Clinical factors associated with genetic diagnosis in suspected neurogenetic disorders in a tertiary care clinic.

PURPOSE: This study aimed to identify phenotypic factors associated with genetic diagnoses in patients with neurodevelopmental disorders and generate a decision tree to assist clinicians in identifying patients most likely to receive a positive result on genetic testing. METHODS: We retrospectively reviewed the charts of 316 patients evaluated in a neurodevelopmental clinic between 2014 and 2019. Patients were categorized based on genetic test results. Analyses were performed to identify variables that discriminate between patients with and without a genetic diagnosis. RESULTS: Patients with a genetic diagnosis were more likely to be female and have a history of motor delay, hypotonia, congenital heart disease, and early intervention. Classification and regression tree analysis revealed that 75% of patients with motor delay had a genetic diagnosis. In patients without motor delay, hypotonia, age of walking, and age at initial evaluation were important indicators of a genetic diagnosis. CONCLUSION: Our findings suggest that motor delay and hypotonia are associated with genetic diagnoses in children with neurodevelopmental disorders. The decision tree highlights patient subsets at greater risk and suggests possible phenotypic screens. Future studies could develop validated decision trees based on phenotypic data to assist clinicians in stratifying patients for genetic testing.

Neurogenetics of Brain Connectivity: Current Approaches to the Study (Review).

Owing to the advances of neuroimaging techniques, a number of functional brain networks associated both with specific functions and the state of relative inactivity has been distinguished. A sufficient bulk of information has been accumulated on changes in connectivity (links between brain regions) in psychopathologies, for example, depression, schizophrenia, autism. Their genetic markers are being actively investigated using a candidate-gene approach or a genome-wide association study. At the same time, there is not much data considering connectivity as an intermediate link in the genotype-pathology chain, although it seems to be a reliable endophenotype, since it demonstrates a high stability and high heritability. In the present review, we consider the results of investigations devoted to the search for biomarkers, molecular and genetic associations of functional, partially anatomical, and effective connectivity. The main approaches to the evaluation of connectivity neurogenetics have been described, as well as specific genetic variants, for which the association with brain connectivity in psychiatric pathologies has been detected.

TTR associated leptomeningeal amyloidosis in a Sri Lankan patient.

OBJECTIVES: This case report aims to contribute to the expanding genotypic-phenotypic spectrum of TTR associated leptomeningeal amyloidosis. METHODS: Neuroimaging and targeted TTR Sanger sequencing were performed on a 52-year-old female presenting with cognitive and motor symptoms. RESULTS: The proband, a Sri Lankan woman, presented with a gradually progressive cognitive decline, followed by a rapid deterioration in motor function and level of consciousness. She had a significant family history of an undiagnosed neurological disorder, characterized by cognitive impairment and early death occurring in the fifth decade of life. Analysis of cerebrospinal fluid (CSF) demonstrated elevated protein levels. CT scan of the brain showed extensive leptomeningeal calcifications and hydrocephalus, and gadolinium enhanced magnetic resonance imaging (MRI) demonstrated extensive leptomeningeal enhancement in the brain and spinal cord. Genetic analysis revealed c.113 A > G, p.D38G mutation in TTR, a rare mutation with characteristic clinic-radiological central nervous system features. DISCUSSION: Leptomeningeal amyloidosis represents the least common subtype of familial transthyretin amyloidosis, which is a life-threatening condition. Among the over 150 identified mutations, few are specifically associated with central nervous system disease. The genetic spectrum and clinical phenotypes including neuroimaging findings continue to expand. It is important to maintain a high index of suspicion for leptomeningeal amyloidosis, particularly when the presentation is not acute or when there are relapsing-remitting symptoms. Consideration of family history and early genetic testing are essential to facilitate appropriate treatment and genetic counselling.

Huntington's disease phenocopy syndromes revisited: a clinical comparison and next-generation sequencing exploration.

BACKGROUND: Genetic testing for Huntington's disease (HD) was initially usually positive but more recently the negative rate has increased: patients with negative HD tests are described as having HD phenocopy syndromes (HDPC). This study examines their clinical characteristics and investigates the genetic causes of HDPC. METHODS: Clinical data from neurogenetics clinics and HDPC gene-panel data were analysed. Additionally, a subset of 50 patients with HDPC underwent whole-genome sequencing (WGS) analysed via Expansion Hunter and Ingenuity Variant Analysis. RESULTS: HDPC prevalence was estimated at 2.3-2.9 per 100 000. No clinical discriminators between patients with HD and HDPC could be identified. In the gene-panel data, deleterious variants and potentially deleterious variants were over-represented in cases versus controls. WGS analysis identified one ATXN1 expansion in a patient with HDPC. CONCLUSIONS: The HDPC phenotype is consistent with HD, but the genotype is distinct. Both established deleterious variants and novel potentially deleterious variants in genes related to neurodegeneration contribute to HDPC.

Cancer stem cells in meningiomas: novel insights and therapeutic implications.

Meningiomas (MGs), which arise from meningothelial cells of the dura mater, represent a significant proportion of primary tumours of the central nervous system (CNS). Despite advances in treatment, the management of malignant meningioma (MMG) remains challenging due to diagnostic, surgical, and resection limitations. Cancer stem cells (CSCs), a subpopulation within tumours capable of self-renewal and differentiation, are highlighted as key markers of tumour growth, metastasis, and treatment resistance. Identifying additional CSC-related markers enhances the precision of malignancy evaluations, enabling advancements in personalised medicine. The review discusses key CSC biomarkers that are associated with high levels of expression, aggressive tumour behaviour, and poor outcomes. Recent molecular research has identified CSC-related biomarkers, including Oct-4, Sox2, NANOG, and CD133, which help maintain cellular renewal, proliferation, and drug resistance in MGs. This study highlights new therapeutic strategies that could improve patient prognosis with more durable tumour regression. The use of combination therapies, such as hydroxyurea alongside diltiazem, suggests more efficient and effective MG management compared to monotherapy. Signalling pathways such as NOTCH and hedgehog also offer additional avenues for therapeutic development. CRISPR/Cas9 technology has also been employed to create meningioma models, uncovering pathways related to cell growth and proliferation. Since the efficacy of traditional therapies is limited in most cases due to resistance mechanisms in CSCs, further studies on the biology of CSCs are warranted to develop therapeutic interventions that are likely to be effective in MG. Consequently, improved diagnostic approaches may lead to personalised treatment plans tailored to the specific needs of each patient.

Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.

Background: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates. Methods: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years. Results: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases. Conclusions: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.

Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions.

MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR-QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinson's disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.

[Autism: associated medical conditions]. / Autismo: condiciones médicas asociadas.

Autism will accompany people throughout life with variations in its evolution and is frequently associated with other neurodevelopmental disorders (intellectual disability, attention deficit hyperactivity disorder, motor clumsiness, language disorder), neuropsychiatric disorders (depression, anxiety, schizophrenia, catatonia), epilepsy, sleep disorders, gastrointestinal disorders. In addition to the disorders typical of autism, we must consider an entire range of conditions, since their identification and adequate treatment will allow a better quality-of-life for people with autism. In 35% of cases, we can identify neurogenetic conditions which will allow us to prevent or identify associated medical entities. In this work we will analyze two groups, in a purely organizational way, medical conditions associated with defined entities (Down, Angelman, Fragile X, Rett, Phelan-McDermid and Timothy syndromes) and those that can be consistently associated in people with autism without an identified entity.

El autismo acompañará a las personas a lo largo de toda la vida, con variaciones en su evolución, está frecuentemente asociado a otros trastornos del neurodesarrollo (discapacidad intelectual, trastorno de déficit de atención e hiperactividad, torpeza motriz, trastorno del lenguaje), trastornos neuropsiquiátricos (depresión, ansiedad, esquizofrenia, catatonía), epilepsia, trastornos de sueño, trastornos gastrointestinales. Además de los trastornos propios del autismo, debemos tener en cuenta todo este abanico de condiciones, ya que su identificación y tratamiento permitirán una mejor calidad de vida. En el 35% de los casos podemos identificar entidades neurogenéticas, lo cual permitirá prevenir o identificar más rápidamente condiciones médicas asociadas. En este trabajo analizaremos dos grupos, de forma puramente organizativa, las condiciones médicas asociadas a entidades definidas (síndromes de Down, Angelman, X frágil, Rett, Phelan-McDermid y Timothy) y las que pueden asociarse consistentemente en personas con autismo sin una entidad identificada.

Repeat expansion disorders.

An increasing number of repeat expansion disorders have been found to cause both rare and common neurological disease. This is exemplified in recent discoveries of novel repeat expansions underlying a significant proportion of several late-onset neurodegenerative disorders, such as CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia syndrome) and spinocerebellar ataxia type 27B. Most of the 60 described repeat expansion disorders to date are associated with neurological disease, providing substantial challenges for diagnosis, but also opportunities for management in a clinical neurology setting. Commonalities in clinical presentation, overarching diagnostic features and similarities in the approach to genetic testing justify considering these disorders collectively based on their unifying causative mechanism. In this review, we discuss the characteristics and diagnostic challenges of repeat expansion disorders for the neurologist and provide examples to highlight their clinical heterogeneity. With the ready availability of clinical-grade whole-genome sequencing for molecular diagnosis, we discuss the current approaches to testing for repeat expansion disorders and application in clinical practice.

CSF1 receptor-related leukoencephalopathy.

A 51-year-old woman developed subacute progressive gait and cognitive difficulties, with depression and anxiety. She had psychomotor slowing, axial rigidity, fixed dystonic posturing of right hand and symmetrical generalised bradykinesia. MR brain scan identified bilateral multifocal non-enhancing high signal intensity in the frontal subcortical and periventricular areas, with corpus callosal thinning and areas of paraventricular diffusion restriction, suggesting an adult-onset leukodystrophy. Genetic analysis identified a heterogenous pathogenic variant in the colony-stimulating factor 1 receptor (CSF1R) causing this autosomal dominant leukoencephalopathy (OMIM 221820). The patient was unusual in having a CSF1R-related leukoencephalopathy without a relevant family history.

Social provisions in patients with mitochondrial diseases.

Background: Mitochondrial diseases often follow a chronic, multimorbid disease course in adults. Like other chronic conditions, mitochondrial diseases present a challenge to public and community health models and patients are potentially at higher risk of social isolation and loneliness. However, there is lack of data on social provisions in mitochondrial diseases. Methods: We performed a cross-sectional observational study on patients with a confirmed genetic or clinical diagnosis of mitochondrial disease, recruited between September 2018 and December 2021. Participants completed the Social Provisions Scale (SPS) as a measure of social support. Designated carers similarly completed the SPS in carer-specific questionnaires. Results: 95 mitochondrial disease patients and 24 designated carers completed the SPS. Social provisions were met for all six subscales of SPS in the mitochondrial disease cohort: (1) guidance 90.5% (n=86), (2) reassurance of self-worth 82.8% (n=77), (3) social integration 88.4% (n=84), (4) attachment 83.2% (n=79), (5) opportunity of nurturance, 61.1% (n=58) and (6) reliable alliance 95.8% (n=91). All social provisions were also met in the carer cohort. Conclusion: Patients with mitochondrial diseases and their carers demonstrate a high perceived level of social support in the setting of a tertiary referral centre specialised in mitochondrial disease despite the burden of chronic disease.

Genome-wide association reveals a locus in neuregulin 3 associated with gabapentin efficacy in women with chronic pelvic pain.

Chronic pelvic pain (CPP) in women with no obvious pelvic pathology has few evidence-based treatment options. Our recent multicenter randomized controlled trial (GaPP2) in women with CPP and no obvious pelvic pathology showed that gabapentin did not relieve pain overall and was associated with more side effects than placebo. We conducted an exploratory genome-wide association study using eligible GaPP2 participants aiming to identify genetic variants associated with gabapentin response. One genome-wide significant association with gabapentin analgesic response was identified, rs4442490, an intron variant located in Neuregulin 3 (NRG3) (p = 2·11×10-8; OR = 18·82 (95% CI 4·86-72·83). Analysis of a large sample of UK Biobank participants demonstrated phenome-wide significant brain imaging features of rs4442490, particularly implicating the orbitofrontal cortex. NRG3 is expressed predominantly in central nervous system tissues and plays a critical role in nervous system development, maintenance, and repair, suggesting a neurobiologically plausible role in gabapentin efficacy and potential for personalized analgesic treatment.

Neuromuscular junction disorders: mimics and chameleons.

Neuromuscular junction (NMJ) disorders represent a heterogenous group of acquired and congenital disorders that present in variable and distinctive ways. The diagnosis is typically reached through a combination of clinical, serological, pharmacological and electrophysiological evaluation. While the diagnosis can be fairly straightforward in some cases, the overlap with other neurological disorders can make diagnosis challenging, particularly in pure ocular presentations and in seronegative patients. The over-reliance on serological tests and electrophysiological evaluation in isolation can lead to misdiagnosis. In this article, we provide an overview of the NMJ disorders, discuss red flags for the key differential diagnoses (mimics) and report the atypical ways in which NMJ disorders may present (chameleons).

Combined central and peripheral demyelination in two siblings, immune mediated or genetic?

We report unusual cases of combined central and peripheral demyelination in two siblings related to pregnancy, each presenting with progressive tetraparesis and cranial nerve palsies. The elder sister had a relapsing-remitting course with optic nerve dysfunction and died during a relapse from respiratory insufficiency. The younger sister presented with disorientation and acute-onset limb and facial weakness. She responded well to corticosteroid therapy. Their clinical presentation, response to immunomodulatory therapy, nerve conduction studies, cerebrospinal fluid and histology supported an acquired demyelinating cause. Whole-exome sequencing identified variants in two genes not previously linked to this clinical phenotype. Serological tests for antibody-mediated demyelination were negative. Despite the undefined pathogenesis, these cases provide a platform to explore the confluence of genetic, immune and environmental factors in the context of acquired demyelination. We discuss the differential diagnosis and a diagnostic approach to such cases from the perspectives of neuroimmunology and neurogenetics.