Recurrent Encephalopathy Research Articles

Membranoproliferative glomerulonephritis in a child with congenital portosystemic shunt.

Congenital portosystemic shunts (CPSS) are rare congenital vascular anomalies characterized by abnormal connections between the portal vein and systemic circulation, bypassing the liver. They can lead to complications such as recurrent encephalopathy, liver nodules, portopulmonary hypertension, and neurocognitive issues due to hyperammonemia and rarely kidney involvement. Hepatic hemodynamic changes can lead to liver nodules and hepatocellular carcinoma, particularly in extrahepatic shunts. We describe here an 11-year-old girl with type 1 intrahepatic portosystemic shunt with focal nodular hyperplasia in the liver, presenting with nephrotic syndrome that was diagnosed as membranoproliferative glomerulonephritis on kidney biopsy and that responded partially to therapy with immunosuppressants.

ATP1A3 Disease Spectrum Includes Paroxysmal Weakness and Encephalopathy Not Triggered by Fever.

Heterozygous pathogenic variants in ATP1A3, which encodes the catalytic alpha subunit of neuronal Na+/K+-ATPase, cause primarily neurologic disorders with widely variable features that can include episodic movement deficits. One distinctive presentation of ATP1A3-related disease is recurrent fever-triggered encephalopathy. This can occur with generalized weakness and/or ataxia and is described in the literature as relapsing encephalopathy with cerebellar ataxia. This syndrome displays genotype-phenotype correlation with variants at p.R756 causing temperature sensitivity of ATP1A3. We report clinical and in vitro functional evidence for a similar phenotype not triggered by fever but associated with protein loss-of-function. We describe the phenotype of an individual with de novo occurrence of a novel heterozygous ATP1A3 variant, NM_152296.5:c.388_390delGTG; p.(V130del). We confirmed the pathogenicity of p.V130del by cell survival complementation assay in HEK293 cells and then characterized its functional impact on enzymatic ion transport and extracellular sodium binding by two-electrode voltage clamp electrophysiology in Xenopus oocytes. To determine whether variant enzymes reach the cell surface, we surface-biotinylated oocytes expressing N-tagged ATP1A3. The proband is a 7-year-old boy who has had 2 lifetime episodes of paroxysmal weakness, encephalopathy, and ataxia not triggered by fever. He had speech regression and intermittent hand tremors after the second episode but otherwise spontaneously recovered after episodes and is at present developmentally appropriate. The p.V130del variant was identified on clinical trio exome sequencing, which did not reveal any other variants possibly associated with the phenotype. p.V130del eliminated ATP1A3 function in cell survival complementation assay. In Xenopus oocytes, p.V130del variant Na+/K+-ATPases showed complete loss of ion transport activity and marked abnormalities of extracellular Na+ binding at room temperature. Despite this clear loss-of-function effect, surface biotinylation under the same conditions revealed that p.V130del variant enzymes were still present at the oocyte's cell membrane. This individual's phenotype expands the clinical spectrum of ATP1A3-related recurrent encephalopathy to include presentations without fever-triggered events. The total loss of ion transport function with p.V130del, despite enzyme presence at the cell membrane, indicates that haploinsufficiency can cause relatively mild phenotypes in ATP1A3-related disease.

FADD gene pathogenic variants causing recurrent febrile infection-related epilepsy syndrome: Case report and literature review.

FIRES and NORSE are clinical presentations of disease processes that, to date, remain unexplained without an established etiology in many cases. Neuroinflammation is thought to have paramount importance in the genesis of these conditions. We hereby report the clinical, EEG, brain MRI, and genetic findings of a nuclear family with recurrent febrile-related encephalopathy with refractory de novo Status Epilepticus. Whole-exome sequencing (WES) revealed a homozygous p.C105W pathogenic variant of FADD gene (FAS-associated protein with death domain, FADD), known to cause ultrarare forms of autosomal recessive immunodeficiency that could be associated with variable degrees of lymphoproliferation, cerebral atrophy, and cardiac abnormalities. The FADD-related conditions disrupt FAS-mediated apoptosis and can cause a clinical picture with the characteristics of FIRES. This observation is important because, on one hand, it increases the number of reported patients with FADD deficiency, showing that this disorder may present variable expressivity, and on the other hand, it demonstrates a genetic cause of FIRES involving a cell-mediated inflammation regulatory pathway. This finding supports early treatment with immunomodulatory therapy and could represent a new avenue of research in the field of new onset refractory status epilepticus and related conditions.

Teenager With Recurrent Ataxia, Ophthalmoplegia, and Encephalopathy Associated With Demyelination: From the National Multiple Sclerosis Society Case Conference Proceedings

A 15-year-old adolescent boy developed subacute ataxia, encephalopathy, ophthalmoplegia, and dysarthria following a sore throat. An MRI examination revealed multifocal enhancing and nonenhancing supratentorial white matter and symmetric brainstem lesions. After 2 additional presentations with worsening symptoms and lesion accumulation, he was ultimately successfully treated with rituximab for his condition.

Liver Transplantation in a Woman with Mahvash Disease

SummaryMahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

Abernethy Syndrome with Left Renal Artery Stenosis: Our first experience

Abernethy syndrome is defined as the congenital diversion of portal blood away from the liver either end-to-side shunt or, side-to-side shunt. Here we are reporting a case of a 15-year-old boy presented with recurrent encephalopathy and uncontrolled hypertension. Persistent rise in blood ammonia level was noted with normal other biochemical parameters. Ultrasound and Doppler study of the abdomen revealed drainage of the portal vein into the inferior vena cava and a small size of the left kidney. Renal artery angiogram and hepatic angiogram were performed, which confirmed the diagnosis of Type 1B Abernethy syndrome with left renal artery stenosis. After counseling the patient and his parents and taking consent, he has been treated with Left renal artery angioplasty, antihypertensive along supportive treatment. The treatment of Abernethy syndrome depends on its type, associated congenital anomalies, and complications. If possible closer of thes hunt is the mainstay of treatment but in case of type 1 malformation with the absence of the possibility to close the shunt may require a liver transplant. J Rang Med Col. September 2023; Vol. 8, No. 2: 56-59

Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders

PurposeIndividuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. MethodsWe reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. ResultsIndividuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. ConclusionIndividuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Portal Systemic Encephalopathy without Significant Changes of Chronic Liver Disease: A Case Report

Introduction: Determining the etiology of an encephalopathy can be challenging for the neurologists, especially when the preliminary investigations do not indicate any significant biochemical or other systemic abnormality. Portosystemic shunts maybe easily missed and may present as recurrent encephalopathy with elevated serum ammonia or cerebrospinal glutamate levels. These shunts maybe easily identified in the presence of overt chronic liver disease, but maybe easily missed in patients with cryptogenic liver disease or in congenital abnormalities of the intrahepatic vascular system without an associated chronic liver disease. Materials and Methods: The triple-phase computed tomography (CT) or contrast magnetic resonance imaging can demonstrate the extent of portal vein thrombosis, map the extent of the portosystemic collateral, and aid in planning the treatment in patients with difficult anatomy of the portosystemic collaterals. Treatment regimens for patients with portosystemic shunts manifesting as hyperammonemic encephalopathy include restriction of oral protein intake, lactulose administration, oral nonabsorbable antibiotics, closure of the endovascular shunt, or finally, liver transplant. We present a case of a 55-year-old female with seizure disorder presenting with recurrent episodes of encephalopathy with elevated serum ammonia without the overt signs of chronic liver disease with identification of portosystemic shunting on a triple-phase CT of the abdomen. Conclusion: Specialized investigations to identify the presence of portosystemic collaterals should be conducted in patients with cryptogenic encephalopathy with elevated serum ammonia.

Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension.

Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.

Discovering spontaneous intracranial hypotension after failed middle meningeal artery embolization for subdural hematomas: illustrative cases.

Spontaneous intracranial hypotension (SIH) is a relatively rare and underdiagnosed disease. SIH can lead to subdural hematomas (SDHs) and other complications. SDHs secondary to SIH are difficult to manage, with no consensus in management, and SDHs commonly recur if underlying SIH is not treated. A 46-year-old male with vague sensory and orientation symptoms presented with bilateral SDHs, which were treated with middle meningeal artery (MMA) embolization and burr hole evacuation. The patient improved initially but had recurrent encephalopathy and SDHs. The patient received 3 epidural blood patches (EBPs) over 8 days with continued improvement. A 78-year-old female presented with headaches, and imaging revealed a left chronic SDH. She underwent MMA embolization and mini-craniotomy for SDH evacuation. Her symptoms returned and imaging revealed a recurrent SDH. Pan spine computed tomography myelography showed a high thoracic cerebrospinal fluid (CSF) leak. She underwent 3 EBPs over 8 days with neurological improvement and stabilization of her SDH. The authors show that, if SDH recurs after initial treatment with MMA embolization, then SIH should be strongly considered and treated with EBPs. Further investigation is required to determine the role of targeted or blind EBPs and the use of imaging to find the source of occult CSF leaks causing SIH.

Recurrent encephalopathy associated with pegylated beta-interferon treatment

A 62-year-old woman with a history of multiple sclerosis (MS) presented with recurrent episodes of confusion, dysarthria and gait difficulties. These episodes occurred about 3 days after administration of pegylated interferon-beta-1a (Plegridy®) and resolved spontaneously in around 4 days. The brain MRI scan, laboratory findings and cerebrospinal fluid analysis during these episodes were negative for other causes of encephalopathy. She discontinued treatment with interferon and was started on teriflunomide, experiencing no recurrence of symptoms. We believe that interferon was responsible for this patient's recurrent encephalopathic syndrome, possibly due to its effects on inflammatory cytokines and endothelial dysfunction.

The Case | Hyperammonemia in a non-cirrhotic hemodialysis patient

A 78-year-old woman presented with recurrent encephalopathy after hemodialysis initiation. Her medical history included end-stage renal disease, congestive heart failure, and cerebral infarction. Her medication included aspirin, losartan, carvedilol, pravastatin, and lansoprazole. Maintenance hemodialysis was initiated because of refractory volume overload. Two days after dialysis initiation, she was noted to be comatose with hyperammonemia (205 μg/dl). Branched-chain amino acid infusion was administered, resulting in improvement of her mental status.

Late onset hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome, presenting as recurrent metabolic encephalopathy, A case report

and importance: Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome (OMIM 238970) seems to be an autosomal recessive disorder caused by a mitochondrial ornithine transporter 1 deficiency, which results in urea cycle dysfunction. HHH is the most uncommon of the urea cycle diseases, with less than 100 cases recorded. A previously healthy 29 year old male presented to the emergency department complaining of decreased level of consciousness. CT scan, Cerebro-spinal-fluid analysis and toxicology screen were non-significant. Extended serum analysis showed elevated levels of ammonia. Urgent amino acid level analysis showed elevated ornithine. Follow up genetic testing showed that the patient is homozygous for the mutation c.44delG in exon 3 of SLC25A15 gene. In this case, HHH syndrome presented as a late-onset metabolic encephalopathy. For diagnosis; elevated levels of ammonia, ornithine accompanied by the abovementioned genetic mutation confirms the diagnosis. Treatment focuses on reduction of the ammonia levels using sodium benzoat, citrulline or arginine, and low protein diet. HHH syndrome, which is a urea cycle disorder, can present as a late-onset metabolic encephalopathy. High suspicion for genetic causes of metabolic encephalopathy should be maintained even for older patients without prior diagnosis in childhood/adolescence.

Recurrent Hyperammonemia in a Cirrhotic Patient With a Ureterosigmoidostomy

The patient is a 68-year-old female with history of bladder exstrophy status post multiple surgeries with eventual cystectomy and ureterosigmoidostomy at 10-12 years old, nonalcoholic fatty liver disease complicated by cirrhosis (Model for End-Stage Liver Disease [MELD] Score 15), and recurrent encephalopathy. She initially presented 1 year ago with acute hyperammonemic encephalopathy, presumably due to hepatic dysfunction, and she was discharged with lactulose and rifaximin. However, the patient experienced four subsequent admissions for encephalopathy despite medical compliance, and she was referred to Hepatology clinic for consideration of liver transplantation.

Mitochondrial Disease Masquerading as Recurrent Encephalopathy

A young male who was a diabetic presented with gradually progressive hearing loss, recurrent episodic behavioral abnormality, easy fatigability, proximal weakness, and seizures. The patient was evaluated in detail to find out the etiology of encephalitis. The serum autoimmune encephalitis panel was negative. On magnetic resonance imaging of the Brain, there was temporoparietal T2 and fluid-attenuated inversion recovery hyperintensity. In the magnetic resonance spectroscopy study, a lactate peak was found. So, the patient was evaluated for mitochondrial illness mitochondrial encephalopathy lactic acidosis with stroke-like symptoms) and it was confirmed by a genetic study. This case illustrates that though it is a rare disease, always a strong clinical index of suspicion is required for the diagnosis of mitochondrial disorders in case of multisystem involvement so that diagnosis would not be missed.

A Case of Maple Syrup Urine Disease Diagnosed in Adulthood

Classic maple syrup urine disease (MSUD) is typically diagnosed in newborns, whereas nonclassic forms may manifest at any age. We describe a 58-year-old man presenting with recurrent encephalopathy, found with a nonclassic form of MSUD. This patient case highlights the importance of considering inborn errors of metabolism in the differential diagnosis of adult patients presenting with neurologic symptoms of unclear cause.

Recurrent Encephalopathy with Metabolic Acidosis and Hypoglycemia: Do not Forget Fructose Metabolism.

Recurrent Encephalopathy with Metabolic Acidosis and Hypoglycemia: Do not Forget Fructose Metabolism.

Phenotypic Pleiotropy in Arginase Deficiency: A Single Center Cohort.

Arginase deficiency is considered a masquerader of diplegic cerebral palsy. The rarity of hyperammonemic crisis and the slowly progressive course has made it a unique entity among the urea cycle defects. The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency. This retrospective study included children and adolescents aged <18 years with a biochemical or genetic diagnosis of arginase deficiency from May 2011 to May 2022. Data were collected from the hospital's electronic database. The clinical presentation, laboratory parameters at baseline and during metabolic decompensation, neuroimaging, electroencephalography findings, and molecular studies were analyzed. About 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male: female ratio was 2.7:1. Consanguineous parentage was observed in all children. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. Seizures occurred in all children. Epilepsy with electrical status in slow wave sleep and West syndrome was noted in three children. All children had elevated ammonia and arginine at the time of metabolic crisis. The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Spastic diparesis, recurrent encephalopathy, presence of family history, and elevated serum arginine levels must alert the clinician to suspect arginase deficiency. Atypical presentations in our cohort include frequent metabolic crises and epileptic encephalopathy. Early identification and management will ensure a better neurodevelopmental outcome.

Variable clinical severity in TANGO2 deficiency: Case series and literature review.

Biallelic pathogenic variants in the TANGO2 (transport and Golgi organization 2 homolog) gene have been identified as causing a rare metabolic disorder characterized by susceptibility to recurrent rhabdomyolysis, lactic acidosis, encephalopathy, and life-threatening tachyarrhythmias. Recently published reports suggest variable clinical severity and phenotypes. This study details five new patients from two families with biallelic pathogenic variants in the TANGO2 gene identified by whole exome sequencing and includes the largest number of affected individuals from a single family reported to date. We document significant intrafamilial variability and highlight that milder phenotypes may be underrecognized. We present biochemical and clinical data to help highlight the features that aid in consideration of this condition in the differential with disorders of fatty acid oxidation. We also present a comprehensive literature review summarizing the molecular, clinical, and biochemical findings for 92 individuals across 13 publications. Of the 27 pathogenic variants reported to date, the recurrent exons 3-9 deletion represents the most common variant seen in 42% of individuals with TANGO2 deficiency. Common clinical features seen in >70% of all individuals include acute metabolic crisis, rhabdomyolysis, neurologic abnormalities, developmental delay, and intellectual disability. Findings such as elevated creatine kinase, hypothyroidism, ketotic hypoglycemia, QT prolongation, or abnormalities of long-chain acylcarnitines and urine dicarboxylic acids should raise clinical suspicion for this life-threatening condition.

In-house multiplex ligation-dependent probe amplification assay for citrin deficiency: analytical validation and novel exonic deletions in SLC25A13.

Citrin deficiency is one of the most common inborn errors of metabolism in East Asians, which may manifest as neonatal cholestasis, failure to thrive and dyslipidaemia, or recurrent hyperammonaemic encephalopathy. Its molecular diagnosis requires confirmation of the presence of biallelic pathogenic variants in SLC25A13 gene by sequencing, and analysis for a common insertion IVS16ins3kb. However, patients with compatible biochemical features but only one monoallelic pathogenic variant have remained a diagnostic challenge. Here we report the development, validation and application of a multiplex ligation-dependent probe amplification (MLPA) assay using an in-house oligonucleotide probemix and a customised Coffalyer.NET worksheet for detection of exonic copy number variations in SLC25A13. With this MLPA assay, we successfully identified the presence of a heterozygous exonic deletion in SLC25A13 in three of 15 (20%) unrelated individuals with only one monoallelic pathogenic variant detected using conventional methods. Three exonic deletions, two novel involving exon 14 and one reported involving exon 5, were subsequently confirmed with Sanger sequencing. In summary, we developed, evaluated, and demonstrated the clinical utility of an in-house MLPA assay to look for exonic deletions in SLC25A13 in patients with citrin deficiency. With the discovery of novel deletions, MLPA should be considered a test of choice for molecular diagnosis of citrin deficiency when the sequencing result is inconclusive.