Cheng-yuan Mao

CHCHD2 gene mutations in familial and sporadic Parkinson's disease

Mutations in CHCHD2 gene have been reported in autosomal dominant Parkinsons disease (ADPD). However, there is still lack of evidence supported CHCHD2 mutations lead to ADPD in other populations. We performed whole exome sequencing, positron emission tomography (PET), and haplotype analyses in an ADPD pedigree and then comprehensively screened for CHCHD2 gene mutations in additional 18 familial parkinsonism pedigrees, 364 sporadic PD patients, and 384 healthy controls to assess the frequencies of known and novel rare nonsynonymous CHCHD2 mutations. We identified a heterozygous variant (c.182C>T; p.Thr61Ile) in the CHCHD2 gene in the ADPD pedigree. PET revealed a significant reduction in dopamine transporter binding in the putamen and caudate nucleus of the proband, similar to idiopathic PD. The single nucleotide variant 5C>T (Pro2Leu) in CHCHD2 was confirmed to have a significantly higher frequency among sporadic PD patients than controls. Our results confirm that ADPD can be caused by CHCHD2 mutations and show that the Pro2Leu variant in CHCHD2 may be a risk factor for sporadic PD in Chinese populations.

Genotype-phenotype correlation in a cohort of paroxysmal kinesigenic dyskinesia cases☆

BACKGROUND Recently, PRRT2 gene mutations have been identified as a causative factor of paroxysmal kinesigenic dyskinesia (PKD). However, evidence is still lacking with respect to the genotype to phenotype correlation in PKD patients. METHODS We recruited a cohort of PKD patients with or without PRRT2 mutations for the study, and followed them for 6 months to observe the response to carbamazepine treatment. RESULTS Thirty-four participants were included in this study; 16 patients were positive for a hot-spot p.R217Pfs 8 heterozygous PRRT2 gene mutation, while the other 18 patients were negative for PRRT2 gene mutations. PRRT2 mutations were found to be associated with a younger age of onset, bilateral presence and a higher frequency of attacks. Furthermore, the follow-up study revealed that p.R217Pfs 8-positive patients showed dramatic improvement with complete abolition of dyskinetic episodes with carbamazepine treatment, while only 7 of the 18 patients without PRRT2 mutations showed a response to the antiepileptic drug. CONCLUSIONS Our study indicated that positivity for PRRT2 mutation is a predictor of younger age of onset and more frequent of attacks in PKD patients. Interestingly, the presence of PRRT2 mutations also predicted a good response to carbamazepine therapy, especially at low dose. Therefore, genetic testing shows potential clinical significance for guiding the choice of medication for individual PKD cases.

A novel compound WISP3 mutation in a Chinese family with progressive pseudorheumatoid dysplasia

BACKGROUND Progressive pseudorheumatoid dysplasia (PPD) is an extremely rare autosomal recessive genetic disease caused by mutation of the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. Here, we characterize the clinical manifestations and features of PPD and screen for WISP3 mutations. MATERIALS AND METHODS We performed genetic testing for PPD in a Chinese family, after investigating the clinical particulars and family history, in addition to 200 healthy individuals, who served as the controls for this study. All 5 exons and the exon-intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) and sequenced directly. RESULTS We identified a missense mutation (c.667T>G, p.C223G) in the maternal allele and a nonsense mutation (c.756C>A, p.C252X) in the paternal allele in the two affected individuals. To our knowledge, the mutation c.756C>A has not been reported previously. In these patients, there was a specific period when their condition markedly improved after having been very serious. Moreover, severe compression of lumbar spinal cord led to conspicuous spinal disorders in the proband. CONCLUSIONS Our study suggests that novel C223G and C252X mutations in exon 4 of the WISP3 gene are responsible for PPD in Chinese patients. Furthermore, we report certain unique phenotypic characteristics in our patients.

A novel RAB39B gene mutation in X-linked juvenile parkinsonism with basal ganglia calcification.

Mutations in RAB39B have been reported as a potential cause of X‐linked Parkinsons disease (PD), a rare form of familial PD. We conducted a genetic analysis on RAB39B to evaluate whether RAB39B mutations are related to PD in the Chinese population.

Calcium Intake and the Risk of Stroke: An Up-dated Meta-analysis of Prospective Studies

BACKGROUND AND PURPOSE Calcium intake has been associated with stroke risk in a prior meta-analysis, however, newly published results are inconsistent. Dairy food benefits on stroke incidence may involve a calcium-related mechanism. We have therefore updated this meta-analysis with particular references to any possibility of a calcium-mediated dairy food risk reduction of stroke risk. METHODS We searched multiple databases and bibliographies for prospective cohort studies. Reports with multivariate-adjusted relative risk (RR) and corresponding 95% confidence intervals (CI) for the association of calcium intake with stroke incidence were considered. RESULTS Ten studies with 371,495 participants and 10,408 stroke events were analyzed. The pooled analysis showed no statistically significant association of the risk of total stroke (RR=0.96; 95% CI: 0.89-1.04) and stroke subtypes with the highest and lowest calcium intake quantiles. Nevertheless, high dairy calcium intake was significantly associated with an approximately 24% reduction of stroke risk. (RR=0.76; 95% CI: 0.66-0.86). Furthermore, a long-term follow-up (>=14 years) was helpful to reduce the risk of stroke (RR=0.67; 95% CI: 0.51-0.88). Additionally, a non-linear dose-response relationship was predicted between calcium intake and stroke risk. CONCLUSIONS Dairy calcium intake is inversely associated with stroke incidence. There is a non-linear dose-response relationship between calcium intake and stroke risk. However, when the follow-up time is long enough, the inverse relationship is independent of dose. Additional large cohort studies are required to illustrate this relationship in detail.

MC1R variants in Chinese Han patients with sporadic Parkinson's disease

Recently, a variant p.R160W in the MC1R gene was identified that increased the risk of Parkinsons disease (PD) in Spanish population. To explore whether the MC1R gene variants are associated with sporadic PD in Chinese population, we performed a case-control comparison study for comprehensive MC1R variant screening in 510 Chinese Han patients and 495 healthy controls as ethnically matched controls. We identify 5 nonsynonymous variants, including rs34090186 (p.R67Q), rs2228479 (p.V92M), rs33932559 (p.I120T), rs885479 (p.R163Q), and rs372152373 (p.R223W). However, variants mentioned previously did not show association with PD. Our results suggest that variants in MC1R do not play a major role in PD in the Chinese population.

Recessive hereditary motor and sensory neuropathy caused by IGHMBP2 gene mutation

Hereditary motor and sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth disease (CMT), is a genetically heterogeneous disorder that affects both sensory and motor peripheral nerves. HMSN is characterized by distal and symmetric muscle atrophy in the lower limbs and hands, foot abnormalities, and distal sensory loss. It is associated with more than 50 causative genes or loci; however, the genetic cause remains undetermined in almost 50% of HMSN cases.1,2

Nerve growth factor for the treatment of spinocerebellar ataxia type 3: an open-label study.

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor (NGF) may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients. Methods: We performed an open-label prospective study in genetically confirmed adult (>18 years old) SCA3 patients. NGF was administered by intramuscular injection (18 &mgr;g once daily) for 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia (SARA). Results: Twenty-one SCA3 patients (10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77.57 ± 2.27) were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48 ± 2.40 to 6.30 ± 1.87 (P < 0.001). Subsections SARA scores also showed significant improvements in stance (P = 0.003), speech (P = 0.023), finger chase (P = 0.015), fast alternating hand movements (P = 0.009), and heel-shin slide (P = 0.001). Conclusions: Our preliminary data suggest that NGF may be effective in treating patients with SCA3.

Exome sequencing reveals novel SPG11 mutation in hereditary spastic paraplegia with complicated phenotypes

We used a combined approach of whole-exome sequencing and candidate mutation validation to identify the disease-causing gene in a hereditary spastic paraplegia (HSP) patient with lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. HSP is a clinically and genetically heterogeneous neurodegenerative disorder characterized by degeneration of the corticospinal tract motor neurons and resulting in progressive lower limb spasticity, often with a complicated phenotype. We identified novel compound heterozygous mutations in the SPG11 gene in this patient as follows: a mutation in exon 32, c.6194C > G transition (p.S2056X) and a novel c.5121+1C > T splicing mutation. Our finding suggests that these novel compound heterozygous mutations in SPG11 are associated with HSP and lower motor neuron involvement, mild cerebellar signs and dysgenesis of the corpus callosum. This study also demonstrates that exome sequencing is an efficient and rapid diagnostic tool for identifying the causes of some complex and genetically heterogeneous neurodegenerative diseases.

Genetic analysis of the TMEM230 gene in Chinese Han patients with Parkinson’s disease

TMEM230 mutations have been recently reported to cause autosomal dominant Parkinson’s disease (PD). However, there are limited studies from different ethnic populations to support the role of TMEM230 in sporadic PD. In this study, we performed a comprehensive TMEM230 mutation screening in 550 sporadic PD patients and 560 controls to elaborate the genetic contribution of TMEM230 to sporadic PD. Overall, we did not find any pathogenic mutations in the coding sequence, while we identified four variants (c.68 + 182G > A, c.78A > G, c.552 + 11A > G and c.174 + 11C > T) both in the patients and controls, and c.68 + 182G > A appeared to be associated with an increased risk of PD (odds ratio 1.782, 95% confidence interval 1.035–3.067, p < 0.05). After Bonferroni correction, however, c. 68 + 182G > A had no significant association with sporadic PD (pc = 0.136, pc > 0.05). Thus our results suggest that TMEM230 gene mutations may be rare in Chinese populations, and the variability of TMEM230 gene may not be a main factor for sporadic PD patients in Chinese Han populations. More evidence is still needed to clarify this question.