Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy

Huin, Vincent; Strubi-Vuillaume, Isabelle; Dujardin, Kathy; Brion, Marine; Delliaux, Marie; Dellacherie, Delphine; Cuvellier, J.; Cuisset, Jean‐Marie; Riquet, Audrey; Moreau, Caroline; Defebvre, Luc; Sablonnière, Bernard; Devos, David

doi:10.1016/j.parkreldis.2017.09.014

Cited by 23 publications

(49 citation statements)

References 14 publications

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“…Furthermore, paroxysmal disorder, such as epilepsy, was also reported in SCA19/22 patients (Huin et al, ; Smets et al, ). In fact, the phenotypic spectrum of SCA19/22 has been widened to include a wide variety of different movement disorders, such as myoclonus, dystonia, and Parkinsonism (Duarri et al, ; Huin et al, ; Kurihara et al, ). Interestingly, myoclonus and dystonia were also observed in our patients carrying the novel p.C317Y and p.P375S mutations (Table ).…”

Section: Discussionmentioning

confidence: 93%

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Novel SCA19/22‐associated KCND3 mutations disrupt human K _V 4.3 protein biosynthesis and channel gating

Hsiao

Liu

et al. 2019

Human Mutation

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Mutations in the human voltage‐gated K+ channel subunit KV4.3‐encoding KCND3 gene have been associated with the autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22). The precise pathophysiology underlying the dominant inheritance pattern of SCA19/22 remains elusive. Using cerebellar ataxia‐specific targeted next‐generation sequencing technology, we identified two novel KCND3 mutations, c.950 G>A (p.C317Y) and c.1123 C>T (p.P375S) from a cohort with inherited cerebellar ataxias in Taiwan. The patients manifested notable phenotypic heterogeneity that includes cognitive impairment. We employed in vitro heterologous expression systems to inspect the biophysical and biochemical properties of human KV4.3 harboring the two novel mutations, as well as two previously reported but uncharacterized disease‐related mutations, c.1013 T>A (p.V338E) and c.1130 C>T (p.T377M). Electrophysiological analyses revealed that all of these SCA19/22‐associated KV4.3 mutant channels manifested loss‐of‐function phenotypes. Protein chemistry and immunofluorescence analyses further demonstrated that these mutants displayed enhanced protein degradation and defective membrane trafficking. By coexpressing KV4.3 wild‐type with the disease‐related mutants, we provided direct evidence showing that the mutants instigated anomalous protein biosynthesis and channel gating of KV4.3. We propose that the dominant inheritance pattern of SCA19/22 may be explained by the dominant‐negative effects of the mutants on protein biosynthesis and voltage‐dependent gating of KV4.3 wild‐type channel.

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Section: Discussionmentioning

confidence: 93%

“…Another intriguing issue on phenotypic heterogeneity in SCA19/22 concerns the extent of intellectual disability (Huin et al, ; Kurihara et al, ; Paucar et al, ; Smets et al, ). Earlier, a Japanese SCA19/22 patient with the p.T377M mutation was not reported to exhibit significant cognitive impairment (Lee et al, ).…”

Section: Discussionmentioning

confidence: 99%

Novel SCA19/22‐associated KCND3 mutations disrupt human K _V 4.3 protein biosynthesis and channel gating

Hsiao

Liu

et al. 2019

Human Mutation

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“…During periods of exacerbation atypical facial movements, orolingual dyskinesia, and complex stereotypies are also reported. 104 a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors Mutations in GRIA4, which encodes an a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit (GluR4) found on excitatory glutamatergic synapses, cause a spectrum of phenotypes from an early infancy or childhood-onset neurodevelopmental disorder (with or without seizures and a clumsy or stiff gait) to DEE with intractable seizures in the first weeks of life. Moreover, dysautonomic manifestations, such as tachycardia, hyperthermia, hypertension, and diaphoresis, are often described.…”

Section: Infantile-onset Epileptic Encephalopathies Associated With Smentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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“…The SCA19/SCA22 phenotype consists of adult-onset and slowly progressive cerebellar ataxia in most cases, frequent cognitive impairment and variable degree of myoclonus, polyneuropathy, and seizures. Mild Parkinsonism has been reported recently in two unrelated French SCA19 families [ 14 ]. The Thr377Met (T377M) mutation in KCND3 has been described only once in a Japanese patient affected by pure cerebellar ataxia [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19

et al. 2018

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Spinocerebellar ataxia type 19 (SCA19), allelic with spinocerebellar ataxia type 22 (SCA22), is a rare syndrome caused by mutations in the KCND3 gene which encodes the potassium channel Kv4.3. Only 18 SCA19/22 families and sporadic cases of different ethnic backgrounds have been previously reported. As in other SCAs, the SCA19/22 phenotype is variable and usually consists of adult-onset slowly progressive ataxia and cognitive impairment; myoclonus and seizures; mild Parkinsonism occurs in some cases. Here we describe a Swedish SCA19/22 family spanning five generations and harboring the T377M mutation in KCND3. For the first time for this disease, 18F-fluorodeoxyglucose PET was assessed revealing widespread brain hypometabolism. In addition, we identified white matter abnormalities and found unusual features for SCA19/22 including early age of onset and fast rate of progression in the late course of disease in the oldest patient of this family.Electronic supplementary materialThe online version of this article (10.1007/s12311-018-0927-4) contains supplementary material, which is available to authorized users.

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Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy

Abstract: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.

Cited by 23 publications

References 14 publications

Novel SCA19/22‐associated KCND3 mutations disrupt human K _V 4.3 protein biosynthesis and channel gating

Novel SCA19/22‐associated KCND3 mutations disrupt human K _V 4.3 protein biosynthesis and channel gating

The expanding spectrum of movement disorders in genetic epilepsies

Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19

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Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy

Abstract: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.

Cited by 23 publications

References 14 publications

Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating

Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating

The expanding spectrum of movement disorders in genetic epilepsies

Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19

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Novel SCA19/22‐associated KCND3 mutations disrupt human K _V 4.3 protein biosynthesis and channel gating

Novel SCA19/22‐associated KCND3 mutations disrupt human K _V 4.3 protein biosynthesis and channel gating