Seizures and epilepsy in hypoglycaemia caused by inborn errors of metabolism.

AIM: The aim of the study was to characterize seizures and epilepsy related to hypoglycaemia. METHOD: We analyzed the files of 170 consecutive patients referred for hypoglycaemia (onset 1h to 4y) caused by inborn errors of metabolism (glycogen storage disease type I, fatty acid ß-oxidation disorders, and hyperinsulinism). RESULTS: Ninety patients (42 males and 48 females; 38 neonates and 52 infants/children) had brief hypoglycaemic seizures (68%) or status epilepticus (32%). Status epilepticus occurred earlier (mean 1.4d) than brief neonatal seizures (4.3d, p=0.02). Recurrent status epilepticus followed initial status epilepticus and was often triggered by fever. Epilepsy developed in 21 patients. In 18 patients, epilepsy followed hypoglycaemic status epilepticus and began with shorter delay when associated with grey matter lesions (1.9mo, standard error of the mean [SEM] 1mo) than with white matter damage (3.3y [SEM 1y], p=0.003). Three patients with hyperinsulinism developed idiopathic epilepsy following brief neonatal seizures. INTERPRETATION: Brief neonatal hyperinsulinaemic hypoglycaemic seizures have characteristics of idiopathic neonatal seizures. Neonatal status epilepticus should be prevented by the systematic measurement of glucose blood level. Recurrent seizures never consist of status epilepticus when following brief initial seizures. Epilepsy is symptomatic of brain damage with shorter delay in the case of grey rather than white matter lesions, except in a few idiopathic cases in which epilepsy and hyperinsulinism may share a common genetic background.

Respiratory chain deficiencies.

Mitochondrial functions are intimately associated with neurological symptoms. Various clinical and biological features are suggestive of energy depletion diseases, such as Leigh syndrome, Alpers syndrome, epilepsy (including myoclonic seizures and status epilepticus), stroke-like episodes, and acute cerebellar ataxia with high lactate peaks on magnetic resonance spectroscopy. Magnetic resonance imaging (MRI) discloses abnormalities in over 90% of the cases presenting with neurological symptoms. Basal ganglionic involvement, the most frequent imaging sign, can be isolated or combined with subtentorial atrophy of both the cerebellum and brainstem. MRS monovoxel proton spectroscopy is useful to reveal high lactate spikes if placed in the putamen and the cerebellar dentate nucleus. Lactate and pyruvate levels are required to exclude pyruvate dehydrogenase deficiency. However, lactate may be normal in the CSF. Clinical and biochemical investigations guide molecular studies, with two major heredities: mtDNA point mutations and autosomal recessive defects that program the majority of respiratory chain subunits. Muscle biopsy is the first test demonstrating the histochemical and ultrastructural alterations in mitochondria, even in diseases in which myopathy is not clinically prominent, and is also a good tissue for biochemical analysis, as the biopsy is not dangerous for the patient. Negative results in skeletal muscle do not exclude respiratory chain deficiency, and a liver biopsy may be necessary whatever the blood AST and ALT levels, to perform biochemical and molecular investigations. Only the identification of nuclear or mitochondrial mutation confirms the diagnosis.

Epileptic phenotypes in children with respiratory chain disorders.

PURPOSE: Epilepsy is a commonly reported but rarely described clinical hallmark of mitochondrial respiratory chain defects (RCDs) with encephalopathy. METHODS: From 1990-2006 we collected data about 56 children with RCD (single, n = 24 or multiple, n = 20 mitochondrial complex deficiencies; mtDNA mutation, n = 11; mtDNA depletion n = 10 of 21; and nuclear gene mutation n = 11). Epileptic features were reviewed retrospectively. RESULTS: First seizures were frequently (47 patients, 82.5%) preceded by failure to thrive, psychomotor delay, ataxia, or multisystemic dysfunction. Sixty percent of the patients had several seizure types. Six age-related epilepsy phenotypes could be identified: status epilepticus complicating neonatal multivisceral deficiency (2 patients), neonatal myoclonic encephalopathy (3 patients), infantile spasms (8 patients), refractory or recurrent status epilepticus (21 patients), epilepsia partialis continua (4 patients), and myoclonic epilepsy (18 patients). Except for infantile spasms, epilepsy was difficult to control in most patients (95%). Valproate was administered to 25 patients, one of whom developed acute liver failure 6 days later. Twenty-two patients (45%) died, half of them within 9 months from the onset of epilepsy. DISCUSSION: In RCD, epilepsy is not only difficult to control but its occurrence often indicates a severe turn in the course of the disease. For one-third of the patients, classical biochemical measures failed to reveal any abnormality and RCD could be detected in the liver only.

Transient magnetic resonance diffusion abnormalities in West syndrome: the radiological expression of non-convulsive status epilepticus?

The purpose of this study was to report patients with pharmacoresistant West syndrome of unknown cause whose magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) showed a transient decrease of diffusion in subcortical structures. Of 20 patients investigated over a 2-year period, three males and three females constitute the present series. They had daily clusters of infantile spasms with hypsarrhythmia for 4 to 24 months before the first investigation. Four were severely hypotonic. All aetiological studies involving intermediary metabolism, peroxysomes, mitochondria, and neurotransmitters in cerebrospinal fluid were negative. Patients underwent DWI when first examined at the mean age of 13 months, and on follow-up examination 6 to 18 months later. Diffusion was decreased in the pallidi and posterior brainstem. It was also decreased for five patients in thalami and for three in dentate nuclei. Repeat MRI, performed when spasms were still present but hypsarrhythmia had ceased, did not show the same abnormalities. Because of recruitment bias, this series probably overestimates the true incidence of such DWI abnormalities. The eventuality of toxic lesions, including some inborn error of metabolism or drug toxicity, is considered unlikely although it could not be excluded. The contribution of the epileptic encephalopathy itself appears the most likely course.

Respiratory chain defects may present only with hypoglycemia.

Hypoglycemia occasionally results from oxidative phosphorylation deficiency, associated with liver failure. Conversely, in some cases of respiratory chain defect, the impairment in glucose metabolism occurs with normal hepatic function. The mechanism for this hypoglycemia remains poorly understood. We report here three unrelated children with hypoglycemia as the presenting symptom associated with oxidative phosphorylation deficiency but without liver dysfunction. Two patients had, respectively, complex III and complex IV deficiency and presented with long fast hypoglycemia. During a fasting test, the first patient showed evidence for impaired gluconeogenesis (progressive increase of plasma lactate and no decrease of alanine levels), whereas the second patient appeared to have impaired fatty acid oxidation (hypoketotic hypoglycemia with increased levels of non esterified fatty acids). The third patient presented with both long and short fast hypoglycemia related to complex IV deficiency. The mechanism of hypoglycemia for this patient may have been partly related to GH insufficiency, whereas impaired glycogen metabolism possibly accounted for short fast hypoglycemia. We suggest that hypoglycemia can be the presenting symptom for respiratory chain defects, through the possible reduction in cofactors resulting from oxidative phosphorylation deficiency, and that respiratory chain defects should therefore be considered in the differential diagnosis of hypoglycemia.

Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy.

A six-day-old girl was referred for severe hepatic failure, dehydratation, axial hypotonia, and both lactic acidosis and ketoacidosis. Biotin-unresponsive pyruvate carboxylase deficiency type B was diagnosed. Triheptanoin, an odd-carbon triglyceride, was administrated as a source for acetyl-CoA and anaplerotic propionyl-CoA. Although this patient succumbed to a severe infection, during the six months interval of her anaplerotic and biochemical management, the following important observations were documented: (1) the immediate reversal (less than 48 h) of major hepatic failure with full correction of all biochemical abnormalities, (2) on citrate supplementation, the enhanced export from the liver of triheptanoin's metabolites, namely 5 carbon ketone bodies, increasing the availability of these anaplerotic substrates for peripheral organs, (3) the demonstration of the transport of C5 ketone bodies-representing alternative energetic fuel for the brain-across the blood-brain barrier, associated to increased levels of glutamine and free gamma-aminobutyric acid (f-GABA) in the cerebrospinal fluid. Considering that pyruvate carboxylase is a key enzyme for anaplerosis, besides the new perspectives brought by anaplerotic therapies in those rare pyruvate carboxylase deficiencies, this therapeutic trial also emphasizes the possible extended indications of triheptanoin in various diseases where the citric acid cycle is impaired.

Coenzyme Q(10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits.

While there have been major advances in both the identification of the molecular basis and our understanding of mitochondrial pathology, the clinical management of patients with mitochondrial respiratory chain disease is still essentially supportive. Quinones are the only pharmacological agents that have proven some efficacy when, and only when, given to patients presenting with quite specific respiratory chain defects. In this article, after a short presentation of the coenzyme Q(10) molecule, its origin and distribution in human body, we summarize our present knowledge on its several physiological functions. We next discuss the rational that justifies using different types of quinones in the therapy of mitochondrial disorders. We finally briefly review the available data obtained in the therapy of mitochondrial disorders by using quinones as either substitutive electron carriers or antioxidant compounds.