, and 13 of its respiratory chain proteins. mtDNA depletion occurs when mtDNA levels are quantitatively significantly decreased, usually with <1 residual molecule per mitochondrion (normal number of 2–10) (1). In a single cell normal and mutated mtDNA may coexist (ie, heteroplasmy). The threshold of mutated mtDNA for a deleterious phenotype is variable and mtDNA depletion is tissue specific. It may be expressed in a single organ or multiple organs, resulting in diverse clinical manifestations. In addition to liver failure in infancy (1), other clinical manifestations of mtDNA deletion syndrome (MDS) include myopathy or encephalomyopathy, lactic acidosis, heart failure, renal tubulopathy, and neurological abnormalities (2). Liver transplantation is a potential treatment option for end-stage liver disease from MDS. Contraindications to transplantation, including involvement of vital organs such as the brain, need to be actively investigated (3). The severity of extrahepatic involvement may be variable. Mild extrahepatic involvement may not be a contraindication to transplantation. We report on a child with liver failure from MDS with apparent neurodevelopmental progress who was referred for liver transplantation evaluation and found to have unique and new brain magnetic resonance imaging (MRI) findings not evident from a previous MRI study. CASE REPORT A 5-month-old Caucasian female patient of nonconsanguineous parents presented to our hospital with failure to thrive (poor weight gain over 2 months). Conception was assisted by the maternal use of clomiphene. She was born without any complications with a birth weight of 3.274 kg. She had neonatal jaundice at 2 weeks of age (total bilirubin, 195 mmol/L; conjugated bilirubin, 10 mmol/L), which spontaneously resolved. Her gross motor development at presentation was mildly delayed. She had a mild head lag, sat with support, rolled from back to front, transferred objects from hand to hand, and used a coarse ulnar grasp. She fixed and followed with her eyes, turned toward sounds, cooed, and smiled. Physical examination revealed an alert and interactive child. Her weight was less than the third percentile for age and her length and head circumference were at the 50th percentile for age. She was not obviously jaundiced with no scleral icterus. The liver was soft and palpated at 4 cm below the costal margin with no splenomegaly. She exhibited mild to moderate hypotonia. The rest of her examination findings were within normal limits. Initial investigations revealed a hemoglobin level of 123 g/L, platelet count of 381 × 109/L, white blood cell count of 11 × 109/L, albumin level of 44 g/L, alkaline phosphatase level of 160 U/L, aspartate aminotransferase level of 108 U/L, alanine aminotransferase level of 62 U/L, γ-glutamyl transpeptidase level of 290 U/L, total bilirubin level of 71 mmol/L, conjugated bilirubin level of 26 mmol/L, and International Normalized Ratio of 1.2. She had normal levels of creatinine, urea, sodium, potassium, chloride, glucose, lactate:pyruvate, pyruvate, α-1-antitrypsin, ferritin, and creatine kinase. Her bicarbonate level was low (17 mmol/L). She had elevated levels of ammonia (67 mmol/L), α-fetoprotein (79,220 kU/L), serum lactate (3.7 mmol/L), cerebrospinal fluid lactate (4.1 mmol/L), qualitative fecal fat (4+), anion gap (18), partial thromboplastin time (50), and alanine (1200 mmol/L). The remainder of her amino acid levels were normal. The ceruloplasmin level was low at 0.10 g/L, with normal levels of urinary copper. Other normal investigations included head computed tomography, MRI of the brain, auditory brainstem response, visual evoked potential, bone marrow aspirate, echocardiography, ophthalmology evaluation, sweat chloride test, oligosaccharide and mucopolysaccharide screen, acylcarnitine profile, very long chain fatty acid profile, and isoelectric focusing of serum transferrin. The results of the urine organic acids, amino acids, reducing substances, and succinylacetone evaluations were normal. Ultrasonography of the abdomen showed hepatomegaly with increased liver echogenicity. A liver biopsy performed at 6 months of age showed pale lobular hepatocytes, focal balloon hepatocytes, cholestasis, mild inflammation, and fibrosis. Electron microscopy confirmed the presence of small droplet lipid vacuoles in the cytoplasm with no definable mitochondrial abnormalities (Fig. 1). mtDNA quantification by polymerase chain reaction analysis conducted at Columbia University on the liver biopsy specimen revealed 85% mtDNA depletion, confirming the diagnosis of MDS. A skeletal muscle biopsy showed immature, infantile skeletal muscle correlating appropriately with hypotonia, focal perimysial infiltrate of macrophages likely secondary to prior injections, and no evidence of mitochondrial abnormalities. Respiratory enzyme analysis on muscle showed a slight reduction of complex IV, but normal complex IV-to-control ratio.FIG. 1: Uranyl acetate and lead citrate stained electron micrograph of a hepatocyte (original magnification × 15,000) shows steatosis (double arrows) and mitochondria (single arrow) with varied size and pale matrix.The medications used during the course of her illness included lansoprazole, pancrelipase, coenzyme Q10, L-carnitine, and ADEK pediatric multivitamin. She was maintained on nasogastric feeds of an elemental formula. Neurodevelopmental Course Our patient showed mild isolated gross motor delay at initial referral. At 8 months of age, she continued to show gross motor delay due to hypotonia with the inability to sit unsupported or maintain head control. At 11 months of age, progress included the ability to tripod sit, lift her head when prone, and use a pincer grasp. She also said “mama” appropriately, understood the word “no” and shook her head, responded to her name, laughed, played peek-a-boo, and displayed object permanence. She mouthed and explored toys orally with a preference of using her right hand. Her tone was difficult to assess due to irritability. No reflexes could be elicited in the lower extremities (concurrent vitamin E level of 9 μmol/L [normal, 5–20 μmol/L]). The remainder of her neurological examination findings were normal. She did not show any indications of developmental regression, seizures, abnormal trend of head circumference, or hearing or visual impairment during her course of illness. Feeding and Nutrition Course The patient continued to demonstrate poor weight gain (significantly less than the fifth percentile). At 11 months of age she received a gastrostomy tube for nutritional support and management of worsening gastroesophageal reflux. Gastroscopy showed marked thickening of the mucosa with edema of the fundus and body of the stomach, with biopsies demonstrating atrophy of antral and oxyntic mucosa and normal histology of the duodenum. Because of worsening regurgitation, she received a gastrojejunostomy tube at 12 months of age. Course of Liver and Neurologic Involvement The liver profile test results gradually worsened, and at 1 year of age showed an aspartate aminotransferase level of 537 U/L, alanine aminotransferase level of 239 U/L, alkaline phosphatase level of 334 U/L, γ-glutamyl transpeptidase level of 125 U/L, total bilirubin level of 174 mmol/L, conjugated bilirubin level of 102 mmol/L, International Normalized Ratio of 2.7, serum lactate level of 8.6 mmol/L, albumin level of 30 g/L, glucose level of 3.3 mmol/L, and ammonia level of 50 μmol/L. She also developed upper gastrointestinal bleeding, with endoscopy revealing mild grade I varices and portal hypertensive gastropathy with no active bleeding. Her liver function continued to deteriorate despite apparent neurodevelopmental progress and she was admitted to the hospital for liver transplantation evaluation. A repeat MRI of the brain performed as a routine part of liver transplantation evaluation showed T2 hyperintensities suggestive of leukoencephalopathy (Figs. 2,3). There was confluent involvement of the corona radiata of the cerebral hemispheres with extension to the subcortical U-fibers, external capsules, and extreme capsules. The T2 hyperintensities corresponded to diffusion abnormalities representing acute disruption of the sodium/potassium pumps in the white matter (ie, acute demyelination). The brain MRI findings posed a significant risk for poor neurological outcome. Therefore, she was declined as a candidate for liver transplantation. She developed subacute fulminant liver failure with encephalopathy, resulting in death 1 week later.FIG. 2: A T2 transverse image at the level of the basal ganglia shows increased T2 signal in the white matter of all lobes, including the external and extreme capsules.FIG. 3: A T2 transverse image at the level of the pons shows bilateral symmetric linear areas of increased signal (single arrows) in the dorsal brainstem, which extended into the medulla oblongata.An autopsy limited to the abdomen at the parents' request showed ascites and visceral congestion. The liver was enlarged and smooth with a glistening capsule. The parenchyma was homogenous, green, and greasy. There were occasional 0.1-cm nodules, which appeared to be fattier than the surrounding liver. Histological sections showed fibrous septae forming a nodular appearance with rare hepatocytes, marked bile duct proliferation, and cholestasis. The rare islands of preserved hepatic parenchyma showed moderate microvesicular steatosis. Respiratory chain enzyme analysis on liver tissue showed a significant decrease in complex IV activity. The dgK gene was sequenced and no mutation was found. A novel mutation in the MPV17 gene was detected; a mutation in the same gene was reported in 2 other families (4). Recently, her younger brother was diagnosed with MDS and also found to possess the same mutation in the MPV17 gene, but he remains well at age 17 months and has only mild liver disease. DISCUSSION We report on a child with subacute fulminant hepatic failure from MDS with a novel mutation in the MPV17 gene presenting with a clinical neurodevelopmental course that poorly correlated with her unique neuroimaging findings. Despite hypotonia and mild global developmental delay predominantly affecting gross motor skills, she showed progress in all areas of development. No regression or new neurological deficits were evident aside from areflexia of her lower limbs. However, the neuroimaging unexpectedly showed new and extensive neurological involvement with severe demyelination, increasing the risk of poor neurological outcome after liver transplantation. In the hepatic form of MDS, the onset of symptoms usually occurs in the first year of life (5). Clinical manifestations of liver disease are variable and include jaundice, hepatomegaly, hematemesis from rapidly progressive liver failure, hypoglycemia, and lactic acidosis (6,7). The genotype and phenotype correlation is poor, as shown by our case and her brother's having the same mutation yet different liver manifestations. The hepatic form of MDS is associated with a high mortality rate. Most patients die in early childhood, and 1 study reported death in all 10 patients with hepatic MDS (6). Liver transplantation is a potential treatment option for end-stage liver disease from MDS. A previous study of 6 children who received liver transplants for liver disease from mitochondrial disorders without extrahepatic manifestations reported that 5 children had positive outcomes, including survival of the perioperative period (3). Central nervous system (CNS) involvement is not uncommon in MDS. It may occur in isolation or in combination with hepatocerebral MDS. Previously described CNS involvement includes seizures with abnormal electroencephalogram discharges, encephalopathy, and abnormal imaging findings (1,8–17). In neuroimaging, cerebral atrophy is common (3,14–16). Signal intensity changes on MRI have been described as T2 hyperintensities in the putamina, corona radiata, and cerebral peduncles. Vu et al (14) described a patient with initial normal MRI findings at 9 months of age; repeat scanning for weakness, hypotonia, and hyporeflexia at 14 months showed incomplete myelination. Morris et al (17) described a patient with developmental regression and tremor with T2 hyperintensities in the putamina and brainstem; at pathological review, these lesions represented the sequela of a metabolic or toxic process rather than necrosis. Therefore, previous cases demonstrate progressive radiological disease associated with neurological decline. However, our patient showed neurodevelopmental gain, which did not parallel findings on MRI. Our patient had a normal MRI brain at 9 months of age. At 1 year of age, the MRI showed unique and widespread findings of signal abnormalities with T2 hyperintensities representing acute demyelination in the subcortical U-fibers, corona radiata of the cerebral hemispheres, external and extreme capsules, and dorsal aspect of the pons extending into the medulla oblongata. We recognize that the severity of CNS involvement in MDS is variable and may be progressive. It also may not be clinically evident. Determination of the extent of involvement is important due to the risk of persistent and possibly progressive CNS involvement. Dubern et al (3) recommend an emergency CNS evaluation by clinical examination for muscle weakness, hypotonia, and cerebellar ataxia; MRI of the brain; cerebrospinal lactate and protein measurements; and fundoscopy for pigmentary retinopathy. In addition, we recommend ongoing clinical neurodevelopmental examination conducted by a pediatric neurologist and serial brain MRI examinations. It is vital when considering liver transplantation for liver failure from MDS to proceed with caution and evaluate for extrahepatic involvement. The extent of neurological involvement is variable and may not be clinically evident; it is not always a contraindication to liver transplantation, but it may yield a serious risk for poor neurological outcome. In our patient repeat neurological imaging detected unique, new, and progressive neurological involvement that was not clinically evident or initially present. Thus, clinical and radiological findings need to be considered. In addition to clinical evaluation, we recommend serial neurological imaging studies for the evaluation of the extent and progression of CNS disease. Acknowledgments The authors thank Drs Salvatore DiMauro and Sara Shanske (Department of Neurology, Columbia College of Physicians and Surgeons, Columbia University, New York) and Dr M. Zeviani (Division of Molecular Neurogenetics, National Neurological Institute “C. Besta,” Milan, Italy) for their work on the mtDNA analysis. The authors also thank Dr M. James Philips (Department of Paediatric Laboratory Medicine, Division of Pathology, Hospital for Sick Children, Toronto) for review of the liver biopsy specimen.

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