Jun-Yi Shen

Paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 110 patients.

Objective: We aimed to investigate the clinical and genetic features of paroxysmal kinesigenic dyskinesia (PKD) in a large population and to analyze the genotype–phenotype correlation of PKD. Methods: We analyzed clinical manifestations and conducted PRRT2 screening in 110 patients with PKD. Clinical data were compared between 91 probands with and without PRRT2 mutations. Results: Among the enrolled participants (45 from 26 families, 65 sporadic cases), 8 PRRT2 mutations were detected in 20 PKD families (76.9%) and 14 sporadic cases (21.5%), accounting for 37.4% (34/91) of the study population. Five mutations (c.649dupC, c.649delC, c.487C>T, c.573dupT, c.796C>T) were already reported, while 3 mutations (c.787C>T, c.797G>A, c.931C>T) were undocumented. A patient harboring a homozygous c.931C>T mutation was shown to have inherited the mutation via uniparental disomy. Compared with non-PRRT2 mutation carriers, the PRRT2 mutation carriers were younger at onset, experienced longer attacks, and tended to present with complicated PKD, combined phenotypes of dystonia and chorea, and a positive family history. A good response was shown in 98.4% of the patients prescribed with carbamazepine. Conclusions: PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset, longer duration of attacks, a complicated form of PKD, combined phenotypes of dystonia and chorea, and a tendency for a family history of PKD. A patient with uniparental disomy resulting in a homozygous c.931C>T mutation is identified in the present study. Carbamazepine is the first-choice drug for patients with PKD, but an individualized treatment regimen should be developed.

TMEM230 stop codon mutation is rare in parkinson's disease and essential tremor in eastern China.

residuals around Jet-PEG, duodenal ulcerations [Fig. 1E/F], stoma infections) complicated symptom allocation (P5). Countermeasures comprised: laparotomy (P1); Jet-PEG transection (P2); intermediate care treatment, temporary cessation of anticoagulation, and blood transfusions (P3); Jet-PEG-removal or exchanges (P4/P5); PEG-removal (P3/ 5); pyloric balloon dilatation (P4); high-dose proton pump inhibitor (P1/P2/P4/P5) and antibiotic treatment (P1/P2/ P4/P5/P6); endoscopies (P1-P5); intensive care and lysis treatment, high-dose vitamin B12 / folate therapy (P6). Outcomes were: full recovery after days (P2) or months (P1); recovery with re-emergence of fluctuations after restart of oral therapy (P3/P5); reduced general condition (P6); death after sepsis probably from purulent enterobacter-cloacae stoma infection from continued secretion (P4). Possible cofactors were: helicobacter pylori gastritis in P1 (eradicated before ulcer complaints, but after LCIG initiation); inflammatory bowel disease in P2 (diagnosed after intestinal invagination); anticoagulation in P3 for atrial fibrillation (aggravating bleeding); infection in P6 (pneumonia treated at the time of pulmonary thrombosis). SAEs affected about 10% of our LCIG patients during long-term therapy, which changed our indication and surveillance procedures. We tend to abstain from starting LCIG in patients with systemic intestinal dysfunction or anticoagulant medication and recommend testing for helicobacter pylori prior to Jet-PEG insertion, allowing timely eradication. Facing continued abdominal pain, we would pragmatically abandon LCIG and remove the tube system earlier. Finally, we try to keep homocysteine, elevated by levodopa and associated with vascular disease, in normal ranges. In P6, excessive homocysteine fell drastically after parenteral administration of 1000 mg cobalamin and 10 mg oral folate per day. Altogether, the cases demonstrate the necessity of close safety monitoring in any LCIG-treatment phase and of multidisciplinary collaboration. They also document the need to define standards for LCIG centers and treatment procedures.

Myotonia congenita: novel mutations in CLCN1 gene

Myotonia congenita belongs to the group of non-dystrophic myotonia caused by mutations of CLCN1gene, which encodes human skeletal muscle chloride channel 1. It can be inherited either in autosomal dominant (Thomsen disease) or recessive (Becker disease) forms. Here we have sequenced all 23 exons and exon-intron boundaries of the CLCN1 gene, in a panel of 5 unrelated Chinese patients with myotonia congenita (2 with dominant and 3 with recessive form). In addition, detailed clinical analysis was performed in these patients to summarize their clinical characteristics in relation to their genotypes. Mutational analyses revealed 7 different point mutations. Of these, we have found 3 novel mutations including 2 missense (R47W, V229M), one splicing (IVS19+2T>C), and 4 known mutations (Y261C,G523D, M560T, G859D). Our data expand the spectrum of CLCN1 mutations and provide insights for genotype–phenotype correlations of myotonia congenita in the Chinese population.

Novel ATM mutations with ataxia-telangiectasia.

Ataxia telangiectasia is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia with onset in childhood, oculocutaneous telangiectasia, increased serum alpha-fetoprotein, immunodeficiency, chromosomal instability, and radiation hypersensitivity. Ataxia-telangiectasia mutated gene (ATM) is one of the known genes to be associated with ataxia telangiectasia. We reported the clinical and genetic findings of three early-onset Chinese patients who demonstrated ataxia, oculomotor apraxia, choreoathetosis, myoclonus and telangiectasia of eyes. Sequence analysis of ATM revealed two known nonsense mutations c.8287C>T and c.9139C>T in the siblings. Though the siblings carried the same mutations, they showed different clinical features involving strephenopodia, exotropia, torsion dystonia, myoclonus and extrapyramidal impairments. The other patient was compound heterozygotes for ATM: c.8911C>T and c.7141_7151delAATGGAAAAAT, both of which were not reported previously and not found in 200 control chromosomes. This study widens the spectrum of mutations and phenotypes in ataxia telangiectasia.

Mutation Analysis of HTRA2 Gene in Chinese Familial Essential Tremor and Familial Parkinson’s Disease

Background. HTRA2 has already been nominated as PARK13 which may cause Parkinsons disease, though there are still discrepancies among these results. Recently, Gulsuner et al.s study found that HTRA2 p.G399S is responsible for hereditary essential tremor and homozygotes of this allele develop Parkinsons disease by examining a six-generation family segregating essential tremor and essential tremor coexisting with Parkinsons disease. We performed this study to validate the condition of HTRA2 gene in Chinese familial essential tremor and familial Parkinsons disease patients, especially essential tremor. Methods. We directly sequenced all eight exons, exon-intron boundaries, and part of the introns in 101 familial essential tremor patients, 105 familial Parkinsons disease patients, and 100 healthy controls. Results. No exonic variant was identified, while one exon-intron boundary variant (rs2241028) and one intron variant (rs2241027) were detected, both with no clinical significance and uncertain function. There was no difference in allele, genotype, and haplotype between groups. Conclusions. HTRA2 exonic variant might be rare among Chinese Parkinsons disease and essential tremor patients with family history, and HTRA2 may not be the cause of familial Parkinsons disease and essential tremor in China.

Novel Mutations in Endoplasmic Reticulum Lipid Raft-associated Protein 2 Gene Cause Pure Hereditary Spastic Paraplegia Type 18

2759 Hereditary spastic paraplegia type 18 (HSP18) is a complicated form of autosomal recessive HSP characterized by progressive weakness and spasticity of the lower extremities, dysarthria, and cognitive decline.[1‐3] In the year 2011, HSP18, also known as Spastic Paraplegia 18 (SPG18), was firstly identified due to a candidate gene endoplasmic reticulum lipid raft‐associated protein 2 (ERLIN2) on chromosome 8p11.2 in one Saudis family.[1] During the past 5 years, another two families with SPG18 due to ERLIN2 mutations have been reported presenting with complicated phenotype.[2,3] Here, we reported a patient born in a nonconsanguineous family who possessed an autosomal recessive pure form of HSP owing to novel mutations in ERLIN2. Patient was characterized by late‐onset spasticity of lower extremities without significant speech involvement or cognitive disability.

Case report: A Chinese child with Andersen–Tawil syndrome due to a de novo KCNJ2 mutation

• We identified one de novo novel mutation in KCNJ2 gene in a Chinese patient with Andersen–Tawil syndrome.

Clinical correlates of decreased plasma coenzyme Q10 levels in patients with multiple system atrophy

INTRODUCTION Multiple system atrophy (MSA) is a progressive neurodegenerative disease. Recent studies revealed decreased coenzyme Q10 (COQ10) levels in the cerebellum and blood samples of MSA patients. But few studies focused on the associations of COQ10 with the clinical symptoms of MSA. In this study, we aimed to quantify plasma COQ10 and characterize its association with clinical features. METHODS We recruited 40 patients with MSA, 30 patients with Parkinsons disease (PD), and 30 healthy participants. Plasma COQ10 was quantified by UPLC-MS. The basic demographic data, motor symptoms, and non-motor symptoms were also assessed. RESULTS Plasma COQ10 levels were significantly different in MSA, PD, and controls (P = 0.001). Post-hoc analysis revealed plasma COQ10 levels in MSA patients were lower than that in controls after adjusting for age, gender, and total cholesterol (P = 0.001). COQ10 levels differentiated MSA patients from controls with modest accuracy (P = 0.001). A sensitivity of 40% and a specificity of 97.5% was calculated with the receiver operating characteristic curve. However, COQ 10 levels did not discriminate between the MSA and PD groups (P = 0.07). Plasma COQ10 levels were correlated with the severity of motor symptoms only in MSA-C patients (b = -0.025, P = 0.009). CONCLUSION The association between decreased COQ10 levels and the severity of motor symptoms in MSA-C patients promotes further research. Plasma COQ10 levels alone may not be a reliable MSA diagnostic biomarker, and cannot be considered a useful biomarker in the differential diagnosis of MSA vs PD.

Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients: Genotype and Phenotype of PRRT2-Negative PKD

Background: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline‐rich transmembrane protein 2 mutations.

The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia

Our study aimed to identify the underlying causes in patients with early onset dementia by clinical and genetic exploration. We recruited a group of 38 patients with early-onset dementia. Firstly, hexanucleotide repeat expansions in C9ORF72 gene were screened in all subjects to exclude the possibility of copy number variation. Then, the whole exome sequencing (WES) was conducted, and the data were analyzed focusing on 89 dementia-related causing and susceptible genes. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. There were no pathogenic expansions in C9ORF72 detected. According to the ACMG standards and guidelines, we identified five known pathogenic mutations, PSEN1 P284L, PSEN1c.857-1G>A, PSEN1 I143T, PSEN1 G209E and MAPT G389R, and one novel pathogenic mutation APP K687N. All these mutations caused dementia with the mean onset age of 38.3 (range from 27 to 51) and rapid progression. Eleven variants with uncertain significance were also detected and needed further verification. The clinical phenotypes of dementia are heterogeneous, with both onset ages and clinical features being influenced by mutation position as well as the causative gene. WES can serve as efficient diagnostic tools for different heterogeneous dementia.