Wo-Tu Tian

Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene

Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.

Limb-girdle congenital myasthenic syndrome in a Chinese family with novel mutations in MUSK gene and literature review

OBJECTIVES To describe the clinical and genetic features of a Chinese congenital myasthenic syndromes (CMS) patient with two novel missense mutations in muscle specific receptor tyrosine kinase (MUSK) gene and review 15 MUSK-related CMS patients from 8 countries. METHODS The patient was a 30-year-old man with chronic progressively proximal limb weakness for 22 years and diagnosed as muscular dystrophy before. Serum creatine kinase (CK) was normal. Repetitive nerve stimulation (RNS) test showed decrements at low rate stimulation. Weakness became worse after conventional doses of pyridostigmine. Mild multiple atrophy of thigh and leg muscle was observed in MRI. Open muscle biopsy and genetic analysis were performed. One hundred healthy individuals were set for control. RESULTS Muscle biopsy showed mild variation in fiber size. Two missense mutations in MUSK gene (p.P650T and p.I795S) were identified in the patient. The mutation of p.I795S was identified in his father and p.P650T in his mother. Both of them were not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. CONCLUSION In this study, we identified a limb-girdle CMS (LG-CMS) patient carrying two novel heterozygous missense mutations in MUSK gene. CMS related genes should be analyzed in patients with limb-girdle weakness, normal CK, decrement of CMAP at RNS and mild change in muscle biopsy or MRI.

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.

Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review

PURPOSE To describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. METHODS The patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. RESULTS One homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. CONCLUSION In this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure.

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 study of exercise tests in paroxysmal kinesigenic dyskinesia

OBJECTIVE To unravel if there was muscular ion channel dysfunction in paroxysmal kinesigenic dyskinesia (PKD) patients using the exercises tests (ET). METHODS Sixty PKD patients including 28 PRRT2 mutations carriers were enrolled in this study, as well as 19 hypokalaemic periodic paralysis (HypoPP) patients as the positive controls and 45 healthy subjects as the negative controls. ET including long exercise test (LET) and short exercise test (SET) was performed in the corresponding subjects. RESULTS In the LET, both the overall PKD patients and HypoPP patients had greater CMAP amplitude and area increments during exercise than healthy controls. At most 25% of PKD patients were identified from the normality with greater amplitude increment than the area. On the contrary, 50% of HypoPP patients were differentiated with greater area increment than the amplitude. More percentage of PRRT2- patients than PRRT2+ patients had abnormal average amplitude increment. Unexpectedly, five PKD patients had abnormal maximum CMAP amplitude decrements after exercise in the LET, and one had abnormal maximum immediate amplitude decrement in the SET. CONCLUSIONS Distinct ET manifestations were found in PKD patients compared to normal controls and HypoPP patients. SIGNIFICANCE Abnormal muscle membrane excitability might be involved in the mechanisms responsible for PKD.

Novel Mutations in SCN4A Gene Cause Myotonia Congenita with Scoliosis

Myotonia congenita (MC) is a group of genetically and clinically heterogeneous congenital neuromuscular channelopathies, typically characterized by the delayed relaxation of the muscles after voluntary contraction, stiffness, hypertrophy, transient weakness, and cramping. MC is caused by mutations in the skeletal muscle chloride channel gene (CLCN1 [OMIM 118425]) and the skeletal muscle sodium channel gene (SCN4A [OMIM 603967]). The Nav1.4 voltage-gated sodium channel encoded by SCN4A is a transmembrane complex that consists of an α subunit associated with an auxiliary β subunit in the muscle. The α subunit is composed of four homologous domains (I–IV), and each domain contains six α-helical transmembrane segments (S1–S6). Mutations clustered in specific areas of the Nav1.4 channel associate with distinct phenotypes according to their positions in the protein.

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.

Depression, anxiety, and quality of life in paroxysmal kinesigenic dyskinesia patients

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder characterized by recurrent dystonic or choreoathetoid attacks triggered by sudden voluntary movements. Under the condition of psychological burden, some patients’ attacks may get worsened with longer duration and higher frequency. This study aimed to assess nonmotor symptoms and quality of life of patients with PKD in a large population. Methods: We performed a cross-sectional survey in 165 primary PKD patients from August 2008 to October 2016 in Rui Jin Hospital, using Symptom Check List-90-Revised (SCL-90-R), World Health Organization Quality of Life-100 (WHOQoL-100), Self-Rating Depression Scale, and Self-Rating Anxiety Scale. We evaluated the differences of SCL-90-R and WHOQOL-100 scores in patients and Chinese normative data (taken from literature) by using the unpaired Students t-test. We applied multivariate linear regression to analyze the relationships between motor manifestations, mental health, and quality of life among PKD patients. Results: Compared with Chinese normative data taken from literature, patients with PKD exhibited significantly higher (worse) scores across all SCL-90-R subscales (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism; P = 0.000 for all) and significantly lower (worse) scores of five domains in WHOQoL-100 (physical domain, psychological domain, independence domain, social relationship domain, and general quality of life; P = 0.000 for all). Nonremission of dyskinesia episodes (P = 0.011) and higher depression score (P = 0.000) were significantly associated with lower levels of quality of life. The rates of depression and anxiety in patients with PKD were 41.2% (68/165) and 26.7% (44/165), respectively. Conclusions: Depression, anxiety, and low levels of quality of life were prevalent in patients with PKD. Co-occurrence of depression and anxiety was common among these patients. Regular mental health interventions could set depression and anxiety as intervention targets. Considering that the motor episodes could be elicited by voluntary movements and sometimes also by emotional stress, and that symptoms may get worsened with longer duration and higher frequency when patients are stressed out, intervention or treatment of depression and anxiety might improve the motor symptoms and overall quality of life in PKD patients.