Biallelic XPR1 mutation associated with primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia with infantile convulsions

BackgroundMutations in the XPR1 gene are associated with primary familial brain calcifications (PFBC). All reported mutations are missense and inherited as an autosomal dominant trait. PFBC patients exhibited movement disorders, neuropsychiatric symptoms, and other associated symptoms with diverse severity, even within the same family.Materials and methodsWe identified and enrolled a patient with PFBC. Clinical data were comprehensively collected, including the age of onset, seizure types and frequency, trigger factors of paroxysmal dyskinesia, response to drugs, and general and neurological examination results. Whole-exome sequencing (WES) was performed to detect pathogenic variants. We further systematically reviewed the phenotypic and genetic features of patients with XPR1 mutations.ResultsThe patient showed bilateral calcification involving basal ganglia and cerebellar dentate. Clinically, he presented as paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) with favorable outcome. We identified a compound heterozygous XPR1 mutation (c.786_789delTAGA/p.D262Efs*6, c.1342C>T/p.R448W), which were inherited from unaffected parents respectively. Further literature review shows a wide range of clinical manifestations of patients with XPR1 mutations, with movement disorders being the most common.ConclusionsThis is the first report of biallelic mutations in XPR1. The findings suggest for the first time a possible link between PKD/IC and XPR1 mutations.     

Early-onset absence epilepsy and paroxysmal dyskinesia

PURPOSE: To report on the association of childhood absence epilepsy and paroxysmal dyskinesia (PD). METHODS: We describe six patients aged 6 to 27 years (mean, 14 years) who were identified in five centers participating in a European study group. Patients had been followed up clinically from the first symptoms and had been studied with video-EEG recordings of absence seizures, videotaping of dyskinetic attacks, and brain magnetic resonance imaging (MRI). RESULTS: Four patients were sporadic, and two were siblings. Age at onset of absence seizures was unusually early (range, 3 months to 3 years 6 months; mean, 16 months), with four children having their first episodes within the first year of life, and the remaining two by age 3 years 6 months. Resistance to multiple appropriate drugs was seen in five children, in four of whom absences improved remarkably when ethosuximide was added. Absences remitted between age 8 and 13 years in the three patients in whom follow-up was long enough. Different types of PD were seen including paroxysmal kinesigenic dyskinesia (one patient), paroxysmal exercise-induced dystonia (three patients), and paroxysmal tonic upgaze (two siblings). In most patients, PD appeared at a later age than, co-occurred with, and outlasted absence seizures. Only in the two siblings with tonic upgaze, dyskinetic attacks had an earlier onset. PD improved with increasing age and did not usually produce severe disability. CONCLUSIONS: There is a widening spectrum of epilepsy and PD syndromes, within which epilepsy has the characteristics of the common idiopathic syndromes, with some atypical features.     

Phenotypic overlap among paroxysmal dyskinesia subtypes: Lesson from a family with PRRT2 gene mutation

Paroxysmal dyskinesia (PD) is a group of rare neurological conditions which was divided into paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exercise-induced dyskinesia (PED) according to their clinical features. PRRT2 gene was initially identified as the major gene responsible for PKD followed by presence of various PRRT2 mutations discovered in families with benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathetosis (ICCA). We describe a family with characteristic PD showing overlaps in clinical pictures among the three PD subgroups, and a nonsense PRRT2 mutation c.649C > T (p.Arg217X) was also detected. This broadens the phenotypic spectrum in PRRT2-related disorders. In addition, an unusual exercise trigger observed in the proband, likely representing an underestimated occurrence, together with the current clinical PD classification is also elucidated.     

A BFIS-like syndrome with late onset and febrile seizures: suggestive linkage to chromosome 16p11.2-16q12.1

Benign familial infantile seizures (BFIS) is a dominant idiopathic epilepsy with partial and secondarily generalized seizures with age of onsetr between 3 and 12 months. Here we describe a four-generation family with some characteristic features of BFIS but with unusual clinical signs, in eight affected members with an unusual clinical phenotype. Onset was consistently between 14 and 20 months of age with clusters of complex-partial or generalized tonic-clonic seizures and a high rate of febrile seizures, which have not been described for BFIS previously. All affected members showed multifocal interictal epileptiform discharges in the EEG. The known loci for benign familial neonatal/infantile seizures (BFNS/BFNIS), generalized epilepsy with febrile seizures plus (GEFS+) and the BFIS locus on chromosome 19q were excluded. Further genetic analysis showed suggestive linkage to the major BFIS locus on chromosome 16 between markers D16S690 and D16S3136. This ;;BFIS-like' syndrome may enlarge the phenotypic spectrum of diseases linked to the chromosome 16 region.     

A heterozygous deletion of PDGFB gene causes paroxysmal kinesigenic dyskinesia with primary familial brain calcification

BackgroundPrimary familial brain calcification (PFBC) is a neurodegenerative disease characterized with calcium deposition in multiple brain regions. Mutations in PDGFB have been discovered in sporadic and familial PFBC cases. While several known variants displayed loss-of function, no complete deletion of platelet-derived growth factor B (PDGFB) has been reported.MethodsFor the diagnostic purpose, brain computerized tomography or magnetic resonance imaging scanning and whole-genome sequencing were performed on the proband and family members in the pedigree.ResultsWe identified a heterozygous PDGFB complete deletion in a Chinese pedigree. The proband presented with paroxysmal kinesigenic dyskinesia (PKD), a rare symptom in PFBC. The proband's mother carrying the same mutation was asymptomatic.ConclusionsFor the first time, we reported a PFBC with a heterozygous deletion of PDGFB, and provided evidence of haploinsufficiency in the pathogenesis of PFBC.     

Linkage analysis and disease models in benign familial infantile seizures: a study of 16 families

PURPOSE: Benign familial infantile seizures (BFIS) is a genetically heterogeneous condition characterized by partial seizures, onset age from 3 to 9 months, and favorable outcome. BFIS loci were identified on chromosomes 19q12-13.1 and 16p12-q12, allelic to infantile convulsions and choreathetosis. The identification of SCN2A mutations in families with only infantile seizures indicated that BFNIS and BFIS may show overlapping clinical features. Infantile seizures also were in a family with familial hemiplegic migraine and mutations in the ATP1A2 gene. We have examined the heterogeneous genetics of BFIS by means of linkage analysis. METHODS: Sixteen families were examined. Probands underwent neurologic examination, at least one EEG recording, and, when possible, brain CT and MRI. Clinical information about relatives was collected. Families with SCN2A or ATP1A2 mutations were excluded from the study. Chromosome 16p and 19q loci were examined by linkage analysis using two models that differed in penetrance rate. Genetic heterogeneity was evaluated with both models. RESULTS: Clinical information was available for 124 members of affected families. BFIS was diagnosed in 69 subjects. One patient without BFIS had a single febrile seizure, and another had rare episodes of paroxysmal dystonia. Evidence of linkage was obtained only for chromosome 16. Moreover, the high penetrance allowed the identification of genetic heterogeneity. CONCLUSIONS: Our data confirm the relevance of the chromosome 16 locus in BFIS and suggest the presence of an additional locus. This study shows that the genetic model used affects the outcome of linkage analysis.     

中国发作性运动诱发性运动障碍诊治指南

发作性运动诱发性运动障碍(PKD)是发作性运动障碍中最常见的类型,以突然运动诱发短暂的不自主运动为特征。由于相对少见,PKD易被误诊为癫痫或其他发作性疾病。为提高临床医生对该病的认识及规范化诊治,我国PKD诊治领域的专家反复讨论撰写了该指南,并在神经遗传学组会议上反复讨论修改后定稿。内容包括PKD的临床表现、诊断、鉴别诊断、治疗及遗传咨询。     

Benign familial infantile seizures: further delineation of the syndrome

Benign familial infantile seizures are an autosomal dominant epilepsy disorder that is characterized by convulsions, with onset at age 3 to 12 months and a favorable outcome. Benign familial infantile seizures have been linked to chromosome 19q whereas infantile convulsions and choreoathetosis syndrome, in which benign familial infantile seizure is associated with paroxysmal choreoathetosis, has been linked to chromosome 16p 12-q12. Many additional families from diverse ethnic backgrounds have similar syndromes that have been linked to the chromosome 16 infantile convulsions and choreoathetosis syndrome region. Moreover, in one large pedigree with paroxysmal kinesiogenic dyskinesias only, the syndrome has also been linked to the same genomic area. Families with pure benign familial infantile seizures may be linked to chromosome 16 as well. In this study, we present a series of 19 families and 24 otherwise healthy infants with benign familial infantile seizures. Two of these families include members affected with benign familial infantile seizures and paroxysmal choreoathetosis. We included patients with normal neurologic examinations, who started having simple partial seizures, complex partial seizures, or apparently generalized seizures without recognized etiology between 2 months and 2 years of age. Neurologic studies were normal, but in all patients, there was a history of similar seizures and age at onset in either the father or the mother. Twenty-four patients (14 girls and 10 boys) were evaluated at our hospital between February 1990 and February 2001. Age at onset, sex, family history of epilepsy and/or paroxysmal dyskinesias, neurologic examination, semiology, distribution, and frequency and duration of seizures were evaluated. Electroencephalographic (EEG) and neuroradiologic studies were also performed. Seizures began between 3 and 22 months of life, with a median age of 5 1/2 months. Nine patients (37.5%) had only apparently generalized seizures, 5 patients (20.8%) had only partial seizures, and 10 patients had both partial and apparently generalized seizures (41.6%). Seizures were invariably brief, occurred during the waking state (100%), and presented mainly in clusters in 12 patients (50%). Interictal EEG was normal in 23 patients (95.8%). Sixteen patients (66.6%) had a confirmed history of convulsions in family members other than parents. Twenty-two patients became seizure free after 30 months of life. Two brothers in the same family had brief paroxysmal episodes of choreoathetosis in the hemibody triggered by stress while awake at 15 and 17 years old, respectively. One of them had paroxysmal choreoathetosis only, and the other was associated with benign familial infantile seizures. One father had brief spontaneous episodes of paroxysmal choreoathetosis when awake at age 18 years. All of them had a good response to antiepilepsy drugs, and neurologic examination and EEG and neuroradiologic studies were normal. Benign familial infantile seizure is a genetic epilepsy syndrome with autosomal dominant inheritance. It may be associated with paroxysmal choreoathetosis (infantile convulsions and choreoathetosis syndrome), which has been linked to the chromosome 16 infantile convulsions and choreoathetosis syndrome region. Patients in families with infantile convulsions and choreoathetosis syndrome could display either benign familial infantile seizures or paroxysmal choreoathetosis or both. It is likely that the disease in families with pure benign familial infantile seizures may be linked to the infantile convulsions and choreoathetosis region as well. We cannot exclude the possibility that the youngest patients may develop choreoathetosis or other dyskinesias later in life.     

Benign familial infantile convulsions: linkage to chromosome 16p12-q12 in 14 families

PURPOSE: Benign familial infantile convulsions (BFIC) is a form of idiopathic epilepsy. It is characterized by clusters of afebrile seizures occurring around the sixth month of life. The disease has a benign course with a normal development and rare seizures in adulthood. Previous linkage analyses defined three susceptibility loci on chromosomes 19q12-q13.11, 16p12-q12, and 2q23-31. However, a responsible gene has not been identified. We studied linkage in 16 further BFIC families. METHODS: We collected 16 BFIC families, without an additional paroxysmal movement disorder, of German, Turkish, or Japanese origin with two to eight affected individuals. Standard two-point linkage analysis was performed. RESULTS: The clinical picture included a large variety of seizure semiologies ranging from paleness and cyanosis with altered consciousness to generalized tonic-clonic seizures. Interictal EEGs showed focal epileptiform discharges in six patients, and three ictal EEGs in three distinct patients revealed a focal seizure onset in different brain regions. In all analyzed families, we found no evidence for linkage to the BFIC loci on chromosomes 19q and 2q, as well as to the known loci for benign familial neonatal convulsions on chromosomes 8q and 20q. In 14 of the families, the chromosome 16 locus could be confirmed with a cumulative maximum two-point lod score of 6.1 at marker D16S411, and the known region for BFIC could be narrowed to 22.5 Mbp between markers D16S690 and D16S3136. CONCLUSIONS: Our data confirm the importance of the chromosome 16 locus for BFIC and may narrow the relevant interval.     

Clinical and genetic study on a new Chinese family with benign familial infantile seizures

Three loci for benign familial infantile seizures (BFIS, traditionally named benign familial infantile convulsions) have been mapped to the chromosome regions of 19q12–13.1, 2q24, and 16p12-q12. We characterized the clinical features of a newly discovered Chinese family with BFIS and investigated whether it is linked to these loci. A four-generation Chinese family was investigated and nineteen family members were examined. Fourteen microsatellite markers covering the three BFIS loci on the chromosome regions of 19q12–13.1, 2q24, and 16p12-q12 were genotyped. Linkage analysis was performed. The main clinical features of our patients include onset of afebrile seizures between 3 and 10 months, normal psychomotor development, normal interictal electroencephalogram (EEG), and autosomal dominant inheritance. Magnetic resonance imaging (MRI) changes were found in the proband. Two-point LOD scores are <−2.0 at the recombination rate of 0.0 for all the markers on the 2q24 region. Multipoint LOD scores are <−3.0 for the regions of 19q12–13.1 and 16p12–q12. Linkage analysis showed no evidence that the disease gene of this BFIS family is linked to the chromosome regions previously identified as the critical regions of the disease. Another chromosome region harboring the disease gene may exist in the new Chinese family.     

Co-occurrence of infantile epileptic seizures and childhood paroxysmal choreoathetosis in one family: clinical, EEG, and SPECT characterization of episodic events.

The co-occurrence of infantile convulsions and childhood paroxysmal choreoathetosis (ICCA syndrome) has recently been reported in several families. The pattern of familial clustering observed is consistent with a single locus mutation which has been mapped onto the pericentromeric region of chromosome 16. We studied the main clinical, electroencephalogram (EEG), and single photon emission computed tomography (SPECT) characteristics of episodic events in a new family presenting clinical features similar to that described in the ICCA syndrome. In the first year of life, a mother and her two daughters suffered from rare afebrile seizures lasting from 30 seconds to 15 minutes. Ictal EEG recording in one daughter at 7 months of age showed bilateral polyspikes with a posterior predominance. In the three patients, epileptic seizures regressed within a few weeks, and never reoccurred. At the age of 7 and 12 years, respectively, the two daughters presented daily brief (20 seconds to 1 minute) involuntary choreoathetotic episodes. In 10 of these attacks, EEG did not show any epileptiform abnormalities. In both sisters, an ictal SPECT was performed during a choreoathetotic episode. Subtracting the ictal SPECT from the interictal SPECT coregistered to magnetic resonance imaging (MRI) revealed significant modifications in the local cerebral perfusion in the sensorimotor cortex, the supplementary motor areas, and pallidum. Carbamazepine completely suppressed paroxysmal dyskinesias. These observations, together with literature data, suggest that in this syndrome, depending on brain maturation, the same genetic abnormality may result in different paroxysmal neurological symptoms.     

Benign focal seizures of adolescence: a prospective study

PURPOSE: To characterize the clinical and EEG findings and evolution of the syndrome of benign focal seizures of adolescence (BFSA), as described by Loiseau et al. METHODS: A prospective study was performed in adolescents with normal clinical and neurologic examinations and normal neuroradiologic studies who had focal seizures that occurred isolated or in a cluster, with or without secondary generalization in the first 24 to 48 h after onset. None of the patients was treated with antiepileptic drugs (AEDs). RESULTS: Between January 1996 and January 2002, 15 patients with BFSA were enrolled in the study. Median age at onset of BFSA was 14 years. Thirteen patients had focal sensory or motor seizures. In two patients, the ictal manifestation was motion arrest associated with oral automatisms. Eight of them evolved to generalized tonic-clonic seizures. Thirteen patients had seizures only when awake, and the other two, both when awake and during sleep. Repeated interictal EEGs were normal, but in four of the patients who had seizures in a cluster, we were able to record an EEG within 8 h after seizure onset. Two of these four patients had focal seizures, and their waking EEG showed focal centroparietal theta activities. The other two patients had secondarily generalized seizures, and their waking EEG showed bilateral theta activities instead. Prognosis was excellent. CONCLUSIONS: BFSA is a well-defined seizure syndrome, recognizable by clinical and EEG features, as described by Loiseau et al. In teenagers with these electroclinical features with a normal neurologic examination and normal neuroradiologic findings, AEDs should be avoided.     

Familial paroxysmal exercise-induced dyskinesia and benign epilepsy: a clinical and neurophysiological study of an uncommon disorder

We report a family with 6 members affected by a long-lasting paroxysmal exertion-induced dyskinesia. Fasting and stress were precipitating factors. All the patients of this family had also epileptic seizures mainly of generalised type with a favourable outcome. All patients were submitted to a neurophysiological study which included somatosensory evoked potentials by median nerve stimulation (MN-SEPs), somatosensory evoked potentials by posterior tibial nerve stimulation (PTN-SEPs), brainstem auditory evoked potentials (BAEPs), visual evoked potentials (VEPs), motor evoked potentials (MEPs) by magnetic transcranial cortical stimulation (TCS) and electromyography (EMG). The neurophysiological findings suggest a hyperexcitability at the muscular and brain membrane levels, probably due to an ion channel disorder. Received: 2 February 2000 / Accepted in revised form: 16 June 2000     

中国人婴儿惊厥伴发作性手足舞蹈徐动征临床特征分析

目的探讨我国婴儿惊厥伴发作性手足舞蹈徐动征(ICCA)患者的临床特点。方法分析诊断为ICCA的5例患者的临床表现、脑电图(EEG)、影像学和治疗转归的临床资料。ICCA的入选标准为：3～20个月出现良性婴儿惊厥(BFIC)和在儿童后期或青春期出现发作性运动源性运动障碍(PKC)。结果5例ICCA患者来自4个家系,男性4例,女性1例。BFIC发病年龄在8～12个月,PKC发病年龄在5岁以后,影像学未见异常,部分患者EEG有局限性放电和慢波增多。卡马西平、苯妥英、拉莫三嗪治疗有效。其中2例合并继发性癫痫。ICCA家系中其他发作性疾病患者共9例。结论ICCA可能为常染色体显性遗传疾病,我国该病患者同时具有BFIC和PKC的特征性表现和治疗转归特点,家系中可能有PKC和其他类型的癫痫患者,说明PKC与癫痫之间可能存在某些相似的发病机理,此还有待于进一步研究。     

A case of congenital myopathy masquerading as paroxysmal dyskinesia

Gastroesophageal reflux (GER) disease is a significant comorbidity of neuromuscular disorders. It may present as paroxysmal dyskinesia, an entity known as Sandifer syndrome. A 6-week-old neonate presented with very frequent paroxysms of generalized stiffening and opisthotonic posture since day 22 of life. These were initially diagnosed as seizures and he was started on multiple antiepileptics which did not show any response. After a normal video electroencephalogram (VEEG) was documented, possibility of dyskinesia was kept. However, when he did not respond to symptomatic therapy, Sandifer syndrome was thought of and GER scan was done, which revealed severe GER. After his symptoms got reduced to some extent, a detailed clinical examination revealed abnormal facies with flaccid quadriparesis. Muscle biopsy confirmed the diagnosis of a specific congenital myopathy. On antireflux measures, those episodic paroxysms reduced to some extent. Partial response to therapy in GER should prompt search for an underlying secondary etiology.     

PRRT2 mutation in Japanese children with benign infantile epilepsy

Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia.     

Infantile spasms combined with partial seizures: electroclinical study of eleven cases

We studied 11 infants (7 males) with combined infantile spasms (IS) and partial seizures. The age of onset of the spasms ranged from 6 days to 9 months. All of the children had neurological or CT/MRI abnormalities, and five also had a family history of epilepsy. The clinical and polygraphic patterns of the clusters of spasms combined with partial seizures were analysed. Ten infants were followed-up for a mean period of 3 years, 4 months (range 1 year 10 months to 4 years 11 months). At the last check-up, the seizures were controlled in 2 patients; the others continued to have spasms and/or partial seizures. All of the patients developed mild to severe pshychomotor retardation. This condition defines a subgroup of infants presenting with IS, which is distinct from West syndrome.

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Sommario Abbiamo studiato 11 bambini (7 maschi) che avevano spasmi infantili nello stesso episodio critico. L'età all'inizio degli spasmi variava da 6 giorni a 9 mesi. Tutti i bambini presentavano anormalità neurologiche o neuroradiologiche, e 5 avevano anche una familiarità epilettica. Abbiamo analizzato gli aspetti clinici e poligrafici dei cluster di spasmi associati a crisi parziali. Dieci di questi bambini vennero seguiti per un periodo medio di 3 anni e 4 mesi. All'ultima visita, le crisi hanno avuto sucessivamente un ritardo psicomotorio da lieve a grave. Questa condizione definisce un sottogruppo particolare, tra i bambini che presentano spasmi infantili, diverso dalla sindrome di West.