Early-onset familial essential tremor is associated with nucleotide expansions of spinocerebellar ataxia in China.

BACKGROUND: Essential tremor (ET) is a neurological disease characterized by action tremor in upper arms. Although its high heritability and prevalence worldwide, its etiology and association with other diseases are still unknown. METHOD: We investigated 10 common spinocerebellar ataxias (SCAs), including SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, SCA36, dentatorubral-pallidoluysian atrophy (DRPLA) in 92 early-onset familial ET pedigrees in China collected from 2016 to 2022. RESULT: We found one SCA12 proband carried 51 CAG repeats within PPP2R2B gene and one SCA3 proband with intermediate CAG repeats (55) with ATXN3 gene. The other 90 ET probands all had normal repeat expansions. CONCLUSION: Tremor can be the initial phenotype of certain SCA. For early-onset, familial ET patients, careful physical examinations are needed before genetic SCA screening.

Spinocerebellar ataxia type 8 presents as progressive supranuclear palsy.

Spinocerebellar ataxia type 8 is a progressive neurodegenerative disease induced by expansion of CTA/CTG repeats in an untranslated region of the ATXN8/ATXN8OS gene. We report an elderly female patient presenting with rigidity, bradykinesia, ataxia and oculomotor defect at the disease onset age of 65 years old without family history, and hummingbird sign in cranial MRI, initially diagnosed as progressive supranuclear palsy (PSP). But genetic test showed that one allele of ATXN8OS gene had more than 131 CTA/CTG repeats which was a full penetrance mutant. It's possible that this is a case of PSP with an ATXN8OS gene mutation that doesn't contribute to the phenotype. Whether the ATXN8OS gene CTA/CTG repeats cause PSP phenotype needs further investigation with larger samples and pathological findings.

Trends in Prevalence and Disability-Adjusted Life-Years of Alzheimer's Disease and Other Dementias in China from 1990 to 2019.

INTRODUCTION: China has the largest population of people with dementia in the world and is estimated to have approximately a quarter of the entire population with dementia worldwide, bringing a heavy burden on the public and healthcare systems. We aimed to analyze the burden of Alzheimer's disease and other dementias in China over the past three decades. METHODS: The data on disease burden owing to Alzheimer's disease and other dementias in China from 1990 to 2019 were extracted from the Global Burden of Disease (GBD) 2019 datasets. The estimated annual percentage changes (EAPCs) were calculated to assess the temporal trends, and the ratio of years lived with disability (YLDs) to disability-adjusted life-years (DALYs) was used as an indicator to evaluate the healthcare system. RESULT: In China, the overall age-standardized rates (ASRs) of the prevalence and DALYs of Alzheimer's disease and other dementias increased from 1990 to 2019, and their EAPCs were 0.66 (95% confidence interval [CI], 0.57-0.75) and 0.26 (95% CI, 0.21-0.31), respectively. ASRs and the total number of dementia in females remained higher than in males, but the upward trend in ASRs among men was more pronounced than in women. The female-to-male ratio of the age-standardized DALY rate peaked in the 75-79 year age group in 2019 (female-to-male ratio of 1.32). The YLDs:DALYs ratio in China experienced a gradual increase and finally stayed above the global average since 2011. CONCLUSION: China has experienced a remarkably rising burden of dementia over the past three decades. The more significant burden of dementia was in females, but the potentially increasing burden of dementia in males cannot be underestimated.

The clinical characteristics of neuronal intranuclear inclusion disease and its relation with inflammation.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a great imitator with a broad spectrum of clinical manifestations that include dementia, parkinsonism, paroxysmal symptoms, peripheral neuropathy, and autonomic dysfunction. Hence, it may also masquerade as other diseases such as Alzheimer's disease, Parkinson's disease, and Charcot-Marie-Tooth disease. Recent breakthroughs on neuroimaging, skin biopsy, and genetic testing have facilitated the diagnosis. However, early identification and effective treatment are still difficult in cases of NIID. OBJECTIVE: To further study the clinical characteristics of NIID and investigate the relationship between NIID and inflammation. METHODS: We systematically evaluated the clinical symptoms, signs, MRI and electromyographical findings, and pathological characteristics of 20 NIID patients with abnormal GGC repeats in the NOTCH2NLC gene. Some inflammatory factors in the patients were also studied. RESULTS: Paroxysmal symptoms such as paroxysmal encephalopathy, stroke-like episodes, and mitochondrial encephalomyopathy lactic acidosis and stroke (MELAS)-like episode were the most common phenotypes. Other symptoms such as cognitive dysfunction, neurogenic bladder, tremor, and vision disorders were also suggestive of NIID. Interestingly, not all patients showed apparent diffusion-weighted imaging (DWI) abnormality or intranuclear inclusions, while abnormal GGC repeats of NOTCH2NLC were seen in all patients. And fevers were noticed in some patients during encephalitic episodes, usually with increasing leukocyte counts and neutrophil ratios. Both IL-6 (p = 0.019) and TNF-α (p = 0.027) levels were significantly higher in the NIID group than in normal controls. CONCLUSION: Genetic testing of NOTCH2NLC may be the best choice in the diagnosis of NIID. Inflammation might be involved in the pathogenesis of NIID.

Association Analysis of 27 Single Nucleotide Polymorphisms in a Chinese Population with Essential Tremor.

Genetic factors play a major role in essential tremor (ET) pathogenesis. This study aimed to assess variant burden in ET-associated genes in a relatively large Chinese population cohort. We genotyped 27 single nucleotide polymorphisms (SNPs) previously reported to be associated with ET by multiplex PCR amplicon sequencing assay in 488 familial and sporadic ET patients and 514 healthy controls (HCs). Then, we performed allelic and genotypic association test by Pearson chi-square test or Fisher's exact test. A total of 1002 samples were included in our analysis, consisting of 488 ET patients and 514 sex and age-matched HCs. For rs10937625, the C allele was linked to increased risk of ET (P = 0.019, OR = 1.503, 95% CI = 1.172-1.928). The carriers of the C/C homozygote and C/T heterozygote showed a significantly higher risk of ET, compared with the T/T homozygote under the dominant model (P = 0.019, OR = 1.628, 95% CI = 1.221-2.170). There were no statistically significant differences in the frequency of other SNPs between ET patients and healthy controls. Rs10937625 (STK32B) may increase the risk of ET in eastern Chinese population.

Burden of Parkinson Disease in China, 1990-2019: Findings from the 2019 Global Burden of Disease Study.

INTRODUCTION: China has the most people with Parkinson disease (PD) in the world and is estimated to have over half of the worldwide PD population. The objective of this study was to analyze the corresponding burden of PD in China for the past decades. METHOD: Data on disease burden related to PD in China were retrieved from the Global Burden of Disease (GBD) 2019 study. The estimated annual percentage changes (EAPCs) were calculated to assess temporal trends, and the ratio of years lived with disability (YLDs) to disability-adjusted life years (DALYs) was used as an index to evaluate the healthcare system. RESULT: Nationally, the burden of PD increased from 1990 to 2019. Although the age-standardized incidence rate (ASIR) increased, the age-standardized death rate (ASDR) and age-standardized DALY rate both decreased. Age-standardized rates of PD in males remained higher than those in females, but trends in ASDR and the age-standardized DALY rate for females showed a pronounced decrease. The most remarkable increase in the ASIR was in individuals aged 45-49 years, with an EAPC of 1.74 (95% confidence interval, 1.26-2.21). The YLDs:DALYs ratio continuously increased compared with global figures and even with countries with high sociodemographic index (SDI). CONCLUSION: Although ASDR and age-standardized DALY rates for PD have been declining, the burden of PD still needs attention as the total numbers have increased over the period. Generally, the greater burden of PD was in males. A sound health system with services tailored to PD continues to be required in the future.

Autosomal dominant sleep-related hypermotor epilepsy associated with a novel mutation of KCNT1.

Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by severe sleep-related rigid hypermotor seizures. The pathogenic genes of ADSHE include genes encoding subunits of the neuronal nicotinic acetylcholine receptor, KCNT1, DEPDC5, NPRL2/3, CABP4, and CRH. Individuals with KCNT1-related ADSHE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems. In this study, a 12-year-old Chinese girl was referred for genetic evaluation of grand mal seizures. She had paroxysmal convulsions of the limbs and loss of consciousness just after falling asleep without obvious triggers. A novel heterozygous missense mutation c.2797C > T (p.Arg933Cys) in exon 24 of the KCNT1 was identified in the proband by whole-exome sequencing and Sanger sequencing, and the clinical symptoms were compatible with ADSHE. The proband's father has been showing similar symptoms for more than 20 years and had the same site mutation. Her mother and sister were physically and genetically normal. The study revealed a novel variant in the KCNT1 and expanded the mutation spectrum for this clinical condition. Our results provide further evidence supporting a causative role in KCNT1 variants in ADSHE.

Neuroimaging evidence of glymphatic system dysfunction in possible REM sleep behavior disorder and Parkinson's disease.

Alpha-synucleinopathy is postulated to be central to both idiopathic rapid eye movement sleep behaviour disorder (iRBD) and Parkinson's disease (PD). Growing evidence suggests an association between the diminished clearance of α-synuclein and glymphatic system dysfunction. However, evidence accumulating primarily based on clinical data to support glymphatic system dysfunction in patients with iRBD and PD is currently insufficient. This study aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship to clinical scores of disease severity in patients with possible iRBD (piRBDs) and those with PD. Further, we validated the correlation between the ALPS index and the prognosis of PD longitudinally. Overall, 168 patients with PD, 119 piRBDs, and 129 healthy controls were enroled. Among them, 50 patients with PD had been longitudinally reexamined. Patients with PD exhibited a lower ALPS index than those with piRBDs (P = 0.036), and both patient groups showed a lower ALPS index than healthy controls (P < 0.001 and P = 0.001). The ALPS index and elevated disease severity were negatively correlated in the piRBD and PD subgroups. Moreover, the ALPS index was correlated with cognitive decline in patients with PD in the longitudinal analyses. In conclusion, DTI-ALPS provided neuroimaging evidence of glymphatic system dysfunction in piRBDs and patients with PD; however, the potential of assessing the pathological progress of α-synucleinopathies as an indicator is worth verifying. Further development of imaging methods for glymphatic system function is also warranted.

Concomitant Othello syndrome and impulse control disorders in a patient with Parkinson's disease: A case report.

BACKGROUND: Othello syndrome (OS) is characterized by delusional beliefs concerning the infidelity of a spouse or sexual partner, which may lead to extreme behaviors. Impulse control disorders refer to behaviors involving repetitive, excessive, and compulsive activities driven by an intense desire. Both OS and impulse control disorders in Parkinson's disease (PD) may be side effects of dopamine agonists. At present, there are only a few case reports and studies related to PD with concomitant OS and impulse control disorders. CASE SUMMARY: We describe a 70-year-old male patient with PD, OS, and impulse control disorders, who presented with a six-month history of the delusional belief that his wife was having an affair with someone. He began to show an obvious increase in libido presenting as frequent masturbation. He had been diagnosed with PD ten years earlier and had no past psychiatric history. In his fourth year of PD, he engaged in binge eating, which lasted approximately one year. Both OS and hypersexuality were alleviated substantially after a reduction of his pramipexole dosage and a prescription of quetiapine. CONCLUSION: Given its potential for severe consequences, OS should be identified early, especially in patients undergoing treatment with dopamine agonists.

Risk factors of impulsive-compulsive behaviors in PD patients: a meta-analysis.

OBJECTIVE: To summarize the reliable risk factors of impulsive-compulsive behaviors (ICBs) in Parkinson's disease (PD) patients through a meta-analysis on studies in which PD-ICBs were diagnosed by clinical interview. METHODS: PubMed, Embase, Web of Science, CNKI and Wanfang databases were searched. We selected studies ensuring that diagnosis of ICBs in PD patients depends on semi-structured interviews according to the clinical diagnostic criteria of ICBs. The Newcastle-Ottawa Scale was used to evaluate quality of the included studies. The analyzed factors included demographic information, clinical characteristics of PD and medications. RESULTS: A total of 856 records were screened and 66 full texts were evaluated, and 13 studies (684 PD patients with ICBs [PD-ICBs] and 3,382 PD patients without ICBs [PD-non-ICBs]) were included. Compared with PD-non-ICBs, PD-ICBs were younger in age (- 3.7 [- 5.53, - 1.87], P < 0.0001), with a greater proportion of males (1.64 [1.21, 2.22], P = 0.001), with a younger age of PD onset (- 5.42 [- 7.87, - 2.97], P < 0.0001) and a longer course of PD (1.30 [0.38, 2.22], P = 0.005). PD-ICBs were also associated with higher HAM-D (1.74 [0.47, 3.01], P = 0.007), more levodopa dosage (1.74 [1.09, 2.77], P = 0.02) and dopamine receptor agonists (DA) use (3.96 [2.74, 5.71), P < 0.00001), and higher average dose (levodopa 117.53 [53.59, 181.46], P = 0.0003; DA 80.03 [46.16, 113.90], P < 0.00001), as well as more amantadine use (2.20 [1.42, 3.40], P = 0.0004). The meta-analysis of most factors showed less heterogeneity, except age, age of onset, PD duration, Hoehn and Yahr stage, MMSE and drug dosage. However, whether rapid eye movement sleep behavior disorder, dyskinesia, genetic polymorphism and other factors are risk factors for PD-ICBs remains unclear. CONCLUSION: This meta-analysis suggests that males, young, early disease onset, long disease duration, depression, dose of levodopa, dopamine receptor agonists and amantadine are risk factors of ICBs in PD patients.

Validation of the Chinese Version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease.

Background: Impulse control and related disorders (ICRDs) have gained recognition as a severe complication of Parkinson's disease (PD) and are connected to poor quality of life and devastating financial and social problems. This study aimed to evaluate the usefulness of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) and estimate the risk factors for ICRDs in Chinese patients with PD. Methods: 207 PD patients were assessed using the QUIP and evaluated for PD motor and nonmotor symptoms. ICRDs were diagnosed via interviews of patients or their caregivers, and the clinical characteristics of patients with and without ICRDs were compared. Results: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the C-QUIP were 95.0, 83.4, 38.0, 99.4, and 84.5%. The prevalence of each disorder among participants diagnosed via interview was pathological gambling (0.5%), hypersexuality (1.9%), compulsive shopping (1.0%), binge eating (3.9%), hobbyism (1.9%), punding (0.5%), walkabout (0.5%), and dopamine dysregulation syndrome (2.9%). PD patients with ICRDs had longer PD duration, higher Hoehn and Yahr stage, Non-Motor Symptoms Scale (NMSS), and Hamilton-Depression Rating Scale (HAMD). Also, they received a larger total daily levodopa equivalent dose (LED), levodopa dosage, and dopamine agonist only LED (DA-LED) than did PD patients without ICRDs. Conclusions: Given its psychometric properties, the C-QUIP is a valid and rapid screening instrument for assessing of ICRDs in PD patients. Higher Hoehn and Yahr staging, NMSS and HAMD scores, a larger mean LED and levodopa dosage are risk factors for ICRDs.

NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders.

The NOTCH2NLC gene 5' untranslated region (UTR) GGC repeat expansion mutations were identified as a genetic contributor of neuronal intranuclear inclusion disease (NIID) in 2019. Since then, the number of reported cases with NOTCH2NLC GGC repeat expansion in Asian and European populations has increased rapidly, indicating that the expanded mutation not only leads to the onset or progression of the NIID, but also may play an important role in multiple progressive neurological disorders, including Parkinson's disease, essential tremor, multiple system atrophy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, leukoencephalopathy, and oculopharyngodistal myopathy type 3. Nevertheless, the underlying pathogenic mechanism of the NOTCH2NLC 5' UTR region GGC repeat expansion in these disorders remains largely unknown. This review aims to present recent breakthroughs on this mutation and improve our knowledge of a newly defined spectrum of disease: NOTCH2NLC-related repeat expansion disorder.

Compound heterozygous mutations in the neuraminidase 1 gene in type 1 sialidosis: A case report and review of literature.

BACKGROUND: Type 1 sialidosis, also known as cherry-red spot-myoclonus syndrome, is a rare autosomal recessive lysosomal storage disorder presenting in the second decade of life. The most common symptoms are myoclonus, ataxia and seizure. It is rarely encountered in the Chinese mainland. CASE SUMMARY: A 22-year-old male presented with complaints of progressive myoclonus, ataxia and slurred speech, without visual symptoms; the presenting symptoms began at the age of 15-year-old. Whole exome sequencing revealed two pathogenic heterozygous missense variants [c.239C>T (p.P80L) and c.544A>G (p.S182G) in the neuraminidase 1 (NEU1) gene], both of which have been identified previously in Asian patients with type 1 sialidosis. All three patients identified in Mainland China come from three unrelated families, but all three show the NEU1 mutations p.S182G and p.P80L pathogenic variants. Increasing sialidase activity through chaperones is a promising therapeutic target in sialidosis. CONCLUSION: Through retrospective analysis and summarizing the clinical and genetic characteristics of type 1 sialidosis, we hope to raise awareness of lysosomal storage disorders among clinicians and minimize the delay in diagnosis.

Chinese patient with cerebrotendinous xanthomatosis confirmed by genetic testing: A case report and literature review.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a treatable autosomal recessive inherited metabolic disorder. It results from a deficiency of sterol 27-hydroxylase (CYP27A1), which is a mitochondrial cytochrome P450 enzyme that catalyzes the hydroxylation of cholesterol and modulates cholesterol homeostasis. Patients with CYP27A1 deficiency show symptoms related to excessive accumulation of cholesterol and cholestanol in lipophilic tissues such as the brain, eyes, tendons, and vessels, resulting in juvenile cataracts, tendon xanthoma, chronic diarrhea, cognitive impairment, ataxia, spastic paraplegia, and peripheral neuropathy. CTX is underdiagnosed as knowledge of the disorder is mainly based on case reports. CASE SUMMARY: A Chinese family with CTX consisting of one patient and four heterozygous carriers was studied. The patient is a 47-year-old male, who mainly had psychiatric signs but without some cardinal features of CTX such as cataracts, cerebellar ataxia, pyramidal signs and chronic diarrhea. There was a significant increase in the concentration of free fatty acid compared to normal range. Doppler ultrasound of the urinary system showed multiple left kidney stones, a right kidney cyst, and a hypoechoic area in the bladder, which could move with body position. Sagittal and axial magnetic resonance imaging (MRI) of the right ankle joint showed apparent enlargement of the right Achilles tendon and upper medial malleolus flexor tendon, abnormal thickening of the plantar fat, and a small amount of exudation around the fascia in front of the Achilles tendon. Cerebral MRI suggested white matter (WM) demyelination and slight cerebral atrophy. The diagnosis was confirmed by targeted sequencing, which identified compound heterozygous mutations in exon 2 and intron 7 of the CYP27A1 gene (c.435G>T, c.1263+1G>A). Treatment for 3 wk with a combination of lipid-lowering and antipsychotic therapy improved his psychiatric symptoms and normalized the levels of serum free fatty acid. Sediments in the bladder disappeared after therapy. CONCLUSION: CYP27A1 genetic analysis should be the definitive method for CTX diagnosis. This case suggests that urinary system diseases may be neglected in CTX patients. The clinical, biological, radiological, and genetic characteristics of CTX are summarized to promote early diagnosis and treatment of this disease.

[Progress of clinical and genetic research on distal hereditary motor neuropathy].

Distal hereditary motor neuropathy (dHMN) is a group of clinically and genetically heterogeneous disorders characterized by progressive distal weakness and atrophy. The onset of dHMN is at mid-adulthood or early childhood, and the symptoms are mainly present in the lower limbs. Besides weakness and atrophy of distal limb muscles, some patients may develop bulbar paralysis, and some may also present with mild sensory disturbance. Decreased or absent tendon reflexes may be discovered. Electromyography may show neurogenic damages. Muscular biopsy may reveal neurogenic amyotrophy. An increasing number of genes have been associated with dHMN. Pathogenesis of dHMN may include formation of protein aggregates, impairment of autophagy pathway, RNA processing, translation synthesis, axonal transport, endoplasmic reticulum stress, calcium channel and neuroprotection. A review for recent progress made on clinical characterization and molecular genetics of dHMN is provided.