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Pathogenic, biallelic variants in SORD were identified in 2020 as a novel cause for autosomal-recessive Charcot-Marie-Tooth disease (CMT) type 2, an inherited neuropathy. SORD codes for the enzyme sorbitol dehydrogenase. Loss of this enzyme's activity leads to an increase of sorbitol in serum. We retrospectively screened 166 patients with axonal neuropathy (predominantly CMT type 2, but including intermediate form of CMT and distal hereditary motor neuropathy (dHMN)) without identified genetic etiology for SORD mutations at a single large German neuromuscular center. Clinical and electrophysiology exam findings were analyzed for genotype-phenotype correlation. Five patients of the total cohort of 166 patients harbored pathogenic variants in SORD (3%). The homozygous frameshift variant c.757delG (p.Ala253Glnfs*27) was the most common (4/5). One additional case carried this variant on one allele only and an additional pathogenic missense variant c.458C > A (p.Ala153Asp) on the other allele. Age of onset ranged from early infancy to mid-twenties, and phenotypes comprised axonal CMT (4) and dHMN (1). Our findings strengthen the importance of screening for pathogenic variants in SORD, especially in patients with genetically unconfirmed axonal neuropathy, especially CMT type 2 and dHMN.
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Enfermedad de Charcot-Marie-Tooth , Fenotipo , Humanos , Enfermedad de Charcot-Marie-Tooth/genética , Femenino , Masculino , Adulto , Mutación , Estudios Retrospectivos , Estudios de Asociación Genética/métodos , Niño , Adolescente , Axones/patología , Adulto Joven , PreescolarRESUMEN
The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.
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Mutations in ITM2B cause familial British, Danish, Chinese and Korean dementias. In familial British dementia (FBD) a mutation in the stop codon of the ITM2B gene (also known as BRI2 ) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer's disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons, and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. Consequently, the ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. Pathological examination of post-mortem tissue support ABri expression in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are the major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. This has implications for our understanding of the role of microglia and the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer's disease.
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A spectrum of neurological disease associated with COVID-19 is becoming increasingly apparent. However, the mechanisms behind these manifestations remain poorly understood, significantly hindering their management. The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a "cytokine storm". We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.
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COVID-19 , Enfermedades del Sistema Nervioso , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas , Humanos , Enfermedades del Sistema Nervioso/etiología , SARS-CoV-2 , Síndrome Post Agudo de COVID-19RESUMEN
Junctophilin-3 belongs to a triprotein junctional complex implicated in the regulation of neuronal excitability and involved in the formation of junctional membrane structures between voltage-gated ion channels and endoplasmic (ryanodine) reticular receptors. A monoallelic trinucleotide repeat expansion located within the junctophilin-3 gene (JPH3) has been implicated in a rare autosomal dominant (AD) late-onset (and progressive) disorder clinically resembling Huntington disease (HD), and known as HD-like 2 (HDL2; MIM# 606438). Although the exact molecular mechanisms underlying HDL2 has not yet been fully elucidated, toxic gain-of-function of the aberrant transcript (containing the trinucleotide repeat) and loss of expression of (full-length) junctophilin-3 have both been implicated in HDL2 pathophysiology. In this study, we identified by whole exome sequencing (WES) a JPH3 homozygous truncating variant [NM_020655.4: c.17405dup; p.(Val581Argfs*137)]. in a female individual affected with genetically undetermined neurodevelopmental anomalies (including delayed motor milestones, abnormal social communication, language difficulties and borderline cognitive impairment) and paroxysmal attacks of dystonia since her early infancy. Our study expands the JPH3-associated mutational spectrum and clinical phenotypes, implicating the loss of Junctophilin-3 in heterogeneous neurodevelopmental phenotypes and early-onset paroxysmal movement disorders.
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Discapacidades del Desarrollo/genética , Trastornos Distónicos/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Alelos , Discapacidades del Desarrollo/patología , Trastornos Distónicos/patología , Femenino , Homocigoto , Humanos , FenotipoRESUMEN
Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.
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Proteínas Adaptadoras Transductoras de Señales , Alelos , Señalización del Calcio , Dendritas/metabolismo , Trastornos Distónicos , Mutación Missense , Células de Purkinje/metabolismo , Transmisión Sináptica , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Sustitución de Aminoácidos , Animales , Dendritas/genética , Trastornos Distónicos/genética , Trastornos Distónicos/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones NoqueadosRESUMEN
X-linked Adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene resulting in the accumulation of very long chain fatty acids (VLCFA). X-ALD is the most common peroxisomal disorder with adult patients (male and female) presenting with progressive spastic paraparesis with bladder disturbance, sensory ataxia with impaired vibration sense, and leg pain. 80% of male X-ALD patients have an adrenal failure, while adrenal dysfunction is rare in women with X-ALD. The objective of this study was to define optimal serum VLCFA cutoff values in patients with X-ALD-like phenotypes for the differentiation of genetically confirmed X-ALD and Non-X-ALD individuals. Three groups were included into this study: a) X-ALD cases with confirmed ABCD1 mutations (n = 34) and two Non-X-ALD cohorts: b) Patients with abnormal serum VCLFA levels despite negative testing for ABCD1 mutations (n = 15) resulting from a total of 1,953 VLCFA tests c) Phenotypically matching patients as Non-X-ALD controls (n = 104). Receiver operating curve analysis was used to optimize VLCFA cutoff values, which differentiate patients with genetically confirmed X-ALD and Non-X-ALD individuals. The serum concentration of C26:0 was superior to C24:0 for the detection of X-ALD. The best differentiation of Non-X-ALD and X-ALD individuals was obtained with a cutoff value of < 1.0 for the C24:0/C22:0 ratio resulting in a sensitivity of 97%, a specificity of 94.1% and a positive predictive value (PPV) of 83.8% for true X-ALD. Our findings further suggested a cutoff of < 0.02 for the ratio C26:0/C22:0 leading to a sensitivity of 90.9%, a specificity of 95.0%, and a PPV of 80.6%. Pearson correlation indicated a significant positive association between total blood cholesterol and VLCFA values. Usage of serum VLCFA are economical and established biomarkers suitable for the guidance of genetic testing matching the X-ALD phenotype. We suggest using our new optimized cutoff values, especially the two ratios (C24:0/C22:0 and C26:0/C22:0), in combination with standard lipid profiles.
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Adrenoleucodistrofia/sangre , Adrenoleucodistrofia/diagnóstico , Ácidos Grasos/sangre , Transportadoras de Casetes de Unión a ATP/genética , Adulto , Anciano , Astrocitos/patología , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. METHODS: We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. RESULTS: Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. INTERPRETATION: Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.
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Distonía/genética , Enfermedades por Almacenamiento Lisosomal/genética , Proteínas de Transporte Vesicular/genética , Adulto , Costo de Enfermedad , Distonía/patología , Exoma/genética , Femenino , Fibroblastos/patología , Predisposición Genética a la Enfermedad/genética , Variación Genética , Humanos , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Persona de Mediana Edad , Mutación/genética , LinajeRESUMEN
Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.
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Infecciones por Coronavirus , Enfermedades del Sistema Nervioso , Pandemias , Neumonía Viral , Adolescente , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Utilización de Medicamentos/estadística & datos numéricos , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Londres/epidemiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/epidemiología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Estudios Retrospectivos , SARS-CoV-2 , Adulto JovenRESUMEN
BACKGROUND: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease. OBJECTIVE: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype. METHODS: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families. RESULTS: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15). CONCLUSIONS: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.
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Enfermedad de Leigh/genética , Proteínas Mitocondriales/genética , Factores de Transcripción/genética , Adolescente , Adulto , Consanguinidad , Femenino , Humanos , Enfermedad de Leigh/diagnóstico por imagen , Enfermedad de Leigh/patología , Enfermedad de Leigh/fisiopatología , Masculino , Linaje , TurquíaRESUMEN
BACKGROUND: Neurofilament light protein is an unspecific biofluid marker that reflects the extent of neuronal/axonal damage and thereby offers the chance monitor disease severity and progression. The objective of this study was to investigate cerebrospinal fluid (CSF) levels of neurofilament light protein in Parkinson's disease (PD) patients with clinical trajectories of motor and cognitive function longitudinally. METHODS: CSF neurofilament light protein levels were assessed in 371 PDsporadic , 126 genetic PD patients (91 PDGBA , 8 PDLRRK2 , 21 PDPRKN/PINK1/DJ1_heterozygous , 6 PDPRKN/PINK1/DJ1_homozygous ), and 71 healthy controls. Participants were followed up longitudinally for up to 8 years. RESULTS: At baseline, mean CSF neurofilament light protein levels were highest in PD patients with cognitive impairment (Montreal Cognitive Assessment score ≤ 25; 1207 pg/mL) but also higher in PD patients with normal cognitive function (757 pg/mL) compared with healthy controls (593 pg/mL; P ≤ 0.001). In healthy controls and in PD patients older age was associated with higher CSF levels of neurofilament light protein (P ≤ 0.001). In PD patients, male gender, older age at onset, longer disease duration, higher Hoehn and Yahr stages, higher UPDRS-III scores, and lower Montreal Cognitive Assessment scores were associated with higher CSF levels of neurofilament light protein (P < 0.01). In patients who developed cognitive impairment during study, CSF neurofilament light protein levels prior to conversion to cognitive impairment were not significantly different compared with CSF neurofilament light protein levels of patients who remained cognitively normal. CONCLUSIONS: Increased CSF levels of neurofilament light protein are associated with cognitive decline and motor impairment in PD. However, this increase seems not a very early event and does not mark the conversion to cognitive impairment beforehand. Therefore, the predictive value needs to be discussed critically. © 2020 International Parkinson and Movement Disorder Society.
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Disfunción Cognitiva/etiología , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Factores de Edad , Anciano , Biomarcadores , Cognición , Progresión de la Enfermedad , Humanos , Masculino , Enfermedad de Parkinson/complicacionesRESUMEN
We report a case of a 62-year-old female diagnosed with functional neurological disorder (FND), where the diagnosis was eventually revised to progressive supranuclear palsy 3 years after symptom onset. FND is a commonly encountered condition and can be diagnosed with a considerable degree of confidence in most cases. FND is associated with significant functional impairment and may occur alongside other neurological disorders, and there is now a growing evidence base for symptom-specific FND treatments. Charting clinical progression of symptoms and serial neuroimaging were useful in refining the diagnosis in this case. Alhough the diagnosis was ultimately revised to a neurodegenerative disorder, a degree of functional overlay likely remained present. The case highlights the importance of recognizing and avoiding diagnostic overshadowing in those with FND.
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Neurodegeneración Asociada a Pantotenato Quinasa , Fosfotransferasas (Aceptor de Grupo Alcohol) , Encéfalo/metabolismo , Humanos , Hierro , Neurodegeneración Asociada a Pantotenato Quinasa/diagnóstico por imagen , Neurodegeneración Asociada a Pantotenato Quinasa/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismoRESUMEN
Hereditary spastic paraplegias (HSP) share as cardinal feature progressive spastic gait disorder. SPG4 accounts for about 25% of cases and is caused by mutations in the SPAST gene. Although HSP is an upper motor neuron disease, the relevance of non-motor symptoms is increasingly recognized because of the potential response to treatment. Our study sets out to evaluate non-motor symptoms and their relevance with regard to health-related quality of life. In 118 genetically confirmed SPG4 cases and age- and gender-matched controls, validated questionnaires were used to evaluate fatigue, depression, pain, and restless legs syndrome. In addition, self-reported medical information was collected concerning comorbidities and bladder, bowel, and sexual dysfunction. In a sub-study, cognition was evaluated using the CANTAB® test-battery and the Montreal Cognitive Assessment in 26 SPG4 patients. We found depression and pain to be significantly increased. The frequency of restless legs syndrome varied largely depending on defining criteria. There were no significant deficits in cognition as examined by CANTAB® despite a significant increase in self-reported memory impairment in SPG4 patients. Bladder, sexual, and defecation problems were frequent and seemed to be underrecognized in current treatment strategies. All identified non-motor symptoms correlated with health-related quality of life, which was reduced in SPG4 compared to controls. We recommend that clinicians regularly screen for depression, pain, and fatigue and ask for bladder, sexual, and defecation problems to recognize and treat non-motor symptoms accordingly to improve quality of life in patients with SPG4.
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Paraplejía/fisiopatología , Paraplejía/terapia , Paraplejía Espástica Hereditaria/fisiopatología , Paraplejía Espástica Hereditaria/terapia , Adulto , Anciano , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Depresión/etiología , Depresión/psicología , Fatiga/etiología , Fatiga/psicología , Incontinencia Fecal/etiología , Femenino , Humanos , Masculino , Trastornos de la Memoria/etiología , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Dolor/etiología , Paraplejía/psicología , Calidad de Vida , Síndrome de las Piernas Inquietas/etiología , Síndrome de las Piernas Inquietas/psicología , Autoinforme , Disfunciones Sexuales Fisiológicas/etiología , Paraplejía Espástica Hereditaria/psicología , Enfermedades de la Vejiga Urinaria/etiología , Adulto JovenRESUMEN
Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.
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Moléculas de Adhesión Celular/genética , Enfermedades Desmielinizantes/genética , Factores de Crecimiento Nervioso/genética , Trastornos del Neurodesarrollo/genética , Adolescente , Adulto , Alelos , Axones/metabolismo , Moléculas de Adhesión Celular/metabolismo , Niño , Preescolar , Enfermedades Desmielinizantes/metabolismo , Femenino , Frecuencia de los Genes/genética , Humanos , Lactante , Masculino , Mutación , Vaina de Mielina/genética , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas/fisiología , Factores de Crecimiento Nervioso/metabolismo , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo/metabolismo , Neuroglía/metabolismo , Linaje , Nervios Periféricos , Isoformas de Proteínas/metabolismo , Nódulos de Ranvier/genética , Nódulos de Ranvier/metabolismoRESUMEN
The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
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Trastornos Heredodegenerativos del Sistema Nervioso/genética , Fenotipo , Paraplejía Espástica Hereditaria/genética , Niño , Estudios de Cohortes , Enfermedades Desmielinizantes/genética , Femenino , Humanos , Masculino , Oxigenasas de Función Mixta/genética , Mutación/genética , Linaje , Estudios Retrospectivos , Paraplejía Espástica Hereditaria/clasificaciónRESUMEN
BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterised by brief attacks of chorea, dystonia, or mixed forms precipitated by sudden movement. METHODS: Observational study with a cohort of 14 PKD patients and genetic testing for PRRT2 mutations. RESULTS: In a series of 14 PKD patients seen in our clinic at the National Hospital of Neurology, Queen Square, from 2012-2017, we noted tics in 11 patients (79%), which stand in stark contrast to the estimated lifetime prevalence of tics estimated to reach 1%. CONCLUSIONS: The two reasons to point out this possible association are the clinical implications and the potential opportunity of a better understanding of shared pathophysiological mechanisms of neuronal hyperexcitability.
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BACKGROUND: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cγ gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia. METHODS: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations. RESULTS: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cγ gene. A total of 10 unique protein kinase Cγ gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11. CONCLUSION: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cγ gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cγ gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.