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Brain : a Journal of Neurology Aug 2023In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later...
In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated with torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with AMC5-TOR1A have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with foetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71%, with higher mortality in males. Death occurred at a median age of 1.2 months (1 week-9 years), due to respiratory failure, cardiac arrest or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.
Topics: Male; Humans; Cross-Sectional Studies; Mutation; Phenotype; Dystonia; Dystonic Disorders; Nervous System Malformations; Molecular Chaperones
PubMed: 36757831
DOI: 10.1093/brain/awad039 -
European Journal of Paediatric Dentistry Sep 2023Otodental syndrome is a rare autosomal dominant condition characterised by a dental phenotype known as globodontia often associated with high-frequency hearing loss....
Otodental syndrome is a rare autosomal dominant condition characterised by a dental phenotype known as globodontia often associated with high-frequency hearing loss. Globodontia occurs both in the decidous and permanent dentition and affects canine and molar teeth.
Topics: Humans; Chromosome Disorders; Hearing Loss, Sensorineural; Tooth Abnormalities; Arthrogryposis
PubMed: 37668456
DOI: 10.23804/ejpd.2023.24.03.03 -
Brain : a Journal of Neurology Oct 2023In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex...
In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.
Topics: Pregnancy; Female; Adult; Humans; Immunoglobulins, Intravenous; Receptors, Cholinergic; Myasthenia Gravis; Autoantibodies; Neuromuscular Diseases; Arthrogryposis
PubMed: 37186601
DOI: 10.1093/brain/awad153 -
International Journal of Molecular... Aug 2023Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models,... (Review)
Review
Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Topics: Humans; Genome-Wide Association Study; Migraine Disorders; Mutation; Arthrogryposis; Blindness; Cerebral Arterial Diseases
PubMed: 37628876
DOI: 10.3390/ijms241612697 -
Cells Aug 2023The cholinergic system plays an essential role in brain development, physiology, and pathophysiology. Herein, we review how specific alterations in this system, through... (Review)
Review
The cholinergic system plays an essential role in brain development, physiology, and pathophysiology. Herein, we review how specific alterations in this system, through genetic mutations or abnormal receptor function, can lead to aberrant neural circuitry that triggers disease. The review focuses on the nicotinic acetylcholine receptor (nAChR) and its role in addiction and in neurodegenerative and neuropsychiatric diseases and epilepsy. Cholinergic dysfunction is associated with inflammatory processes mainly through the involvement of α7 nAChRs expressed in brain and in peripheral immune cells. Evidence suggests that these neuroinflammatory processes trigger and aggravate pathological states. We discuss the preclinical evidence demonstrating the therapeutic potential of nAChR ligands in Alzheimer disease, Parkinson disease, schizophrenia spectrum disorders, and in autosomal dominant sleep-related hypermotor epilepsy. PubMed and Google Scholar bibliographic databases were searched with the keywords indicated below.
Topics: Humans; Cell Membrane; Alzheimer Disease; Arthrogryposis; Brain; Receptors, Nicotinic
PubMed: 37626860
DOI: 10.3390/cells12162051 -
HGG Advances Jul 2023Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as , , and that...
Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as , , and that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as , , and that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., ) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene , , (). encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in and suggests that some functions of are shared in cardiac and skeletal muscle.
Topics: Humans; Arthrogryposis; Actins; Heart Defects, Congenital; Cardiomyopathies; Cardiomyopathy, Dilated; Muscular Diseases; Myosins; Cardiomyopathy, Hypertrophic
PubMed: 37457373
DOI: 10.1016/j.xhgg.2023.100213 -
Genes Jul 2023The vacuolar H-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many...
The vacuolar H-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely and , have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in can cause seizures and that the heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.
Topics: Animals; Mice; Seizures; Causality; Adenosine Triphosphatases; Anxiety; Arthrogryposis; Intellectual Disability; Vacuolar Proton-Translocating ATPases
PubMed: 37628590
DOI: 10.3390/genes14081538 -
Nucleic Acids Research Jan 2024The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational...
The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.
Topics: Humans; Biological Ontologies; Phenotype; Genomics; Algorithms; Rare Diseases
PubMed: 37953324
DOI: 10.1093/nar/gkad1005 -
Nature Neuroscience Aug 2023The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations...
The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers.
Topics: Humans; Alzheimer Disease; Positron-Emission Tomography; Magnetic Resonance Imaging; Neuroimaging; Arthrogryposis; Mutation; Amyloid beta-Peptides
PubMed: 37429916
DOI: 10.1038/s41593-023-01359-8