Absence of mutation in the SLC2A1 gene in a cohort of patients with alternating hemiplegia of childhood (AHC)

Alternating hemiplegia of childhood (AHC) is a rare neuropediatric disorder classically characterized by episodes of hemiplegia developing in the first months of life, various non-epileptic paroxysmal events and global neurological impairment. If the etiology is unresolved, the disorder is highly suspected to be monogenic with DE NOVO autosomal dominant mutations. A missense mutation in the SLC2A1 gene encoding the facilitative glucose transporter-1 (GLUT1) was recently described in a child fulfilling the existing criteria for the diagnosis of AHC, with the exception of age at onset, thus suggesting a clinical overlap between AHC and GLUT1 deficiency syndrome due to SLC2A1 mutations. We have studied a cohort of 23 patients to investigate whether patients with classical AHC harbor SLC2A1 mutations. Automated Sanger sequencing and MLPA analyses failed to detect any SLC2A1 mutations in the 23 patients analyzed, thus excluding mutations of this gene as a frequent cause of classical AHC.     

三例儿童交替性偏瘫的回顾性分析

目的探讨儿童交替性偏瘫病因、临床特点、治疗效果。方法回顾性分析3例儿童交替性偏瘫患者的病因、临床表现及疗效。结果本组3例患者起病年龄均小于18个月,反复发作的交替性偏瘫；进行性的智能障碍,其中1例伴有短暂眼球震颤及眼球活动障碍,1例伴有张力障碍性姿势异常；睡眠可缓解无力及锥体外系症状,应用氟桂嗪治疗后,2例患者发作频率及持续时间降低,1例无效。结论本病病因不明,多为散发,临床表现为18月内起病的发作性交替性偏瘫,辅助检查无特征性改变,氟桂利嗪治疗部分有效。     

Treatment of alternating hemiplegia of childhood with aripiprazole

We report the pharmacological treatment of a case of alternating hemiplegia of childhood (AHC) in a 14-year-old female with an established diagnosis. Although the patient's symptoms are consistent with those of the condition, she did not respond to treatment with haloperidol, flunarizine, or propranolol. Treatment with aripiprazole resulted in a reduction in the frequency, duration, and severity of episodes of alternating hemiplegia, along with other therapeutic benefits. After treatment with aripiprazole was started, the patient was inadvertently given an inactive drug, resulting in a worsening of her hemiplegic episodes, which improved again on rechallenge. A comparison of the pharmacological actions of successful and unsuccessful treatments for AHC is made. Modulation of both dopamine and histamine systems together appears to be important in the treatment of AHC and further investigation of such pharmacotherapies is suggested.     

Alternating hemiplegia of childhood: no mutations in the glutamate transporter EAAT1

Alternating hemiplegia of childhood (AHC) is a severe brain disorder, mainly characterised by episodes of hemiplegia, progressive mental retardation, and other severe paroxysmal and permanent neurological symptoms. Clinically and genetically, there is some overlap with sporadic (SHM) and familial (FHM) hemiplegic migraine, a severe monogenic subtype of migraine. Although no mutations were detected in the FHM1 CACNA1A and FHM2 ATP1A2 genes in sporadic AHC patients, a mutation was found in the FHM2 ATP1A2 gene in a family with AHC. Recently, a missense mutation was found in the SLC1A3 gene that encodes the glutamate transporter EAAT1, in a patient with alternating hemiplegia, episodic ataxia, seizures, and headache. Because of the remarkable clinical similarities and the potential role of glutamate in AHC, we analysed six sporadic patients with AHC for mutations in the SLC1A3 gene. No mutations were found. The SLC1A3 EAAT1 glutamate transporter gene does not seem to be involved in the pathogenesis of AHC.     

Alternating Hemiplegia of Childhood With a de Novo Mutation in ATP1A3 and Changes in SLC2A1 Responsive to a Ketogenic Diet

BackgroundAlternating hemiplegia of childhood (AHC) is a rare condition characterized by an early onset of hemiplegic episodes and other paroxysmal or permanent neurological dysfunctions. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. Regarding the differential diagnosis of AHC, glucose transporter 1 deficiency syndrome may be considered because these two disorders share some paroxystic and nonparoxystic features.Patient and resultsWe report a typical case of AHC harboring a de novo mutation in the ATP1A3 gene, together with a duplication and insertion in the SLC2A1 gene who exhibited marked clinical improvement following ketogenic diet.ConclusionBecause the contribution of the SLC2A1 mutation to the clinical phenotype cannot be definitely demonstrated, the remarkable clinical response after ketogenic diet led us to the hypothesis that ketogenic diet might be effective in AHC as it provides an alternative energy source for the brain.     

儿童交替性偏瘫六例分析

目的探讨儿童交替性偏瘫（ＡＨＣ）的临床特点及治疗方法。方法对６例ＡＨＣ患儿的临床资料进行分析。结果６例患儿的临床特征为出生后１８个月起内病，频繁发作，持续数分钟至数小时；短暂的眼球震颤，肌张力异常，舞蹈徐动样动作，植物神经机能紊乱和认知机能减退；睡眠可缓解无力及锥体外系症状。应用氟桂嗪治疗后，１例患儿发作完全停止，其余５例患儿均显示发作频率和持续时间降低。结论本病的主要特征为１８个月内起病的发作性交替性偏瘫，伴锥体外系症状及智力障碍，氟桂嗪治疗本病有效     

Topiramate: a new agent for patients with alternating hemiplegia of childhood

Alternating hemiplegia of childhood is a rare syndrome characterized by the onset, before 18 months of age, of frequent attacks of alternating paralysis. Here we report the efficacy of topiramate in four patients with alternating hemiplegia of childhood (AHC) that did not respond to flunarizine, as well as in two newly diagnosed patients. Following treatment with topiramate, the frequency and duration of hemiplegic attacks significantly improved in all patients. Additional symptoms such as seizures, migraine, involuntary movements, autonomic symptoms, and impaired mental development also improved. Topiramate is worth trying when treating patients with AHC as a first trial, or a substitute for flunarizine once the latter agent loses effect.     

ATP1A3-related epileptic encephalopathy responding to ketogenic diet

Background

Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na⁺-K⁺ ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported.

Alternating hemiplegia in childhood: 23 cases in Japan.

Alternating hemiplegia in childhood (AHC) has clinically characteristic features which are easily defined and recognizable. Laboratory investigations were basically normal although they were extensively examined during and between attacks. There is still much debate about its etiology, particularly its relation to migraine or epilepsy. Clinical characteristics of identified 23 AHC in Japanese were presented, which were obtained from a large Japanese cooperative study in 1988. AHC may prove not to be as rare as has been thought.     

Alternating hemiplegia of childhood: no mutations in the second familial hemiplegic migraine gene ATP1A2

Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterised by attacks of hemiplegia and mental retardation. AHC has often been associated with migraine. Previously, we have excluded the involvement of the familial hemiplegic migraine (FHM) CACNA1A gene in four patients with AHC. A second gene for FHM was discovered recently: the ATP1A2 gene on chromosome 1q23, coding for the alpha 2 subunit of Na+,K+-ATPase. We performed a mutation analysis of the ATP1A2 gene in six patients, using direct sequencing, but found no mutations in any of the 23 exons. Other cerebral ion channel genes remain candidate genes for AHC.     

Absence of small-vessel abnormalities in alternating hemiplegia of childhood

Objective: To investigate whether Japanese patients with alternating hemiplegia of childhood (AHC) have the similar small-vessel abnormalities in skin reported in European patients with AHC. Methods: Electron microscopic observation of biopsied skin specimens were carried out in six Japanese patients with AHC. All patients (aged 5-17, all boys) had been diagnosed with AHC through their typical clinical courses and symptoms. Results: No abnormal findings in both endothelial cells and smooth muscle cells in skin small-vessels were obtained in the present study, either in the five flunarizine responders or in the one non-responder. Conclusions: From our observations, we hypothesized that there may be some subtypes of AHC. The diverse clinical courses in patients with AHC and the differing efficacy of flunarizine treatment could be explained because of the heterogeneity of AHC subtypes.     

Long-term effect of flunarizine on patients with alternating hemiplegia of childhood in Japan

To determine the effect of flunarizine therapy on patients with alternating hemiplegia of childhood (AHC), we sent a questionnaire by mail to council members of the Japanese Society of Child Neurology. We collected 28 AHC patients, and studied their clinical courses and the effects of drug therapy. All of the patients had received flunarizine. In 18 of the 28 patients, flunarizine reduced the severity, duration, or frequency of the hemiplegic attacks. No other drug was more effective than flunarizine. Some flunarizine non-effective patients were severely deteriorated, for example, they had dementia or were ventilator-assisted. Flunarizine had not only a short-term effect, i.e. it reduced the hemiplegic attacks, but also a long-term effect on the motor and intellectual development in some patients with AHC. Flunarizine is still an essential drug for treating AHC.     

Benign nocturnal alternating hemiplegia of childhood: The first clinical report with paroxysmal events home‐video recordings

Benign familial nocturnal alternating hemiplegia of childhood (BNAHC) is a rare disorder characterized by recurrent attacks of hemiplegia, arising from sleep without progression to neurological or intellectual impairment. It is distinct from the malignant, relatively more common, alternating hemiplegia of childhood (AHC), complicated by developmental deterioration, cognitive impairment, and permanent neurological deficits such as choreoathetosis. The authors add a new case of BNAHC to the pertinent literature and report, for the first time, a video with the typical nocturnal hemiplegic attacks in order to improve knowledge about this disorder among child neurologists and pediatricians and increase the possibility of clarifying its pathogenesis and molecular basis. © 2008 Movement Disorder Society     

Successful trial of amantadine hydrochloride for two patients with alternating hemiplegia of childhood

We report here the efficacy of amantadine hydrochloride for two patients with alternating hemiplegia of childhood (AHC) that did not respond to flunarizine. Amantadine was administered to one patient at age one year and seven months and to the other at age 25 years. The frequencies and duration of the hemiplegic attacks significantly improved in both patients. However, the attacks gradually returned to the previous level after a significant reduction in seizures for three years in the younger patient with ongoing AHC. Our therapeutic results further support the hypothesis that glutamate and NMDA receptors are involved in inducing alternating hemiplegic attacks, because amantadine as well as its derivative, memantine, are clinically available non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, with neuroprotective effects. Amantadine is worth trying when treating patients with AHC as a first trial or a substitute for flunarizine once the latter agent looses effect.     

Alternating hemiplegia of childhood or familial hemiplegic migraine?: A novel ATP1A2 mutation

Alternating hemiplegia of childhood (AHC) is typically distinguished from familial hemiplegic migraine (FHM) by infantile onset of the characteristic symptoms and high prevalence of associated neurological deficits that become increasingly obvious with age. Expansion of the clinical spectrum in FHM recently has begun to blur the distinction between these disorders. We report a novel ATP1A2 mutation in a kindred with features that bridge the phenotypic spectrum between AHC and FHM syndromes, supporting a possible common pathogenesis in a subset of such cases. Mutation analysis in classic sporadic AHC patients and in an additional five kindreds in which linkage to the ATP1A2 locus could not be excluded failed to identify additional mutations.     

Abnormal cerebral glucose metabolism in alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is a rare and intractable disorder of unknown cause. To determine cerebral neuronal function in five patients with AHC (two adults and three children), we analyzed brain glucose metabolism by positron emission tomography (PET) using 2-deoxy-2 [(18)F] fluoro-d-glucose (FDG), performed between hemiplegic attacks. Interictal FDG-PET revealed abnormal cerebral glucose metabolism; all patients showed low glucose metabolism in the frontal lobes with some laterality, and three had low glucose metabolism in the ipsilateral putamen. The adult patients also showed low glucose metabolism and mild atrophy in the cerebellum. Glucose metabolism in the brainstem was virtually normal for all patients. The areas of low glucose metabolism indicated local or regional neuronal damage, possible reflecting progressive neurological symptoms. AHC might therefore result from focal abnormal glucose metabolism in the brain occurring progressively or permanently, particularly in the frontal lobes and the cerebellum.     

Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene

Alternating hemiplegia of childhood (AHC) is a rare neurological disease mainly caused by mutations in the ATP1A3 gene and showing varied clinical severity according to genotype. Patients with a p.Gly755Ser (p.G755S) mutation, one of minor genotypes for AHC, were recently described as having a mild phenotype, although their long-term outcomes are still unclear due to the lack of long-term follow up. Here, we demonstrate the full clinical course of a 43-year-old female AHC patient with p.G755S mutation. Although her motor dysfunction had been relatively mild into her 30?s, she showed a subsequent severe aggravation of symptoms that left her bedridden, concomitant with a recent recurrence of seizure status. The seizures were refractory to anti-epileptic drugs, but administration of flunarizine improved seizures and the paralysis.Our case suggests that the phenotype of AHC with p.G755S mutation is not necessarily mild, despite such a presentation during the patient’s younger years.     

Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation

ATP1A3, the gene encoding the α3‐subunit of the Na⁺/K⁺‐ATPase pump, has been involved in four clinical neurological entities: (1) alternating hemiplegia of childhood (AHC); (2) rapid‐onset dystonia parkinsonism (RDP); (3) CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; and (4) early infantile epileptic encephalopathy. Here, we report on a 34‐year‐old female presenting with a new ATP1A3‐related entity involving a relapsing encephalopathy characterized by recurrent episodes of cerebellar ataxia and altered consciousness during febrile illnesses. The term RECA is suggested – relapsing encephalopathy with cerebellar ataxia. The phenotype of this patient, resembling mitochondrial oxidative phosphorylation defects, emphasizes the possible role of brain energy deficiency in patients with ATP1A3 mutations. Rather than multiple overlapping syndromes, ATP1A3‐related disorders might be seen as a phenotypic continuum.     

Neuroradiological findings in Sturge-Weber syndrome (SWS) and isolated pial angiomatosis

In 14 children with Sturge-Weber syndrome, cortical calcifications on CT scan was present in 12, localized brain atrophy in 10, enlargement of the choroid plexus in 7, and abnormal veins in 7. Cortical enhancement was present on 12 CTs performed shortly after an episode of severe seizures or hemiplegia but was absent or considerably less marked at a distance from the acute episodes. We suggest that cortical enhancement is related to seizure activity and/or blood-brain disturbances rather than to the extension of pial angioma.     

A boy with nystagmus, refractory dystonia and apneic attack due to alternating hemiplegia of childhood

We herein report the findings of a 2-year-6-month-old boy, who had been experiencing monocular pendular nystagmus, strabismus, and episodic eye deviation nystagmus, intractable dystonia and apneic attack which all began when he was 2 days of age. He underwent a complete blood count test, blood chemistry test, analysis of amino acids in the blood and urine, analysis of pyruvate/lactate in blood and cerebrospinal fluid, head computed tomography and magnetic resonance imaging and no abnormal results were identified. His attacks were resistant to multiple antiepileptic and dopaminergic drugs. He showed transient left and/or right hemiplegia after nystagmus, dystonia and/or apneic attacks at 8-months of age with retardation in intelligence. We diagnosed him to have alternating hemiplegia of childhood (AHC). We were unsure how to deal with his attacks after he was discharged from the hospital, however, resuscitation with the ambu bag by his mother at home and the intravenous infusion of diazepam or thiamylal at the hospital together was proven to be an effective method for treating his severe apneic attacks. The effect of diazepam and amantadine on these attacks was transient, however, the administration of flunarizine with amantadine resulted in an improvement in his attacks. We therefore consider the administration of flunarizine to be essential for the effective treatment of AHC in this case.