The clinical spectrum associated with ATP1A2 variants in Chinese pediatric patients

PurposeTo evaluate the clinical spectrum associated with ATP1A2 variants in Chinese children with hemiplegia, migraines, encephalopathy or seizures.MethodsSixteen children (12 males and 4 females), including ten patients with ATP1A2 variants whose cases had been published previously, were identified using next-generation sequencing.ResultsFifteen patients had FHM2 (familial hemiplegic migraine type 2), including three who had AHC (alternating hemiplegia of childhood) and one who had drug-resistant focal epilepsy. Thirteen patients had DD (developmental delay). The onset of febrile seizures, which occurred between 5 months and 2 years 5 months (median 1 year 3 months) was earlier than the onset of HM (hemiplegic migraine), which occurred between 1 year 5 months and 13 years (median 3 years 11 months). Disturbance of consciousness subsided first, at 40 h to 9 days (median 4.5 days); hemiplegia and aphasia were resolved slowly, taking 30 min to 6 months (median 17.5 days) for the former and 24 h to over 1 year (median 14.5 days) for the latter. Cranial MRI showed edema in the cerebral hemispheres, mainly the left hemisphereacute attacks. All thirteen FHM2 patients recovered to baseline in 30 min to 6 months. Fifteen patients had between 1 and 7 (median 2) total attacks between the baseline and follow-up timepoints. We report twelve missense variants, including a novel variant ATP1A2 variant, p.G855E.ConclusionsThe known genotypic and phenotypic spectra of Chinese patients with ATP1A2-related disorders were further expanded. Recurrent febrile seizures and DD combined with paroxysmal hemiplegia and encephalopathy should raise the clinical suspicion of FHM2. The avoidance of triggers and thus the prevention of attacks may be the most effective therapy for FHM2.     

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.

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.     

Auditory-perceptual voice and speech evaluation in ATP1A3 positive patients

IntroductionBulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls.MethodsWe analyzed recordings in 32 RDP subjects (male = 21, female = 11) and 29 mutation negative controls (male = 15, female = 14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction.ResultsThe presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p < 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9–11 dysfunction (54%, p = 0.048), speech/swallowing dysfunction (96%, p = 0.0003); and oral dystonia (88%, p = 0.001).ConclusionsQuantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.     

Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia

BackgroundRapid-onset dystonia–parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms.Case reportWe describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified.DiscussionThis RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.     

A de novo p.Arg756Cys mutation in ATP1A3 causes a distinct phenotype with prolonged weakness and encephalopathy triggered by fever

Patients with a mutation at Arg756 in ATP1A3 have been known to exhibit a distinct phenotype, characterized by prolonged weakness and encephalopathy, triggered by febrile illness. With only eight reports published to date, more evidence is required to correlate clinical features with a mutation at Arg756. Here we report an additional case with an Arg756Cys mutation in ATP1A3. A four-year-old boy showed mild developmental delay with recurrent paroxysmal episodes of weakness and encephalopathy from nine months of age. Motor deficits, which included bilateral hypotonia, ataxia, dysmetria, limb incoordination, dysarthria, choreoathetosis, and dystonia, were observed from one year and three months. Whole-exome sequencing detected a heterozygous de novo variant at c.2266C > T (p.Arg756Cys) in ATP1A3. The episodic course and clinical features of this case were consistent with previously reported cases with mutations at Arg756. Furthermore, his phenotype of marked ataxia was more similar to that of an Arg756Cys patient with relapsing encephalopathy and cerebellar ataxia syndrome, than to those with Arg756His and Arg756Leu mutations. This report therefore provides evidence of genotype-phenotype correlations in ATP1A3-related disorders as well as in patients with mutations at Arg756 in ATP1A3.     

Benign nocturnal alternating hemiplegia of childhood: A new case with unusual findings

It has been described a neuro developmental disorder labelled “Benign nocturnal alternating hemiplegia of childhood” (BNAHC) characterized by recurrent attacks of nocturnal hemiplegia without progression to neurological or intellectual impairment. We report a female patient who at 11 months revealed a motionless left arm, unusual crying without impairment of consciousness and obvious precipitating factors. The attacks occur during sleep in the early morning with lack of ictal and interictal electroencephalographic abnormalities, progressive neurological deficit, and cognitive impairment. Unlike previous reports of BNAHC our patient come from a family with a history of both migraine, hemiplegic migraine, and sleep disorders. Our study remarks on the typical features described in previous studies and stresses the uncommon aspects that could help to identify the disorder which is likely to have been underestimated. Despite some clinical similarities between BNAHC and familiar hemiplegic migraine and alternating hemiplegia of childhood, the genetic analyses of our patient did not reveal genetic mutations found in both disorders.     

Movement disorders rounds: Atypical cases in two Chinese families with novel variants in ATP1A3

ATP1A3-related dystonia is a disorder with high heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 gene. Here, 2 atypical cases carring 2 de-novo ATP1A3 variants with RDP-CAPOS overlapping phenotype or continuous hemi-dystonia are described.     

Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report

A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8?months, and 2, 4, and 37?years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452G?>?A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review.     

ATP1A3-related epilepsy: Report of seven cases and literature-based analysis of treatment response

ATP1A3 related disease is a clinically heterogeneous condition currently classified as alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss. Recently, it has become apparent that a remarkably large subgroup is suffering from often difficult-to-treat epilepsy. The aim of the present study was to assess the prevalence and efficacy of commonly used anti-epileptic-drugs (AEDs) in patients with ATP1A3 related seizures. Therefore, we performed a retrospective study of patients in combination with a systematic literature-based review. Inclusion criteria were: verified ATP1A3 mutation, seizures and information about AED treatment. The literature review yielded records for 188 epileptic ATP1A3 patients. For 14/188 cases, information about anti-epileptic treatment was available. Combined with seven unpublished records of ATP1A3 patients, a sample size of 21 patients was reached. Most used AED were levetiracetam (n = 9), phenobarbital (n = 8), valproic acid (n = 7), and topiramate (n = 5). Seizure reduction was reported for 57% of patients (n = 12). No individual AEDs used (either alone or combined) had a success rate over 50%. There was no significant difference in the response rate between various AEDs. Ketogenic diet was effective in 2/4 patients. 43% of patients (n = 9) did not show any seizure relief. Even though Epilepsy is a significant clinical issue in ATP1A3 patients, only a minority of publications provide any information about patients’ anti-epileptic treatment. The findings of treatment effectiveness in only 57% (or lower) of patients, and the non-existence of a clear first-line AED in ATP1A3 related epilepsy stresses the need for further research.     

Alternating hemiplegia of childhood and a pathogenic variant of ATP1A3: a case report and pathophysiological considerations

We describe a case of a child suffering from alternating hemiplegia with a heterozygous p. E815K pathogenic variant of ATP1A3. The patient started to present abnormal eye movements in the first days of life, followed by the appearance at 2 months of dystonic episodes, and later on, by recurrent episodes of alternating hemiplegia more often on the right side. A severe epilepsy started at the age of 2 years with episodes of status epilepticus since the onset which frequently recurred, requiring admission to the intensive care unit. MRI showed bilateral mesial temporal sclerosis and a left‐sided ischaemic lesion. Interictal EEG showed bilateral abnormalities, whereas postictal EEG after status epilepticus showed overt slowing on the left side, suggesting a predominant involvement of ictal activity of the left hemisphere. We hypothesize that in our patient, the left hemisphere might have been more prominently affected by the pathogenetic abnormalities underlying alternating hemiplegia of childhood, rendering it more prone to early ischaemic lesions and recurrent unilateral status epilepticus. We speculate whether alternating hemiplegia of childhood shares some common pathophysiological mechanisms with familial hemiplegic migraine that may be associated with a pathogenic variant of ATP1A2.     

Benign nocturnal alternating hemiplegia of childhood: Two cases with positive evolution

Benign nocturnal alternating hemiplegia (BNAH) of childhood is distinct from the classic form of malignant alternating hemiplegia of childhood [1]. It is characterized by hemiplegic attacks occurring exclusively during sleep [2]. It can be misdiagnosed as migraine, nocturnal frontal lobe epilepsy, benign rolandic epilepsy, Panayiotopoulos syndrome, or sleep-related movement disorder [1], [2], [3] and [4]. Only nine patients have been described to date, with typically, a normal development [1], [5], [6] and [7]. In order to insist about the benignity of the affection, we report two cases: a new three-year-old boy suffering from BNAH and a patient already published to show positive evolution at fourteen years of age. BNAH is a rare disorder but may be underdiagnosed. Making an early diagnosis can help to describe to the parents the good prognosis without treatment.     

Focal dystonia in a case of SYNE1 spastic-ataxia: Expanding the phenotypic spectrum

Synaptic nuclear envelope protein-1 (SYNE1) related cerebellar ataxia also called ARCA1 or SCAR8, manifests as a relatively pure cerebellar ataxia or with additional neurological involvement. Dystonia is rarely seen in SYNE1 ataxia and to the best of our knowledge, there are only three reports of dystonia in patients with SYNE1 ataxia. This report describes a 22-year-old woman with chronic progressive spastic-ataxia of 3-year duration with additional focal dystonia of the right upper limb. Patient had cerebellar atrophy on MRI brain and a novel pathogenic homozygous variant in exon 74 of the SYNE1 gene (p.Gln4047Ter).     

Epileptic encephalopathy with features of rapid‐onset dystonia Parkinsonism and alternating hemiplegia of childhood: a novel combination phenotype associated with ATP1A3 mutation

Mutations in ATP1A3 have been found to cause rapid‐onset dystonia Parkinsonism, alternating hemiplegia of childhood, epileptic encephalopathy and other syndromes. We report a four‐year, nine‐month‐old boy with episodes of frequent and recurrent status epilepticus, who first began having generalized tonic‐clonic seizures at four months of age. Development was normal until the age of four months, and markedly slowed down after the onset of seizures. Between the age of seven months and two and a half years, the patient had recurrent attacks of unilateral and bilateral hemiplegia. At the age of 21 months, after a febrile illness with status epilepticus, he regressed and developed continuous severe dystonia and bradykinesia with superimposed intermittent painful dystonic spasms. Extensive neurological and genetic workup revealed a de novo p.V589F ATP1A3 mutation (NM_152296.5:c.1765G>T, NC_000019.9:g.42482344C>A). This is a novel mutation associated with a novel phenotype that shares features with epileptic encephalopathy, alternating hemiplegia of childhood, and rapid‐onset dystonia Parkinsonism.     

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.     

Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature

SCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Polymicrogyria, a disorder of progenitor cells proliferation and migration, is an unanticipated finding for an ion channel dysfunction.     

Hemidystonia with polymicrogyria is part of ATP1A3-related disorders

IntroductionPathogenic variants in ATP1A3 cause various phenotypes of neurological disorders, including alternating hemiplegia of childhood 2, CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and rapid-onset dystonia-parkinsonism (RDP). Early developmental and epileptic encephalopathy has also been reported. Polymicrogyria has recently been added to the phenotypic spectrum of ATP1A3-related disorders.Case report.We report here a male patient with early developmental delay who at 12 months presented dystonia of the right arm which evolved into hemidystonia at the age of 2. A cerebral MRI showed bilateral perisylvian polymicrogyria with intact basal ganglia. Whole-exome and whole-genome sequencing analyses identified a de novo new ATP1A3 missense variant (p.Arg914Lys) predicted pathogenic. Hemidystonia was thought not to be due to polymicrogyria, but rather a consequence of this variant.ConclusionThis case expands the phenotypic spectrum of ATP1A3-related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition.     

Startle Epilepsy with Infantile Hemiplegia: Report of Two Cases Improved by Surgery

Summary: Purpose : To study the effectiveness of surgical therapy on 2 patients with startle epilepsy with infantile brain damage (SEIBD), a rare but distinctive epileptic syndrome characterized by motor seizures resistant to antiepileptic drugs (AEDs).
Methods: The patients with SEIBD both had hemiplegia, due to gross contralateral hemispheric lesions, and suffered from tonic postural seizures, frequently provoked by sudden unexpected somatosensory stimuli on the paretic side of the body. These attacks occasionally caused the patients to drop to the floor, and mild-to-moderate injuries had been sustained; they were resistant to all currently available AEDs. Consequently, these daily drop attacks severely restricted the patients' social lives and school participation. Both patients underwent corpus callosotomy and resection of epileptogenic premotor and supplementary motor lesions. One patient also underwent additional multiple subpial transections of the primary sensorimotor area.
Results: Seizures, as well as quality of life, improved dramatically in both patients after surgery.
Conclusions: Startle epilepsy with infantile hemiplegia is distinct epileptic syndrome characterized by structural brain damage restricted primarily to one hemisphere, large ipsilateral epileptogenic lesions involving the perisensorimotor area, refractory startle-provoked drop attacks, and a good response to epilepsy surgery.