Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 in patients with unknown spinocerebellar ataxia: a Thai multicentre study.

BACKGROUND: About 50 % of Thai patients with adult-onset spinocerebellar ataxia (SCA) was Machado-Joseph disease (MJD), SCA1, SCA2 and SCA6. The author investigated further on less common SCAs in the patients without any known mutations. METHODS: DNA samples of 82 index patients who were genetically excluded MJD, SCA1, SCA2, SCA6, SCA7 and dentatorubro-pallidoluysian atrophy (DRPLA) were examined. Analysis of SCA8, SCA10, SCA12, SCA17 and SCA19 genes were comprehensively performed. Normal range of trinucleotide repeat expansion sizes of TATA-box-binding protein gene (TBP) were also determined in 374 control subjects. RESULTS: Eight patients carried ≥42 CAG/CAA repeat allele in the TBP consistent with SCA17. The pathological repeat alleles ranged from 42 to 57 repeats. All patients had significant degree of cognitive dysfunction. Other non-ataxic phenotypes comprised of parkinsonism, chorea, dystonia and myoclonus. A sporadic patient carried a heterozygous 41-repeat allele developed chronic progressive cerebellar degeneration commenced at the age of 28 years. Whilst, 2 % of the control subjects (8/374) carried the 41-repeat allele. Five of the carriers were re-examined, and revealed that four of them had parkinsonism and/or cognitive impairment without cerebellar signs. Analysis of other types of SCAs was all negative. CONCLUSIONS: This is the first study of SCA8, SCA10, SCA12, SCA17 and SCA19 in Thais. SCA17 appears to be an important cause of ataxia in Thailand. Although, the pathological cut-off point of the TBP repeat allele remains unclear, the finding suggests that the 41-repeat may be a pathological allele resulting late-onset or mild phenotype. Apart from ataxia, cognitive impairment and parkinsonism may be clinical presentations in these carriers.

Clinical analysis of adult-onset spinocerebellar ataxias in Thailand.

BACKGROUND: Non-ataxic symptoms of spinocerebellar ataxias (SCAs) vary widely and often overlap with various types of SCAs. Duration and severity of the disease and genetic background may play a role in such phenotypic diversity. We conducted the study in order to study clinical characteristics of common SCAs in Thailand and the factors that may influence their phenotypes. METHODS: 131 (49.43%) out of 265 Thai ataxia families with cerebellar degeneration had positive tests for SCA1, SCA2, Machado-Joseph disease (MJD) or SCA6. The study evaluated 83 available families including SCA1 (21 patients), SCA2 (15), MJD (39) and SCA6 (8). Comparisons of frequency of each non-ataxic sign among different SCA subtypes were analysed. Multivariate logistic regression analyses were undertaken to analyze parameters in association with disease severity and size of CAG repeat. RESULTS: Mean ages at onset were not different among patients with different SCAs (40.31 ± 11.33 years, mean ± SD). Surprisingly, SCA6 patients often had age at onset and phenotypes indistinguishable from SCA1, SCA2 and MJD. Frequencies of ophthalmoparesis, nystagmus, hyperreflexia and areflexia were significantly different among the common SCAs, whilst frequency of slow saccade was not. In contrast to Caucasian patients, parkinsonism, dystonia, dementia, and facial fasciculation were uncommon in Thai patients. Multivariate logistic regression analysis demonstrated that ophthalmoparesis (p < 0.001) and sensory impairment (p = 0.025) were associated with the severity of the disease. CONCLUSIONS: We described clinical characteristics of the 4 most common SCAs in Thailand accounting for almost 90% of familial spinocerebellar ataxias. There were some different observations compared to Caucasian patients including earlier age at onset of SCA6 and the paucity of extrapyramidal features, cognitive impairment and facial fasciculation. Severity of the disease, size of the pathological CAG repeat allele, genetic background and somatic heterogeneity of pathological alleles may influence clinical expressions of these common SCAs.

Spinocerebellar Ataxia type 17 presenting with progressive myoclonic epilepsy.

•SCA17 should be included in the differential diagnoses of PMEs.•SCA17 is characterized by cerebellar features, myoclonic epilepsy, cognitive decline, psychiatric features, and chorea.•Subtle clinical signs like chorea can provide additional diagnostic clues to SCA17(HDL4), a Huntington disease phenocopy.

Treatment of slow-channel congenital myasthenic syndrome in a Thai family with fluoxetine.

The slow-channel congenital myasthenic syndrome is an autosomal dominant neuromuscular disorder caused by mutations in different subunits of the acetylcholine receptor. Fluoxetine, a common antidepressant and long-lived open-channel blocker of acetylcholine receptor, has been reported to be beneficial in the slow-channel congenital myasthenic syndrome. Here we report a prospective open label study of fluoxetine treatment in some affected members of a Thai family with slow-channel congenital myasthenic syndrome caused by a novel p.Gly153Ala (c.518G > C) mutation in CHRNA1 in the AChR α subunit. These patients showed significant clinical improvement following fluoxetine treatment but their respiratory function responded variably.

Analysis of exon 8 of ATP7B gene in Thai patients with Wilson disease.

OBJECTIVE: Determine the frequency of mutations in exon 8 of ATP7B gene. MATERIAL AND METHOD: The exon 8 of ATP7B gene in twenty 20 unrelated Thai patients with Wilson disease (WD) was analyzed RESULTS: Three heterozygous mutations were identified in four patients. The Arg778Leu (G2333T) and 2299insC mutations have been previously reported. The authors also identified a novel missense mutation, Thr766Arg (C2297G). Despite the Arg778Leu mutation being common in East Asian populations, its frequency in Thais was only 5% in the presented patients. CONCLUSION: Sequencing of the exon 8 of the ATP7B gene is insufficient for the diagnostic service testing in Thais.

Radiological Characteristics of Extraocular Muscles in Myasthenia Gravis Patients with Ocular Manifestations: A Case-Control Study.

PURPOSE: To analyze radiological characteristics of the extraocular muscles (EOMs) in myasthenia gravis (MG) patients with ocular manifestations. PATIENTS AND METHODS: This retrospective case-control study included all MG cases with ocular manifestations, who attended a neuro-ophthalmology clinic at a university hospital, Bangkok, from April 2009 to June 2018. They experienced double vision and ophthalmoplegia. Control participants had normal eye movements. Orbital scans were thoroughly reviewed. We measured muscle thickness (MT) of the superior rectus, inferior rectus, medial rectus and lateral rectus muscles in both eyes using magnetic resonance imaging or computed tomography scan. The sum of the muscle thickness at all sites was calculated (MTsum). Comparisons of the mean MT of each muscle type and the mean MTsum between the MG and control groups were performed by using Student's t-test. MRI signal intensities of the EOMs were also recorded. RESULTS: Twenty MG cases and 20 controls were included in the study. The mean MTsum was 23.7 (standard deviation 4.8) mm in the MG group and 32.6 (3.5) mm in the controls. There were statistically significant differences between the two groups with respect to the mean MT and mean MTsum (p <0.001). In the MG group, there was a negative correlation between the MTsum and disease duration (p= 0.03). By using coronal T2-weighted orbital MRI with fat suppression (T2W/FS), the most frequent finding was isointensity with central hypointensity of the EOMs in the MG group. CONCLUSION: Atrophic EOMs were frequently found in the MG group, particularly in chronic cases. Isointensity with central hypointensity of EOMs on T2W/FS was also common in the MG group. These findings highlight the importance of muscle involvement in MG and may be helpful for clinical decision-making.

Aberrant proteins expressed in skin fibroblasts of Parkinson's disease patients carrying heterozygous variants of glucocerebrosidase and parkin genes.

Parkinson's disease (PD) is a neurodegenerative disorder that affects movement, and its development is associated with environmental and genetic factors. Genetic variants in GBA and PARK2 are important risk factors implicated in the development of PD; however, their precise roles have yet to be elucidated. The present study aimed to identify and analyse proteins from the skin fibroblasts of patients with PD carrying heterozygous GBA and PARK2 variants, and from healthy controls. Liquid chromatography coupled with tandem mass spectrometry and label-free quantitative proteomics were performed to identify and compare differential protein expression levels. Moreover, protein-protein interaction networks were assessed using Search Tool for Retrieval of Interacting Genes analysis. Using these proteomic approaches, 122 and 119 differentially expressed proteins from skin fibroblasts of patients with PD carrying heterozygous GBA and PARK2 variants, respectively, were identified and compared. According to the results of protein-protein interaction and Gene Ontology analyses, 14 proteins involved in the negative regulation of macromolecules and mRNA metabolic processes, and protein targeting to the membrane exhibited the largest degree of differential expression in the fibroblasts of patients with PD with a GBA variant, whereas 20 proteins involved in the regulation of biological quality, NAD metabolic process and cytoskeletal organization exhibited the largest degree of differential expression in the fibroblasts of patients with PD with a PARK2 variant. Among these, the expression levels of annexin A2 and tubulin ß chain, were most strongly upregulated in the fibroblasts of patients with GBA-PD and PARK2-PD, respectively. Other predominantly expressed proteins were confirmed by western blotting, and the results were consistent with those of the quantitative proteomic analysis. Collectively, the results of the present study demonstrated that the proteomic patterns of fibroblasts of patients with PD carrying heterozygous GBA and PARK2 variants are different and unique. Aberrant expression of the proteins affected by these variants may reflect physiological changes that also occur in neurons, resulting in PD development and progression.

Effects of handwriting exercise on functional outcome in Parkinson disease: A randomized controlled trial.

Parkinson disease (PD) patients frequently experience micrographia and difficulty writing, which could potentially impact their quality of life. This study aimed to determine whether handwriting exercise could improve fine manual motor function in PD. The study was a randomized controlled trial assessing the efficacy of a 4-week handwriting exercise using a newly developed handwriting practice book. The primary endpoint was an improvement in the time used to complete the handwriting test. Secondary endpoints were accuracy of the writing performance, patient's subjective rating scale of their handwriting and a UPDRS part III motor examination. Of a total of 46 subjects, 23 were randomly assigned to the handwriting exercise group. After 4 weeks, the mean time used to complete the test was significantly lower in the exercise group, compared to the control group (143.43 ±â€¯34.02 vs. 175 ±â€¯48.88 s, p = 0.015). Mean time used to complete the handwriting test decreased from the baseline by 16.16% in the exercise group, but increased by 3.63% in the control group (p < 0.001). Significant improvements were also observed by assessing the subjective rating scale and the UPDRS part III scores. The 4-week handwriting exercise using the studied handwriting practice book appears to promote an improvement in writing speed and motor function of hands. The optimal duration and frequency of the exercise, the quantity and characteristic of the letters in the handwriting practice book, and the benefits of the exercise in other languages merit further studies.

Evaluation of Retinal Nerve Fiber Layer and Ganglion Cell Layer Thickness in Alzheimer's Disease Using Optical Coherence Tomography.

OBJECTIVE: To evaluate the feasibility of using optical coherence tomography (OCT) for the detection of Alzheimer's disease (AD), by measuring the thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell layer and inner plexiform layer (GCL-IPL). MATERIAL AND METHODS: This was a single-center, cross-sectional study. The study included 29 patients with AD (mean age ± standard deviation: 75.61 ± 6.24 years) and 29 healthy age- and sex-matched controls. All participants underwent cognitive evaluations using the Montreal Cognitive Assessment test. Measurements of the RNFL thickness, as well as GCL-IPL thickness, were obtained for all participants using OCT. Both RNFL and GCL-IPL parameters were adjusted for best-corrected visual acuity, hypertension, diabetes and dyslipidemia. RESULTS: The mean RNFL thickness was significantly thinner in the AD group than in the control group (85.24 and 90.68 µm, respectively, adjusted P=0.014). The superior quadrant was thinner in the AD group (adjusted P=0.033). The thicknesses did not differ significantly between groups for the other quadrants. The mean GCL-IPL thickness in the AD (68.81 µm) was significantly thinner than that in the controls (76.42 µm) (adjusted P=0.014). Overall, there was a negative correlation between age and mean RNFL; and between age and GCL-IPL thickness (r=-0.338, P=0.010 and r=-0.346, P=0.008, respectively). CONCLUSION: The mean RNFL and GCL-IPL thicknesses were thinner in the AD group than in the control group. These findings suggest that RNFL and GCL-IPL thickness may be biological markers for AD.

Etiologies of Acute Optic Neuritis in Thailand: An Observational Study of 171 Patients.

PURPOSE: To analyze the demographic patterns, clinical characteristics and etiologies of acute optic neuritis (ON). METHODS: This retrospective observational study included patients with acute ON who presented to a university hospital in Bangkok, Thailand, between January 2010 and March 2020. The demographic details, clinical characteristics and etiologies of acute ON were evaluated. RESULTS: A total of 171 patients were included in the study (78.4% [n=134] female; mean age 45 years [standard deviation 15.4 years]; 32.2% [n=55] bilateral involvement). The most common type of acute ON was idiopathic (51.5%), followed by neuromyelitis optica spectrum disorder (NMOSD, 30.9%), other autoimmune disorders (9.9%), myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD, 5.3%), multiple sclerosis (MS, 1.8%), and postinfection (0.6%). In the other autoimmune disorders group, 2 patients developed systemic lupus erythematosus (1.2%), 2 Sjogren's syndrome (1.2%), 1 RA (0.6%), 1 anti-NMDAR (0.6%), 3 anti-Jo1 (1.8%), 2 c-ANCA (1.2%), 1 anti-centromere (0.6%), and 5 nonspecific autoimmune disorders (2.9%). In the idiopathic group, 38.6% developed single isolated ON, 1.8% relapsing isolated ON and 11.1% chronic relapsing inflammatory optic neuropathy. CONCLUSION: The most common form of acute ON in this study, similar to other Asian countries, was idiopathic. Idiopathic-ON shared some phenotypes with NMOSD and MOGAD. We also reported patients with anti-NMDAR, anti-Jo1, c-ANCA and anti-centromere disorders. Improvements in antibody detection have widened the range of possible etiologies of acute ON. The study highlighted the important role of antibodies in creating effective treatments in the future.

Clinical Characteristics of HIV-Associated Optic Neuritis.

INTRODUCTION: Acute optic neuritis (ON) has been increasingly reported in patients infected with human immunodeficiency virus (HIV). We aimed to describe clinical characteristics of HIV-infected patients with ON. MATERIALS AND METHODS: This observational retrospective study was performed from January 2008 to January 2016 in a university hospital in Bangkok, Thailand. Demographic data and clinical manifestations were retrospectively reviewed. RESULTS: We included 10 HIV-infected patients and divided them into two groups: infectious and non-infectious ON. There were six patients in the infectious ON group (five males, mean age 33.6 years, median CD4 cell counts during ON episodes 36.5 cells/µL, high viral loads, median initial visual acuity [VA] 1.7, median VA difference [initial VA - follow-up VA] 0). Four patients developed cryptococcal meningitis and 2 developed neuro-syphilis. They were treated with amphotericin B plus fluconazole and penicillin G sodium, respectively. There were four patients in the non-infectious ON group (two males, mean age 44.3 years, median CD4 cell count during acute ON 157.5 cells/µL, undetectable viral loads, median initial VA 1.3, and median VA difference 1.2). They were given corticosteroid treatments. There were no statistically significant differences between the two groups with respect to age, sex, and initial VA. There were statistically significant differences in median VA difference and median CD4 cell counts between the two groups (p=0.02 and 0.03, respectively). There was a significant correlation between CD4 counts and duration in three non-infectious ON patients treated with antiretroviral therapy (ART, p<0.001). DISCUSSION: Patients with infectious ON had low initial CD4 counts and high viral loads. Patients with non-infectious ON had increasing CD4 cell counts and undetectable HIV viral load following ART. The findings are highly suggestive of immune reconstitution inflammatory syndrome. The CD4 cell counts and viral loads may help to identify the type of acute ON in HIV-infected patients and establish proper therapies.

Clinical features of familial Parkinson's disease in Thai patients.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease. Most cases are sporadic, but family history is also observed in certain cases. This study aimed to describe the clinical features of familial PD in Thai patients. METHOD: The study included five female and three male patients from a Malay family of consanguineous parents who were evaluated for clinical study. Every patient was examined initially at the outpatient unit of the family medicine department. The diagnosis was later confirmed by a team of neurologists at the division of neurology, department of medicine. The patients were first seen and evaluated in 1999, with subsequent evaluation in 2005 and 2008. RESULTS: Clinical features such as tremor, rigidity, bradykinesia and postural instability were similar to those of the classical idiopathic PD, but age of onset was earlier. The interval between the onset of parkinsonism and first presentation was 1-3 years, and PD was diagnosed within 1-4 years of the onset of parkinsonism. The median age at disease onset was 31 years (range 27 to 49 years). The severity of clinical symptoms and signs was different among affected family members, from stage I to IV of the Hoehn and Yahr stage scale. Motor dysfunction and other complications were observed. The family history suggested that the condition was being passed on only from the maternal side. CONCLUSIONS: The clinical features of familial PD are generally indistinguishable from classical PD, although the diagnosis may be difficult in atypical presentations such as palpitation, anxiety and insomnia. The disease tends to develop earlier in younger siblings. Family members were at greater risk of autosomal recessive disorders that are homozygous for a particular recessive gene mutation due to consanguineous parents. On the other hand, specific ethnicity, very early onset of symptoms, rapid progression of the disease, and high family incidence suggested autosomal dominant inheritance. Since each family member displayed different symptoms and signs, this may have indicated variable penetrance of the PD gene, but the results are not conclusive due to lack of medical records from other relatives and genetic studies.

Idiopathic hypertrophic cranial pachymeningitis.

Idiopathic hypertrophic cranial pachymeningitis is a rare chronic inflammatory process of unknown origin that can cause neurological deficits owing to thickening of the dura. Patients with this condition commonly present with cranial neuropathy accompanied by localized headache. The clinical features, neuroimaging findings, histopathological features and treatment outcomes for three patients with this condition are reported here. The first patient presented with subacute dull headache in the left temporal area followed by left abducens nerve palsy. The second patient suffered from a cranial nerve IX-XII lesion accompanied by an occipital headache and the third patient presented with left optic neuropathy and mild headache in the frontal area. In all patients, MRI of the brain revealed prominent dural thickening, and histopathological study of the dura revealed chronic inflammatory cell infiltration. Combined therapy with corticosteroid and immunosuppressive drugs was effective, resulting in almost complete resolution of the symptoms and signs, except for visual impairment in one patient.

Trinucleotide repeat expansion of TATA-binding protein gene associated with Parkinson's disease: A Thai multicenter study.

INTRODUCTION: Spinocerebellar ataxia type 17 (SCA17) is an inherited cerebellar degeneration associated with trinucleotide repeat expansions in the TATA-binding protein gene (TBP). Low-range expansions of TBP have recently been described in association with Parkinson's disease (PD). However, these low-range expansion alleles were also observed in healthy individuals. Prior distinct findings may result from reduced penetrance or age-dependent susceptibility, which may influence phenotypic expression. METHODS: A case-control study of 456 PD patients and 374 control subjects was conducted. Data and blood samples were collected during 2008-2013. Control subjects were individuals over 65 years old without parkinsonism. Sizes of TBP trinucleotide repeats were analyzed. All available carriers of the TBP repeat of ≥40 repeats were re-examined. RESULTS: A high prevalence of carriers of TBP repeat expansion ≥41 developed PD, mainly at an advanced age. Half of these carriers had onset after 70 years of age (range 34-84). Seven participants carried expansion alleles of ≥42, and all had PD. Fourteen participants (six patients and eight controls) carried a heterozygous 41-repeat allele. At the current mean age of 79 years and mean follow-up period of 4 years, three out of the eight control carriers of the 41-repeat allele developed PD, while none of the thirteen asymptomatic carriers of the 40-repeat allele did. CONCLUSIONS: A high prevalence of PD was observed in carriers of low-range expansions of TBP (41-45 repeats), especially in elderly. This finding suggests that cut-off value for pathological TBP repeat expansion appear to be 41.

Episodic ataxia type 2: an uncommon inherited CNS channelopathies.

The author reports the first Thai patient with a rare inherited ataxic disorder characterized by intermittent episodes of ataxia, headache and vertigo. The patient was well between attacks despite persistent nystagmus on examination. Magnetic resonance imaging of the brain revealed cerebellar atrophy. All symptoms were ameliorated by acetazolamide therapy. This clinical syndrome was previously described as acetazolamide-responsive episodic ataxia which was subsequently shown to be associated with mutations in a alpha1A-subunit of P/Q type voltage-gated calcium channel gene, known as 'episodic ataxia type 2'. Clinical and molecular aspects of episodic ataxia type 2 were also reviewed.

Differentiation of dementia with Lewy bodies, Alzheimer's disease and vascular dementia by cardiac 131I-meta-iodobenzylguanidine (MIBG) uptake (preliminary report).

OBJECTIVE: Differentiation of dementia with Lewy bodies (DLB), vascular dementia (VAD), and Alzheimer's disease (AD) is difficult in clinical practice. Several new techniques have been used for differentiation of various types of dementia. Among these techniques 123I-meta-iodobenzylguanidine (MIBG) uptake was reported to have benefit in distinguishing DLB from AD. The authors study the role of MIBG as a tool for differentiation of DLB, AD and VAD. METHOD: Patients with dementia were recruited to the study by DSMIIIR criteria. Diagnosis of each dementia type was made by standard clinical criteria. Brain imagings and 131I-MIBG uptake were performed in all the studied patients. RESULTS: Five DLB, 3 AD and 3 VAD patients were clinically diagnosed. The heart/mediastinum (H/M) ratio in 4 out of 5 in DLB was significantly lower than H/M ratio in patients with AD and VAD. AD patients had the highest uptake of MIBG MIBG uptake of VAD patients was in the range between AD and DLB but the values were close to the AD group. CONCLUSIONS: 131I-MIBG is helpful in differentiating DLB from AD.

Detection of JC virus infection in progressive multifocal leukoencephalopathy: the first documented case in Thailand.

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating brain disease caused by human polyoma JC virus (JCV). This disease is an important cause of morbidity and mortality in AIDS patients. Definite diagnosis currently requires a brain biopsy. PCR for JCV of CSF, an emerging diagnostic tool, has a high specificity for the diagnosis of PML in patients with characteristics on clinical and neuroradiological findings. The authors report a 36-year-old woman who presented with prolonged fever, progressive weakness, and slow speech for 2 months. Clinical features and MRI findings were compatible with PML. Qualitative PCR for JCV of CSF showed a positive result. This report emphasizes the yield of PCR, the CSF for JCV in a diagnosis of PML, which may reduce the need for a brain biopsy in such cases.