Paroxysmal Dyskinesia in Children: from Genes to the Clinic
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background and Purpose Paroxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children. Methods Fifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records. Results Forty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups. Conclusions This study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.
Abstract
Background and Purpose Paroxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children. Methods Fifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records. Results Forty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups. Conclusions This study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.
참고문헌 (28)
- Demirkiran M, "Paroxysmal dyskinesias: clinical features and classification", Ann Neurol, 38, pp.571~579 (1995)
- Lance JW, "Familial paroxysmal dystonic choreoathetosis and its differentiation from related syndromes", Ann Neurol, 2, pp.285~293 (1977)
- Montagna P, "Nocturnal paroxysmal dystonia and nocturnal wandering", Neurology, 42(7 Suppl 6), pp.61~67 (1992)
- Bhatia KP, "Paroxysmal dyskinesias", Mov Disord, 26, pp.1157~1165 (2011)
- Tsao CY, "Effective treatment with oxcarbazepine in paroxysmal ki-nesigenic choreoathetosis", J Child Neurol, 19, pp.300~301 (2004)
- Bruno MK, "Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria", Neurology, 63, pp.2280~2287 (2004)
- Ono S, "Mutations in PRRT2 responsible for paroxysmal kinesigenic dyskinesias also cause benign familial infantile convulsions", J Hum Genet, 57, pp.338~341 (2012)
- Liu Q, "Mutations in PRRT2 result in paroxysmal dyskinesias with marked variability in clinical expression", J Med Genet, 49, pp.79~82 (2012)
- Dale RC, "Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine", Dev Med Child Neurol, 54, pp.958~960 (2012)
- Gardiner AR, "PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine", Neurology, 79, pp.2115~2121 (2012)
- Neville BG, "Exercise induced steroid dependent dystonia, ataxia, and alternating hemiplegia associated with epilepsy", J Neurol Neurosurg Psychiatry, 65, pp.241~244 (1998)
- Guerrini R, "Autosomal recessive rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp: delineation of the syndrome and gene mapping to chromosome 16p12-11.2", Ann Neurol, 45, pp.344~352 (1999)
- Lee HY, "The gene for paroxysmal non-kinesigenic dyskinesia encodes an enzyme in a stress response pathway", Hum Mol Genet, 13, pp.3161~3170 (2004)
- Chen WJ, "Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia", Nat Genet, 43, pp.1252~1255 (2011)
- Suls A, "Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1", Brain, 131, pp.1831~1844 (2008)
- Gardiner AR, "The clinical and genetic heterogeneity of paroxysmal dyskinesias", Brain, 138, pp.3567~3580 (2015)
- Fusco C, "Novel phenotype in a family with infantile convulsions and paroxysmal choreoathetosis syndrome and PRRT2 gene mutation", Brain Dev, 36, pp.183~184 (2014)
- Wang HX, "Mutation analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative paroxysmal kinesigenic dyskinesia patients", Chin Med J (Engl), 129, pp.1017~1021 (2016)
- Richards RN, "Paroxysmal dystonic choreoathetosis. A family study and review of the literature", Neurology, 18, pp.461~469 (1968)
- Richards S, "Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology", Genet Med, 17, pp.405~424 (2015)
- Valtorta F, "PRRT2: from paroxysmal disorders to regulation of synaptic function", Trends Neurosci, 39, pp.668~679 (2016)
- Erro R, "The epileptic and nonepileptic spectrum of paroxysmal dyskinesias: channelopathies, synaptopathies, and transportopathies", Mov Disord, 32, pp.310~318 (2017)
- 윤진영, "Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation", Journal of Clinical Neurology, 10(1), pp.50~54 (2014), 대한신경과학회[DOI]
- Meneret A, "PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population", Neurology, 79, pp.170~174 (2012)
- Huang XJ, "Paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 110 patients", Neurology, 85, pp.1546~1553 (2015)
- Bruno MK, "Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia", Neurology, 68, pp.1782~1789 (2007)
- Liang S, "A case of familial paroxysmal nonkinesigenic dyskinesia due to mutation of the PNKD gene in Chinese Mainland", Brain Res, 1595, pp.120~126 (2015)
- Yeh TH, "Familial paroxysmal nonkinesigenic dyskinesia: clinical and genetic analysis of a Taiwanese family", J Neurol Sci, 323, pp.80~84 (2012)