Inborn errors of creatine metabolism and epilepsy

Creatine metabolism disorders include guanidinoacetate methyltransferase (GAMT) deficiency, arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CT1‐encoded by SLC6A8 gene) deficiency. Epilepsy is one of the main symptoms in GAMT and CT1 deficiency, whereas the occurrence of febrile convulsions in infancy is a relatively common presenting symptom in all the three above‐mentioned diseases. GAMT deficiency results in a severe early onset epileptic encephalopathy with development arrest, neurologic deterioration, drug‐resistant seizures, movement disorders, mental disability, and autistic‐like behavior. In this disorder, epilepsy and associated abnormalities on electroencephalography (EEG) are more responsive to substitutive treatment with creatine monohydrate than to conventional antiepileptic drugs. AGAT deficiency is mainly characterized by mental retardation and severe language disorder without epilepsy. In CT1 deficiency epilepsy is generally less severe than in GAMT deficiency. All creatine disorders can be investigated through measurement of creatine metabolites in body fluids, brain proton magnetic resonance spectroscopy (¹H‐MRS), and molecular genetic techniques. Blood guanidinoacetic acid (GAA) assessment and brain H‐MRS examination should be part of diagnostic workup for all patients presenting with epileptic encephalopathy of unknown origin. In girls with learning and/or intellectual disabilities with or without epilepsy, SLC6A8 gene assessment should be part of the diagnostic procedures. The aims of this review are the following: (1) to describe the electroclinical features of epilepsy occurring in inborn errors of creatine metabolism; and (2) to delineate the metabolic alterations associated with GAMT, AGAT, and CT1 deficiency and the role of a substitutive therapeutic approach on their clinical and electroencephalographic epileptic patterns.     

Inborn errors of metabolism causing epilepsy

Seizures may be the first and the major presenting feature of an inborn error of metabolism (IEM), for example in a neonate with pyridoxine‐dependent epilepsy. In other IEMs, seizures may be preceded by other major symptoms: by a reduced level of consciousness in a child with an organic acidaemia or urea cycle defect; or by loss of skills, progressive weakness, ataxia, and upper motor signs in a child with a lysosomal storage disorder or peroxisomal leukodystrophy. This review concentrates on those IEMs for which specific treatment is available. The common metabolic causes of seizures vary according to the age at presentation. Features from the history, examination, imaging, and first line biochemical investigations can all provide clues to an inborn error. This review attempts to delineate these and to provide a guide to the specific tests that can be used to make the diagnosis of disorders with specific treatment.     

Inborn errors of metabolism

Inborn errors of metabolism often cause neurological dysfunction. These disorders are most common in childhood, but adult-onset forms with a different clinical presentation are encountered, examples being Pompe disease, Tay-Sachs disease, metachromatic leukodystrophy, Gaucher disease, and Maroteaux-Lamy disease. In the evaluation of a patient with a possible inborn error of metabolism, simple screening tests may aid in the diagnosis and provide direction for more comprehensive laboratory analysis. In most cases, diagnosis can be established without a brain biopsy through biochemical and ultrastructural analysis of peripheral tissues, blood, and urine. New clinical, genetic, and biochemical variants of inherited metabolic disorders are being recognized through wider application of screening tests, improved specificity of laboratory analysis, cell complementation experiments, and the identification of enzyme activator factors. Accurate diagnosis is important for medical management, determining prognosis, and genetic counseling.     

Inborn errors of metabolism for child neurology residents

Inborn errors of metabolism (IEMs) are individually rare, but collectively common, and impose a burden on affected individuals, their families and society that is disproportionate to their individual incidence and prevalence. Child neurologists should be able to recognize the possibility of an IEM as the cause of their patients' symptoms and signs, and utilize online and print resources to initiate an appropriate work up and referrals. The foundation of this knowledge is an understanding of the mechanisms of IEMs, coupled with a practical classification of the relevant diseases, and knowledge of the resources available to make diagnoses and devise treatment plans. They should also be prepared to manage affected children as part of a multidisciplinary team that draws on the skills of other professionals and community organizations. Because of rapid advances in diagnostic technology and the improving survival of children with IEMs, all child neurologists should anticipate caring for children and families with IEMs, and must acquire the ability to diagnose and manage these disorders as part of their residency training, recognizing that maintenance of this competence requires a commitment to life-long learning.     

Inborn errors of metabolism: a cause of abnormal brain development

Brain malformations are caused by a disruption in the sequence of normal development by various environmental or genetic factors. By modifying the intrauterine milieu, inborn errors of metabolism may cause brain dysgenesis. However, this association is typically described in single case reports. The authors review the relationship between brain dysgenesis and specific inborn errors of metabolism. Peroxisomal disorders and fatty acid oxidation defects can produce migration defects. Pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, and maternal phenylketonuria preferentially cause a dysgenetic corpus callosum. Abnormal metabolism of folic acid causes neural tube defects, whereas defects in cholesterol metabolism may produce holoprosencephaly. Various mechanisms have been proposed to explain abnormal brain development in inborn errors of metabolism: production of a toxic or energy-deficient intrauterine milieu, modification of the content and function of membranes, or disturbance of the normal expression of intrauterine genes responsible for morphogenesis. The recognition of a metabolic disorder as the cause of the brain malformation has implications for both the care of the patient and for genetic counseling to prevent recurrence in subsequent pregnancies.     

Common errors made in the diagnosis and treatment of epilepsy

Learning from one's mistakes is the best learning tool in medicine and this applies as well to epilepsy. This article is a compilation of some of the frequent mistakes that are made in the evaluation and management of patients with epilepsy. It encompasses errors in the clinical diagnosis that result in the choice of the erroneous antiepileptic drug (AED), errors in the way auxiliary tests like the electroencephalogram and magnetic resonance imaging studies are ordered, mistakes in the recognition of subclinical status epilepticus, errors in the selection of AEDs, consequences of the failure to factor in the pharmacokinetic and pharmacodynamic properties of AEDs in the choice and dosification of medication, misconceptions on the expectations of therapeutic effect of AEDs, delay in recognition of refractory epilepsy with consequent delay in a timely identification of patients whose epilepsy can be cured with surgical treatment, and mistakes in the recognition and management of comorbid psychiatric disorders. In addition to a discussion of the reasons for the errors, the article provides practical solutions.     

International symposium on Inborn errors of metabolism in humans held in Interlaken,Switzerland, 1980

The 18th meeting of the Society for the Study of Inborn Errors of Metabolism (SSIEM) was a joint meeting with the International Society for Inborn Errors of Metabolism, and was a sequel to their meeting in Tel Aviv in 1977. The SSIEM, founded in 1963 following a symposium entitled Neurometabolic disorders in childhood, exists to promote an exchange of ideas between professional workers in different disciplines who are interested in the biochemical basis of inherited diseases. One of the ways it pursues this aim is by arranging annual meetings on particular topics. In the past subjects have included: Biochemical approaches to mental handicap in children; Inborn errors of skin, hair and connective tissue; Organic acidurias; Carbohydrate metabolism; and more broadly based topics, such as Treatment and Medico-social management. The Society also publishes a quarterly journal and has a membership of over 300, including members from overseas as well as the UK and Eire.     

Inborn errors of urea synthesis

Inborn errors of urea synthesis can present in the newborn period as a catastrophic illness or later in childhood or adulthood with an indolent course punctuated by hyperammonemic episodes. Because symptoms mimic other neuropsychiatric disorders, it is common for there to be a delay in diagnosis, often with dire consequences. Diagnosis relies on the combination of clinical suspicion and the measurement of ammonium, lactate, and amino acids in plasma and organic acids and orotic acid in urine. Treatment involves nitrogen restriction combined with the stimulation of alternate pathways of waste nitrogen excretion. More recently liver transplantation has been performed as enzyme replacement therapy. The outcome is poor in children who survive prolonged neonatal hyperammonemic coma, with most manifesting developmental disabilities. The etiology of neuronal injury in this disorder is unclear but may involve some combination of ammonia/amino acid accumulation, neurotransmitter alterations, and excitotoxic injury. Gene therapy holds the promise of improved treatment in the future.     

Clinical features, diagnosis, and treatment of dysphoric states and psychoses associated with epilepsy

Although dysphoric states and psychoses represent clinically relevant psychiatric complications in patients with epilepsy, their symptomatologies are complex and therefore frequently underrecognized and undertreated in daily psychiatric routine. Detecting dysphoric states and psychoses secondary to the psychotropic effects of various antiepileptic drugs is often challenging, even for the most experienced psychiatrists. This article gives an overview of epidemiology, clinical features, diagnosis, and therapy of interictal, peri-ictal, and alternative dysphoric states and psychoses in patients with epilepsy. Further, potential drug interactions between antiepileptic and psychiatric medications are discussed.     

Juvenile myoclonic epilepsy: clinical and EEG features

We aimed to characterize the clinical profile and EEG features of 43 patients with juvenile myoclonic epilepsy. In a retrospective design we studied the records of, and re-interviewed, 43 patients diagnosed with JME from the epilepsy clinic data base. Furthermore, available EEGs were re-evaluated. Of the patients 72% were female and 28% male. Average age of onset was 13 (5.5–22) years for absences, 16 (5.2–25) years for myoclonic seizures, and 16 (8–29) years for generalized tonic–clonic seizures. Forty-two percent reported asymmetric or unilateral myoclonic jerks. Commonly reported precipitating factors were sleep deprivation (84%), stress (70%), and alcohol consumption (51%). EEG findings included rapid spike-wave and polyspike-wave.     

Dystonia: clinical features,genetics, and treatment

PURPOSE OF REVIEW: The present review covers recent advances in dystonia research related to dystonia genetics and treatment. These have led to the discovery of novel dystonia genes and loci, to changing classification schemes, and to the introduction of improved and new treatment options. RECENT FINDINGS: Currently 13 different forms of dystonia can be distinguished on a genetic basis (dystonia types 1-13). Recently, a novel gene locus (DYT13) was detected in a family with segmental dystonia, and the gene causing myoclonus-dystonia was identified (SGCE). Furthermore, a novel mutation in the DYT1 gene is associated with a myoclonus-dystonia phenotype. Regarding dystonia treatment, patients refractory to botulinum toxin type A can now be treated with botulinum toxin type B. Selective peripheral denervation remains an effective form of treatment for patients with secondary, but probably not with primary botulinum toxin treatment failure. Finally, a renaissance of functional surgical ablative procedures has taken place, with high frequency deep brain stimulation being introduced in dystonia treatment. Bilateral pallidotomy or pallidal stimulation may provide major benefit especially in patients with generalized, disabling dystonia with the most dramatic improvements in dystonia type 1 patients. Neurostimulation may also be effective in primary segmental axial dystonia, myoclonus-dystonia, and tardive dystonia. SUMMARY: The recent mapping of additional dystonia gene loci, the identification of novel dystonia genes, and the characterization of proteins encoded by these genes have enhanced our understanding of various forms and aspects of the dystonias and have opened up new avenues for research. Treatment options include both medical and surgical therapies, with deep brain simulation being the most recent development.     

Cardiac asystole in epilepsy: clinical and neurophysiologic features

PURPOSE: Cardiac asystole provoked by epileptic seizures is a rare but important complication in epilepsy and is supposed to be relevant to the pathogenesis of sudden unexplained death in epilepsy (SUDEP). We sought to determine the frequency of this complication in a population of patients with medically intractable epilepsy and to analyze the correlation between EEG, electrocardiogram (ECG), and clinical features obtained from long-term video-EEG monitoring. METHODS: Retrospective analysis of the clinical records of hospitalized patients from May 1992 to June 2001 who underwent long-term video-/EEG monitoring. RESULTS: Of a total of 1,244 patients, five patients had cardiac asystole in the course of ictal events. In these patients, 11 asystolic events, between 4 and 60 s long in a total of 19 seizures, were registered. All seizures had a focal origin with simple partial seizures (n = 13), complex partial seizures (n = 4), and secondarily generalized seizures (n = 2). One patient showed the longest asystole ever reported (60 s) because of a seizure. Cardiac asystole occurred in two patients with left-sided temporal lobe epilepsy (TLE) and in three patients with frontal lobe epilepsy (FLE; two left-sided, one bifrontal). Two patients reported previous cardiac disease, but only one had a pathologic ECG by the time of admission. Two patients had a simultaneous central ictal apnea during the asystole. None of the patients had ongoing deficits due to the asystole. CONCLUSIONS: These findings confirm that seizure-induced asystole is a rare complication. The event appeared only in focal epilepsies (frontal and temporal) with a lateralization to the left side. A newly diagnosed or known cardiac disorder could be a risk factor for ictal asystole. Abnormally long postictal periods with altered consciousness might point to reduced cerebral perfusion during the event because of ictal asystole. Central ictal apnea could be a frequent associated phenomenon.     

Adult-onset idiopathic generalized epilepsy: clinical and behavioral features

PURPOSE: To identify and define clinical and behavioral features of patients with adult-onset idiopathic generalized epilepsy (IGE). METHODS: We reviewed the charts of 313 IGE patients at the NYU Comprehensive Epilepsy Center over the past 5 years to identify patients with adult onset (18 years old or older). We excluded patients with childhood or adolescent symptoms that suggested absence, myoclonic, or tonic-clonic seizures, as well as those with a history of significant head injury or other known causes of localization-related epilepsy. RESULTS: Forty-two (13.4%) patients had a clear onset of IGE in adulthood; average age of onset was early 20s (mean, 23.8 years; range, 18-55 years). Twenty-one patients had adult myoclonic epilepsy (AME, 50%), and three had generalized tonic-clonic seizures on awakening (GTCS-A, 7%). More than two thirds (n=30) are well controlled with current antiepileptic drugs (AEDs), and almost 90% are currently employed (n=37). One third were diagnosed and treated for mental disorders, including depression (n=12), anxiety (n=7), obsessive-compulsive personality disorder (n=2), and postictal psychosis (n=1). CONCLUSIONS: Adult-onset IGE is associated with a good prognosis. An association may exist between psychological disorders, psychotropic medication, and level of seizure control in adults with IGE.