Outcomes after liver transplantation in MPV17 deficiency (Navajo neurohepatopathy): A single-center case series.

BACKGROUND: MPV17-related mitochondrial DNA maintenance defect (MPV17 deficiency) is a rare, autosomal recessive mitochondrial DNA depletion syndrome with a high mortality rate in infancy and early childhood due to progression to liver failure. Liver transplantation for children with MPV17 deficiency has been considered controversial due to uncertainty about the potential progression of extrahepatic manifestations following liver transplantation. METHODS: We describe our institution's experience for two infants diagnosed with infantile MPV17 deficiency who presented in acute on chronic liver failure, but with normal development and normal neurological status who successfully underwent liver transplantation. RESULTS: Both patients underwent successful liver transplantation with normal development and neurological status at 3 years and 16 months post-transplant, respectively. CONCLUSIONS: In this rare disease population, we describe two infants with MPV17 deficiency who underwent liver transplantation for acute on chronic liver failure who continue to have normal development, without progression of neurological disease. MPV17 deficiency should not be considered a contraindication to liver transplantation.

Chronic acquired hepatocerebral degeneration presenting with Meige's syndrome and behavioral symptoms fully reversed by liver transplantation.

Chronic acquired hepatocerebral degeneration (CAHD) is a rare neurologic syndrome occurring in patients with chronic liver disease, resulting in the combination of movement disorders and cognitive\behavioral changes. Its pathogenesis is debated and the symptoms are poorly responsive to medical therapy. Meige's syndrome is a form of cranial dystonia, considered an idiopathic form of adult onset dystonia. We report a 60-year-old man with HCV-related liver cirrhosis and hepatocarcinoma who developed Meige's syndrome associated with cognitive and behavioral manifestations, unrelated to acute metabolic derangement. CAHD was diagnosed. Liver transplantation reversed the clinical picture and MR abnormalities, reinforcing the idea that CAHD is a potentially reversible syndrome, which may be healed by liver transplantation and should not be considered a contraindication for this operation.

Acquired hepatocerebral degeneration and hepatic encephalopathy: one or two entities?

BACKGROUND AND PURPOSE: Acquired hepatocerebral degeneration (AHD) and hepatic encephalopathy (HE) are neurological complications of chronic liver disease (CLD) with portosystemic shunt. While HE is common, AHD is a rare entity, and the clinical imaging relationships observed in small series lack validation in large patient cohorts. The aim of this study was to characterize a cohort of AHD patients and to explore possible associations with HE coexistence. METHODS: We performed a retrospective analysis of patients with a working AHD diagnosis, between 2008 and 2019. Clinical, laboratory, imaging and neuropsychological results at first neurological observation were reviewed and compared between the 'AHD' group and the 'AHD with HE' group. RESULTS: A total of 76 patients were recruited. The most frequent neurological manifestations were neuropsychiatric (93.4%) and extrapyramidal (84.2%). Only 38% of patients had hypermanganesemia. Compared with the AHD group, the AHD with HE group had more hyperkinetic movement disorders (71.4% vs. 38.5%; P = 0.05), a higher number of patients on the dementia spectrum (57.7% vs. 20%; P = 0.04), higher median ammonia levels (P = 0.014) and more widespread cortico-subcortical and pyramidal involvement on brain magnetic resonance imaging. Nineteen patients underwent liver transplantation, with significantly improved survival (P = 0.006). DISCUSSION: Hepatic encephalopathy and AHD often coexist in the same patient. Seventy-six patients with CLD and AHD were evaluated, making this one of the largest reported AHD cohorts. Blood manganese level was a weak diagnostic marker in AHD. Early liver function restoration through liver transplantation improved survival. Our report provides a detailed description of the phenotype and long-term outcome of AHD, with relevance for diagnosis and treatment.

Atypical neuroimaging findings in patients with acquired hepatocerebral degeneration.

BACKGROUND: Acquired hepatocerebral degeneration (AHD) is now widely recognized by physicians. Although hyperintensity in the bilateral globus pallidus in T1-weighted magnetic resonance images (MRIs) are characteristic neuroimaging findings, accumulating reports indicate that atypical neuroimaging findings are not rare. This study aimed to describe the spectrum of atypical neuroimaging findings and related factors in patients with AHD. METHODS: From February 2017 to January 2019, a retrospective study was conducted of 28 patients with AHD in the Shengjing Hospital of China Medical University. The neurological manifestations, clinical parameters, and biochemical and neuroimaging findings were analyzed. RESULTS: Among 28 patients, 14 patients were diagnosed with viral hepatitis-caused hepatocirrhosis, which was the most common cause of AHD. Resting tremor, cognitive impairment, and parkinsonian gait were the most common neurologic symptoms. Bilateral globus pallidus T1-weighted hyperintensity was detected in 26 patients (26/28, 92.9%). Ten patients (10/28, 35.7%) were determined to have an atypical neuroimaging finding. Binary logistic regression analysis indicated that age at onset of neurologic symptoms (odds ratio = 1.29, 95% confidence interval [CI] 1.03-1.61; p = 0.030) and Child-Pugh scores (odds ratio = 2.52, 95% CI, 1.01-6.31; p = 0.048) were independently associated with atypical neuroimaging findings in AHD. CONCLUSION: The clinical manifestations of AHD are diverse; resting tremor, cognitive impairment, and parkinsonian gait were the most common. More than one third of patients had atypical neuroimaging findings. Age at onset of neurologic symptoms and Child-Pugh scores may be important predictors of atypical neuroimaging findings in patients with AHD.

Whole exome sequencing reveals two novel compound heterozygous mutations in TWNK as a cause of the hepatocerebral form of mitochondrial DNA depletion syndrome: a case report.

BACKGROUND: Although Mitochondrial DNA depletion syndrome (MDS) can be classified into three forms: myopathic, encephalomyopathic and hepatocerebral form, it is difficult to identify its form due to its clinical heterogeneity. Therefore, it is very important to conduct molecular genetic analysis on suspected patients. This study presented a male 38 weeks and 5 days infant with liver cytolysis and leukodystrophy. CASE PRESENTATION: A male infant proband was admitted to the department of NICU for feeding intolerance, irregular rhythm of respiration, hypoglycemia, lactic acidosis, liver cytolysis and neurological abnormalities. He was onset of mild jaundice with leukodystrophy and high lactate and phenylderivatives for urine organic acids on the 7th day. Whole exome sequencing (WES) and Sanger sequencing were performed to screen and confirm the suspicious pathogenic mutations. The results revealed this proband carried two compound heterozygous mutations in TWNK: c.1186 C > T / p.Pro396Ser and c.1844 G > C / p.Gly615Ala inherited by an autosomal recessive form from his parents, of which protein conservative analysis and structural modeling supported the pathogenicity of the two mutations. Unfortunately, the conditions described above were not improved until he was discharged from the hospital on the 23rd day and died at 4 months of age. CONCLUSIONS: In this study, we investigated a Chinese family with the hepatocerebral form of MDS and conducted WES and Sanger sequencing to explore the causative mutations for this proband born from non-consanguineous and healthy parents. We identified two novel TWNK c.1186 C > T/ c.1844 G > C compound heterozygous mutations which were probably the disease-causing mutations of hepatocerebral form of MDS and described the clinical manifestations of the proband, which expanded the phenotypic spectrum of MDS caused by variants in TWNK. This study also emphasized WES technology can provide the genetic diagnosis of Mendelian genetic disease.

Implications of Manganese in Chronic Acquired Hepatocerebral Degeneration.

Neurological symptoms can be one of the over-riding symptoms in patients with liver cirrhosis. Patients can present with subtle changes in mood or neurological function due to hepatic encephalopathy (HE), to more severe presentations including stupor and coma. While HE, in its severe form, can be clinically easy to diagnose, more subtle forms may be more difficult to recognize. Other neurological diseases may indeed be overlooked in the context of cirrhosis or confuse the physician regarding the diagnosis. Chronic acquired hepatocerebral degeneration (CAHD) is an uncommon problem occurring in patients with cirrhosis characterised by a Parkinsonian-like neurological presentation with damage to the brain secondary to manganese (Mn) deposition. Here we describe a case of a patient with a neurological presentation of liver disease with a review of the current CAHD literature. In conclusion, CAHD is a rare condition occurring in liver cirrhosis that should always be considered in patients with neurological manifestations of chronic liver disease.

Acquired hepatocerebral degeneration (AHD): a peculiar neurological impairment in advanced chronic liver disease.

We discuss the case of a rare and often unrecognized neurologic syndrome, called Acquired Hepatocerebral Degeneration (AHD), observed in patients with advanced liver disease and portosystemic shunts. The clinical manifestations can be very heterogeneous and in our case included a combination of cerebellar and extrapyramidal signs, arisen in a period of few days. Brain Magnetic Resonance Imaging (MRI) showed, in T1-weighted images, diffuse bilateral hyper intensities in basal ganglia and biemispheric brain and cerebellar cortices, resembling paramagnetic deposits. No other neurological impairments, like stroke, infection or neoplasia, were found. It was excluded an episode of acute hepatic encephalopathy. We also ruled out Wilsonian degeneration, iron overload and autoimmune encephalitis and we lastly found high manganese levels as the possible cause of the brain paramagnetic deposits. Even though either serum Mn determination or its accumulation in the brain are not specific for AHD, however the chronic and progressively worsening of the neurological manifestations advocated a degenerative condition, possibly AHD. We finally opted for the early restoration of liver function by OLT, and we observed complete clinical symptoms' resolution and partial MRI reversal after a follow up of 6 months.

Magnetic resonance imaging findings in diagnosis and prognosis of Wilson disease.

Wilson disease (WD) is a rare autosomal recessive disorder characterized by excessive copper deposition in the body, principally in the liver and the brain. There is a wide spectrum of clinical presentations, but the most significant and basic symptoms of the disease can be divided into hepatic, neurologic, and psychiatric manifestations. Magnetic resonance imaging (MRI) provides more detailed anatomical information than computed tomography of the brain, especially of the structure of the basal ganglia and brain stem. In this review, we want to evaluate the correlation between MRI findings and clinical features of WD.

Novel c.191C>G (p.Pro64Arg) MPV17 mutation identified in two pairs of unrelated Polish siblings with mitochondrial hepatoencephalopathy.

This study reports clinical, biochemical and histopathological findings associated with a novel homozygous MPV17 mutation in four patients with mitochondrial depletion syndrome. The severe course of the disease, which started in the first weeks of life, was dominated by a failure to thrive, hypotonia and liver dysfunction, with relatively mild neurological involvement. All affected infants died by 1 year of age. Laboratory findings included progressive liver failure (hypertransaminasaemia, icterus, and coagulopathy), recurrent hypoglycaemia, lactic acidaemia, hyperferritinaemia, and increased transferrin saturation. Histological and ultrastructural analyses uncovered significant lipid accumulation in hepatocytes and myocytes. A severe decrease in the mitochondrial/nuclear DNA (mtDNA/nDNA) ratio was found post-mortem in the livers (and in one muscle specimen) of both examined patients. Oxidative phosphorylation system (OXPHOS) Western blotting revealed low levels of complexes I, III and IV subunits. The highlights of our findings are as follows: (i) The novel p.Pro64Arg mutation is the second recurrent MPV17 mutation reported. The phenotype associated with the p.Pro64Arg mutation differs from the phenotype of the relatively common p.Arg50Gln mutation, suggesting the existence of a genotype-phenotype correlation. (ii) Tissues collected from patients during autopsy may be useful for both mtDNA/nDNA ratio assessment and OXPHOS Western blotting.

Case report: Recurring and treatment-resistant depression in acquired hepatocerebral degeneration due to a congenital portosystemic shunt.

Introduction: Acquired hepatocerebral degeneration (AHD) is a neurological condition associated with cerebral manganese (Mn) accumulation caused by portosystemic shunts (PSS), usually because of advanced liver disease. AHD is diagnosed by the identification of T1-weighted brain magnetic resonance imaging (MRI) hyperintensities coupled with the presence of PSS and neurological symptoms. Clinical presentations primarily involve motor dysfunction and cognitive impairment. As a result of the frequently concurrent hepatic encephalopathy, the psychiatric symptoms of AHD alone remain unclear. This report is the first documentation of unique psychiatric symptoms of AHD due to a congenital PSS (CPSS) and suggests the efficacy of shunt embolization in achieving sustained remission of psychiatric symptoms in such cases. Methods: A 57-year-old Japanese woman presented with recurrent severe depression, pain, and somatosensory hallucinations, along with fluctuating motor dysfunction, including parkinsonism, and cognitive impairments. Psychiatric interventions, including antidepressants, antipsychotics or electroconvulsive therapy, had limited efficacy or did not prevent relapse. Results: T1-weighted MRI showed bilateral hyperintensity in the globus pallidus. No history of Mn exposure or metabolic abnormalities, including copper, was identified. Furthermore, no evidence of liver dysfunction or hyperammonemia was found. Eventually, a gastrorenal shunt was observed on contrast-enhanced abdominal computed tomography. The diagnosis of AHD due to CPSS was made based on the clinical manifestations and abnormal imaging findings. Shunt embolization was performed, which prevented the relapse of psychiatric symptoms and substantially reduced the T1-weighted MRI hyperintensities. Conclusions: This case highlights the potential involvement of AHD in adult-onset psychiatric symptoms, even in the absence of liver disease. Furthermore, this case underscores the efficacy of shunt embolization in treating the psychiatric symptoms of AHD due to CPSS.

Navigating Diagnostic Challenges: A Case of Acquired Hepatocerebral Degeneration Presenting as Worsening Hepatic Encephalopathy in Chronic Liver Disease.

This case report details the complex diagnostic odyssey of a 60-year-old female grappling with chronic liver disease, initially diagnosed with hepatic encephalopathy (HE). Despite initial treatment with lactulose and rifaximin, her neurological symptoms worsened, leading to the identification of concurrent acquired hepatocerebral degeneration (AHD). This condition is characterised by cognitive decline, movement disorders and distinctive imaging abnormalities. The discussion highlights the challenges in distinguishing AHD from HE, underscoring the sophisticated diagnostic and management strategies required for such intricate cases in the realm of chronic liver disease. LEARNING POINTS: Recognizing coexisting conditions: emphasize the importance of identifying acquired hepatocerebral degeneration (AHD) alongside hepatic encephalopathy (HE) in patients with chronic liver disease. This recognition is crucial for comprehensive assessments and understanding the progression of neurological symptoms.Addressing management challenges: highlight the complexities of managing AHD due to limited therapeutic options and potentially irreversible outcomes. Discuss the challenges in decision-making, such as considering liver transplantation for patients with advanced neurological symptoms, and the need for exploring alternative therapeutic strategies.Conducting comprehensive evaluations: stress the significance of thorough evaluations in patients with chronic liver disease presenting with neurological symptoms. This comprehensive approach can help uncover underlying conditions like AHD, which may require different management strategies than those initially considered.

Acquired Parkinson's Disease in Alcoholic Cirrhosis: The Rarest Association.

Hepatic encephalopathy is the most common neurologic complication of liver cirrhosis, whereas acquired hepatocerebral degeneration (AHD) is an underappreciated neurologic manifestation. Parkinsonism, ataxia, and neuropsychiatric symptoms are its defining characteristics. In individuals with chronic parenchymal liver disease with portosystemic shunting, it is an underrecognized etiology of psychomotor retardation. It has been hypothesized that the etiology of AHD is due to manganese buildup in the basal ganglia. This case report details a hepatocerebral degeneration (AHD) case in a patient with chronic parenchymal liver disease who improved after taking a dopamine agonist.

Trace Element Imbalances in Acquired Hepatocerebral Degeneration and Changes after Liver Transplant.

Brain manganese (Mn) accumulation is a key feature in patients with acquired hepatocerebral degeneration (AHD). The role of trace elements other than Mn in AHD needs to be clarified. In this study, using inductively coupled plasma mass spectrometry, we aimed to evaluate blood levels of trace elements in patients with AHD before and after liver transplantation (LT). Trace element levels in the AHD group were also compared with those of healthy controls (blood donors, n = 51). Fifty-one AHD patients were included in the study (mean age: 59.2 ± 10.6 years; men: 72.5%). AHD patients had higher levels of Mn, Li, B, Ni, As, Sr, Mo, Cd, Sb, Tl and Pb and a higher Cu/Se ratio, and lower levels of Se and Rb. Six patients (two women; mean age 55 ± 8.7 years) underwent LT, and there was an improvement in neurological symptoms, a significant increase in the Zn, Se and Sr levels, and a decrease in the Cu/Zn and Cu/Se ratios. In summary, several trace element imbalances were identified in AHD patients. Liver transplantation resulted in the improvement of neurological manifestations and the oxidant/inflammatory status. It is possible that observed changes in trace element levels may play a role in the pathophysiology and symptomatology of AHD.

MPV17 mutation-related mitochondrial DNA depletion syndrome: A case series in infants.

MPV17 is a mitochondrial inner membrane protein, involved in transporting deoxynucleotides into the mitochondria. Pathogenic MPV17 mutations can cause mitochondrial deoxyribonucleic acid (DNA) depletion syndrome, which has a varied presentation with neurological, muscular and hepatic involvement. Presentation as liver failure is relatively uncommon. Here, we report four infants from four separate families with pathogenic, homozygous MPV17 mutations. All had predominant hepatic involvement with cholestasis, lactic acidosis and hypoketotic hypoglycemia. Three of them had presented with liver failure. Interestingly, one of them showed fluctuating liver functions, which worsened with infection and improved after aggressive treatment with antibiotics and supplements. Two of the four cases died in infancy, while the other two improved on conservative management with medium-chain triglyceride-based diet, vitamin supplements, co-enzyme Q and carnitine. The two surviving children are alive at 12 and 25 months of age with native liver with normal to mildly deranged liver function and no neurological dysfunction. Next-generation sequencing confirmed the diagnosis in all of our cases. One of the detected mutations, c.55delC (p.Gln19ArgfsTer3) is a novel pathogenic frameshift mutation, while another mutation c.388G>C (p.Ala130Pro), which was previously reported in Single Nucleotide Polymorphism Database in heterozygous form, is being predicted as likely pathogenic in our case series. We, therefore, propose mutation testing for MPV17 gene during evaluation of indeterminate infantile liver failure, especially those with hypoglycemia and raised plasma lactate.

Mitochondrial Hepatopathy.

Mitochondrial hepatopathies are a subset of mitochondrial diseases defined by primary dysfunction of hepatocyte mitochondria leading to a phenotype of hepatocyte cell injury, steatosis, or liver failure. Increasingly, the diagnosis is established by new sequencing approaches that combine analysis of both nuclear DNA and mitochondrial DNA and allow for timely diagnosis in most patients. Despite advances in diagnostics, for most affected children their disorders are relentlessly progressive, and result in substantial morbidity and mortality. Treatment remains mainly supportive; however, novel therapeutics and a more definitive role for liver transplantation hold promise for affected children.

Acquired Hepatocerebral Degeneration After a Splenorenal Shunt in the Sub-Saharan Africa Context: A Case Report and Brief Review of Literature.

Acquired hepatocerebral degeneration (AHD) is a neurologic syndrome caused by liver dysfunction and long-standing portosystemic shunting. The pathogenesis of the condition is predominantly considered to be related to the deposition of manganese in parts of the brain due to shunting. We report a case of a 25-year-old male who underwent splenectomy and splenorenal shunt for recurrent upper GI bleeding (UGIB) due to esophageal varices caused by non-cirrhotic portal hypertension (NCPH). He presented with bradykinesia, hypophonia, gait instability, and rigidity of the lower extremities 18 months after the procedure was done.

MPV17-related Hepatocerebral Mitochondrial DNA Depletion Syndrome.

Mitochondrial DNA (mtDNA) depletion syndrome comprises diseases resulting from a deficiency of proteins involved in mtDNA synthesis. MPV17 is a mitochondrial membrane protein whose mutation causes mitochondrial deoxynucleotide insufficiency. MPV17-related hepatocerebral mtDNA depletion syndrome is a rare autosomal recessive disease. This case report describes the clinical manifestations of MPV17-related hepatocerebral mtDNA depletion syndrome analyzed by performing whole-exome sequencing (WES). A 17-month-old girl presented with developmental delay, jaundice, and failure to thrive. The laboratory findings revealed cholestatic hepatitis, increased lactate-to-pyruvate ratio, and prolongation of the prothrombin time. She developed a hypoglycemic seizure. Brain magnetic resonance imaging revealed extensive demyelination of the white matter. WES detected the p.Leu151fs and p.Pro98Leu variants in MPV17. Her parents and sibling were found to be MPV17 heterozygous carriers. She was administered supportive treatment, such as replacement of fat-soluble vitamins and cornstarch to prevent further hypoglycemic events. The patient is currently being considered for liver transplantation. Overall, WES can help diagnose hepatocerebral mtDNA depletion syndrome in patients with hepatopathy, developmental delay, lactic acidosis, and hypomyelination based on brain magnetic resonance imaging.

Acquired hepatocerebral degeneration in a metastatic neuroendocrine tumor long-term survivor - an update on neuroendocrine neoplasm's treatment: A case report.

BACKGROUND: Metastatic small bowel low-grade neuroendocrine tumors (NETs) have a good prognosis. Surgery is the only curative treatment; however, this may induce advanced liver disease, particularly in long-term survivor patients. Acquired hepatocerebral degeneration or Parkinsonism in cirrhosis is characterized by rapidly progressive extrapyramidal symptoms in patients with advanced liver disease. CASE SUMMARY: A 70-year-old man presented to the emergency department with diminished consciousness and disorientation, and was diagnosed with hepatic encephalopathy. The patient was diagnosed in 1993 with a metastatic small bowel NET, for which he twice underwent hepatic surgery, with metastatic resection in 1993 and a right hepatectomy in 2002 to remove two hepatic metastases. In 2003, the patient started first-line chemotherapy and in 2004 started the first of three consecutive biological treatments, followed by radio-molecular therapy, achieving stable disease for 14 years. Disease progression was identified and he underwent an endoscopic retrograde cholangiopancreatography. However, in 2019 advanced liver disease was identified. We diagnosed the development of acquired hepatocerebral degeneration, an unusual long-term side effect after multiple hepatic procedures. CONCLUSION: The importance of regular and ongoing surveillance in long-term NET survivors who undergo hepatic procedures should be integrated into the therapeutic management plan, as some of these negative outcomes could be prevented.

Manganese, a Likely Cause of 'Parkinson's in Cirrhosis', a Unique Clinical Entity of Acquired Hepatocerebral Degeneration.

With idiopathic Parkinson's disease being a common entity, parkinsonism in acquired hepatocerebral degeneration (AHD) in the context of Manganese (Mn) has gained importance in recent years. An insight into the pathomechanisms behind this disease has been put forth. How can Mn as a divalent metal exert its effect in leading to chronic neurodegenerative disorder? Secondary to decreased excretion in liver cirrhosis, Mn significantly alters the striatal dopaminergic system. Management of this debilitating disease also focuses on different aspects where Mn has been involved in the pathogenesis. We have put forth the details behind Mn effects in Parkinson's, which will be a guide for better understanding and management of this disease. A literature search was performed using PubMed as a sole database, and all the articles were peer-reviewed. The author tried to follow the PRISMA guidelines. Inclusion criteria were set for 10 years, with most studies with in the last seven years. All types of study designs were included relevant to the topic, clearly delineating the pathomechanisms of Mn in the disease and also its management. After extensive research, through the PubMed database, we found that Parkinson's disease is one of the neurological complications in advanced liver cirrhosis. Mn is an essential element behind its pathogenesis; it works at different cellular levels to promote neurotoxicity. From its influx to its effects on dopamine transporters (DAT), where it disrupts dopamine homeostasis also altering postsynaptic dopamine (D2) receptors, it disrupts mitochondria and the endoplasmic reticulum (ER) promotes oxidative stress and neuroinflammation. Misfolding of alpha-synuclein (α-Syn) is promoted on chronic exposure to Mn where α-Syn from being neuroprotective becomes neurotoxic. It also alters glutaminergic and gabaergic neurotransmission. In a nutshell, the diversity of its effect on nigrostriatal denervation is challenging. The importance of neuroimaging and various approaches to management is also discussed. AHD, an uncommon entity in advanced liver cirrhosis, needs more awareness so that it can be diagnosed earlier and better therapeutic options can be sought. Our study highlighted Mn mechanisms behind this clinical entity, putting forth grounds for a better understanding of this disease. Advanced research targeting Mn for managing this disease will be revolutionary.