Carnitine prevents Reye-like syndrome in atypical carnitine deficiency

A patient with repeated episodes of a Reye-like syndrome was studied. Serum and muscle carnitine levels were normal, but there was an apparent accumulation of muscle lipid and glycogen. Ragged-red fibers were present in the muscle. Prolonged fasting (20 hours) induced hypoglycemia, lactic acidosis, an increase in free fatty acids, and hyperammonemia. There was an accompanying sizeable reduction in the serum free carnitine level. Fasting with L-carnitine administration resulted in milder changes in these laboratory measures. Administration of L-carnitine, (100 mg/kg/day) led to clinical improvement as evidenced by fewer attacks and a normal Gowers sign.     

Serum and urinary carnitine and organic acids in Reye syndrome and Reye-like syndrome

Free and acyl-carnitine in serum and urine, and urinary organic acids were measured in 6 patients with Reye syndrome and Reye-like syndrome. The free and total carnitine concentrations were significantly reduced in serum during the acute phases of the diseases. Thus, the ratio of acylcarnitine to free carnitine was significantly increased. Urinary excretion of acylcarnitine was greatly increased, and the acylcarnitine to total carnitine ratio was therefore greater than in controls. The urinary organic acids comprised large amounts of lactic acid, dicarboxylic acids and ketone bodies. It is suggested that carnitine deficiency is induced as more carnitine is consumed to buffer the increased amount of toxic acyl-CoA compounds metabolized from free fatty acids and the many organic acids. These results indicate that administration of L-carnitine should generally be considered in patients with Reye syndrome and Reye-like syndrome.     

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.     

Somatic evoked potential evaluation of cerebral status in Reye syndrome

Median nerve somatic evoked potentials (SEPs) were serially recorded in 12 Reye syndrome patients from shortly after admission to discharge. Recovery was clinically satisfactory in nine, unsatisfactory in two, and one died. All SEP components were absent or markedly depressed in initial recordings. Early progressive recovery of primary cortical components was associated with patient survival; lack of it was associated with death. Progressive recovery of SEP components later than 100 msec was associated with satisfactory clinical recovery; failure of recovery of these components was associated with residual neuropsychological deficit. Evaluation of late component recovery required comparison with age-dependent SEP configurations in normal children which differ from adults. We conclude that serial SEP recording is of significant value and superior to the EEG in early prognosis for survival, prognosis for clinically satisfactory or unsatisfactory recovery, and general evaluation of neurologic status in Reye syndrome.     

Pontocerebellar hypoplasia type 2 and Reye-like syndrome

Pontocerebellar hypoplasia is an autosomal recessive syndrome with onset during the fetal period. Two subtypes of pontocerebellar hypoplasia have been described on the basis of clinical and neuropathologic criteria. Pontocerebellar hypoplasia type 2 is characterized by progressive microcephaly, early onset of extrapyramidal dyskinesia, and near absence of motor and cognitive development, without signs of either spinal or peripheral involvement. We report a clinical observation of a patient with pontocerebellar hypoplasia type 2, a 3-year-old girl with progressive microcephaly, dystonic limb movements, and absence of motor and cognitive development. Cranial magnetic resonance imaging revealed pontocerebellar hypoplasia. At the age of 2 years, she suffered a Reye-like syndrome that worsened her condition. Differential diagnosis was established with intrauterine injuries, other malformative syndromes, and neurodegenerative or neurometabolic disorders, which can be associated with cerebellar hypoplasia.     

Neuropathologic findings in Reye syndrome

Brain tissue from three patients with a clinical diagnosis of Reye syndrome was compared with tissue from three control patients. All Reye syndrome patients demonstrated cytotoxic cerebral edema, with swelling of astrocyte foot processes, which was not seen in controls. Myelin sheath splitting was seen both in controls and patients, but myelin blebs were uncommon in both. Mitochondrial changes also were not seen. Although cerebral edema is a nonspecific finding, it appears to be characteristic of Reye syndrome.     

Reye syndrome and reye-like syndrome

Reye syndrome is an acute metabolic encephalopathy, largely affecting children and adolescents. In Reye-like syndrome, because of inborn errors of metabolism, hypoglycemia, hypoketonemia, elevated ammonia, and organic aciduria are often evident. It is well-known that fatty-acid oxidation defects can present as Reye-like syndrome. The most commonly diagnosed metabolic disorder in association with Reye syndrome has been medium-chain acyl coenzyme A dehydrogenase deficiency. The present consensus seems to be that Reye syndrome is very rare, and that any child suspected of manifesting this disorder should undergo investigations for inborn errors of metabolism. We recently treated a child with "Reye-like illness" who possibly manifested a long-chain acyl dehydrogenase deficiency, and who had also ingested aspirin. We discuss the possible pathogenesis of the disorder in this child. The end results of mitochondrial dysfunction in Reye syndrome and Reye-like illness may be similar.     

The thalamus and midbrain in Reye syndrome

A previously healthy 5 1/2-year-old male had Reye syndrome. He presented in coma with apnea 1 week after a viral infection and following 2 days of vomiting and progressive obtundation. He was in coma with dystonic posturing and intact brainstem function. Laboratory evaluation revealed initial hypoglycemia, and markedly elevated liver enzymes, prolonged clotting times, and elevated ammonia levels. No underlying metabolic disorder was present, and the patient completely recovered. On a modified diffusion-weighted image magnetic resonance imaging scan, restriction of diffusion in the thalamus and midbrain was observed. While abnormalities of the thalamus and midbrain have previously been reported, this is the first report of diffusion-weighted imaging indicating early impairment of water diffusion, a finding more commonly observed with stroke.     

Liver histopathology in clinical Reye syndrome

Analysis of the liver histopathology in 19 children with clinical Reye syndrome (RS) revealed that nine had diffuse panlobular steatosis, one giant cell hepatitis, one a mild choledochal cyst with inflammation, two multifocal spotty necrosis and one multiple centrilobular necrosis, the other five being normal. Four of the nine patients with diffuse panlobular steatosis showed microvesicular fatty droplets with central nuclei, which was consistent with findings characteristic for typical RS. Two cases showed a periportal area dominant macrovesicular fatty change, which was highly suggestive for metabolic disorder. In the other three cases, the findings were so variable in terms of the size of lipid droplets and the location of nuclei in hepatocytes that it was not possible to provide any clue for defining a diagnosis. These results confirmed the legitimacy of the diagnostic criteria of RS which included a liver biopsy as one of the mandatory conditions. They also indicated that RS-mimicking clinical pictures can be presented by miscellaneous conditions in which liver histology does not necessarily helpful in establishing definite diagnosis.     

Current status of the congenital myasthenic syndromes

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Clinical, electrophysiologic, and morphologic studies have paved the way for detecting CMS-related mutations in proteins residing in the nerve terminal, the synaptic basal lamina, and in the postsynaptic region of the motor endplate. The disease proteins identified to date include choline acetyltransferase (ChAT), the endplate species of acetylcholinesterase (AChE), β2-laminin, the acetylcholine receptor (AChR), rapsyn, plectin, Na(v)1.4, the muscle specific protein kinase (MuSK), agrin, downstream of tyrosine kinase 7 (Dok-7), and glutamine-fructose-6-phosphate transaminase 1 (GFPT1). Myasthenic syndromes associated with centronuclear myopathies were recently recognized. Analysis of properties of expressed mutant proteins contributed to finding improved therapy for most CMS. Despite these advances, the molecular basis of some phenotypically characterized CMS remains elusive. Moreover, other types of CMS and disease genes likely exist and await discovery.     

Frontal behavioral syndromes and functional status in probable Alzheimer disease.

OBJECTIVE:/Method: The authors used the Frontal Systems Behavior Scale (FrSBe) to determine the frequency of frontal behavioral syndromes in 49 subjects with mild-to-moderate dementia and 23 subjects with severe dementia of Alzheimer disease (AD) and 23 healthy control (HC) participants. RESULTS:/Conclusions: Frontal behavior syndromes occurred with higher frequency in AD. Apathy and executive dysfunction were elevated both in mild-to-moderate and severe AD. Disinhibition was elevated only in severe AD. In AD, apathy was associated with difficulty in basic activities of daily living (ADL), whereas executive dysfunction was related to impairment in instrumental ADLs.     

Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases

The high incidence of acute encephalopathy in East Asia suggests the role of genetic factors in its pathogenesis. It has recently been reported that variations of the CPT II (carnitine palmitoyl transferase II) gene may be associated with fatal or severe cases of influenza-associated encephalopathy. In the present study, we examined the genotype of CPT II in cases of acute encephalopathy associated with various preceding infections. Twenty-nine Japanese patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) or acute necrotizing encephalopathy (ANE) were studied. The frequency of F352C of CPT II exon 4 was significantly higher in patients than in controls. All patients who had allele C in F352C had allele I in V368I and allele M in M647V (CIM haplotype), which reportedly decreases CPT II activity to one third of that with FIM or FVM haplotype. The frequency of CIM haplotype was significantly different between patients and controls, but not between AESD and ANE. Our results revealed that having at least one CIM allele is a risk factor for the onset of acute encephalopathy, regardless of its antecedent infections.     

Reye syndrome and drug induced encephalopathy]

Reye syndrome, characterized by acute encephalopathy, selective liver damages, a fatty degeneration in visceral organs and miserable prognosis, is probably caused by various drugs, especially antipyretic such as acetylsalicylate. The incidence of the disease has been decreased by prohibition of administration of aspirin for children with high fever, especially caused by influenza infection in western countries, also in Japan. The pathophysiology of the disease has extensively studied, however, still being unknown to be dissolved. Our previous study of lipid analysis of brain from experimental measles encephalitis revealed an increase of cholesterol ester and decrease of sphingomyelin. As cholesterol ester is synthesized from cholesterol and fatty acids catalyzed by acylCoA-acyltransferase(ACAT), ACAT activity can be increased in the experimental animal brain. In the present report, ACAT m-RNA could not be expressed in control brain but in the experimental animal brain, so ACAT may play a role in pathogenesis of Reye syndrome.     

Relative Carnitine Deficiency in Autism

A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p=0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.     

Reye syndrome: monoamine metabolites in ventricular fluid

Concentrations of homovanillic acid (HVA) were markedly elevated in the ventricular fluid of 15 children with Reye syndrome (median, 887 ng per milliliter) compared to 7 controls (median, 282 ng per milliliter), but 5-hydroxyindoleacetic acid (5-HIAA) values were comparable (medians of 198 and 189 ng per milliliter, respectively). The ratio of 5-HIAA to HVA was significantly lower in patients with Reye syndrome (0.26) than in controls (0.51). Serial samples demonstrated wide fluctuations in HVA concentration, but not in that of 5-HIAA. Monoamine metabolite concentrations were not correlated with serum ammonia, increased intracranial pressure, morbidity, or mortality. Increased HVA in Reye syndrome may reflect cerebral ischemia and release of vasoactive amines (particularly dopamine) into the brain and cerebrospinal fluid (CSF).