GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia.

Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Because of the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia.

Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy.

OBJECTIVE: Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. METHOD: Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. RESULTS: The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. SIGNIFICANCE: Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation.

Outcome and predictors of interstitial radiosurgery in the treatment of gelastic epilepsy.

BACKGROUND: Gelastic epilepsy due to hypothalamic hamartomas is usually a severe condition encompassing both epileptic seizures and an epileptic encephalopathy associated with behavioral and cognitive impairments. Here we report the effects of interstitial radiosurgery in the treatment of this generally pharmacoresistant epilepsy syndrome. METHODS: Twenty-four consecutive patients (3-46 years of age, 7 women, mean age 21.9 years, mean duration of epilepsy 17.6 years) with gelastic epilepsy due to MR-ascertained hypothalamic hamartoma and a minimum follow-up period of 1 year were included in this evaluation. Treatment was performed by interstitial radiosurgery using stereotactically implanted (125)I seeds. Effects of treatment on seizure frequency and possible side effects were assessed prospectively. Factors influencing outcome and side effects were analyzed statistically. RESULTS: After a mean 24-month follow-up period following the last radiosurgical treatment, 11/24 patients were seizure free or had seizure reduction of at least 90% (Engel class I and II), in some cases only after repeated treatment. The duration of epilepsy prior to radiosurgery negatively influenced outcome. Treatment was well tolerated in most patients. Headache, fatigue, and lethargy were transient side effects associated with the development of brain edema extending from the implantation site in five patients. Four patients had a weight gain of more than 5 kg which was severe in two patients. The majority of those patients whose cognitive functions initially deteriorated showed subsequent recovery of cognitive functions, but episodic memory in two patients showed persistent decline at 1 year follow-up. Longer disease duration increased the risk for cognitive side effects, and larger hamartoma size and eccentric seed positioning increased the risk for radiogenic brain edema. Neither perioperative mortality nor neurologic impairments, visual field defects, or endocrinologic disturbances were encountered following treatment. CONCLUSION: Interstitial radiosurgery was efficacious in significantly improving gelastic epilepsy in about half of the patients treated in this series. Weight gain may occur as a side effect, whereas other severe side effects reported following microsurgical removal of the hamartoma were absent. The study results strongly suggest early causal treatment, as chances for seizure control are higher and the risk for cognitive side effects is lower in patients with shorter disease duration.

Interstitial radiosurgery in the treatment of gelastic epilepsy due to hypothalamic hamartomas.

The authors evaluated a new stereotactic radiosurgical approach in seven patients with gelastic epilepsy due to hypothalamic hamartomas. Stereotactic implantation of 125I-seeds into the hamartoma was feasible in six patients. At follow-up at least 1 year after interstitial radiotherapy, two patients had become seizure-free within 2 months, and two others had only persisting auras. There were no major perioperative or postoperative side effects.

[Aspects of long-term management of children with myelomeningocele. Analysis of the last 10 years from the neuropediatric-neurosurgical viewpoint]. / Aspekte der Langzeitbetreuung von Kindern mit Myelomeningozele. Analyse der letzten 10 Jahre aus neuropädiatrisch-neurochirurgischer Sicht.

BACKGROUND: Both the use of a selective policy of treatment of newborns with myelomeningocele and the right time of back closure are still controversially discussed. We report our experiences in the long-term care of children with myelomeningocele. METHODS: 103 newborns with myelomeningocele (n = 94) and meningocele (n = 9) born 1980 to 1990 and cared for regularly at the Olgahospital's pediatric clinic were followed up from the neuropediatric-neurosurgical point of view. Postpartum we predominantly practised a selective policy of treatment. RESULTS: 15 of 21 children (71.4%) not operated on died during the first days or months of life, 6 (28.6%) survived. 70 were operated selectively, of which 9 (12.9%) died, 61 (87.1%) survived with mainly good result. There were no differences in the survival rate and frequency/type of postoperative complications with respect to the time of the back closure. 31 children with myelomeningocele (33%) had CNS anomalies other than the Arnold-Chiari-Malformation, mostly being a dys- or aplasia of the corpus callosum and a deformed ventricle system. These were diagnosed almost exclusively by CT or MRT scan. CONCLUSIONS: We still predominantly practised a selective policy of treatment of newborns with myelomeningocele with mainly good results.

[Miller-Dieker syndrome (type I lissencephaly) with specific EEG changes]. / Miller-Dieker-Syndrom (Lissenzephalie Typ I) mit spezifischen EEG-Veränderungen.

We present the case report of a girl with a subtype of Lissencephaly syndrome, type I, "Miller-Dieker syndrome", pointing out the specific EEG features in infancy and early childhood. The following pathognomonic EEG manifestations may confirm the diagnosis of an lissencephalic syndrome: abnormally fast background activity of an extraordinary high voltage increasing with age, missing topographic structuring, no reactivity to sleep or medication, unusually high-voltaged sharp-slow-wave complexes.