Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.

BACKGROUND: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations. OBJECTIVES: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients. METHODS: Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients. RESULTS: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN. CONCLUSIONS: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.

From parasomnia to agrypnia excitata - An illustrative case on diagnostic approach.

The diagnostic approach to sleep-related movements disorders is seldom discussed. We report a case of fatal familial insomnia who initially presented with persistent limb movements in sleep, which later progressed to a state of agrypnia excitata. Here, the evaluation of abnormal movements in sleep is discussed using a step-by-step diagnostic approach. Although no cure is available for fatal familial insomnia, prompt recognition of this condition is important to facilitate proper management, including the involvement of interdisciplinary neuropalliative care.

A KMT2B Frameshift Variant Causing Focal Dystonia Restricted to the Oromandibular Region After Long-Term Follow-up.

KMT2B-linked dystonia (DYT-KMT2B) is a childhood-onset dystonia syndrome typically beginning in the lower limbs and progressing caudocranially to affect the upper limbs with eventual prominent craniocervical involvement. Despite its recent recognition, it now appears to be one of the more common monogenic causes of dystonia syndromes. Here, we present an atypical case of DYT-KMT2B with oromandibular dystonia as the presenting feature, which remained restricted to this region three decades after symptom onset. This appears to be the first reported case of DYT-KMT2B from Southeast Asia and provides further supporting evidence for the pathogenic impact of the KMT2B c.6210_6213delTGAG variant.

New insights from a multi-ethnic Asian progressive supranuclear palsy cohort.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare, disabling, neurodegenerative disease, with few studies done in Asian populations. METHODS: We prospectively characterized the clinical features and disease burden in a consecutively-recruited multi-ethnic Asian PSP cohort. Patients were extensively phenotyped using the Movement Disorder Society (MDS-PSP) clinical diagnostic criteria and the PSP-Clinical Deficits Scale (PSP-CDS). Caregiver burden was measured using the modified Zarit Burden Interview (ZBI). Investigations (neuroimaging and genetic tests) were reviewed. RESULTS: There were 104 patients (64.4% male; 67.3% Chinese, 21.2% Indians, 9.6% Malays), consisting of 48.1% Richardson syndrome (PSP-RS), 37.5% parkinsonian phenotype (PSP-P), and 10.6% progressive gait freezing phenotype (PSP-PGF). Mean age at motor onset was 66.3 ± 7.7 years, with no significant differences between the PSP phenotypes. Interestingly, REM-sleep behaviour disorder (RBD) symptoms and visual hallucinations (considered rare in PSP) were reported in 23.5% and 22.8% of patients, respectively, and a family history of possible neurodegenerative or movement disorder in 20.4%. PSP-CDS scores were highest (worst) in PSP-RS; and correlated moderately with disease duration (rs = 0.45, P < 0.001) and weakly with caregiver burden (rs = 0.22, P = 0.029) in the overall cohort. Three of 48 (6.3%) patients who had whole-exome sequencing harboured pathogenic/likely pathogenic GBA variants. CONCLUSIONS: Significant heterogeneity in clinical features and disease burden, and high rates of RBD symptoms, visual hallucinations, and familial involvement were observed in this relatively large cohort. Our findings highlight important considerations when assessing Asian patients, and provide further support for the notion of overlapping neurobiology between PSP and Lewy body disorders.

Genetic study of early-onset Parkinson's disease in the Malaysian population.

BACKGROUND: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants. OBJECTIVES: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort. METHODS: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes. CONCLUSIONS: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.

Malnutrition and related factors in Filipino patients with Parkinson's disease: results from a pilot study.

Aim: Emerging evidence demonstrates a bidirectional relationship between nutritional status and Parkinson's disease (PD). Our aim was to determine the local prevalence of malnutrition and associated factors among Filipino PD patients. Materials & methods: We assessed the nutritional status of 95 PD patients using the body mass index (BMI) and Subjective Global Assessment (SGA) and identified malnutrition-associated factors. Results & conclusion: In our sample, the mean BMI was 24.5 ± 4.2 kg/m2. Consistent with published estimates, five (5.3%) patients were classified as underweight and 57 (60%) patients were classified as overweight/obese. A total of 30 (31.6%) patients had abnormal nutritional status based on SGA. Weight-adjusted levodopa equivalent daily dose was a significant factor (p = 0.032) for BMI, while dysphagia and higher weight-adjusted levodopa equivalent daily dose were found to be predictive of abnormal nutritional status using SGA (adjusted odds ratio of 8.85 [95% CI: 1.59-49.17; p = 0.015] and 1.10 [95% CI: 1.02-1.20; p = 0.021], respectively).