Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway.

Introduction: Developmental and epileptic encephalopathies (DEE) is a group of epilepsies where the epileptic activity, seizures and the underlying neurobiology contributes to cognitive and behavioral impairments. Uncovering the causes of DEE is important in order to develop guidelines for treatment and follow-up. The aim of the present study was to describe the clinical picture and to identify genetic causes in a patient cohort with DEE without known etiology, from a Norwegian regional hospital. Methods: Systematic searches of medical records were performed at Drammen Hospital, Vestre Viken Health Trust, to identify patients with epilepsy in the period 1999-2018. Medical records were reviewed to identify patients with DEE of unknown cause. In 2018, patients were also recruited consecutively from treating physicians. All patients underwent thorough clinical evaluation and updated genetic diagnostic analyses. Results: Fifty-five of 2,225 patients with epilepsy had DEE of unknown etiology. Disease-causing genetic variants were found in 15/33 (45%) included patients. Three had potentially treatable metabolic disorders (SLC2A1, COQ4 and SLC6A8). Developmental comorbidity was higher in the group with a genetic diagnosis, compared to those who remained undiagnosed. Five novel variants in known genes were found, and the patient phenotypes are described. Conclusion: The results from this study illustrate the importance of performing updated genetic investigations and/or analyses in patients with DEE of unknown etiology. A genetic cause was identified in 45% of the patients, and three of these patients had potentially treatable conditions where available targeted therapy may improve patient outcome.

Pyruvate dehydrogenase deficiency. / Pyruvatdehydrogenase-mangel.

Pyruvate dehydrogenase deficiency is a rare mitochondrial disease leading to energy deficiency in the cells. This particularly affects the central nervous system, resulting in a broad range of neurological symptoms.

Dietary therapy for epilepsy. / Diettbehandling av epilepsi.

Children with pharmacoresistant epilepsy should be offered ketogenic dietary therapy. The diet, which is rich in fat and low in carbohydrate, has a beneficial effect in reducing seizures in this patient group. It may also have a beneficial effect in adults, but there is less evidence than in children. Dietary treatment of epilepsy is a specialist therapy, and in order to adhere to the diet, strong motivation of the patient and relatives as well as close follow-up from the specialist health service are necessary.

GLUT1-deficiency syndrome: Report of a four-generation Norwegian family with a mild phenotype.

INTRODUCTION: Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variation of clinical phenotypes. Familial variants are often milder than de novo cases, and may therefore remain undiagnosed. The aim of this study was to characterize the clinical course of GLUT1-DS in a four-generation Norwegian family where the oldest generations had never received any treatment. METHOD: Through interviews and clinical investigations, we characterized a family of 26 members, where 11 members had symptoms strongly suggesting GLUT1-DS. All members were offered genetic testing of the SLC2A1 gene. Affected members were offered treatment with ketogenic diet, and the effect of the treatment was registered. RESULTS: We sequenced the SLC2A1 gene in 13 members, and found that 10, all with symptoms, had the c.823G>A (p.Ala275Thr) variant. All affected members had experienced early-onset epilepsy, paroxysmal exercise-induced dyskinesias, and most had mild learning disability. Moreover, some had symptoms and signs of a distal neuropathy in addition to reduced sense of orientation and excessive daytime sleep. Their load of symptoms had decreased over the years, although that they never had received any treatment. Nevertheless, those who started dietary treatment all experienced an improved quality of life. CONCLUSION: We report a four-generation family with GLUT1-DS where the disease has a mild course, even when untreated. In addition to classical GLUT1-DS features, we also describe symptoms which have never been reported in GLUT1-DS previously. As such, this family extends the phenotypic spectrum of GLUT1-DS and underlines the importance of diagnosing also relatively mildly affected patients, even in adult life, as they also seem to benefit from dietary treatment.

Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study.

The aim of this study was to investigate the effects of ketogenic diet (KD) on cognitive function in patients with glucose transporter protein 1 deficiency syndrome (GLUT1-DS). Six patients with GLUT1-DS who were referred to the National Centre for Epilepsy in Norway during the period of November 2011-September 2013 were included. They were diagnosed with GLUT1-DS on the basis of early-onset seizures and developmental delay (with or without movement disorders or microcephaly) in addition to CSF-to-blood glucose ratio below 0.5. They were all treated with either classical KD or modified Atkins diet (MAD). The effect of the diet with >90% reduction in the seizure frequency was, in retrospect, considered as a support for the diagnosis. The patients underwent standardized neuropsychological assessment before the diet was initiated, and they were reassessed after a minimum of six months on the diet. The neuropsychological tests were individually selected for each patient in order to match their cognitive level. The main finding was a considerable improvement in several aspects of neuropsychological functioning after 6-17 months of dietary treatment in all the six patients. The greatest progress was seen in the youngest children. Our findings suggest that early diagnosis and dietary treatment are important in order to prevent developmental delay. However, also adults with GLUT1-DS may profit from dietary treatment by improving alertness, setting the stage for enhanced learning capacity, as well as physical endurance and quality of life.

Occurrence of GLUT1 deficiency syndrome in patients treated with ketogenic diet.

Glucose transporter 1 deficiency syndrome (GLUT1-DS) is a treatable metabolic encephalopathy caused by a mutation in the SLC2A1 gene. This mutation causes a compromised transport of glucose across the blood-brain barrier. The treatment of choice is ketogenic diet, with which most patients become seizure-free. At the National Centre for Epilepsy, we have, since 2005, offered treatment with ketogenic diet (KD) and modified Atkins diet (MAD) to children with difficult-to-treat epilepsy. As we believe many children with GLUT1-DS are unrecognized, the aim of this study was to search for patients with GLUT1-DS among those who had been responders (>50% reduction in seizure frequency) to KD or MAD. Of the 130 children included, 58 (44%) were defined as responders. Among these, 11 were already diagnosed with GLUT1-DS. No mutations in the SLC2A1 gene were detected in the remaining patients. However, the clinical features of these patients differed considerably from the patients diagnosed with GLUT1-DS. While 9 out of 10 patients with GLUT1-DS became seizure-free with dietary treatment, only 3 out of the 33 remaining patients were seizure-free with KD or MAD treatment. We therefore conclude that a seizure reduction of >50% following dietary treatment is not a suitable criterion for identifying patients with GLUT1-DS, as these patients generally achieve complete seizure freedom shortly after diet initiation.

Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study.

AIM: The aim of this study was to characterize patients diagnosed with glucose transporter protein-1 deficiency syndrome (GLUT-1 DS) clinically and genetically, and to evaluate the effect of treatment with the classic ketogenic or modified Atkins diet. METHOD: We retrospectively studied medical records of 10 patients diagnosed with GLUT-1 DS. Four females and six males with a median age of 15 years were included. RESULTS: The study illustrates the genetic and clinical heterogeneity of GLUT-1 DS. Analysis of the SLC2A1 gene disclosed a variety of mutation types. The time between onset of symptoms and diagnosis was more than 11 years on average. The outcome in those with early diagnosis and intervention was surprisingly good. All but one patient with the classic phenotype became seizure free after treatment with the classic ketogenic or modified Atkins diet. Acetazolamide was effective in one patient with paroxysmal exercise-induced dyskinesia. A point prevalence of GLUT-1 DS in Norway was estimated as 2.6 per 1,000,000 inhabitants. INTERPRETATION: Although the long-term prognosis in patients with GLUT-1 DS partly depends on the underlying genetics, our study supports the assumption that early initiation of treatment with a ketogenic diet may positively affect the outcome.

[Epilepsy surgery--assessment and patient selection]. / Epilepsikirurgi--utredning og pasientseleksjon.

BACKGROUND: Considerable progress in diagnostic imaging and video EEG monitoring has improved the possibilities of localising the epileptogenic zone of the brain in patients with epilepsy. Despite the fact that epilepsy surgery can therefore be offered to more patients today than previously, relatively few patients are referred for an assessment for surgery. The aim of this review is to provide a brief account of the patient selection procedures and the investigations prior to epilepsy surgery. METHOD: The review is based on a literature search in PubMed and the personal experiences of the authors in this field. RESULTS: If the epilepsy does not respond to any kind of pharmacological treatment, and idiopathic generalised epilepsy and pseudoresistance have been ruled out, the patient should be evaluated for surgery. The evaluation is multidisciplinary, and the aim is to localise the epileptogenic zone, which can be identified by both structural and functional abnormalities. It must be determined before the operation whether the zone can be removed without leaving severe neurological or cognitive impairment. The best results after epilepsy surgery are seen in patients with a morphological substrate, particularly temporal lobe epilepsy associated with hippocampal sclerosis. INTERPRETATION: Epilepsy surgery plays an ever more important role in the treatment of patients with drug resistant seizures. Doctors who treat epileptic patients should refer candidates for surgery at an early stage of the disease.

[Glucose transporter protein type 1 (GLUT-1) deficiency syndrome]. / Glukosetransportprotein type 1-mangel.

BACKGROUND: Glucose is the brain's main source of energy. To pass the blood-brain barrier, glucose transporter protein type 1 (GLUT-1) is essential. Mutations in the SLC2A1 gene which codes for GLUT-1 may therefore compromise the supply of glucose to the brain. The aim of this review is to describe the clinical consequences of such mutations, with special emphasis on GLUT-1 encephalopathy. MATERIAL AND METHODS: This review is based on a non-systematic literature search in PubMed and the authors' experience within the field. RESULTS: Epileptic or epilepsy-like are usually the first symptom in children with the GLUT-1 deficiency syndrome. Later on these children suffer delayed psychomotor development, microcephaly, ataxia, spasticity or movement disorders. EEG abnormalities may develop. GLUT-1 deficiency syndrome should be suspected in children with epilepsy-like seizures and delayed development combined with a low content of glucose in spinal fluid. The diagnosis is confirmed by genetic testing. Treatment is a ketogenic diet, as ketone bodies pass the blood-brain barrier using other transport proteins than GLUT-1. INTERPRETATION: GLUT-1-deficiency syndrome is a rare metabolic encephalopathy which is not well known and probably underdiagnosed. An early diagnosis and early start of a ketogenic diet may give these children a normal or nearly normal life.

Do sleep-deprived EEG recordings reflect spike index as found in full-night EEG recordings?

The sleep EEGs of many children with neurodevelopmental disorders reveal epileptiform activity. The aim of this study was to compare spike index (SI) in full-night recordings with SI in sleep-deprived EEGs in the morning; EEGs were obtained over 24 hours using ambulatory equipment. Sixteen children between the ages of 7 and 12 years were included in the study. They had to wake up at 3:00 AM and go to sleep again at 7:30 AM. Epileptiform activity was quantified, and SIs of full-night and morning recordings were compared. Two patients did not fall asleep. In one recording there was a technical problem that made calculations impossible. SIs calculated from EEGs obtained during a short nap in the morning were comparable to those calculated from full-night recordings. There seems to be a higher failure rate during morning recordings because of patients not falling asleep.