RESUMEN
The most frequent clinical manifestation of borreliosis in Switzerland is erythema migrans, with about 2500 patients each year. Neurological manifestations are rare, mostly hyperalgesic radiculitis (Bannwarth syndrome), aseptic meningitis or cranial nerve involvement. We report the first Swiss patient with meningovasculitis due to neuroborreliosis, with recurrent multiple ischemic strokes in multiple vascular territories. The treatment with ceftriaxone stopped the progression, but the patient is still suffering from severe invalidating cognitive disorders. We also comment on the pathophysiology and review the literature of other clinical cases.
Asunto(s)
Grupo Borrelia Burgdorferi , Isquemia Encefálica/etiología , Neuroborreliosis de Lyme/complicaciones , Meningitis/etiología , Accidente Cerebrovascular/etiología , Vasculitis del Sistema Nervioso Central/etiología , Antiinfecciosos/uso terapéutico , Western Blotting , Isquemia Encefálica/patología , Ceftriaxona/uso terapéutico , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Humanos , Neuroborreliosis de Lyme/patología , Neuroborreliosis de Lyme/psicología , Imagen por Resonancia Magnética , Masculino , Meningitis/patología , Persona de Mediana Edad , Accidente Cerebrovascular/patología , Vasculitis del Sistema Nervioso Central/patologíaRESUMEN
Twenty-three patients with late onset argininosuccinate lyase deficiency (ASLD) were identified during a 27-year period of newborn screening in Austria (1:95,600, 95% CI=1:68,036-1:162,531). One additional patient was identified outside the newborn screening with neonatal hyperammonemia. Long-term outcome data were available in 17 patients (median age 13 years) ascertained by newborn screening. Patients were treated with protein restricted diet and oral arginine supplementation during infancy and childhood. IQ was average/above average in 11 (65%), low average in 5 (29%), and in the mild intellectual disability range in 1 (6%) patients. Four patients had an abnormal EEG without evidence of clinical seizures and three had abnormal liver function tests and/or evidence of hepatic steatosis. Plasma citrulline levels were elevated in four patients. Plasma ammonia levels were within normal range prior and after a protein load in all patients. Seven different mutations were identified in the 16 alleles investigated. Four mutations were novel (p.E189G, p.R168C, p.R126P, and p.D423H). All mutations were associated with low argininosuccinate lyase activities (0-15%) in red blood cells. Newborn screening might be beneficial in the prevention of chronic neurologic and intellectual sequelae in late onset ASLD, but a proportion of benign variants might have contributed to the overall favorable outcome as well.
Asunto(s)
Aciduria Argininosuccínica/diagnóstico , Aciduria Argininosuccínica/genética , Adolescente , Adulto , Arginina/sangre , Arginina/uso terapéutico , Austria , Niño , Preescolar , Citrulina/sangre , Electroencefalografía , Femenino , Estudios de Seguimiento , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Resultado del TratamientoRESUMEN
Elevated concentrations of pipecolic acid have been reported in plasma and CSF of patients with pyridoxine-dependent epilepsy, but its molecular background is unclear. To investigate any further association of pyridoxine and pipecolic acid metabolism, we have performed an animal trial and have measured the concentration of pipecolic acid in brain tissue of rats with nutritional pyridoxine deficiency and in control littermates. Concentrations of pyridoxal phosphate were significantly reduced in brain tissue of pyridoxine-deficient rats (p < 0.001), while concentrations of pipecolic acid were not significantly different from the normally nourished control group (p = 0.3). These data indicate that a direct association of pyridoxine and pipecolic acid metabolism is unlikely. We therefore assume that the characteristic elevation of pipecolic acid in pyridoxine-dependent epilepsy could rather be a secondary phenomenon with the primary defect of pyridoxine-dependent epilepsy being located outside the pipecolic acid pathway.
Asunto(s)
Encéfalo/metabolismo , Epilepsia/etiología , Errores Innatos del Metabolismo/diagnóstico , Ácidos Pipecólicos/metabolismo , Piridoxina/deficiencia , Piridoxina/metabolismo , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Modelos Animales de Enfermedad , Epilepsia/patología , Femenino , Masculino , Errores Innatos del Metabolismo/metabolismo , Ácidos Pipecólicos/sangre , Ácidos Pipecólicos/líquido cefalorraquídeo , Fosfato de Piridoxal/metabolismo , Ratas , Factores de Tiempo , Vitamina B 6/metabolismoRESUMEN
UNLABELLED: A 2.5-year-old boy presented with acute metabolic decompensation in whom 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) lyase deficiency was diagnosed. Four days after metabolic decompensation, a stroke-like encephalopathy with tonic clonic convulsion of the left arm and leg and coma developed. Brain oedema and subsequent demarcation and atrophy were observed mainly within the supply areas of the right anterior and middle cerebral artery and to a lesser extent in various sites within the right hemisphere. Residual neurological deficits included spastic paresis of the left arm and leg. and left supranuclear facial palsy and aphasia, indicating bilateral diffuse brain affection. CONCLUSION: In the presented patient with HMG-CoA lyase deficiency, stroke-like encephalopathy occurred days after metabolic decompensation indicating ongoing (intracerebral) metabolic derangement. Monitoring of the intracerebral accumulation of toxic metabolites by magnetic resonance spectroscopy and of cerebral haemodynamics might be useful for a better understanding of the pathogenetic mechanisms of stroke-like encephalopathy and to identify patients at risk.
Asunto(s)
Encefalopatías Metabólicas/etiología , Trastornos Cerebrovasculares/etiología , Oxo-Ácido-Liasas/deficiencia , Encefalopatías Metabólicas/diagnóstico , Edema Encefálico/etiología , Preescolar , Humanos , Imagen por Resonancia Magnética , Masculino , Convulsiones/etiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Hyperhomocyst(e)inemia is strongly associated with occlusive arterial disease. A direct effect of homocysteine on the proliferation of smooth muscle cells was proposed recently. This observation led us to examine the effect of homocysteine on cyclin-dependent kinase, the starter of mitosis and reflecting proliferation. METHODS AND RESULTS: Seventy Him:OFA rats were divided into seven groups. For 12 weeks, 10 rats were fed homocysteine 25 mg/kg body weight per day, 10 were fed 50 mg/kg body wt per day, and 10 were fed 100 mg/kg body weight per day; 10 were given homocysteic acid 100 mg/kg body weight per day, 10 were administered cysteine 100 mg/kg body weight per day, and 10 were given ascorbic acid 270 mg/kg body weight per day. Ten remained untreated and served as controls. Aortic cyclin-dependent kinase was determined at the transcriptional (mRNA) and protein levels. Phosphokinase C and aortic homocyst(e)ine also were evaluated in aortic tissue. Aortic cyclin-dependent kinase protein was significantly (P = .0001) elevated in the three homocysteine-treated groups, and mRNA cyclin-dependent kinase levels were significantly elevated in the rats given the 50 and 100 mg/kg body weight per day protocol. Endothelial damage was shown at higher homocysteine doses as reflected by circulating ACE and von Willebrand factor changes. Proliferation of cells of the aortic wall by bromodeoxyuridine incorporation could be shown in the high-dose homocysteine group only. CONCLUSIONS: Our findings indicate that homocysteine specifically stimulates aortic cyclin-dependent kinase at the transcriptional level, with the possible consequence of proliferation of aortic cells as revealed by incorporation of bromodeoxyuridine in the aortic wall.
Asunto(s)
Aorta/metabolismo , Quinasas Ciclina-Dependientes/fisiología , Homocisteína/farmacología , Animales , Aorta/citología , Aorta/efectos de los fármacos , Bromodesoxiuridina/metabolismo , División Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Peptidil-Dipeptidasa A/sangre , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas , Factor de von Willebrand/metabolismoRESUMEN
Increased plasma homocyst(e)ine is strongly correlated with occlusive arterial diseases. A series of different hypotheses have been reported including involvement of free oxygen radicals and therefore oxidative stress. We determined plasma homocyst(e)ine and homocysteic acid levels after oral low dose homocysteine thiolactone administration to rats for a period of six weeks. Plasma levels of homocyst(e)ine and triglycerides were significantly elevated in the group fed homocysteine thiolactone. GC/MS determination of ketone body formation showed that the underlying mechanism for the increase of triglycerides seems to be inhibition of fatty acid oxidation. Homocysteic acid was detected in the experimental group exclusively. The present study showing a homocyst(e)ine correlated increase of plasma triglycerides by the inhibition of fatty acid oxidation may well propose an additional role of triglycerides for vascular pathology. The presence of homocysteic acid in the experimental group only would support the free oxygen radical hypothesis for the development of vascular changes but homocysteic acid as a potent neurotransmitter could play an independent role in the pathogenesis.