TMEM151A Variants Cause Paroxysmal Kinesigenic Dyskinesia: A Large-Sample Study.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one-third of PKD patients are attributed to proline-rich transmembrane protein 2 (PRRT2) mutations. OBJECTIVE: We aimed to explore the potential causative gene for PKD. METHODS: A cohort of 196 PRRT2-negative PKD probands were enrolled for whole-exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case-control analysis, was applied to identify the candidate genes. Another 325 PRRT2-negative PKD probands were subsequently screened with Sanger sequencing. RESULTS: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A-related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A-positive and PRRT2-positive groups. CONCLUSIONS: We consolidated mutations in TMEM151A causing PKD with the aid of case-control analysis of a large-scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A-related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A-related PKD. © 2021 International Parkinson and Movement Disorder Society.

The Phenotypic and Genetic Spectrum of Paroxysmal Kinesigenic Dyskinesia in China.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is a spectrum of involuntary dyskinetic disorders with high clinical and genetic heterogeneity. Mutations in proline-rich transmembrane protein 2 have been identified as the major pathogenic factor. OBJECTIVES: We analyzed 600 paroxysmal kinesigenic dyskinesia patients nationwide who were identified by the China Paroxysmal Dyskinesia Collaborative Group to summarize the clinical phenotypes and genetic features of paroxysmal kinesigenic dyskinesia in China and to provide new thoughts on diagnosis and therapy. METHODS: The China Paroxysmal Dyskinesia Collaborative Group was composed of departments of neurology from 22 hospitals. Clinical manifestations and proline-rich transmembrane protein 2 screening results were recorded using unified paroxysmal kinesigenic dyskinesia registration forms. Genotype-phenotype correlation analyses were conducted in patients with and without proline-rich transmembrane protein 2 mutations. High-knee exercises were applied in partial patients as a new diagnostic test to induce attacks. RESULTS: Kinesigenic triggers, male predilection, dystonic attacks, aura, complicated forms of paroxysmal kinesigenic dyskinesia, clustering in patients with family history, and dramatic responses to antiepileptic treatment were the prominent features in this multicenter study. Clinical analysis showed that proline-rich transmembrane protein 2 mutation carriers were prone to present at a younger age and have longer attack duration, bilateral limb involvement, choreic attacks, a complicated form of paroxysmal kinesigenic dyskinesia, family history, and more forms of dyskinesia. The new high-knee-exercise test efficiently induced attacks and could assist in diagnosis. CONCLUSIONS: We propose recommendations regarding diagnostic criteria for paroxysmal kinesigenic dyskinesia based on this large clinical study of paroxysmal kinesigenic dyskinesia. The findings offered some new insights into the diagnosis and treatment of paroxysmal kinesigenic dyskinesia and might help in building standardized paroxysmal kinesigenic dyskinesia clinical evaluations and therapies. © 2020 International Parkinson and Movement Disorder Society.

Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients.

BACKGROUND: Paroxysmal kinesigenic dyskinesia is the most common type of paroxysmal dyskinesia. Approximately half of the cases of paroxysmal kinesigenic dyskinesia worldwide are attributable to proline-rich transmembrane protein 2 mutations. OBJECTIVE: The objective of this study was to investigate potential causative genes and clinical characteristics in proline-rich transmembrane protein 2-negative patients with paroxysmal kinesigenic dyskinesia. METHODS: We analyzed clinical manifestations and performed exome sequencing in a cohort of 163 proline-rich transmembrane protein 2-negative probands, followed by filtering data with a paroxysmal movement disorders gene panel. Sanger sequencing, segregation analysis, and phenotypic reevaluation were used to substantiate the findings. RESULTS: The clinical characteristics of the enrolled 163 probands were summarized. A total of 39 heterozygous variants were identified, of which 33 were classified as benign, likely benign, and uncertain significance. The remaining 6 variants (3 novel, 3 documented) were pathogenic and likely pathogenic. Of these, 3 were de novo (potassium calcium-activated channel subfamily M alpha 1, c.1534A>G; solute carrier family 2 member 1, c.418G>A; sodium voltage-gated channel alpha subunit 8, c.3640G>A) in 3 sporadic individuals, respectively. The other 3 (paroxysmal nonkinesiogenic dyskinesia protein, c.956dupA; potassium voltage-gated channel subfamily A member 1, c.765C>A; Dishevelled, Egl-10, and Pleckstrin domain containing 5, c.3311C>T) cosegregated in 3 families. All 6 cases presented with typical paroxysmal kinesigenic dyskinesia characteristics, except for the Dishevelled, Egl-10, and Pleckstrin domain containing 5 family, where the proband's mother had abnormal discharges in her temporal lobes in addition to paroxysmal kinesigenic dyskinesia episodes. CONCLUSIONS: Our findings extend the genotypic spectrum of paroxysmal kinesigenic dyskinesia and establish the associations between paroxysmal kinesigenic dyskinesia and genes classically related to other paroxysmal movement disorders. De novo variants might be a cause of sporadic paroxysmal kinesigenic dyskinesia. © 2018 International Parkinson and Movement Disorder Society.

Positive association of serum FUT8 activity with renal tubulointerstitial injury in IgA nephropathy patients.

BACKGROUND: α-1,6 Fucosyltransferase (FUT8) appears to play an essential role in the pathogenesis of renal fibrosis. However, it remained unknown whether FUT8 also contributed to renal fibrosis in immunoglobulin A nephropathy (IgAN). In the present study, we explored the association of serum FUT8 activity with renal tubulointerstitial injury in IgAN patients. METHODS: Serum FUT8 activity was measured in 135 IgAN patients and 68 healthy controls from January 2016 to December 2018. The relationships of serum FUT8 activity with clinical and pathological features were analyzed. RESULTS: Relative to healthy controls, IgAN patients had significantly higher serum FUT8 activity and upregulation of renal FUT8 protein (p < .05). Among IgAN patients, there was a positive correlation of serum FUT8 activity with renal FUT8 protein expression (p < .05). Multivariable logistic regression analyses showed that serum FUT8 activity was significantly associated with serum creatinine and eGFR (p < .05). Based on a cut-off value determined from ROC curve analysis, we divided IgAN patients into a low serum FUT8 activity group (≤12.2 pmol/h/mL, n = 40) and a high serum FUT8 activity group (>12.2 pmol/h/ml, n = 95). The high serum FUT8 activity group had a higher Oxford T score, increased inflammatory cell infiltration, more severe fibrosis and poor renal function (p < .05). CONCLUSION: Serum FUT8 activity was positive association with renal tubulointerstitial injury in IgAN patients.

A proposed synergistic effect of CSF1R and NMUR2 variants contributes to binge eating in hereditary diffuse leukoencephalopathy with spheroids.

BACKGROUND: The genetic mechanisms of binge eating (BE) as a disease identity remain obscure. BE is usually viewed as a part of the behavioral variant of frontotemporal dementia (bvFTD) features. We encountered a family with hereditary diffuse leukoencephalopathy with spheroids (HDLS) that manifested uniformly with binge-eating-onset dementia. The genetic factors associated with the rare phenotype were investigated. METHODS: The detailed phenotypes of the patients were described. We performed whole-exome sequencing (WES) of family members and repeat-primed PCR to analyze the patients' expansion size of C9orf72, a well-established gene causing FTD. The WES results of additional HDLS patients without BE manifestations were also investigated. RESULTS: All affected individuals had a BE-dementia-epilepsy pattern of disease progression. A recurrent disease-causing mutation in CSF1R established the diagnosis of HDLS in the family. No abnormalities in the expansion size of C9orf72 were detected. The concurrence of a recurrent CSF1R mutation and a rare variant in NMUR2, a gene functionally related to BE, was revealed in the affected family members. No potentially pathogenic variants in other known BE-associated genes were identified. Both the NMUR2 variant and the CSF1R mutation cosegregated with the BE-dementia-epilepsy phenotype in the family. In three additional HDLS patients without BE, no pathogenic variants in NMUR2 were detected. CONCLUSIONS: We propose that synergistic genetic effects of NMUR2 and CSF1R variants may exist and contribute to the development of the BE phenotype in HDLS. NMUR2 is one of the potential susceptible genes in BE and may contribute in a background of a disrupted structural neuronetwork. Further studies in other BE-related disorders are required.

Identification of a novel loss-of-function C9orf72 splice site mutation in a patient with amyotrophic lateral sclerosis.

Abnormal expansion of a hexanucleotide GGGGCC repeat in the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasians. However, the underlying pathologic mechanisms remain controversial, and both loss-of-function and gain-of-function models have been proposed. To gain further insight into these mechanisms, we performed mutation analysis of C9orf72 in 276 Han Chinese patients with ALS. We identified GGGGCC expansions in 2 cases of sporadic ALS with 38 and 63 repeats, as well as a novel splice site mutation (c.601-2A>G) in a third case. These genetic alterations were not detected in 332 control patients without neurological disease. Intriguingly, functional analysis revealed that the splice site mutation disrupted the reading frame, creating a premature stop codon (p.I201fsX235). Decreased levels of the mutant messenger RNA were detected in patient cells, suggesting that it may undergo nonsense-mediated messenger RNA decay. Taken together, these results demonstrate that C9orf72 mutation is infrequently associated with ALS in Han Chinese patients and suggest that a splice site mutation in C9orf72 may lead to loss of function due to haploinsufficiency of the resulting protein.

Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS.

OBJECTIVE: To identify the disease-causing gene of a family with upper limb predominant, slowly progressive amyotrophic lateral sclerosis (ALS), which was diagnosed as flail arm syndrome (FAS). METHODS: After causation of 24 known ALS genes was excluded by targeted next-generation sequencing, whole-exome sequencing was applied in the FAS family. Cellular localization of mutant hnRNPA1 was examined in transfected HeLa cells. An additional 251 Chinese patients with ALS (including 7 sporadic FAS) underwent mutation screening of hnRNPA1. RESULTS: We detected a novel missense mutation in hnRNPA1, c.862/1018C>T (p.P288S/P340S), which cosegregated with disease in the FAS family. The residue is highly conserved across species and exists in the encoded PY nuclear localization signal of hnRNPA1 protein. Mutant hnRNPA1 showed altered intracellular localization, resulting in formation of cytoplasmic inclusions that colocalized with stress granules in transfected cells. Further mutation screening of hnRNPA1 in additional patients with FAS and typical ALS detected 2 rare variants with unknown significance. These variants lie in the prion-like domain of hnRNPA1 long isoform, which was detected exclusively in the CNS. CONCLUSIONS: Our results suggest that hnRNPA1 is the causative gene in the family with flail arm ALS. This further expanded the disease phenotype of hnRNPA1 mutations.

Quick genetic screening using targeted next-generation sequencing in patients with tuberous sclerosis.

Tuberous sclerosis complex is an autosomal dominant disorder characterized by hamartomas in multiple organ systems. Mutations in the 2 large genes TSC1 and TSC2 have been demonstrated to be associated with tuberous sclerosis complex by various mutation screening methods. Targeted next-generation sequencing for genetic analysis is performed in the current study and is proved to be less cost, labor, and time consuming compared with Sanger sequencing. Two de novo and 1 recurrent TSC2 mutation in patients with tuberous sclerosis complex were revealed. Clinical details of patients were described and the underlying mechanism of the 2 novel TSC2 mutations, c.245G>A(p.W82X) and c.5405_5408dupACTT(p.P1803Lfs*25), were discussed. These results added to variability of TSC mutation spectrum and suggest that targeted next-generation sequencing could be the primary choice over Sanger sequencing in future tuberous sclerosis complex genetic counseling.

Re-evaluation of PRRT2 mutations in paroxysmal disorders.

Mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Other paroxysmal disorders like febrile seizures, migraine, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia have also been shown to be associated with this gene. We re-evaluated PRRT2 mutations and genetic-clinical correlations in additional cases with PKD/ICCA and other paroxysmal disorders. Two novel mutations in PRRT2 were revealed in PKD/ICCA cases, while no mutations were detected in other diseases, which suggests BFIE and PKD are still core phenotypes of PRRT2-related spectrum disorders.