Autosomal Dominant Locus Research Articles

Insights into the pathophysiology of DFNA44 hearing loss associated with CCDC50 frameshift variants.

Non-syndromic sensorineural hearing loss (SNHL) is the most common sensory disorder, and it presents a high genetic heterogeneity. As part of our clinical genetic studies, we ascertained a novel mutation in CCDC50 (c.828_858del, p.(Asp276Glufs*40)) segregating with the hearing impairment in a Spanish family with autosomal dominant DFNA44 SNHL that is predicted to disrupt the protein function. To gain insight into the mechanism behind DFNA44 mutations, we analysed two Ccdc50 presumed loss-of-function mouse mutants which showed normal hearing thresholds up to 6 months old, thus indicating that haploinsufficiency is unlikely to be the pathogenic mechanism. We then carried out in vitro studies on a set of artificial mutants and on the p.(Asp276Glufs*40) and p.(Phe292Hisfs*37) human mutations, and determined that only the mutants containing the six amino acid sequence CLENGL as part of their aberrant protein tail showed an abnormal distribution consisting of perinuclear aggregates of the CCDC50-encoded protein Ymer. Therefore, we conclude that the CLENGL sequence is necessary to form the aggregates. Taken together the in vivo and in vitro results obtained in this study suggest that the two Spanish mutations in CCDC50 exert their effect through a dominant-negative or gain of function mechanism rather than by haploinsufficiency.

A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

Genetic analysis of Bphse and Shs, novel loci controlling hypersensitivity to histamine in mice

Abstract Histamine (HA) is a biogenic amine produced by mast cells and basophils that regulates many physiological processes including acute and chronic inflammation, immune regulation, and immediate hypersensitivity reactions. Previously, we mapped Bphs, the autosomal dominant locus in mice controlling hypersensitivity to HA following exposure to either Bordetella pertussis or pertussis toxin (PTX) to chromosome 6 (Chr6). Positional candidate gene cloning identified Bphs as HA H1 receptor (Hrh1/H1R). The Bphs-susceptible H1R allele possesses the Pro263, Val312 and Pro330 haplotype while the Bphs-resistant H1R allele have the Leu263, Met312 and Ser330 haplotype. Unexpectedly, when we tested a panel of inbred wild-derived strains for Bphs, we discovered strains e.g. MOLF/EiJ, that are phenotypically Bphs-susceptible despite carrying the resistant H1R allele. Phylogenetically, these strains are confined to a unique branch of wild-derived strains. This supports the existence of an evolutionary selected mechanism capable of complementing Hrh1resistance. Linkage analysis mapped the locus to Chr6, in linkage disequilibrium (LD) with Hrh1. We have designated this locus Bphs-enhancer (Bphse). Additionally, we identified a second Hrh1-linked gene in aged and CFA immunized SJL/J mice controlling HA hypersensitivity in the absence of Bordetella pertussis/PTX-sensitization. We have designated this spontaneous histamine sensitivity (Shs/Shs). Taken together, these data support the existence of a LD domain harboring multiple genes that control hypersensitivity to HA. The identification of the genes underlying both Bphse and Shs has the potential to significantly extend our understanding of the genetic control of HA signaling.

Genomic analysis in patients with myxomatous mitral valve prolapse: current state of knowledge

BackgroundMyxomatous mitral valve prolapse is a common cardiac abnormality. Morbus Barlow is characterized by excess myxomatous leaflet tissue, bileaflet prolapse or billowing, chordae elongation and annular dilatation with or without calcification. Extensive myxoid degeneration with destruction of the normal three-layered leaflet tissue architecture is observed histologically in such patients. Autosomal dominant inheritance with an age and sex-dependent expression has long been recognised. This review explores the current understanding of the genetics of bileaflet prolapse, with a focus on genetic analysis and the role for echocardiographical screening of the first degree relatives of affected patients.MethodsSystematic literature searches were performed using PubMed and Embase up to September 2017. In Disse et al.’s study (study one) first degree relatives of 25 patients with Morbus Barlow who underwent mitral valve repair were screened for bileaflet valve prolapse. In Nesta et al.’s study one family with three living generations of 43 individuals with 9 confirmed cases of MVP was screened. Genotyping was performed in four families for 344 microsatellite markers from Chromosome 1 to 16.ResultsIn study one, autosomal dominant inheritance was shown in four pedigrees. Genome-wide linkage analysis of the most informative pedigree (24 individuals, three generations) showed a significant linkage for markers mapping to chromosome 16p. Linkage to this locus was confirmed in a second family within the same study, but was excluded in the remaining two pedigrees. In study two an autosomal dominant locus was mapped to chromosome 13. 8 of the 9 individuals affected were found to suffer from bileaflet prolapse.ConclusionsBarlow’s disease is a heritable trait but the genetic causes remain largely elusive. Ch16p11.2-p12.1 is the only locus proven to be associated with bileaflet prolapse. Locus 13.q31.3-q32.1 was shown to cause bileaflet as well as posterior leaflet prolapse. This review intends to make physicians aware of genetic causes of myxomatous mitral valve prolapse, thereby emphasising the importance of cardiological examination of first-degree relatives of patients with Morbus Barlow. Integrated and more comprehensive studies are needed for identification of genes involved in this heterogenic disease. Further genomic studies may facilitate more individualised and accurate risk assessment and may help to develop possible preventive stategies for patients in the future.

Investigation of Genetic Aetiology in Neurodegenerative Ataxias: Recommendations from the Group of Neurogenetics of Centro Hospitalar São João, Portugal

In recent decades, a long and increasing list of monogenic neurodegenerative ataxias has been identified, allowing for better characterization of the pathophysiology, phenotype and prognosis of this heterogeneous group of disorders, while also revealing potential new therapeutic targets. However, the heterogeneity and complexity of the genotype-phenotype relationships and the high costs of molecular genetics often make it difficult for clinicians to decide on a molecular investigation based on an unbiased rational plan. Clinical history is essential to guide the diagnostic workup, but often the phenotype does not hold enough specificity to allow for predicting the genotype. The Group of Neurogenetics of the Centro Hospitalar São João, a multidisciplinary team of neurologists and geneticists with special interest in neurogenetic disorders, devised consensus recommendations for the investigation of the genetic aetiology of neurodegenerative ataxias in clinical practice, based on international consensus documents (currently containing potentially outdated information) and published scientific evidence on this topic. At the time these recommendations were written, there were around 10 well described autosomal recessive loci and more than 27 autosomal dominant loci for neurodegenerative ataxias. This document covers, in a pragmatic way, the rational process used for the genetic diagnosis of neurodegenerative ataxias, with specific recommendations for the various groups of these heterogeneous diseases, per the Portuguese reality.

Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3

Aim: Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy. Methods: A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis. Results: All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected. Conclusion: We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56.

Sequence analysis of the Ras-MAPK pathway genes SOS1, EGFR & GRB2 in silver foxes (Vulpes vulpes): candidate genes for hereditary hyperplastic gingivitis.

Hereditary hyperplastic gingivitis (HHG) is an autosomal recessive disease that presents with progressive gingival proliferation in farmed silver foxes. Hereditary gingival fibromatosis (HGF) is an analogous condition in humans that is genetically heterogeneous with several known autosomal dominant loci. For one locus the causative mutation is in the Son of sevenless homologue 1 (SOS1) gene. For the remaining loci, the molecular mechanisms are unknown but Ras pathway involvement is suspected. Here we compare sequences for the SOS1 gene, and two adjacent genes in the Ras pathway, growth receptor bound protein 2 (GRB2) and epidermal growth factor receptor (EGFR), between HHG-affected and unaffected foxes. We conclude that the known HGF causative mutation does not cause HHG in foxes, nor do the coding regions or intron-exon boundaries of these three genes contain any candidate mutations for fox gum disease. Patterns of molecular evolution among foxes and other mammals reflect high conservation and strong functional constraints for SOS1 and GRB2 but reveal a lineage-specific pattern of variability in EGFR consistent with mutational rate differences, relaxed functional constraints, and possibly positive selection.

A splice variant in KRT71 is associated with curly coat phenotype of Selkirk Rex cats.

One of the salient features of the domestic cat is the aesthetics of its fur. The Selkirk Rex breed is defined by an autosomal dominant woolly rexoid hair (ADWH) abnormality that is characterized by tightly curled hair shafts. A genome-wide case – control association study was conducted using 9 curly coated Selkirk Rex and 29 controls, including straight-coated Selkirk Rex, British Shorthair and Persian, to localize the Selkirk autosomal dominant rexoid locus (SADRE). Although the control cats were from different breed lineages, they share recent breeding histories and were validated as controls by Bayesian clustering, multi-dimensional scaling and genomic inflation. A significant association was found on cat chromosome B4 (Praw = 2.87 × 10−11), and a unique haplotype spanning ~600 Kb was found in all the curly coated cats. Direct sequencing of four candidate genes revealed a splice site variant within the KRT71 gene associated with the hair abnormality in Selkirk Rex.

Whole exome sequencing identified a novel zinc-finger gene ZNF141 associated with autosomal recessive postaxial polydactyly type A

BackgroundPostaxial polydactyly (PAP) type A is characterised by well-formed functionally developed 5th digit duplication in hands and/or feet. It is genetically heterogeneous condition, inherited both in autosomal recessive and dominant...

A Commentary on Identification of an autosomal dominant locus for intracranial aneurysm through a model-based family collection in a geographically limited area

A Commentary on Identification of an autosomal dominant locus for intracranial aneurysm through a model-based family collection in a geographically limited area

Identification of an autosomal dominant locus for intracranial aneurysm through a model-based family collection in a geographically limited area

Intracranial aneurysm (IA) is characterized by an abnormal bulging of one of the arteries in the brain and is heavily affected by genetic factors. Although IA is a very serious disease because of its severity and prevalence in the general public, the gene causing IA has not yet been identified due mainly to the lack of definitive genetic loci for the disease. Following a model-based family collection that recruited families from a geographically limited area that inherited IA as an autosomal dominant trait, we conducted a genome-wide linkage analysis. Significant evidence of linkage to IA was found on chromosome 8p22.2 with a maximum two-point logarithm of the odds ratio score of 3.61 under an autosomal dominant model of inheritance. The methods described in this study could be applied to localize disease-causing genes of other complex diseases through either a genome-wide linkage analysis or a genome-wide association study.

A high-penetrance form of late-onset torsion dystonia maps to a novel locus (DYT21) on chromosome 2q14.3-q21.3

The primary dystonias are a genetically heterogeneous group of disorders that can be subdivided in pure dystonias, dystonia-plus syndromes, and paroxymal dystonia. Four pure autosomal dominant dystonia loci have been mapped to date, DYT1, 6, 7, and 13, with varying penetrance. We report the mapping of a novel locus for a late-onset form of pure torsion dystonia in a family from northern Sweden. The disease is inherited in an autosomal dominant manner with a penetrance that may be as high as 90%. The torsion dystonia locus in this family was mapped to chromosome 2q14.3-q21.3 using an Illumina linkage panel. We also confirmed the linkage, using ten tightly linked microsatellite markers in the region, giving a maximum LOD score of 5.59 for marker D2S1260. The disease-critical region is 3.6-8.9 Mb depending on the disease status of one individual carrying a centromeric recombination. Mutational analysis was performed on 22 genes in the disease-critical region, including all known and hypothetical genes in the smaller, 3.6-Mb region, but no disease-specific mutations were identified. Copy number variation analysis of the region did not reveal any deletions or duplications. In order to increase the chances of finding the disease gene, fine-mapping may be necessary to decrease the region of interest. This report will hopefully result in the identification of additional dystonia families with linkage to the same locus, and thereby, refinement of the disease critical region.

A novel mutation of RPGR gene in an X-Linked Chinese family with retinitis pigmentosa

Purpose To localize and identify the gene and mutations causing an X-linked Chinese family with retinitis pigmentosa. Methods An XLRP Chinese family was ascertained and patients underwent ophthalmological examinations. Blood samples were collected and genomic DNA was extracted. Linkage scan was performed on genomic DNA from affected and unaffected family members using microsatellite markers flanking 17 known autosomal dominant loci and markers covering the entire X chromosome. Mutation screening of RPGR gene was carried out by direct DNA sequence analysis. Results A genome wide scan yielded a lod score of 2.7 at θ = 0 with DXS1068 and 3.29 at θ = 0 with DXS993. This region harbors the RPGR gene. Direct DNA sequence analysis reveals one base pair deletion, gORF15 + 556delA, in all affected individuals. The deletion results in the frameshift change of RPGR gene and produces a truncated protein. Conclusions We identified a novel mutation, gORF15 + 556delA (p.Lys184fs), in a Han Chinese family with retinitis pigmentosa. This mutation expands the mutation spectrum of RPGR and helps to study molecular pathogenesis of RP further.

Involvement of T-cell receptor-β alterations in the development of otosclerosis linked to OTSC2

Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-beta (TCR-beta) mRNA expression and percentage of blood circulating TCR-alphabeta(+) T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28(null) cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.

CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome

<i>CHN1</i> mutations are not a common cause of sporadic Duane's retraction syndrome

Mapping of a new locus for congenital anomalies of the kidney and urinary tract on chromosome 8q24

Congenital anomalies of the kidney and urinary tract (CAKUT) account for the majority of end-stage renal disease in children (50%). Previous studies have mapped autosomal dominant loci for CAKUT. We here report a genome-wide search for linkage in a large pedigree of Somalian descent containing eight affected individuals with a non-syndromic form of CAKUT. Clinical data and blood samples were obtained from a Somalian family with eight individuals with CAKUT including high-grade vesicoureteral reflux and unilateral renal agenesis. Total genome search for linkage was performed using a 50K SNP Affymetric DNA microarray. As neither parent is affected, the results of the SNP array were analysed under recessive models of inheritance, with and without the assumption of consanguinity. Using the non-consanguineous recessive model, a new gene locus (CAKUT1) for CAKUT was mapped to chromosome 8q24 with a significant maximum parametric Logarithm of the ODDs (LOD) score (LOD(max)) of 4.2. Recombinations were observed in two patients defining a critical genetic interval of 2.5 Mb physical distance flanked by markers SNP_A-1740062 and SNP_A-1653225. We have thus identified a new non-syndromic recessive gene locus for CAKUT (CAKUT1) on chromosome 8q24. The identification of the disease-causing gene will provide further insights into the pathogenesis of urinary tract malformations and mechanisms of renal development.

Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease

To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 x 10(-12)) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 x 10(-9)). We also detected strong associations at SNCA on 4q22 (P = 7.35 x 10(-17)) and LRRK2 on 12q12 (P = 2.72 x 10(-8)), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

A novel autosomal dominant deafness locus (DFNA58) maps to 2p12‐p21

Clinical GeneticsVolume 75, Issue 5 p. 490-493 A novel autosomal dominant deafness locus (DFNA58) maps to 2p12-p21 K Lezirovitz, Corresponding Author K Lezirovitz Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilKarina Lezirovitz, PhDDepartamento de Genética e Biologia EvolutivaInstituto de BiociênciasUniversidade de São PauloRua do Matão, 277 sala 349, CEP 05508-090C.P. 11461, 05422-970, São Paulo, SPBrazilTel./fax: 55-11-3091-7478e-mail: littlefelis@rocketmail.comSearch for more papers by this authorMCC Braga, MCC Braga Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorRS Thiele-Aguiar, RS Thiele-Aguiar Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorMTBM Auricchio, MTBM Auricchio Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorPL Pearson, PL Pearson Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorPA Otto, PA Otto Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorRC Mingroni-Netto, RC Mingroni-Netto Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this author K Lezirovitz, Corresponding Author K Lezirovitz Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilKarina Lezirovitz, PhDDepartamento de Genética e Biologia EvolutivaInstituto de BiociênciasUniversidade de São PauloRua do Matão, 277 sala 349, CEP 05508-090C.P. 11461, 05422-970, São Paulo, SPBrazilTel./fax: 55-11-3091-7478e-mail: littlefelis@rocketmail.comSearch for more papers by this authorMCC Braga, MCC Braga Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorRS Thiele-Aguiar, RS Thiele-Aguiar Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorMTBM Auricchio, MTBM Auricchio Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorPL Pearson, PL Pearson Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorPA Otto, PA Otto Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this authorRC Mingroni-Netto, RC Mingroni-Netto Centro de Estudos do Genoma Humano, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, BrazilSearch for more papers by this author First published: 28 April 2009 https://doi.org/10.1111/j.1399-0004.2008.01130.xCitations: 9Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume75, Issue5May 2009Pages 490-493 RelatedInformation

Autosomal‐dominant locus for restless legs syndrome in French‐Canadians on chromosome 16p12.1

We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.

Les dyskinésies paroxystiques kinésigéniques : une « canalopathie » ? Étude de 19 cas

Introduction Paroxysmal kinesigenic dyskinesia (PKD) is characterized by brief episodes of dystonia and choreoathetosis triggered by sudden voluntary movements. Disease onset is seen in the first or second decade. The attacks typically last less than one minute. Three autosomal dominant PKD loci are identified: EKD1, EKD2 and EKD3. EKD1 has an overlap with the locus of the “Infantile Convulsion and Choreoathetosis (ICCA) syndrome”. The favorable natural history, the episodic nature of the symptoms and their sensitivity to anticonvulsant therapy suggest channelopathy as a mechanism of PKD. Patients and methods We reviewed the clinical features, the family history, the treatment response, the evolution and the technical investigations in 19 affected individuals. Results All cases were idiopathic. Ten patients had a positive familial history. Three patients suffered from ICCA syndrome. Some atypical features were seen, such as the association of kinesigenic and nonkinesigenic attacks and the presence of migraine, ataxia, seizures and myoclonus. Acetazolamide responsiveness was seen in two patients. Conclusion The coexistence of PKD and nonkinesigenic dyskinesia in several patients confirms the earlier described presence of intermediary forms, nonrepresented in the current classification of paroxysmal dyskinesias. Our study results suggest channel dysfunction and basal ganglia involvement in the pathophysiology of PKD.