Evolutionary studies of disease-associated genes provide crucial insights into pathological mechanisms and potential therapeutic targets. Polyglutamine spinocerebellar ataxias (SCAs) are human neurodegenerative diseases caused by toxic expanded CAG repeats. Studies on SCA1 have shown that a paralog of the causing-gene can partially rescue protein function and alleviate the neuropathology. The most common SCA, Machado-Joseph disease (MJD/SCA3), caused by mutated ataxin-3 gene (ATXN3), has no treatment currently available. Its paralog ataxin-3 like (ATXN3L) remains largely unexplored. Here, we identify three new retrotransposition events of ATXN3: ATXN3L0 in Euarchontoglires, ATXN3L2 in Simiformes, and ATXN3L3 in Cercopithecidae, in addition to ATXN3L (herein called ATXN3L1) originated in Haplorrhini. ATXN3 and ATXN3L1 are both under purifying selection throughout primate evolution, maintaining about 70% of amino acid identity. Also, the high conservation of ATXN3L1 Josephin domain hints at functional redundancy with the parental disease-associated ATXN3. ATXN3L2 presents a remarkable nucleotide similarity to ATXN3 (79%) in an interrupted reading frame, which may produce a regulatory RNA. Conversely, ATXN3L0 is likely a non-functional retrocopy and ATXN3L3 is absent in humans with no relevance for the disease. The comparison of (CAG)n interruption patterns of the different paralogs in several primates elucidates the process leading to the currently observed pure long tracts in human ATXN3, responsible for disease when expanded. This study intends to pioneer the identification of new paralogs of SCA-associated genes and the use of phylogenetic analyses to explore their potential role for targeted therapies.

Communicating genetic information within families living with inherited genetic conditions (IGCs), especially incurable and progressive late-onset neurodegenerative diseases (LONDs), presents significant challenges. To date, no literature review has specifically addressed this issue in families with LONDs. To fill this gap, a scoping review was conducted following PRISMA and JBI guidelines. Four databases (Scopus, Web of Science, PubMed, and PsycInfo) were searched, resulting in 31 articles for analysis. Six categories were identified: (i) from whom to whom: communication transmitters and receivers, (ii) what to tell: content and details of communication, (iii) how to tell: communication approach, (iv) when to tell: timing of communication, (v) barriers and reasons for not communicating, and (vi) facilitators and reasons for communicating. Sharing information about LONDs is a multi-step, deliberative process involving several transmitters and receivers. It typically begins with first-degree relatives, with women often assuming a pivotal role in the gathering and dissemination of information, and extends to the wider family. This process includes assessing the family member's subjective experiences and the potential impact of the information. Fear of stigmatization and discrimination are notable barriers, while feelings of responsibility and moral obligation toward family members are strong motivators for transmitters to communicate. The studies included in this review were all retrospective, primarily utilized a qualitative design, and predominantly focused on families with Huntington's disease. Prospective studies are needed to investigate disclosure decision-making in families with other LONDs and to explore how the potential availability of clinical trials for testing new drugs might influence family communication.

Process studies explore the content and dynamics established during genetic counseling (GC), allowing a greater understanding of what happens. No literature review has specifically examined how family communication of genetic information has been addressed in GC process studies. To fill this gap, a scoping review was conducted. Scopus, Web of Science, PubMed, and PsycInfo were searched, resulting in 21 articles for analysis. Most studies were retrospective (n = 19) and qualitative (n = 15) and involved hereditary cancer syndromes (n = 13). Studies analyzed how family communication of genetic information is addressed in GC by either focusing on patients' experiences and perspectives, or genetic healthcare professionals' (GHP) roles and scope of practice. All studies reported that GHP address family communication with patients, but their practices were heterogeneous and influenced by contextual factors. Practices to address family communication included providing guidance to inform the family (n = 19), materials to support communication (n = 16), psychosocial assessment (n = 11), and additional support (n = 18). Our findings suggest that the approach to family communication in GC draws on both teaching and counseling models, although with greater emphasis on the former. This is consistent with integrated models of GC. Future prospective process studies using observational data could enhance our understanding of patient-professional interactions and their influence on patient decision-making regarding family communication of genetic information.

Background and ObjectivesHereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are rare neurologic disorders that often represent opposite ends of a shared clinical spectrum. Spastic ataxia, defined by the co-occurrence of cerebellar syndrome and overt spasticity, remains comparatively underexplored and is associated with relatively few genetic causes. The aim of this study was to characterize the clinical and genetic features of spastic ataxia in a large HCA cohort and compare them with those of nonspastic HCA.MethodsA prospective HCA cohort was initiated in 2017, incorporating annual assessments following a structured and standardized protocol. Spastic ataxia was defined as ataxia occurring in conjunction with spasticity grade >= 2 on the Modified Ashworth Scale. Patients meeting this criterion were identified; their clinical and genetic data were analyzed and compared with those of patients with nonspastic forms of HCA. The Movement Disorder Society's nomenclature for genetic disorders was adopted, using dual-prefix notation for combined phenotypes (e.g., HSP/ATX for spastic ataxia), except for entities such as MJD/SCA3 or ARSACS, which are more readily recognized by their original designations.ResultsOf 249 patients assessed (164 families), 56 (22.5%; from 46 families) exhibited a spastic ataxia phenotype. Compared with nonspastic HCA, these patients had earlier onset and longer disease duration. Spastic ataxia was significantly associated with autosomal recessive inheritance and conventional (nonrepeat expansion) variants. Thirty-eight probands (80.8%) had a definite genetic diagnosis, involving 22 causal genes. The most frequent diagnoses were ARSACS (17.4%), ATX-SYNE1 (6.5%), ATX-ANO10, HSP/ATX-KIF1C, HSP/ATX-PGN, HSP-ZFYVE26, MxMD-ATP13A2, and ATX/HSP-KCNA2 (4.3% each). A noncerebellar presentation was observed in 30 patients with spastic ataxia (53.6%) while 26 (46.6%) had cerebellar onset. After adjustment for disease duration, patients with spastic ataxia had significantly higher baseline scores on the Scale for the Assessment and Rating of Ataxia, reflecting a greater disease burden. In addition, falls were more frequent in this group.DiscussionSpastic ataxia represented a clinically and genetically distinct subgroup within HCA, marked by recessive inheritance, large genetic heterogeneity, and more severe motor impairment. Greater awareness of its heterogeneous presentations and progressive disability over time is crucial for timely diagnosis, genetic counseling, and development of tailored management strategies for these patients.

The application of whole-exome sequencing (WES) for diagnostic purposes has the potential to unravel secondary findings unrelated with the primary reason of testing. Some of those might be of high clinical utility and comprise disease-causing variants in genes, related to lifethreatening and clinically actionable diseases. Clarifying the allelic frequencies of such variants in specific populations is a crucial step for the large-scale deployment of genomic medicine. We analysed medically relevant variants in the 81 genes from the American College of Medical Genetics and Genomics (ACMG) v3.2 list of actionable loci, using WES data from a diagnostic laboratory cohort of 3,972 persons, tentatively resampled to represent the Portuguese population geographic distribution. We identified medically actionable variants in 6.2% of our cohort, distributed across several disease domains: cardiovascular disorders (3.0%), cancer predisposition (2.0%), miscellaneous disorders (1.1%), and metabolic disorders (0.1%). Additionally, we estimated a frequency of heterozygotes for recessive disease alleles of 11.1%. Overall, our results suggest that medically actionable findings can be identified in approximately 6.2% of persons from our population. This is the first study estimating medically actionable findings in Portugal. These results provide valuable insight for patients, healthcare providers, and policymakers involved in advancing genomic medicine at the national and international level.

The application of whole-exome sequencing (WES) for diagnostic purposes has the potential to unravel secondary findings unrelated with the primary reason of testing. Some of those might be of high clinical utility and comprise disease-causing variants in genes, related to life-threatening and clinically actionable diseases. Clarifying the allelic frequencies of such variants in specific populations is a crucial step for the large-scale deployment of genomic medicine. We analysed medically relevant variants in the 81 genes from the American College of Medical Genetics and Genomics (ACMG) v3.2 list of actionable loci, using WES data from a diagnostic laboratory cohort of 3972 persons, tentatively resampled to represent the Portuguese population geographic distribution. We identified medically actionable variants in 6.2% of our cohort, distributed across several disease domains: cardiovascular disorders (3.0%), cancer predisposition (2.0%), miscellaneous disorders (1.1%), and metabolic disorders (0.1%). Additionally, we estimated a frequency of heterozygotes for recessive disease alleles of 11.1%. Overall, our results suggest that medically actionable findings can be identified in approximately 6.2% of persons from our population. This is the first study estimating medically actionable findings in Portugal. These results provide valuable insight for patients, healthcare providers, and policymakers involved in advancing genomic medicine at the national and international level.

Background: Hereditary cerebellar ataxia (HCA) represents a complex group of disorders, with a wide spectrum of neurological symptoms. Among these, non-ataxia movement disorders (MD) have been increasingly acknowledged, with variable frequency across different forms. Objectives: To characterize the type and frequency of MD in patients with HCA. To identify factors associated with MD and analyze their impact on disability. Methods: We conducted a prospective study starting in 2017, with annual visits according to a structured protocol. Patients were selected from the study database and their clinical and genetic features analyzed. Results: The cohort comprised 193 symptomatic patients. Machado-Joseph disease (MJD, also SCA3 or ATX-ATXN3) and cerebellar ataxia, neuropathy and vestibular areflexia syndrome (ATX-RFC1) were the most common autosomal dominant (AD) or recessive forms, with a frequency of 14.0% and 15.0%, respectively. MD were present in 95 (54.4%), with dystonia being the most common (49.2%). Tremor was identified in 10.9%, Parkinsonism in 4.1% and chorea in 3.6% patients. Myoclonus and tics were rare (2.6% and 0.5%). The presence of MD was associated with AD inheritance and ATXN3. MD, regardless of type, correlated with higher SARA score at baseline, increased fall frequency, confinement to wheelchair, and earlier occurrence of falls and of permanent use of walking aid. Conclusions: Movement disorders, particularly dystonia, were common in our cohort. This highlights the possible role of the cerebellum in MD, but also extra-cerebellar involvement in some HCA. Presence of MD significantly worsened motor disability, highlighting the need for strategies of early identification and tailored management.

Background and Objectives:Hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are rare neurologic disorders that often represent opposite ends of a shared clinical spectrum. Spastic ataxia, defined by the co-occurrence of cerebellar syndrome and overt spasticity, remains comparatively underexplored and is associated with relatively few genetic causes. The aim of this study was to characterize the clinical and genetic features of spastic ataxia in a large HCA cohort and compare them with those of nonspastic HCA. Methods:A prospective HCA cohort was initiated in 2017, incorporating annual assessments following a structured and standardized protocol. Spastic ataxia was defined as ataxia occurring in conjunction with spasticity grade ≥2 on the Modified Ashworth Scale. Patients meeting this criterion were identified; their clinical and genetic data were analyzed and compared with those of patients with nonspastic forms of HCA. The Movement Disorder Society's nomenclature for genetic disorders was adopted, using dual-prefix notation for combined phenotypes (e.g., HSP/ATX for spastic ataxia), except for entities such as MJD/SCA3 or ARSACS, which are more readily recognized by their original designations. Results:Of 249 patients assessed (164 families), 56 (22.5%; from 46 families) exhibited a spastic ataxia phenotype. Compared with nonspastic HCA, these patients had earlier onset and longer disease duration. Spastic ataxia was significantly associated with autosomal recessive inheritance and conventional (nonrepeat expansion) variants. Thirty-eight probands (80.8%) had a definite genetic diagnosis, involving 22 causal genes. The most frequent diagnoses were ARSACS (17.4%), ATX-SYNE1 (6.5%), ATX-ANO10, HSP/ATX-KIF1C, HSP/ATX-PGN, HSP-ZFYVE26, MxMD-ATP13A2, and ATX/HSP-KCNA2 (4.3% each). A noncerebellar presentation was observed in 30 patients with spastic ataxia (53.6%) while 26 (46.6%) had cerebellar onset. After adjustment for disease duration, patients with spastic ataxia had significantly higher baseline scores on the Scale for the Assessment and Rating of Ataxia, reflecting a greater disease burden. In addition, falls were more frequent in this group. Discussion:Spastic ataxia represented a clinically and genetically distinct subgroup within HCA, marked by recessive inheritance, large genetic heterogeneity, and more severe motor impairment. Greater awareness of its heterogeneous presentations and progressive disability over time is crucial for timely diagnosis, genetic counseling, and development of tailored management strategies for these patients.

Tau tubulin kinase 2 (TTBK2) is a ubiquitous serine-threonine protein kinase implicated in diverse cellular processes, including microtubule regulation, ciliogenesis, synaptic signaling, and the phosphorylation of key proteins like TDP-43. Despite its relevance, many aspects of TTBK2 function in both physiological and pathological conditions remain poorly understood. Truncating variants in TTBK2 gene cause spinocerebellar ataxia type 11 (SCA11), a rare form of autosomal dominant cerebellar ataxia. However, the functional consequences and pathogenic potential of missense variants have yet to be elucidated. In this study, we developed a CRISPR/Cas9 knock-in cell model harboring a missense variant in TTBK2 kinase domain (NM_173500.4:c.625 C > T; p.Leu209Phe) to evaluate its impact on TTBK2 expression, associated protein levels, and phosphoproteomic profiles. TTBK2 missense variant (TTBK2-L209F) was associated with reduced TTBK2 protein levels, altered levels of cytoskeleton-related proteins, and impaired kinase activity, namely toward TDP-43. Phosphoproteomic analyses identified dysregulation in pathways linked to gene regulation, protein degradation, cytoskeletal organization, and TGF-β signaling. These findings provide valuable insights into the biological roles of TTBK2 in cellular signaling. Moreover, this study underscores the importance of functional studies to better understand the consequences of TTBK2 missense variants, particularly those affecting the kinase domain, and their potential contribution to disease.

Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative diseases characterized by lower limb spasticity and weakness. To date, over 80 genes have been associated with HSP, but many families remain without a molecular diagnosis. In this study, linkage analysis and whole-exome sequencing (WES) were performed to identify the causal gene in a HSP family with autosomal recessive inheritance. Multipoint linkage analysis revealed a maximum significant multipoint LOD score of 4.6 on chromosome 4. WES analysis focused on this region led to the identification of a homozygous missense variant in AIMP1 (c.223G>A). Minigene assays showed that the presumed missense variant in AIMP1 caused loss of the exon 3 donor splice site. Ultimately, this led to the use of an alternative splice site within the intron and the insertion of a premature stop codon. The identification of a novel AIMP1 causal variant contributes to the growing list of HSP genes. Furthermore, it shows that, considering also previous reported cases, disruption of AIMP1 causes a spectrum of disorders ranging from intellectual disability to more complex neurodegenerative diseases.

Machado–Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia caused by a polyglutamine-coding CAG repeat expansion in the ATXN3 gene. While the CAG length correlates negatively with the age at onset, it accounts for approximately 50