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Abstract: Huntington''s disease (HD) is caused by the abnormal expansion of CAG repeats in the huntingtin gene (HTT). The adjacent proline-rich region, which also has a CCG polymorphism among people of different races, may also affect the pathogenesis of HD. To study the effect of this polymorphism on patients with HD in mainland China, 53 HD mutant alleles were examined. The results showed that 54.72% of the HD mutant alleles had 10-repeat alleles, and the remaining 45.28% had 7-repeat alleles. Moreover, comparison of the clinical features between the two groups revealed no significant difference. We also investigated its effect on the aggregates in vitro. No significant difference was detected when the morphology and size of the aggregates with the two polymorphisms was compared in cells. Given these findings, it was quite reasonable to suppose that the CCG polymorphism may not influence the pathogenesis of patients with HD in mainland China. [Copyright &y& Elsevier]

Abstract: Objective: To investigate the predisposing background for the instability of CAG expansions of the HTT gene in a Chinese population. Methods: Genotyping and haplotyping of CAG and CCG repeats of the HTT gene were carried out in 32 unrelated HD patients and 95 non-HD control individuals of Han origin, using capillary electrophoresis and DNA sequencing. The frequencies of different CCG repeats were compared between mutant and wild-type HTT genes. In controls, the comparison of the mean CAG repeat size was performed among different CCG repeats. Results: A total of five alleles of CCG repeats were distinguished, in which four were present in HD chromosomes. In the CCG alleles, (CCG)10 showed a higher frequency in mutant HTT genes relative to wild-type ones, and the highest mean CAG repeat size was observed in the (CCG)10 background. Additionally, a haplotype of (CAG)32–(CCG)10 was found in the control group. Conclusion: Our findings indicate that HTT mutation is likely of multiple origins in the Chinese population. Among the origins, more new HTT mutations may arise from the (CCG)10 than from other CCG alleles, which suggests that the (CCG)10 allele may represent a predisposing background for CAG expansion in Chinese populations. Therefore, in comparison with Europeans, the significantly lower prevalence of Huntington''s disease in Chinese individuals may not be due to the absence of the predisposing background for CAG expansion but instead may partly result from the lower frequency of the predisposing haplotype for CAG instability in the population. [Copyright &y& Elsevier]

Abstract: Background: Occurrence of nonprogressive juvenile-onset spinal muscular atrophy (SMA) predominantly in males suggests a possibility of X-linked disorder but there is no such report addressing this problem. Aims: To evaluate CAG repeat expansion of androgen receptor (AR) gene in patients with nonprogressive juvenile-onset SMA. Setting: Tertiary medical teaching institute. Subjects and methods: Patients fulfilling the diagnostic criteria of nonprogressive juvenile-onset SMA were included. Detailed clinical evaluation and pedigree charting were done in all. Nerve conduction study, electromyography and cervical spinal MRI were carried out. From peripheral venous blood, DNA was separated and AR gene CAG repeat exon polymorphism was assayed using polymerase chain reaction (PCR) in conjugation with genotyping and Gene scan soft ware. Number of CAG repeats was compared with normal controls. Results: 25 patients with nonprogressive juvenile-onset SMA from 24 families were included and their mean age was 22.2 years. Age at the time of disease onset ranged between 15 and 30 years with a mean duration of illness 2.6 years. None of the patients had testicular atrophy or gynecomastia. C7-T1 myotomal wasting and weakness although was unilateral to begin with but became bilateral in 16 and 4 more patients had evidences of subclinical involvement of the other side as revealed by EMG. Spinal MRI revealed cord atrophy at C6-8 vertebral level in 16 patients. CAG repeat study of AR gene was carried out in 16 patients. The number of CAG repeats in patients ranged between 15 and 39 (median 21) which were within the normal range. Conclusion: Abnormal CAG repeat expansion of AR gene is not found in patients with nonprogressive juvenile-onset SMA. [Copyright &y& Elsevier]

Abstract: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominantly inherited disorder characterized by cerebellar ataxia, dysarthria and nystagmus. The molecular background for the disorder is a CAG repeat expansion in the CACNA1A gene located on chromosome 19. The size of SCA6 expanded alleles is usually stable, and variation in repeat size over successive generations is rare. We report a Danish family with one case of SCA6 resembling a sporadic case of spinocerebellar ataxia. Analysis of the CACNA1A gene showed meiotic CAG repeat instability in the transmission from a 70-year-old woman with no subjective symptoms to her symptomatic son. The CAG repeat size expanded from 22 repeats in the mother to 23 repeats in the proband. This case demonstrates maternal repeat instability and clinical anticipation in a family with SCA6. [Copyright &y& Elsevier]

Abstract: Mutations in the brain-specific P/Q type Ca2+ channel α1 subunit gene, CACNA1A, have been identified in three clinically distinct disorders, spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2), and familial hemiplegic migraine type 1 (FHM1). SCA6 is associated with small expansions of a CAG repeat at the 3′ end of the gene, while point mutations are mostly responsible for its two allelic disorders, FHMI and EA2. From the electrophysiological point of view, while FHMI mutations lead to a gain of function [Tottene A, Fellin T, Pagnutti S, Luvisetto S, Striessnig J, Fletcher C, et al. Familial hemiplegic migraine mutations increase Ca(2+) influx through single human CaV2.1 channels and decrease maximal CaV2.1 current density in neurons. Proc Natl Acad Sci 99 (20) (2002) 13284–13289.], EA2 mutations usually generate a loss of channel function [Guida S, Trettel F, Pagnutti S, Mantuano E, Tottene A, Veneziano L, et al. Complete loss of P/Q calcium channel activity caused by a CACNA1A missense mutation carried by patients with episodic ataxia type 2. Am J Hum Genet 68 (3) (2001) 759–764, Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 277 (9) (2002) 6960–6966.]. In the present study, we describe a child affected by permanent non-fluctuating limb and trunk ataxia with a quite early age of onset. Interestingly, the size of the CACNA1A triplet repeat region in the patient is within the normal range while he carries a novel de novo missense mutation in this gene, p.R1664Q. Although functional data are not available, based on the literature data indicating that severe reductions in P/Q-type channel activity favour episodic and/or progressive ataxic symptoms [Wappl E, Koschak A, Poteser M, Sinnegger MJ, Walter D, Eberhart A, et al. Functional consequences of P/Q-type Ca2+ channel Cav2.1 missense mutations associated with episodic ataxia type 2 and progressive ataxia. J Biol Chem 2002;277(9):6960–6966.], we hypothesize that the functional consequence of the mutation here identified is a partial loss of the Ca channel function. In conclusion, the clinical and molecular findings reported here suggest the opportunity to screen for point mutation in this gene, even patients with a clinical phenotype for some aspects slightly different from the typical picture more commonly associated to SCA6, EA2 or FHM1 diseases. [Copyright &y& Elsevier]

The pons is one of the brain areas demonstrating selective degeneration in Machado–Joseph disease (MJD), which is caused by the expansion of a polyglutamine stretch in the protein called ataxin-3. Although the resultant pontine atrophy is readily recognized by magnetic resonance imaging (MRI), the features and natural process of atrophy are not fully understood. To characterize them, we analyzed the midsagittal images of the pons obtained by MRI. We found a difference in atrophy between the pontine base and tegmentum. The reduced size of the pontine tegmentum was prominent early after the onset of clinical symptoms. No overlap was seen in the range of the area of pontine tegmentum between MJD and controls. The quotient of atrophy of the pontine tegmentum divided by age correlated well with the CAG repeat number. In contrast, the area of the pontine base correlated negatively with disease duration. Particularly, the size of the pontine base remained in the range of controls for a relatively long time after the onset of symptoms. These results suggest that the atrophic process is not uniform in the pons in MJD and that the different patterns of atrophy may be derived from the differential vulnerability in pontine structures. [Copyright &y& Elsevier]

In a Chinese family with Spinocerebellar ataxia type 12 (SCA12), presenting with action tremor, mild cerebellar dysfunction, and hyperreflexia, genetic testing revealed abnormal CAG repeat length in the brain-specific protein phosphatase 2, regulatory subunit B, beta isoform ( PPP2R2B ) gene. To our knowledge, this is the first report on patients with SCA12 presenting with prominent cerebral white matter change besides cerebral and/or cerebellar atrophy. [ABSTRACT FROM AUTHOR]