Neurogenetic Diseases Research Articles

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Revisit TBCK-A Pseudo Kinase or a True Kinase

Since the initial identification of TBCK (formerly MGC16169) in 2010, significant advances have been made in understanding the role of TBCK mutations in neurodevelopmental disorders such as TBCK encephalopathy. However, the precise function and detailed mechanisms of TBCK remain largely unexplored. Previous studies, including our own, suggest that aberrant expression or mutations in TBCK can impact cell growth, division, and cytoskeleton assembly, contributing to both cancer and neurogenetic diseases. Despite this, the specific domains within TBCK responsible for these functions are still unclear. Notably, mutations in the TBC domain have been implicated in disrupting mTOR pathways, linking TBCK dysfunction to neurogenetic disorders and cancers. Given TBCK’s diverse roles, we have focused on its putative kinase domain. Through comprehensive analysis using tools such as Kinase Tree, AlphaFold2, APE DNA editor, DOG 1., and SMART, we discovered that TBCK lacks the key “D” residue in the conserved “HRD” and “DFG” motifs compared with typical protein kinases PKA and SRC, suggesting TBCK functions as a pseudokinase. Intriguingly, gene ontology analysis from recent RNA-seq data indicates TBCK’s involvement in regulating protein phosphorylation. This suggests that TBCK may influence protein phosphorylation either directly through its potential kinase domain or indirectly via interactions with other proteins. To uncover the full spectrum of TBCK’s roles in neurogenetic disorders and cancer, urgent high-throughput analyses are necessary to identify its interacting partners.

Long-read sequencing and optical genome mapping identify causative gene disruptions in noncoding sequence in two patients with neurologic disease and known chromosome abnormalities.

Despite advances in next generation sequencing (NGS), genetic diagnoses remain elusive for many patients with neurologic syndromes. Long-read sequencing (LRS) and optical genome mapping (OGM) technologies improve upon existing capabilities in the detection and interpretation of structural variation in repetitive DNA, on a single haplotype, while also providing enhanced breakpoint resolution. We performed LRS and OGM on two patients with known chromosomal rearrangements and inconclusive Sanger or NGS. The first patient, who had epilepsy and developmental delay, had a complex translocation between two chromosomes that included insertion and inversion events. The second patient, who had a movement disorder, had an inversion on a single chromosome disrupted by multiple smaller inversions and insertions. Sequence level resolution of the rearrangements identified pathogenic breaks in noncoding sequence in or near known disease-causing genes with relevant neurologic phenotypes (MBD5, NKX2-1). These specific variants have not been reported previously, but expected molecular consequences are consistent with previously reported cases. As the use of LRS and OGM technologies for clinical testing increases and data analyses become more standardized, these methods along with multiomic data to validate noncoding variation effects will improve diagnostic yield and increase the proportion of probands with detectable pathogenic variants for known genes implicated in neurogenetic disease.

Copy number variations in autistic children.

Autism spectrum disorder (ASD) manifests as a neurodevelopmental condition marked by challenges in social communication, interaction and the performing of repetitive behaviors. The prevalence of autism increases markedly on an annual basis; however, the etiology remains incompletely understood. Cytogenetically visible chromosomal abnormalities, including copy number variations (CNVs), have been shown to contribute to the pathogenesis of ASD. More than 1% of ASD conditions can be explained based on a known genetic locus, whereas CNVs account for 5-10% of cases. However, there are no studies on the Saudi Arabian population for the detection of CNVs linked to ASD, to the best of our knowledge. Therefore, the aim of the present study was to explore the prevalence of CNVs in autistic Saudi Arabian children. Genomic DNA was extracted from the peripheral blood of 14 autistic children along with four healthy control children and then array-based comparative genomic hybridization (aCGH) was used to detect CNVs. Bioinformatics analysis of the aCGH results showed the presence of recurrent and non-recurrent deletion/duplication CNVs in several regions of the genome of autistic children. The most frequent CNVs were 1q21.2, 3p26.3, 4q13.2, 6p25.3, 6q24.2, 7p21.1, 7q34, 7q11.1, 8p23.2, 13q32.3, 14q11.1-q11.2 and 15q11.1-q11.2. In the present study, CNVs in autistic Saudi Arabian children were identified to improve the understanding of the etiology of autism and facilitate its diagnosis. Additionally, the present study identified certain possible pathogenic genes in the CNV region associated with several developmental and neurogenetic diseases.

Cross-Sectional Analysis of Exome Sequencing Diagnosis in Patients With Neurologic Phenotypes Facing Barriers to Clinical Testing.

Exome sequencing (ES) demonstrates a 20-50 percent diagnostic yield for patients with a suspected monogenic neurologic disease. Despite the proven efficacy in achieving a diagnosis for such patients, multiple barriers for obtaining exome sequencing remain. This study set out to assess the efficacy of ES in patients with primary neurologic phenotypes who were appropriate candidates for testing but had been unable to pursue clinical testing. A total of 297 patients were identified from the UCLA Clinical Neurogenomics Research Center Biobank, and ES was performed, including bioinformatic assessment of copy number variation and repeat expansions. Information regarding demographics, clinical indication for ES, and reason for not pursuing ES clinically were recorded. To assess diagnostic efficacy, variants were interpreted by a multidisciplinary team of clinicians, bioinformaticians, and genetic counselors in accordance with the American College of Medical Genetics and Genomics variant classification guidelines. We next examined the specific barriers to testing for these patients, including how frequently insurance-related barriers such as coverage denials and inadequate coverage of cost were obstacles to pursuing exome sequencing. The cohort primarily consisted of patients with sporadic conditions (n = 126, 42.4%) of adult-onset (n = 239, 80.5%). Cerebellar ataxia (n = 225, 75.8%) was the most common presenting neurologic phenotype. Our study found that in this population of mostly adult patients with primary neurologic phenotypes that were unable to pursue exome sequencing clinically, 47 (15.8%) had diagnostic results while an additional 24 patients (8.1%) had uncertain results. Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES because of insurance barriers, of whom 14 (15.9%) had diagnostic findings, representing 29.8% of all patients with diagnostic findings. In addition, the incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of 8 pathogenic repeat expansions (17.0% of all diagnostic findings) including 3 of the common spinocerebellar ataxias and 2 patients with Huntington disease. These findings underscore the importance and value of clinical ES as a diagnostic tool for neurogenetic disease and highlight key barriers that prevent patients from receiving important clinical information with potential treatment and psychosocial implications for patients and family members.

Clinical and genetic features of dominant Essential Tremor in Tuscany, Italy: FUS, CAMTA1, ATXN1 and beyond

ObjectiveEssential Tremor (ET) is one of the most common neurological disorders. In most instances ET is inherited as an autosomal dominant trait with age-related penetrance (virtually complete in advanced age); however, ET genetics remains elusive. The current study aims to identify possibly pathogenic genetic variants in a group of well-characterized ET families. Methods34 individuals from 14 families with dominant ET were clinically evaluated and studied by whole exome sequencing studies (after excluding trinucleotide expansion disorders). ResultsMost patients had pure ET. In 4 families, exome studies could identify a genetic variant potentially able to significantly alter the protein structure (CADD >20, REVEL score > 0.25), shared by all the affected individuals (in CAMTA1, FUS, MYH14, SGCE genes). In another family there were two variants in dominant genes (PCDH9 and SQSTM1). Moreover, an interrupted “intermediate” trinucleotide expansion in ATXN1 (“SCA1”) was identified in a further family with pure ET. ConclusionCombining our observations together with earlier reports, we can conclude that ET genes confirmed in at least two families to date include CAMTA1 and FUS (reported here), as well as CACNA1G, NOTCH2NLC and TENM4. Most cases of familial ET, inherited with an autosomal dominant inheritance, may result from “mild” variants of many different genes that, when affected by more harmful genetic variants, lead to more severe neurological syndromes (still autosomal dominant). Thus, ET phenotype may be the “mild”, incomplete manifestation of many other dominant neurogenetic diseases. These findings further support evidence of genetic heterogeneity for such disease(s).Author's keywords: cerebellar ataxias, movement disorders, neurogenetics, rare neurological disorders, tremor.

The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.

A case of adrenomyeloneuropathy caused by a novel point mutation in the ABCD1 gene and functional verification.

Adrenoleukodystrophy is a rare neurogenetic disease, and adrenomyeloneuropathy is the most common phenotype in adults. The clinical data of a patient with adrenoleukodystrophy and spinal-peripheral neuropathy caused by a novel point mutation in exon 4 of the ABCD1 gene (c.1256T > G (p.Val419Gly)) were retrospectively analyzed. Furthermore, we constructed wild-type and mutant vectors of the ABCD1 (NM0000334) gene to validate the effect of this mutation on the expression of the ABCD1 gene and protein and to explore the mechanism of X-linked adrenoleukodystrophy occurrence and development to identify therapeutic targets for clinical treatment.

Patients with rare neurogenetic diseases experience decades of diagnostic delay and enacted stigma: An illustrative case series from Kenya

Patients with rare neurogenetic diseases experience decades of diagnostic delay and enacted stigma: An illustrative case series from Kenya

Two rare autosomal recessive neurological disorders identified by combined genetic approaches in a single consanguineous family with multiple offspring.

Neurodevelopmental disorders (NDDs) refer to a broad range of diseases including developmental delay, intellectual disability, epilepsy, autism spectrum disorders, and attention-deficit/hyperactivity disorder caused by dysfunctions in tightly controlled brain development. The genetic backgrounds of NDDs are quite heterogeneous; to date, recessive or dominant variations in numerous genes have been implicated. Herein, we present a large consanguineous family from Turkiye, who has been suffering from NDDs with two distinct clinical presentations. Combined in-depth genetic approaches led us to identify a homozygous frameshift variant in NALCN related to NDD and expansion of dodecamer repeat in CSTB related to Unverricht-Lundborg disease (ULD). Additionally, we sought to functionally analyze the NALCN variant in terms of mRNA expression level and current alteration. We have both detected a decrease in the level of premature stop codon-bearing mRNA possibly through nonsense-mediated mRNA decay mechanism and also an increased current in patch-clamp recordings for the expressed truncated protein. In conclusion, increased consanguinity may lead to the revealing of distinct rare neurogenetic diseases in a single family. Exome sequencing is generally considered the first-tier diagnostic test in individuals with NDD. Yet we underline the fact that customized approaches other than exome sequencing may be used as in the case of ULD to aid diagnosis and better genetic counseling.

The Diagnostic Landscape of Adult Neurogenetic Disorders.

Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

Neuropsychological assessment in rare pediatric neurogenetic disorders: considerations for cross-cultural clinical research

ABSTRACT Neuropsychological assessment in rare neurodevelopmental disorders has provided clinicians and researchers with a more comprehensive view of natural history as well as opportunities for additional endpoints in treatment trials. While challenges to protocol development have been addressed in the literature, cultural considerations have been overly broad resulting in limited utility when including mixed international samples. Using experiences over the past five years with the development of ten different protocols for neurogenetic rare diseases, this paper presents further considerations for protocol development that are culturally sensitive to international samples. Recommendations are offered across areas including participants from multiple countries; cognitive, sensory and motor impairments; psychometrics; and assessment logistics. A neuropsychological assessment selection checklist that guides researchers and clinicians through considerations and a standard operating procedure that provides guidance on thinking through the assessment process are offered.

BK Channelopathies and KCNMA1-Linked Disease Models.

Novel KCNMA1 variants, encoding the BK K+ channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation.

End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases.

No effective cure is available for neurogenetic diseases such as Huntington disease, spinocerebellar ataxias, and Friedreich ataxia, all of which cause progressive motor, cognitive, and psychiatric symptoms leading, in the long term, to severe communication (among other) impairments. In end-of-life situations, advanced directives (indications formulated by the patient about end-of-life choices) are one decision-making resource for relatives, caregivers, and health care professionals. Given the slowly progressive nature of these diseases, the related disabilities, and their hereditary component, patients, caregivers, and neurologists are often at a loss concerning the right course of action to take. Our study's aim was to explore patients' and caregivers' perceptions, needs, and expectations around anticipated end-of-life discussions and advanced directives. DIRAGENE is an observational, cross-sectional, mixed-methods study with a patient-centered component and a primary caregiver-centered component. Observations include disease severity, psychosocial, and emotional scales; in-house questionnaires; and semidirected interviews. We included 124 participants, of which 81 were patients and 43 primary caregivers. Only 16% of the participants knew specifically about advanced directives and 7% had written documents vs 30% and 18% in the general French population, respectively, adjusted for age. Qualitative analysis of the interviews with 15 couples showed notable dissimilarities in ideas about advanced directives between patients and caregivers and that the underlying pathology, severity, and inheritability are less relevant factors regarding end-of-life discussions than age, environment, prior experiences with death, and history of family illness. Most patients (95%) and caregivers (98%) found that participating in the study was helpful in bringing awareness to end-of-life issues, wished to prioritize discussing them with loved ones, and requested assistance in managing them throughout the course of the disease. Being affected by severe neurogenetic diseases does not seem to prompt individuals to give much thought to end-of-life planning. However, patients and caregivers welcome comprehensive information and expect progressive support from trained health care professionals in having such discussions. Routine integration of these conversations into medical management through a holistic and adapted approach will benefit patients with illnesses with unfavorable long-term prognoses.

Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of neurodegeneration with brain iron accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression and to estimate sample sizes for clinical trials. We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for the Unified Parkinson's Disease Rating Scale (UPDRS), Barry-Albright Dystonia (BAD) scale, Schwab and England Activities of Daily Living (SE-ADL) scale and the Pediatric Quality of Life Inventory (PedsQL). We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9 years and the median diagnostic delay was 5 years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16 years with the disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale score showed no significant progression over time. The SE-ADL scale and the patient- and parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points, respectively. No patient subpopulations were identified based on longitudinal trajectories. Our cross-sectional results define the order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help to shorten diagnostic delay and aid in counselling patients, parents and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.

Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.

H - 17 Neuropsychological Assessment in Rare Pediatric Neurogenetic Disorders: Considerations for Clinical Research.

Approximately 80% of rare diseases in childhood have a genetic cause. Neuropsychological assessments offer a greater understanding of the clinical presentation and trajectory of neurogenetic disorders. Given the rarity of the conditions, the limited funding allocated to study psychosocial factors, the diversity within the patient populations (e.g., country of origin, clinical phenotypes), and the limitations of our tools, there are no clear guidelines for evaluations. We aim to present a systematic approach to create assessment protocols that track disease progression and/or efficacy of therapeutic interventions. Our gene therapy program has created nine assessment protocols to evaluate conditions ranging from epileptic encephalopathies, lysosomal storage, neuromuscular, and mitochondrial diseases. Through review of past protocols, we created a neuropsychological assessment selection checklist (NASC) and standard operating procedure (SOP) checklist. The NASC systematizes updated multidisciplinary disease knowledge and relevant desirable outcomes (e.g., cognitive, motor, quality of life). Cultural elements (e.g., beliefs around health, disease, testing) and necessary accommodations (e.g., interpreters, sensory impairments) must be considered. Additional sociocultural and socioeconomic information of the sample is germane not only to contextualize results but also to help narrow possible tools. The SOP aims to increase standardization (e.g., starting points) and maximize use of the data collected (e.g., deferment reasons.). Neuropsychological assessments offer a wealth of cognitive, behavioral, emotional, and adaptive functioning data that is crucial to better understand the progression and treatment of rare neurogenetic diseases. Cultural considerations and in-depth clinical and assessment skills are essential to creating evaluation protocols that are valid, useful, and comprehensive.

Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia.

Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient's disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as "of uncertain significance" only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist's careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.

Ap4s1 truncation leads to axonal defects in a zebrafish model of spastic paraplegia 52.

Biallelic mutations in AP4S1, the σ4 subunit of the adaptor protein complex 4 (AP-4), lead to autosomal recessive spastic paraplegia 52 (SPG52). It is a subtype of AP-4-associated hereditary spastic paraplegia (AP-4-HSP), a complex childhood-onset neurogenetic disease characterized by progressive spastic paraplegia of the lower limbs. This disease has so far lacked effective treatment, in part due to a lack of suitable animal models. Here, we used CRISPR/Cas9 technology to generate a truncation mutation in the ap4s1 gene in zebrafish. The ap4s1 truncation led to motor impairment, delayed neurodevelopment, and distal axonal degeneration. This animal model is useful for further research into AP-4 and AP-4-HSP.

Parkinsonism in complex neurogenetic disorders: lessons from hereditary dementias, adult-onset ataxias and spastic paraplegias.

Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of Parkinson's disease, the most common cause of parkinsonism, and atypical parkinsonian disorders. However, parkinsonism can be a manifestation of complex neurological and neurodegenerative genetically determined disorders, which have a vast and heterogeneous motor and non-motor phenotypic features. Hereditary dementias, adult-onset ataxias and spastic paraplegias represent only few of this vast group of neurogenetic diseases. This review will provide an overview of parkinsonism's clinical features within adult-onset neurogenetic diseases which a neurologist could face with. Understanding parkinsonism and its characteristics in the context of the aforementioned neurological conditions may provide insights into pathophysiological mechanisms and have important clinical implications, including diagnostic and therapeutic aspects.