Jean-Marc Burgunder

Association of GWAS loci with PD in China

Genome‐wide association studies (GWAS) have identified numerous single‐nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinsons disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case–control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS‐linked data and research on ethnic specific effect of common variants.

Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China

Mutations in GBA gene have been reported to be in patients with Parkinsons disease (PD) from different ethnic populations, including Taiwanese Chinese. To explore whether mutation in GBA is also associated with PD in Mainland China, we have now a case control study. The occurrence of the GBA L444P mutation was analyzed in an independent cohort of PD patients and controls from Mainland China. This mutation was present in 20/616 (3.2%) of PD compared with 1/411 (0.2%) of controls (odds ratio, OR=13.76, 95% Confidence interval, CI: 1.84-102.92, p=0.001). All carriers harbored the heterozygous genotype. In a subset analysis, the frequency of this mutation was higher both in early onset (EOPD) and late onset PD (LOPD) than in controls. However, no difference in clinical characteristics, such as gender, age at onset, onset symptoms, Hoehn-Yahr stage and UPDRS, was found between L444P carriers and non-carriers. In addition, we also explored the potential relationship between GBA L444P mutation and LRRK2 G2385R and R1628P variants in patients with PD. But no association was found, either. In conclusion, our data suggest that the GBA L444P mutation plays an important role in the development of PD also in Han-Chinese patients from Mainland China.

Deep brain stimulation of the globus pallidus internal improves symptoms of chorea-acanthocytosis

Chorea-acanthocytosis is a rare autosomal recessive disorder. To date, treatment is only symptomatic and supportive. Results from the few reports of chorea-acanthocytosis patients treated with deep brain stimulation (DBS) have been inconsistent. We present case reports for two patients with chorea-acanthocytosis who received DBS treatment and compare the outcomes with results from the literature. Both patients showed the typical clinical features of chorea-acanthocytosis with motor symptoms resistant to medical treatment. Chorea was significantly improved following low-frequency DBS treatment in both patients. However, dystonia was only mildly improved. Four chorea-acanthocytosis patients treated with DBS treatment have been reported in the literature. One patient had improvement with low-frequency DBS stimulation, while another two had improvement with higher-frequency DBS. One patient, however, did not improve with either low-frequency or high-frequency DBS. Bilateral DBS to the GPi can improve chorea and dystonia in some patients with intractable chorea-acanthocytosis. However, selection criteria for the most promising candidates must be defined, and the long-term benefits evaluated in clinical studies.

Clinical feature and DYT1 mutation screening in primary dystonia patients from South-West China

Background:  Clinical presentation and DYT1 status amongst Chinese patients with primary dystonia have not been well studied.

Novel mutation in the ceruloplasmin gene causing a cognitive and movement disorder with diabetes mellitus

In a Chinese woman who had diabetes mellitus, undetectable ceruloplasmin, hand tremor, neck dystonia, and cognitive disturbances, genetic analyses revealed a novel homozygous mutation (848G>C or W283S) in exon 5 in the ceruloplasmin gene. Another member with a milder phenotype was also affected by this mutation. The healthy sister was heterozygous at the same position. Aceruloplasminemia has not yet been reported in China. This case suggests that increased awareness should be paid to this disorder in the presence of the typical symptoms.

VPS35 Asp620Asn and EIF4G1 Arg1205His mutations are rare in Parkinson disease from Southwest China

The Asp620Asn mutation in the vacuolar protein sorting protein 35 (VPS35) gene and the Arg1205His mutation in the eukaryotic translation initiation factor 4 gamma 1 (EIF4G1) gene were identified in autosomal dominant late-onset familial and sporadic Parkinson disease (PD) patients in a Caucasian population. However, the frequencies of these 2 mutations among Chinese PD patients are unknown. We examined these mutations in a large cohort consisting of 609 PD patients and 600 healthy control subjects from Southwest China. Our results suggest that the Asp620Asn mutation in VPS35 and the Arg1205His mutation in EIF4G1 do not play a role in PD in the Southwest China population. The novel Arg1205Cys mutation in EIF4G1 detected in the current study should be further studied among other Asian patients.

Diffusion tensor imaging of two unrelated Chinese men with hereditary spastic paraplegia associated with thin corpus callosum

Hereditary spastic paraplegia (HSP) associated with thin corpus callosum is a rare autosomal recessive neurodegenerative disorder characterized by an abnormally thin corpus callosum, normal motor development, slowly progressive spastic paraparesis and cognitive deterioration. To investigate and localize abnormalities in the brains of two Chinese patients with HSP-TCC, with mutations in the spatacsin gene. Diffusion tensor imaging (DTI) was used to determine the mean diffusion (MD) and fractional anisotropy (FA) in the brains of the patients in comparison to 20 healthy subjects. Voxel-based analysis (VBA) of both the diffusion and anisotropy values were performed using statistical parametric mapping (SPM). Significant changes with MD increase and FA reduction were found in the already known lesions including the corpus callosum, cerebellum and thalamus. In addition, changes were also found in regions that appear to be normal in conventional MRI, such as the brain stem, internal capsule, cingulum and subcortical white matter including superior longitudinal fascicle and inferior longitudinal fascicle. Neither increase in FA nor reduction in MD was detected in the brain. Our study provides clear in vivo MR imaging evidence of a more widespread brain involvement of HSP-TCC. MD is more sensitive than FA in detecting lesions in thalamus and subcortical white matter, suggesting that MD may be a better marker of the disease progression.

Assessment of D216H DYT1 polymorphism in a Chinese primary dystonia patient cohort

Background:  The D216H single‐nucleotide polymorphism (SNP) (rs1801968) in DYT1 exon 4 has been suggested to be a genetic modifier in primary dystonia.

PRRT2 mutation screening in patients with paroxysmal kinesigenic dyskinesia from Southwest China.

Proline‐rich transmembrane protein 2 (PRRT2) has recently been identified as a causative gene of paroxysmal kinesigenic dyskinesia (PKD). However, the frequencies of its mutations and their correlation with the clinical features of PKD remain largely unknown.

Two novel mutations in the SPG11 gene causing hereditary spastic paraplegia associated with thin corpus callosum

Hereditary spastic paraplegia (HSP) associated with thin corpus callosum (TCC) is an autosomal recessive complicated HSP characterized by normal motor development, followed by slowly progressive spastic paraparesis and mental deterioration. Recently, mutations of the SPG11 gene encoding the spatacsin protein have been identified as a major cause of HSP-TCC. SPG11 is located on chromosome 15q21.1, contains 40 exons and encodes a protein of 2,443 amino acids. Spatacsin function is not yet known, however, its widespread expression in the central nervous system and its highly conserved sequence among species indicate an important and essential role. Up to date, 10 mutations including four nonsense mutations, four small deletions and two small insertions of the SPG11 gene were found in 12 families of ARHSP-TCC. Here, we described two novel mutations of the SPG11 gene in two unrelated Chinese patients with HSP-TCC. Patient 1, a 24-year-old man, presented with a progressive speech disorder with mental deterioration impairing school performance(s) from the age of 7 years on. From the age of 14 onwards, he also developed leg stiffness and gait disturbance. There was no consanguinity, family history was unremarkable, and his birth and motor development had been normal. Neurologic examination at age 24 showed dysarthria, left foot muscle atrophy, lower limb symmetric spasticity, upper limb ataxia, and unsteady tandem walking. His Mini Mental State Examination (MMSE) score was 14/30. Ceruloplasmin was normal. Motor nerve conduction of the left peroneal nerve showed lowered amplitude. EMG examination showed denervation potentials in the anterior tibial muscles and the left gastrocnemius muscle. Brain MR Images (Fig 1a–c) disclosed thinning of the corpus callosum, especially in its anterior parts, slight hyperintense signal alterations in the periventricular white matter, as well as mild thalamic and cerebellar atrophy. Spinal cord MRI was normal. Patient 2, a 26-year-old man, born from consanguineous parents, suffered from slowly progessive dysarthria, accompanied by a gait disorder from the age of 18 onwards. He had difficulty in walking without assistance by the age of 23. His MMSE score was 6/30. Besides the dysarthria, and paraspasticity, there was additional hand muscle atrophy, and mild weakness of the lower limbs. Nerve conduction was normal. In the brain MRI (Fig 1d–f) there was slight enlargement of the lateral ventricles and a thin corpus callosum. Spine MRI revealed atrophy of the thoracic cord. Some of the dysarthria and spasticity symptoms of the patients improved under treatment with baclofen (45 mg/day) and D2 receptor agonist (Piribedil, 50 mg bid). Sequencing of the SPG11 gene revealed a novel homozygous small deletion (c.4307_4308del, Fig. 2A) in exon 25 in the first patient leading to a frameshift and early termination at amino acid residue 1,442. This was not found in 100 control chromosomes studied by direct sequencing (Fig. 2B). A homozygous c.5977C>T substitution was found in exon 31 in the second patient (Fig. 2C), leading to a termination at amino acid residue 1,993. All PCR products of exon 31 of 50 healthy controls were cut into 210 bp and 320 bp with Sall (Fig. 2E). This restriction site which is found in normal chromosomes was lost in patient 2. A homozygous c.833A>G substitution was also detected in exon 5 of the same patient (Fig. 2F), leading to an amino acid change (p.278N>S). This is likely a polymorphism since 4 out of 50 healthy controls were heterozygote for the same change (Fig. 2G). The two novel mutations found in the present report lead to a stop codon, providing further evidence for a loss of function mechanism. The difference of the severity and onset age of these two patients may be due to differences in spatacsin dysfunction resulting from the two mutations. However, a precise genotype-phenotype correlation is not yet possible, due to the small overall number of patients with SPG11 mutations described so far. This report points to the importance of screening the SPG11 gene for additional mutations in more families with HSP-TCC.