RESUMO
Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAAâ¢TTC repeat expansion in FGF14 . Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAAâ¢TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells, and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAAâ¢TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14 . We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAAâ¢TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure and late-onset cerebellar involvement in SCA27B.
RESUMO
The factors driving or preventing pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 (GAA)·(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a common 5'-flanking variant in 70.34% of alleles analyzed (3,463/4,923) that represents the phylogenetically ancestral allele and is present on all major haplotypes. This common sequence variation is present nearly exclusively on nonpathogenic alleles with fewer than 30 GAA-pure triplets and is associated with enhanced stability of the repeat locus upon intergenerational transmission and increased Fiber-seq chromatin accessibility.
Assuntos
Alelos , Fatores de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Haplótipos , Variação Genética , Loci GênicosRESUMO
The autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS: OMIM #617062) is a rare neurodevelopmental disorder first described in 2016. Features include developmental delay (DD), intellectual disability (ID), behavioral problems, hypotonia, language deficits, congenital heart abnormalities, and non-specific dysmorphic facial features. OCNDS is caused by heterozygous pathogenic variants in CSNK2A1 (OMIM *115440; NM_177559.3). To date, 160 patients have been diagnosed worldwide. The number will likely increase due to the growing use of exome sequencing (ES) and genome sequencing (GS). Here, we describe a novel OCNDS patient carrying a CSNK2A1 variant (NM_177559.3:c.140G>A; NP_808227.1:p.Arg47Gln). Phenotypically, he presented with DD, ID, generalized hypotonia, speech delay, short stature, microcephaly, and dysmorphic features such as low-set ears, hypertelorism, thin upper lip, and a round face. The patient showed several signs not yet described that may extend the phenotypic spectrum of OCNDS. These include prenatal bilateral clubfeet, exotropia, and peg lateral incisors. However, unlike the majority of descriptions, he did not present sleep disturbance, seizures or gait difficulties. A literature review shows phenotypic heterogeneity for OCNDS, whether these patients have the same variant or not. This case report is an opportunity to refine the phenotype of this syndrome and raise the question of the genotype-phenotype correlation.
Assuntos
Caseína Quinase II , Transtornos do Neurodesenvolvimento , Criança , Humanos , Masculino , Caseína Quinase II/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Sequenciamento do Exoma , Predisposição Genética para Doença , Heterozigoto , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Mutação , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/diagnóstico , FenótipoRESUMO
Global meat consumption has risen steadily in recent decades, with heterogeneous growth rates across regions. While meat plays a critical role in providing essential nutrients for human health, excessive consumption of meat, particularly red and processed meat, has also been associated with a higher risk of certain chronic diseases. This has led public authorities, including the World Health Organization, to call for a reduction in meat consumption. How governments can effectively reduce the health costs of meat consumption remains a challenge as implementing effective policy instruments is complex. This paper examines health-related policy instruments and potential economic mechanisms that could reduce meat consumption. Health-related taxation could be the most effective instrument. Other policy instruments, such as informational and behavioral instruments, along with regulations, could discourage meat consumption depending on the policy design. We also provide evidence on the link between meat consumption and the environment, including climate, biodiversity, water use, and pollution. Promoting healthy behaviors by reducing meat consumption can then have environmental co-benefits and promote broader sustainable development goals. We also discuss the policy-related challenges that need to be addressed to meet environmental co-benefits.
Assuntos
Política de Saúde , Carne , Humanos , Carne/efeitos adversos , Desenvolvimento Sustentável , ImpostosRESUMO
Background: GAA-FGF14 ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of the FGF14 gene. Initial studies revealed cerebellar atrophy in 74-97% of patients. A more detailed brain imaging characterization of GAA-FGF14 ataxia is now needed to provide supportive diagnostic features and earlier disease recognition. Methods: We performed a retrospective review of the brain MRIs of 35 patients (median age at MRI 63 years; range 28-88 years) from Quebec (n=27), Nancy (n=3), Perth (n=3) and Bengaluru (n=2) to assess the presence of atrophy in vermis, cerebellar hemispheres, brainstem, cerebral hemispheres, and corpus callosum, as well as white matter involvement. Following the identification of the superior cerebellar peduncles (SCPs) involvement, we verified its presence in 54 GAA-FGF14 ataxia patients from four independent cohorts (Tübingen n=29; Donostia n=12; Innsbruck n=7; Cantabria n=6). To assess lobular atrophy, we performed quantitative cerebellar segmentation in 5 affected subjects with available 3D T1-weighted images and matched controls. Results: Cerebellar atrophy was documented in 33 subjects (94.3%). We observed SCP involvement in 22 subjects (62.8%) and confirmed this finding in 30/54 (55.6%) subjects from the validation cohorts. Cerebellar segmentation showed reduced mean volumes of lobules X and IV in the 5 affected individuals. Conclusions: Cerebellar atrophy is a key feature of GAA-FGF14 ataxia. The frequent SCP involvement observed in different cohorts may facilitate the diagnosis. The predominant involvement of lobule X correlates with the frequently observed downbeat nystagmus.
RESUMO
BACKGROUND: Whether spinocerebellar ataxia 27B (SCA27B) may present as a cerebellar multiple system atrophy (MSA-C) mimic remains undetermined. OBJECTIVES: To assess the prevalence of FGF14 (GAA)≥250 expansions in patients with MSA-C, to compare SCA27B and MSA-C clinical presentation and natural history. METHODS: FGF14 expansion screening combined with longitudinal deep-phenotyping in a prospective cohort of 195 patients with sporadic late-onset cerebellar ataxia. RESULTS: After a mean disease duration of 6.4 years, 111 patients were not meeting criteria for MSA-C while 24 and 60 patients had a final diagnosis of possible and probable MSA-C, respectively. 16 patients carried an FGF14 (GAA)≥250 expansion in the group not meeting MSA-C criteria (14.4%), 3 patients in the possible MSA-C group (12.5%), but none among probable MSA-C cases. SCA27B patients were evolving more slowly than probable MSA-C patients. CONCLUSIONS: FGF14 (GAA)≥250 expansion may account for MSA look-alike cases and should be screened among slow progressors.
Assuntos
Atrofia de Múltiplos Sistemas , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Estudos Prospectivos , Ataxias Espinocerebelares/diagnóstico , Cerebelo , Degenerações Espinocerebelares/diagnósticoRESUMO
Objectives: Paroxysmal ataxia is typically characterized by early-onset attacks of cerebellar ataxia. Late-onset cerebellar ataxia (LOCA) comprises a group of neurodegenerative disorders mainly characterized by adult-onset progressive cerebellar ataxia. A deep intronic expansion of a GAA triplet in the FGF14 gene encoding fibroblast growth factor 14 has recently been identified as a frequent cause of LOCA. Methods: We describe a patient with paroxysmal ataxia/dysarthria due to a FGF14 repeat expansion and 3 affected family members. Results: The 4 patients had paroxysmal ataxia/dysarthria occurring between 45 and 50 years as the initial manifestation of a FGF14 repeat expansion. The index case was investigated in detail. We have provided a video showing one of her paroxysmal episodes that could be triggered by alcohol, coffee, exertion, emotion, or cigarette smoking. Brain MRI revealed mild cerebellar atrophy, and oculography showed a subclinical downbeat nystagmus. Treatment with acetazolamide resulted in remarkable improvement. Discussion: Paroxysmal dysarthria/ataxia should prompt the clinician to test for FGF14 repeat expansion/SCA27B, especially when the paroxysmal attacks are associated with late-onset cerebellar ataxia and/or a family history consistent with a dominant disorder.
RESUMO
Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70-100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures.
Assuntos
Transtornos do Neurodesenvolvimento , Patologia Molecular , Humanos , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Metilação de DNA , BiomarcadoresRESUMO
BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. METHODS: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. FINDINGS: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. INTERPRETATION: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. FUNDING: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.
Assuntos
Ataxia Cerebelar , Ataxia de Friedreich , Criança , Humanos , Ataxia/diagnóstico , Ataxia/genética , Austrália , Canadá , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Estudos Transversais , Ataxia de Friedreich/genéticaRESUMO
Ashton C et al report a retrospective multi-centre cohort of 34 patients from Canada, France, Austria and Australia with spinocerebellar ataxia 27B, describing the common feature of episodic ataxia and other episodic features, as well as the inefficacy of acetazolamide in these patients.
RESUMO
OBJECTIVE: Heterozygous variations in microtubule-associated serine/threonine kinase 1 gene (MAST1) were recently described in the mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCCCHCM, MIM 618273), revealing the importance of the MAST genes family in global brain development. To date, patients with MAST1 gene mutations were mostly young children with central nervous system involvement, impaired motor function, speech delay, and brain magnetic resonance imaging (MRI) abnormalities. Here, we report the clinical presentation of an adult patient with a rare and de novo MAST1 mutation with central hypogonadism that could extend this phenotype. METHODS: A panel of 333 genes involved in epilepsy or cortical development was sequenced in the described patient. Routine biochemical analyses were performed, and hormonal status was investigated. RESULT: We report a 22-year-old man with a de novo, heterozygous missense variant in MAST1 (Chr19(GRCh37):g.12975903G > A, NP_055790.1:p.Gly517Ser). He presented with an epileptic encephalopathy associated with cerebral malformations, short stature, hypogonadotropic hypogonadism, and secondary osteopenia. CONCLUSION: This is the first patient with MAST1 gene mutation described with central hypogonadism, which may be associated with the phenotype of MCCCHCM syndrome.
Assuntos
Hipogonadismo , Leucoencefalopatias , Malformações do Sistema Nervoso , Criança , Masculino , Humanos , Pré-Escolar , Adulto Jovem , Adulto , Malformações do Sistema Nervoso/genética , Leucoencefalopatias/genética , Mutação , Microtúbulos , Hipogonadismo/genéticaRESUMO
To assess the impact of taxation on the consumption of sugar-sweetened beverages (SSBs) most economic studies using household data consider the average consumer. Individual consumption is, however, very heterogeneous. In this paper, we propose a three-step methodology to evaluate the impact of SSB taxation on individual consumption. First, we use a disaggregation method to recover individual consumption from observed household consumption. Second, we estimate the demand for different categories of households. Finally, we simulate the impact of a tax policy on individual consumption. We find a high level of heterogeneity in consumption. Adults, both men and women, consume a greater quantity of SSBs than children. More importantly, for any given age category, the average consumption of SSBs increases with body mass index (BMI). Among heavy consumers of SSBs, obese and overweight people are over-represented. In France, a 0.20/l tax on SSBs might decrease sugar intake by more than 2 kg per year on average and by more than 5 kg, roughly 3 teaspoons/day, for 5% of the adult population. Moreover, overweight and obese men and women, who correspond to 41% of the adult population, represent 56% of the last five percentiles of the distribution of the variation in sugar intake. This is a key result because the objective of taxation is to decrease the consumption of individuals who are more at risk, that is those who are overweight and obese. We also show that classical method of the assessment of tax policies based on per-capita consumption underestimate the effect of the tax for obese adults by 9%. Finally, we estimate that a 0.20/l tax on SSBs might avoid about 640 deaths (about 1.6% of the considered diseases) as a consequence of the decrease in SSB consumption.
Assuntos
Bebidas Adoçadas com Açúcar , Adulto , Masculino , Criança , Humanos , Feminino , Sobrepeso/epidemiologia , Bebidas , Impostos , Obesidade/epidemiologia , AçúcaresRESUMO
The factors driving initiation of pathological expansion of tandem repeats remain largely unknown. Here, we assessed the FGF14 -SCA27B (GAA)â¢(TTC) repeat locus in 2,530 individuals by long-read and Sanger sequencing and identified a 5'-flanking 17-bp deletion-insertion in 70.34% of alleles (3,463/4,923). This common sequence variation was present nearly exclusively on alleles with fewer than 30 GAA-pure repeats and was associated with enhanced meiotic stability of the repeat locus.
RESUMO
BACKGROUND: Heterozygous GAA expansions in the FGF14 gene have been related to autosomal dominant cerebellar ataxia (SCA27B-MIM:620174). Whether they represent a common cause of sporadic late-onset cerebellar ataxia (SLOCA) remains to be established. OBJECTIVES: To estimate the prevalence, characterize the phenotypic spectrum, identify discriminative features, and model longitudinal progression of SCA27B in a prospective cohort of SLOCA patients. METHODS: FGF14 expansions screening combined with longitudinal deep-phenotyping in a prospective cohort of 118 SLOCA patients (onset >40 years of age, no family history of cerebellar ataxia) without a definite diagnosis. RESULTS: Prevalence of SCA27B was 12.7% (15/118). Higher age of onset, higher Spinocerebellar Degeneration Functional Score, presence of vertigo, diplopia, nystagmus, orthostatic hypotension absence, and sensorimotor neuropathy were significantly associated with SCA27B. Ataxia progression was ≈0.4 points per year on the Scale for Assessment and Rating of Ataxia. CONCLUSIONS: FGF14 expansion is a major cause of SLOCA. Our natural history data will inform future FGF14 clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Ataxia Cerebelar , Ataxias Espinocerebelares , Degenerações Espinocerebelares , Humanos , Ataxia/complicações , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/complicações , Estudos Prospectivos , Ataxias Espinocerebelares/genética , Degenerações Espinocerebelares/epidemiologia , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/complicaçõesRESUMO
BACKGROUND: Many clinical trials have reported the use of mesenchymal stromal cells (MSCs) following the indication of severe SARS-CoV-2 infection. However, in the COVID19 pandemic context, academic laboratories had to adapt a production process to obtain MSCs in a very short time. Production processes, especially freezing/thawing cycles, or culture medium have impacts on MSC properties. We evaluated the impact of an intermediate cryopreservation state during MSC culture to increase production yields. METHODS: Seven Wharton's jelly (WJ)-MSC batches generated from seven different umbilical cords with only one cryopreservation step and 13 WJ-MSC batches produced with intermediate freezing were formed according to good manufacturing practices. The identity (phenotype and clonogenic capacities), safety (karyotype, telomerase activity, sterility, and donor qualification), and functionality (viability, mixed lymphocyte reaction) were analyzed. RESULTS: No significant differences between MSC production processes were observed, except for the clonogenic capacity, which was decreased, although it always remained above our specifications. CONCLUSIONS: Intermediate cryopreservation allows an increase in the production yield and has little impact on the basic characteristics of MSCs.
RESUMO
Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated a strategy to detect FGF14 GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Method comparison showed that capillary electrophoresis of long-range PCR amplification products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, - 2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, - 27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, - 7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, - 41.93 to 39.15]). Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. We also identified 9 French patients (9/53; 17%) and 2 of their relatives who carried an FGF14 (GAA)≥250 expansion. This novel strategy reliably detected and sized FGF14 GAA expansions, and compared favorably to long-read sequencing.
Assuntos
Ataxia de Friedreich , Ataxias Espinocerebelares , Humanos , Canadá , Ataxia de Friedreich/genética , Ataxias Espinocerebelares/genética , Expansão das Repetições de TrinucleotídeosRESUMO
BACKGROUND: Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported. METHODS: This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria. RESULTS: Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size. CONCLUSIONS: This study's high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.