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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.

Hereditary ataxias, especially when presenting sporadically in adulthood, present a particular diagnostic challenge owing to their great clinical and genetic heterogeneity. Currently, up to 75% of such patients remain without a genetic diagnosis. In an era of emerging disease‐modifying gene‐stratified therapies, the identification of causative alleles has become increasingly important. Over the past few years, the implementation of advanced bioinformatics tools and long‐read sequencing has allowed the identification of a number of novel repeat expansion disorders, such as the recently described spinocerebellar ataxia 27B (SCA27B) caused by a (GAA)•(TTC) repeat expansion in intron 1 of the fibroblast growth factor 14 (FGF14) gene. SCA27B is rapidly gaining recognition as one of the most common forms of adult‐onset hereditary ataxia, with several studies showing that it accounts for a substantial number (9–61%) of previously undiagnosed cases from different cohorts. First natural history studies and multiple reports have already outlined the progression and core phenotype of this novel disease, which consists of a late‐onset slowly progressive pan‐cerebellar syndrome that is frequently associated with cerebellar oculomotor signs, such as downbeat nystagmus, and episodic symptoms. Furthermore, preliminary studies in patients with SCA27B have shown promising symptomatic benefits of 4‐aminopyridine, an already marketed drug. This review describes the current knowledge of the genetic and molecular basis, epidemiology, clinical features and prospective treatment strategies in SCA27B. Spinocerebellar ataxia 27B is caused by a (GAA)•(TTC) repeat expansion in intron 1 of FGF14 and is a common cause of adult‐onset ataxia, accounting for 9–61% of previously undiagnosed cases in different ethnically diverse cohorts. The core phenotype consists of a late‐onset slowly progressive pan‐cerebellar syndrome with frequent oculomotor signs. Episodic symptoms, visual disturbances and downbeat nystagmus are commonly observed in patients with SCA27B. 4‐Aminopyridine is a promising symptomatic treatment.

BackgroundSTUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia.ObjectiveWe aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.MethodsRetrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).ResultsHere, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).ConclusionEven though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.

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.

Peroxisomal biogenesis disorders (PBDs) consist of a heterogeneous group of autosomal recessive diseases, in which peroxisome assembly and proliferation are impaired leading to severe multisystem disease and early death. PBDs include Zellweger spectrum disorders (ZSDs) with a relatively mild clinical phenotype caused by PEX1 , (MIM# 602136), PEX2 (MIM# 170993), PEX6 (MIM# 601498), PEX10 (MIM# 602859), PEX12 (MIM# 601758), and PEX16 (MIM# 603360) mutations. Three adult patients are reported belonging to a non-consanguineous French family affected with slowly progressive cerebellar ataxia, axonal neuropathy, and pyramidal signs. Mental retardation and diabetes mellitus were optional. The age at onset was in childhood or in adolescence (3–15 years). Brain MRI showed marked cerebellar atrophy. Biochemical blood analyses suggested a mild peroxisomal defect. With whole exome sequencing, two mutations in PEX10 were found in the three patients: c.827G>T (novel) causing the missense change p.Cys276Phe and c.932G>A causing the missense change p.Arg311Gln. The phenotypic spectrum related to PEX10 mutations includes slowly progressive, syndromic recessive ataxia.

JC virus (JCV) causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients. There is currently no effective specific antiviral treatment and PML management relies on immune restoration. Prognosis markers are crucially needed in this disease because of its high mortality rate. In this work, we investigated the compartmentalization of JCV strains as well as the humoral neutralizing response in various matrices to further understand the pathophysiology of PML and define markers of survival. Four patients were included, of which three died in the few months following PML onset. Cerebrospinal fluid (CSF) viral loads were the highest, with plasma samples having lower viral loads and urine samples being mostly negative. Whether at PML onset or during follow-up, neutralizing antibody (NAb) titers directed against the same autologous strain (genotype or mutant) were the highest in plasma, with CSF titers being on average 430-fold lower and urine titers 500-fold lower at the same timepoint. Plasma NAb titers against autologous genotype or mutant were lower in non-survivor patients, though no neutralization “blind spot” was observed. The surviving patient was followed up until nine months after PML onset and presented, at that time, an increase in neutralizing titers, from 38-fold against the autologous genotype to around 200-fold against PML mutants. Our results suggest that patients’ humoral neutralizing response against their autologous strain may play a role in PML outcome, with survivors developing high NAb titers in both plasma and CSF.

Clinical examination showed atrophy and a marked weakness of right hypothenar and interossei muscles (grade 1/5 on Medical Research Council scale) and a mild weakness of right thumb abduction and wrist extension (4/5). A cervical MRI performed in neutral position revealed no radiculopathy or myelopathy but a clear dilation of posterior soft tissues veins on T1-weighted sequences with gadolinium infusion (figure 1). HD is a rare but disabling disease of cervical spinal cord resulting in unilateral or asymmetric severe amyotrophy and weakness of distal arms in young male patients.1 Differential diagnosis with amyotrophic lateral sclerosis and other disorders is important to estimate correctly the prognosis and to discuss specific therapy.2 HD diagnosis is difficult because it is based on the demonstration of a forward displacement of dural sac on cervical MRI in flexion position.

There is too little research on parenthood apprehension and decision making among lesbian couples, particularly in the Canadian and Quebec context. It is crucial to consider the concerns of these couples in a society marked by gendered and heteronormative norms, which could lead to stress as well as worry. Five Quebec lesbian couples wishing to begin the process of creating a family were interviewed through a joint qualitative semistructured interview. These couple's aspirations to parenthood were explored using the abductive thematic analysis within the phenomenological approach. The lesbian couples reported a lack of role models who resembled their future parenting model. All participants mentioned having the same motivations for starting a family as heterosexual cisgender couples did, and they planned to divide family responsibilities flexibly without necessarily conforming to traditional gender norms. The findings from the qualitative analysis suggested that in Quebec's liberal social dynamic, the ideology of homoparenthood is almost indistinguishable from traditional parenthood in the minds of lesbian couples. These women see themselves simply as future mothers who, despite being in a same-sex/gender relationship, will welcome a child with love, balance, and care. According to them, they will potentially face less common challenges than heterosexual cisgender couples, but their relationship status is not perceived as having an impact on their willingness and ability to raise children. This study provides a better understanding of the perceptions and apprehensions of lesbian couples contemplating parenthood in 2023. Il y a trop peu de recherches sur l'appréhension et la prise de décision en matière de parentalité chez les couples de lesbiennes, particulièrement dans le contexte canadien et québécois. Il est crucial de prendre en compte les préoccupations de ces couples dans une société marquée par des normes genrées et hétéronormatives, ce qui peut être source de stress et d'inquiétude. Cinq couples de lesbiennes québécoises souhaitant entamer le processus de création d'une famille ont été interrogés dans le cadre d'un entretien qualitatif semi-structuré. Les aspirations de ces couples à la parentalité ont été explorées à l'aide d'une analyse thématique abductive dans le cadre d'une approche phénoménologique. Les couples de lesbiennes ont fait état d'un manque de modèles ressemblant à leur futur modèle parental. Toutes les participantes ont déclaré avoir les mêmes motivations pour fonder une famille que les couples hétérosexuels cisgenres, et elles prévoyaient de répartir les responsabilités familiales avec souplesse sans nécessairement se conformer aux normes traditionnelles en matière de genre. Les résultats de l'analyse qualitative suggèrent que dans la dynamique sociale libérale du Québec, l'idéologie de l'homoparentalité est presque indiscernable de la parentalité traditionnelle dans l'esprit des couples de lesbiennes. Ces femmes se voient simplement comme de futures mères qui, malgré une relation de même sexe/genre, accueilleront un enfant avec amour, équilibre et soin. Selon elles, elles seront potentiellement confrontées à des défis moins courants que les couples hétérosexuels cisgenres, mais leur statut relationnel n'est pas perçu comme ayant un impact sur leur volonté et leur capacité à élever des enfants. Cette étude permet de mieux comprendre les perceptions et les appréhensions des couples de lesbiennes qui envisagent la parentalité en 2023. Public Significance Statement This study highlights the unique perspectives and apprehensions of lesbian couples in Quebec as they contemplate parenthood, emphasising the need for more inclusive role models and support systems. By understanding these couples' motivations and challenges, we can better support diverse family structures and promote social acceptance as well as equality in parenting.

In this study, a large repeat expansion in a noncoding part of FGF14 was found to cause late-onset cerebellar ataxia, which underscores the importance of noncoding regions in the search for causes of disease.

Spastic paraplegia type 3A (SPG3A) is the second most common form of hereditary spastic paraplegia (HSP). This autosomal-dominant-inherited motor disorder is caused by heterozygous variants in the ATL1 gene which usually presents as a pure childhood-onset spastic paraplegia. Affected individuals present muscle weakness and spasticity in the lower limbs, with symptom onset in the first decade of life. Individuals with SPG3A typically present a slow progression and remain ambulatory throughout their life. Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability). For 2 of the 3 patients, these phenotypes led to the initial diagnosis of cerebral palsy (CP). These individuals carried novel ATL1 pathogenic variants (a de novo ATL1 missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a homozygous missense variant (p.Tyr367His)). The parents carrying the heterozygous frameshift and missense variants were asymptomatic. Through these observations, we increase the knowledge on genotype–phenotype correlations in SPG3A and offer additional proof for possible autosomal recessive forms of SPG3A, while raising awareness on these exceptional phenotypes. Their ability to mimic CP also implies that genetic testing should be considered for patients with atypical forms of CP, given the implications for genetic counseling.