Enzymdefekte des Harnstoffzyklus in der Differentialdiagnose der akuten Enzephalopathie im Erwachsenenalter Diagnostik und aktuelle Therapiekonzepte

Six enzyme defects of the urea cycle have been described. Ornithine transcarbamylase deficiency is the most frequent of these diseases. The cumulative frequency is 1:8000. Most patients become symptomatic in childhood, but onset of symptoms may occur later in childhood or even adulthood. The patients present with recurrent episodes of an unspecific acute encephalopathy, seizures and clouding of consciousness to a variable degree. Focal neurological signs such as hemiparesis, aphasia or ataxia may also occur. These episodes may be triggered by infection, protein overload or drugs. Diagnostic are increased blood ammonia levels. Characteristic patterns of plasma amino acids and the determination of orotic acid in the urine mostly discriminate the individual disorders. Further diagnostic steps include the allopurinol challenge test, liver or skin biopsy for measurement of enzyme activity and molecular genetic studies. Treatment requires restriction of protein intake, supplementation of arginine and activation of alternative pathways of nitrogen excretion with benzoate or phenylbutyrate. Untreated, the acute episode may be lethal. Long-term treatment improves the clinical outcome considerably. Urea cycle defects should be included in the differential diagnosis of any encephalopathy or coma of unclear origin, and blood ammonia should be determined early in the evaluation of such patients.     

Fatal initial adult-onset presentation of urea cycle defect

BACKGROUND: Ornithine transcarbamylase (OTC) deficiency presents most commonly with neonatal hyperammonemic coma. The gene is on the X chromosome, but the disease may manifest as a dominant trait. Mutations that lead to later-onset presentations may lead to life-threatening disease and may be unrecognized, particularly when the first clinical disease occurs in adulthood. OBJECTIVE: To document the clinical and metabolic consequences of a mutation in the OTC gene. DESIGN: Case reports. SETTING: A metabolic/biochemical genetic referral service. MAIN OUTCOME MEASURES: Clinical and biochemical observations in 3 generations of a family. RESULTS: A mutation in codon 208 of exon 6 in the OTC gene was found in a family in which the proband died of hyperammonemia at 52 years of age. CONCLUSIONS: Diagnosis of late-onset presentations of urea cycle defect in adults may be delayed. Heightened awareness could lead to effective treatment.     

A female carrier of ornithine carbamoyltransferase deficiency masquerading as attention deficit-hyperactivity disorder

Many females who are heterozygous for ornithine carbamoyltransferase (OTC) deficiency are asymptomatic or intermittently symptomatic with great phenotypic variability. Therefore, the diagnosis of this condition is occasionally a challenge and is often delayed. A 12-year-old girl who was initially diagnosed as having attention deficit-hyperactivity disorder (ADHD) became comatose and developed right-sided hemiparesis during her psychiatric admission. Brain magnetic resonance imaging indicated diffuse but extensive swelling in the left hemisphere with multiple lesions suggestive of an old infarction. Repeated evaluations revealed hyperammonemia and orotic aciduria, and she was diagnosed as having an OTC deficiency. Genetic analysis revealed a heterozygous mutation of N47I in the X-linked OTC gene. Her mental status and hemiparesis improved after hyperammonemia treatment. Here, we report a rare case of a manifestating female carrier with severe symptoms of OTC deficiency masquerading as ADHD.     

Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation

BACKGROUND: Lethal hyperammonemic coma has been reported in 2 adults after lung transplantation. It was associated with a massive elevation of brain glutamine levels, while plasma glutamine levels were normal or only slightly elevated. In liver tissue, glutamine synthetase activity was markedly reduced, and the histologic findings resembled those of Reye syndrome. The adequacy of therapy commonly used for inherited disorders of the urea cycle has not been adequately evaluated in patients with this form of secondary hyperammonemia. OBJECTIVE: To determine whether hemodialysis, in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy, would be efficacious in a patient with hyperammonemic coma after solid-organ transplantation. DESIGN: Case report. SETTING: A children's hospital. PATIENT: A 41-year-old woman with congenital heart disease developed a hyperammonemic coma with brain edema 19 days after undergoing a combined heart and lung transplantation. METHODS: Ammonium was measured in plasma. Amino acids were quantitated in plasma and cerebrospinal fluid by column chromatography. The effectiveness of therapy was assessed by measuring plasma ammonium levels and intracranial pressure and performing sequential neurological examinations. RESULTS: The patient had the anomalous combination of increased cerebrospinal fluid and decreased plasma glutamine levels. To our knowledge, she is the first patient with this complication after solid-organ transplantation to survive after combined therapy with sodium phenylacetate, sodium benzoate, arginine hydrochloride, and hemodialysis. Complications of the acute coma included focal motor seizures, which were controlled with carbamazepine, and difficulty with short-term memory. CONCLUSIONS: The aggressive use of hemodialysis in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy may allow survival in patients after solid-organ transplantation. An acute acquired derangement in extra-central nervous system glutamine metabolism may play a role in the production of hyperammonemia in this illness that resembles Reye syndrome, and, as in other hyperammonemic disorders, the duration and degree of elevation of brain glutamine levels may be the important determining factors in responsiveness to therapy.     

Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo

Acute hyperammonemia (HA) causes cerebral edema and brain damage in children with urea cycle disorders (UCDs) and in patients in acute liver failure. Chronic HA is associated with developmental delay and mental retardation in children with UCDs, and with neuropsychiatric symptoms in patients with chronic liver failure. Astrocytes are a major cellular target of hyperammonemic encephalopathy, and changes occurring in these cells are thought to be causally related to the brain edema of acute HA. To study the effect of HA on astrocytes in vivo, we crossed the Otc(spf) mouse, a mouse with the X-linked UCD ornithine transcarbamylase (OTC) deficiency, with the hGFAP-EGFP mouse, a mouse selectively expressing green fluorescent protein in astrocytes. We used FACS to purify astrocytes from the brains of hyperammonemic and healthy Otcspf/GFAP-EGFP mice. RNA isolated from these astrocytes was used in microarray expression analyses and qRT-PCR. When compared with healthy littermates, we observed a significant downregulation of the gap-junction channel connexin 43 (Cx43) the water channel aquaporin 4 (Aqp4) genes, and the astrocytic inward-rectifying potassium channel (Kir) genes Kir4.1 and Kir5.1 in hyperammonemic mice. Aqp4, Cx43, and Kir4.1/Kir5.1 are co-localized to astrocytic end-feet at the brain vasculature, where they regulate potassium and water transport. Since, NH4+ ions can permeate water and K+-channels, downregulation of these three channels may be a direct effect of elevated blood ammonia levels. Our results suggest that alterations in astrocyte-mediated water and potassium homeostasis in brain may be key to the development of the brain edema.     

Clinical features of carbamyl phosphate synthetase-I deficiency in an adult

Carbamyl phosphate synthetase-I (CPS-I) catalyzes the first reaction required for the conversion of ammonia to urea through the urea cycle. Severe CPS-I deficiency causes marked hyperammonemia with encephalopathy in infancy and usually results in death within the first few months of life. We describe a 33-year-old woman whose CPS-I activity is less than 5% of normal. She has had mild, intermittent symptoms throughout life but has never experienced severe encephalopathy. Although mildly retarded, she has no major neurological deficits. Therapy with a low-protein diet, lactulose, and sodium benzoate has prevented recurrence of hyperammonemia and symptoms. Cranial computed tomographic scans demonstrate prominent lucency of cerebral white matter, and cerebral evoked potential recordings indicate slowed central conduction. These findings suggest that the metabolic disturbances in this patient may have adversely affected central myelin formation or maintenance. This woman represents, to our knowledge, the oldest reported patient with CPS-I deficiency, and the case illustrates the need to consider urea cycle disorders in the differential diagnosis of intermittent neurological symptoms regardless of the patient's age.     

Unusual biochemical and clinical features in a girl with ornithine transcarbamylase deficiency

A girl, ultimately diagnosed as having profound ornithine transcarbamylase (OTC) deficiency, presented as a neonate with feeding intolerance, irritability, and seizures without concurrent hyperammonemia. Developing normally until ten months of age, the girl subsequently experienced two episodes of hyperammonemia, which were associated with focal seizures and residual hemiparesis. She continued to have profound neurologic impairment and seizures and died at 26 months of age, despite appropriate dietary protein restriction, sodium benzoate, and arginine supplementation. Symptomatic OTC deficiency has not been previously reported unassociated with hyperammonemia. The recurrent cerebrovascular episodes are distinctly uncommon in patients with urea cycle enzymopathies.     

Recurrent acute necrotizing encephalopathy in a korean child: the first non-caucasian case

Acute necrotizing encephalopathy is characterized by fever, seizures, acute encephalopathy, and rapid progression to coma. It is usually associated with viral illness and shows characteristic brain magnetic resonance imaging features, including symmetrical involvement of bilateral thalami, brain stem, white matter, and cerebellum. After the first report of recurrent or familial cases in 2003, similar cases were found exclusively in American and European regions. The association with Ran-binding protein 2 gene was identified in 75% of familial or recurrent cases. This report describes a previous healthy 22-month-old boy who recurrently manifested typical clinical and radiological characteristics of acute necrotizing encephalopathy. His neurological outcome worsened with repeated episodes. There was no family history of acute necrotizing encephalopathy and no mutation in the coding region of Ran-binding protein 2 (RANBP2) gene. This is the first reported case of recurrent acute necrotizing encephalopathy in a non-Caucasian family.     

Heliox use in the treatment of acute hyperammonemia.

The objective of this study was to evaluate a new method for the treatment of acute hyperammonemia with a helium-oxygen mixture (heliox). We conducted a prospective, randomized, controlled study of male Sprague-Dawley rats. Experimental hyperammonemia was induced by 7 days of a high-ammonia diet. Subsequently, the animals were randomly divided into two groups: the study group treated with heliox breathing for 24 hours and a control group breathing room air for 24 hours. A prospective, randomized, controlled laboratory animal study was conducted at an animal research facility. The baseline plasma ammonia level was 9.49 +/- 10.96 micromol/L. After 7 days of a high-ammonia diet, the plasma ammonia level rose to 31.53 +/- 8.86 micromol/L. There was a significant statistical difference between the plasma ammonia level following 24 hours of heliox therapy (23.14 +/- 13.97 micromol/L) and the ammonia level in the control group (42.31 +/- 24.25 micromol/L) (P < .05). Heliox breathing was found to be an efficient treatment modality for decreasing plasma ammonia levels in an animal model. Further studies are required to evaluate its potential application in the treatment of patients with hyperammonemia.     

Computed tomography findings in thiamine deficiency-induced coma

Although brain magnetic resonance imaging is a more sensitive diagnostic tool in the evaluation of coma, noncontrast head computed tomography (CT) may demonstrate highly specific findings in some cases of coma. We present a case of thiamine deficiency-induced coma associated with acute necrosis of fornices documented on CT and review cardinal neuroimaging features of Wernicke encephalopathy. Acute fornices necrosis is a novel finding on head CT suggestive of thiamine deficiency.     

Ornithine transcarbamylase deficiency presenting as encephalopathy during adulthood following bariatric surgery

BACKGROUND: Neurological complications following bariatric surgery are rare. Whereas nutritional deficiencies are the most common cause of neurological symptoms, the unmasking of previously subclinical metabolic disorders can also lead to significant morbidity. OBJECTIVE: To characterize the clinical presentation, serum biochemical fluctuations, and functional enzymatic analysis of a case of functional ornithine transcarbamylase deficiency unmasked by a dietary change following bariatric surgery. DESIGN: Case report. SETTING: Tertiary referral center, hospital (inpatient) setting. PATIENT: A 29-year-old woman who presented with intermittent encephalopathy associated with recurrent hyperammonemia. INTERVENTIONS: Clinical, biochemical, and mutational studies. RESULTS: The pattern of intermittent hyperammonemia and encephalopathy following oral and parenteral nutrition suggested a urea cycle abnormality. Functional enzymatic assay results showed markedly reduced ornithine transcarbamylase activity in the absence of known coding mutations. CONCLUSION: Previously asymptomatic ornithine transcarbamylase deficiency should be suspected in adult patients who develop recurrent hyperammonemia and encephalopathy following bariatric surgery.     

Portosystemic shunts: An underdiagnosed but treatable cause of neurological and psychiatric disorders

Portosystemic shunts (PSS) remain an unrecognized cause of neurological or psychiatric disorders. Here we report 5 patients with neuropsychiatric presentations of PSS. Main presentations encompassed progressive Parkinsonism, organic psychosis, recurrent coma, recurrent delusion, cognitive decline and posterior cortical atrophy. None of our patients had a known history of liver disease and laboratory analyses of liver function were normal or only slightly perturbed. Only 16 similar cases of PSS revealed by neurological or psychiatric symptoms were found in the English literature. Clinical presentations were similar to our patients but asterixis, cerebellar symptoms and spastic paraparesis were noticed in some cases. EEG could be normal or could show non specific slow waves or even, rarely, triphasic slow waves. The most frequent and specific diagnostic features included hyperammonemia, abnormal brain magnetic resonance spectroscopy and visualization of the shunts by ultrasonography or abdominal imaging techniques. Therefore, in otherwise unexplained neuropsychiatric disturbances, ammonia should be routinely measured and, if elevated, a dedicated gastroenterologist or an expert radiologist should be consulted for potential PSS examination. Treatment of the shunts or of the hyperammonemia resulted in marked neurological or psychiatric improvement in all cases.     

Cystathionine betasynthase and MTHFR deficiencies in adults

INTRODUCTION: Homocysteine lies at an important metabolic branch point; it may be either converted to cystathionine through the transsulfuration pathway, or methylated to form methionine. Hyperhomocysteinemia may result from hereditary defects affecting one of these reactions. STATE OF ART: Cystathionine beta synthase or 5,10-methylenetetrahydrofolate deficiency can both result in homocystinuria. Current knowledge about biochemical mechanisms leading to hyperhomocysteinemia, clinical and radiological features, pathogenesis and treatment are reviewed, focusing on late onset forms of these diseases which can be diagnosed in adulthood. CBS deficiency is characterized by lens dislocation, skeletal abnormalities, neurologic disturbances and thromboembolism. MTHFR deficiency leads to various neurological symptoms, ranging from developmental delay to encephalopathy, including motor and gait abnormalities, seizures, psychiatric manifestations and rarely strokes. The treatment of CBS deficiency depends on vitamin B6, whereas MTHFR deficiency can be efficiently treated by vitamin B12, folic acid, and betaine. PERSPECTIVES: Homocysteinemia should be measured in patients with unexplained neurological manifestations or thromboembolism.     

Acute encephalopathy with hyperammonemia and dicarboxylic aciduria during calcium hopantenate therapy: a patient report

We report a 3-year-old Japanese girl who developed acute encephalopathy while receiving calcium hopantenate (Calcium D-(+)-4-(2, 4-dihydroxy-3,3-dimethylbutyramido) butyrate hemihydrate). She had hyperammonemia, elevated CPK, lactic acidemia and pyruvic acidemia, however, she did not show elevated SGOT or SGPT. Calcium hopantenate has been used in Japan for the treatment of mental retardation with behavior abnormalities. Recently there have been three reports on the occurrence of Reye-like syndrome in patients receiving this drug. Clinical signs and laboratory data of these patients are similar to those of Reye syndrome. Calcium hopantenate causes pantothenic acid deficiency in the young rat, which may reduce the content of coenzyme A. If this drug decreases coenzyme A biosynthesis, it may reduce beta-oxidation of fatty acids and levels of dicarboxylic acids would increase because of increasing omega-oxidation. We suspect that there is a possible relationship between the occurrence of acute encephalopathy and calcium hopantenate therapy.     

Ultrastructural findings in citrullinaemia in Holstein-Friesian calves

Summary Ultrastructural findings in the brains and livers of four calves affected with citrullinaemia due to a hereditary deficiency of the urea cycle enzyme arginosuccinate synthetase are described. The calves were affected in the 1st week of life with severe neurological disease characterised by depression, head pressing, stupor, convulsions and coma, accompanied by marked elevation of plasma citrulline and increasing plasma ammonia levels. Lesions included mild to moderate diffuse astroglial oedema in the cerebrocortical grey matter, and mild to severe hepatocellular hydropic change. The onset of the severe neurological signs was correlated with increasing levels of plasma ammonia, and the cerebral lesions were considered consistent with a bovine hyperammonaemic encephalopathy.Supported in part by an Australian Wool Corporation postgraduate scholarship (PAWH)     

Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats

Patients with liver cirrhosis may present hepatic encephalopathy with a wide range of neurological disturbances and alterations in sleep quality and in the sleep‐wake circadian rhythm. Hyperammonemia is a main contributor to the neurological alterations in hepatic encephalopathy. We have assessed, in an animal model of chronic hyperammonemia without liver failure, the effects of hyperammonemia per se on the circadian rhythms of motor activity, temperature, and plasma levels of adrenal corticosteroid hormones. Chronic hyperammonemia alters the circadian rhythms of locomotor activity and of cortisol and corticosterone levels in blood. Different types of motor activity are affected differentially. Hyperammonemia significantly alters the rhythm of spontaneous ambulatory activity, reducing strongly ambulatory counts and slightly average velocity during the night (the active phase) but not during the day, resulting in altered circadian rhythms. In contrast, hyperammonemia did not affect wheel running at all, indicating that it affects spontaneous but not voluntary activity. Vertical activity was affected only very slightly, indicating that hyperammonemia does not induce anxiety. Hyperammonemia abolished completely the circadian rhythm of corticosteroid hormones in plasma, completely eliminating the peaks of cortisol and corticosterone present in control rats at the start of the dark period. The data reported show that chronic hyperammonemia, similar to that present in patients with liver cirrhosis, alters the circadian rhythms of corticosteroid hormones and of motor activity. This suggests that hyperammonemia would be a relevant contributor to the alterations in corticosteroid hormones and in circadian rhythms in patients with liver cirrhosis. © 2009 Wiley‐Liss, Inc.     

A case of ornithine transcarbamylase deficiency presenting severe symptoms in adulthood]

An adult female case of ornithine transcarbamylase (OTC) deficiency is presented in the following. The patient had had past episodes of drowsiness with a duration less than a few minutes several times a year during childhood. She suddenly became comatose at 25 years of age, and died after 13 months of persistent vegetative state. Blood chemistry showed hyperammonemia with no liver cirrhosis or portal-systemic shunt. Plasma amino acid analysis indicated elevated glutamate and glycine levels, and plasma levels of citrulline and arginine to be low. The urinary orotic acid level was high. OTC activity of a liver specimen was 65 percent of the normal level. This is a rare case demonstrating hyperglycinemia and an elevated level of serum OTC. The importance of ruling out defective ureagenesis in adults with disturbed consciousness should be emphasized.     

Carnitine deficiency syndromes

Carnitine deficiency syndromes manifest as metabolic encephalopathy, lipid storage myopathy, or cardiomyopathy. Impairment of long-chain fatty acid metabolism and failure of energy production affect tissues reliant on oxidative metabolism. The accumulation of toxic fatty acyl derivatives impedes gluconeogenesis and urea cycle function which, in turn, causes hypoketotic hypoglycemia, transaminase elevations, and hyperammonemia. Oxidation of accumulated fatty acids through an alternative pathway, omega-oxidation, produces dicarboxylic aciduria. Carnitine must be transported into skeletal muscle. Myopathic carnitine deficiency occurs when this transport mechanism is defective. Most systemic carnitine deficiencies are secondary to other disorders that promote excretion of carnitine as acylcarnitine; however, primary systemic carnitine deficiency, likely due to impaired renal conservation of carnitine, also occurs.     

Acute necrotizing encephalopathy of childhood associated with influenza type B virus infection in a 3-year-old girl

Acute necrotizing encephalopathy of childhood represents a novel entity of acute encephalophathy, predominantly affecting infants and young children living in Taiwan and Japan. It manifests with symptoms of coma, convulsions, and hyperpyrexia after 2 to 4 days of respiratory tract infections in previously healthy children. The hallmark of acute necrotizing encephalopathy of childhood consists of multifocal and symmetric brain lesions affecting the bilateral thalami, brainstem tegmentum, cerebral periventricular white matter, or cerebellar medulla. The etiology and pathogenesis of this kind of acute encephalopathy remain unknown, and there is no specific therapy or prevention. The prognosis is usually poor, and less than 10% of patients recover completely. We report a 3-year-old previously healthy girl presenting with acute necrotizing encephalopathy of childhood associated with influenza type B virus infection, which resulted in severe neurologic sequelae. We also review the current knowledge of the clinical, neuroimaging, and pathologic aspects of acute necrotizing encephalopathy of childhood.     

Valproate-induced hyperammonemia

A patient with carbamyl phosphate synthetase deficiency had four episodes of hyperammonemia, up to 226 μM, associated with valproate (VPA) treatment. These were accompanied by vomiting, lethargy, and coma. A group of epileptic patients receiving VPA remained asymptomatic but had significantly higher mean plasma ammonium levels when compared to epileptic patients receiving other anticonvulsants: 33.6 ± 1.9 (SEM) versus 23.6 ± 1.5 μM. Thus, VPA caused symptomatic hyperammonemia in a patient with an impairment in urea synthesis and resulted in mildly elevated ammonium levels in epileptic patients. These data suggest that ammonium levels should be monitored in patients receiving VPA who exhibit signs of vomiting or lethargy.