RESUMO
BACKGROUND: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare autosomal dominant systemic microvascular disorder attributed to TREX1 (three-prime repair exonuclease-1) gene mutations, often proned to misdiagnosed. METHODS: We reported a case of RVCL-S coexisting with systemic lupus erythematosus due to a mutation in the TREX1 gene. This study provided a summary and discussion of previously documented cases related to TREX1 mutations or RVCL-S. RESULTS: A 39-year-old female patient visited the clinic due to progressive memory loss and speech difficulties. Magnetic resonance imaging results showed corpus callosum atrophy and multiple subcortical calcifications in both brain hemispheres. Genetic testing revealed a TREX1 gene mutation (c.294dupA). Treatment with immunosuppressive therapy for 2 months led to improvements in communication and mobility. We also summarized previously reported cases providing an overview of TREX1 gene mutation or RCVL-S. CONCLUSION: Our case establishes a compelling foundation for future RVCL-S diagnosis and treatment paradigms. Notably, conducting systemic immunity screening in patients with RVCL-S emerges as a strategic approach to prevent potential diagnostic oversights.
Assuntos
Exodesoxirribonucleases , Leucoencefalopatias , Lúpus Eritematoso Sistêmico , Mutação , Humanos , Feminino , Adulto , Exodesoxirribonucleases/genética , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/etiologia , Fosfoproteínas/genética , Erros de Diagnóstico/prevenção & controle , Imageamento por Ressonância Magnética , Vasculite Retiniana/diagnóstico , Vasculite Retiniana/etiologia , Doenças Retinianas , Doenças Vasculares , Doenças Desmielinizantes Hereditárias do Sistema Nervoso CentralRESUMO
OBJECTIVE: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. DESIGN: Cross sectional descriptive study from December 2021 to December 2022. PARTICIPANTS: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. METHODS: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). MAIN OUTCOME MEASURES: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (µm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. RESULTS: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 µm (range, 217-488 µm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18-1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9-6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. CONCLUSIONS: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Assuntos
Eletrorretinografia , Angiofluoresceinografia , Leucoencefalopatias , Imagem Multimodal , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Masculino , Feminino , Estudos Transversais , Tomografia de Coerência Óptica/métodos , Adulto , Angiofluoresceinografia/métodos , Eletrorretinografia/métodos , Pessoa de Meia-Idade , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/fisiopatologia , Campos Visuais/fisiologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/fisiopatologia , Doenças Retinianas/etiologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/fisiopatologia , Vasos Retinianos/patologia , Adulto Jovem , Fundo de Olho , AdolescenteRESUMO
INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one kind of monogenic hereditary small-vessel disease in the brain caused by mutations in the NOTCH3 gene. However, it is rare for CADASIL to recur with different clinical manifestations in 1 patient, and some atypical clinical manifestations can easily lead to misdiagnosis by clinical physicians. CASE CONCERN: A 34-year-old male presented with transient speech disorder accompanied by weakness in the left side of the body for 1 day in June 2020. Magnetic resonance imaging showed acute ischemic infarction in right centrum semiovale, along with multiple abnormal white matter hyperintensities in the brain. Genetic sequencing identified a heterozygous mutation in the NOTCH3 gene. The patient experienced recurrent episodes in 2021 and 2023, with varying clinical symptoms including visual blurring, abnormal limb sensation, and sudden cognitive dysfunction. DIAGNOSIS: The diagnoses of CADASIL is based on clinical manifestations, imaging results, and genetic reports. INTERVISION AND OUTCOMES: The patient was received symptomatic treatment including antiplatelet aggregation therapy, lipid regulation, and plaque stabilization, resulting in improved symptoms. OUTCOMES: During the course of the disease, after medication treatment and rehabilitation exercise, the patient clinical symptoms have significantly improved. Currently, the patient is closely following up and regularly undergoing relevant examinations. LESSONS: In this rare case, we found that CADASIL can recur multiple times in a patient with different clinical symptoms, which can easily lead to clinical misdiagnosis. Clinicians should consider the possibility of CADASIL in young patients with sudden typical neurological dysfunction.
Assuntos
CADASIL , Leucoencefalopatias , Masculino , Humanos , Adulto , CADASIL/complicações , CADASIL/diagnóstico , CADASIL/genética , Receptor Notch3/genética , Encéfalo/patologia , Mutação , Imageamento por Ressonância Magnética , Leucoencefalopatias/complicações , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/patologiaRESUMO
Acute toxic leukoencephalopathy and serotonin syndrome are rare neurological complications associated with various drugs and toxins, some of which overlap. However, the co-occurrence of these conditions is poorly documented. We present the case of a 14-year-old boy who suddenly developed altered consciousness and autonomic dysfunction after consuming excessive quantities of cough remedies containing dextromethorphan, chlorphenamine, dichlorobenzyl alcohol, and amylmetacreson. Magnetic resonance imaging of the brain revealed distinct white matter lesions. With supportive care, the patient rapidly improved, and the magnetic resonance imaging abnormalities disappeared. The swift resolution, typical magnetic resonance imaging findings, and a history of exposure to drugs affecting the central nervous system's serotonergic system suggested concurrent acute toxic leukoencephalopathy and serotonin syndrome. The components of cough medications can be hazardous in overdose due to their potential to enhance serotonin toxicity and cause direct or indirect central nervous system white matter damage. Early recognition and appropriate treatment are essential for recovery.
Assuntos
Overdose de Drogas , Leucoencefalopatias , Síndrome da Serotonina , Masculino , Humanos , Adolescente , Síndrome da Serotonina/induzido quimicamente , Síndrome da Serotonina/diagnóstico , Síndrome da Serotonina/patologia , Overdose de Drogas/complicações , Overdose de Drogas/patologia , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética , TosseRESUMO
Caseinolytic peptidase B homolog (CLPB) is a mitochondrial protein which is highly expressed in brain. Its deficiency may be associated with severe neonatal encephalopathy. This report describes a case of fatal neonatal encephalopathy associated with biallelic stop-gain mutation in CLPB (NM_001258392.3:c.1159C>T/p.Arg387*). Neurologic disorder encompasses pre- and post-natal features including polyhydramnios, intrauterine growth restriction, respiratory insufficiency, lethargy, excessive startle reflex, generalized hypertonia, and epileptic seizures. Brain macroscopic examination demonstrates frontal severe periventricular cystic leukoencephalopathy, along with mild ex-vacuo tri-ventricular dilatation. The most striking immunohistopathologic features are striato-thalamic neurodegeneration and deep white matter loss associated with strong reactive astrogliosis. This report supports that CLPB deficiency should be considered among the neurometabolic disorders associated with severe prenatal-onset neurologic impairment that may result from cystic leukoencephalopathy.
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Epilepsia , Doenças do Recém-Nascido , Leucoencefalopatias , Recém-Nascido , Feminino , Gravidez , Humanos , Endopeptidase Clp/genética , Endopeptidase Clp/metabolismo , Encéfalo/patologia , Epilepsia/metabolismo , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/metabolismo , Códon sem Sentido/metabolismo , Doenças do Recém-Nascido/patologiaAssuntos
Infliximab , Leucoencefalopatias , Neurite Óptica , Psoríase , Humanos , Masculino , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Infliximab/efeitos adversos , Leucoencefalopatias/induzido quimicamente , Leucoencefalopatias/diagnóstico , Imageamento por Ressonância Magnética , Neurite Óptica/induzido quimicamente , Neurite Óptica/diagnóstico , Neurite Óptica/tratamento farmacológico , Psoríase/tratamento farmacológico , Psoríase/induzido quimicamente , AdultoRESUMO
Methotrexate-induced neurotoxicity is a well-defined side-effect of high-dose and intrathecal methotrexate with characteristic clinico-radiological findings and transient nature. Our experience in managing this entity in children with acute lymphoblastic leukemia(ALL) is reported here. All children with de novo ALLregistered from January 2016 through December 2021 who developed methotrexate-induced neurotoxicity were included. Of children with ALL treated during the study period, thirty-three experienced methotrexate induced neurotoxicity with an incidence of 1.25%. Stroke-like symptoms(36.36%; 12/33) were the most common clinical manifestation followed by seizures(30.3%, 10/33). Twenty-three patients had radiological features consistent with methotrexate-induced leukoencephalopathy. With emerging evidence, thirty-one patients were re-challenged with methotrexate (IV/IT), of whom 4 patients had recurrence of symptoms. No long-term neurological sequalae were noted in our cohort, despite rechallenging. Therefore in our study, methotrexate induced neurotoxicity is a self-limiting toxicity and methotrexate can be re-challenged safely without compromising theintensity of CNS-directed therapy.
Assuntos
Leucoencefalopatias , Metotrexato , Síndromes Neurotóxicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Seguimentos , Leucoencefalopatias/induzido quimicamente , Leucoencefalopatias/complicações , Leucoencefalopatias/diagnóstico , Metotrexato/efeitos adversos , Síndromes Neurotóxicas/diagnóstico , Síndromes Neurotóxicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , RadiografiaRESUMO
OBJECTIVE: Leukoencephalopathies are a group of heterogeneous disorders characterized by the degeneration of white matter, resulting in a variety of progressive neurological symptoms. To date, over 60 genes linked to genetic leukoencephalopathies have been discovered through whole-exome sequencing (WES) and long-read sequencing. Nonetheless, the genetic diversity and clinical variability of these disorders among various racial groups remain largely unknown. Therefore, this study aims to analyze the genetic spectrum and clinical features of Chinese adult leukoencephalopathies and compare the genetic profiles in different populations. METHODS: A total of 129 patients suspected of possible genetic leukoencephalopathy were enrolled and underwent WES and dynamic mutation analysis. Bioinformatics tools were used to predict the pathogenicity of these mutations. Skin biopsies were conducted for further diagnosis. Genetic data sources from different populations were collected from published articles. RESULTS: Genetic diagnosis was established in 48.1% of patients, with WES identifying 57 pathogenic or likely pathogenic variants in 39.5% of cases. NOTCH3 and NOTCH2NLC were the most common mutated genes, accounting for 12.4% and 8.5% of cases, respectively. Dynamic mutation analysis revealed NOTCH2NLC GGC repeat expansions in 8.5% of patients. Different mutations resulted in varying clinical symptoms and imaging findings. Comparisons of genetic profiles between different populations showed distinct mutational spectrums in adult leukoencephalopathies. INTERPRETATION: This study highlights the importance of genetic testing for accurate diagnosis and improved clinical management of these disorders. It also sheds light on the genetic heterogeneity of adult leukoencephalopathies across different races, emphasizing the need for further research on this topic.
Assuntos
Leucoencefalopatias , Substância Branca , Adulto , Humanos , População do Leste Asiático , Testes Genéticos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Mutação , Substância Branca/patologiaRESUMO
Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy is a primary microgliopathy characterized by a complex phenotype, which can be easily misdiagnosed with other leukoencephalopathy and neurodegenerative diseases such as frontotemporal dementia. It is estimated to be the most common adult-onset leukodystrophy. Here, we report the case of a 67-year-old man with a history of progressive impairment of behavioral and cognitive functions, including apathy, inhibition, tendency to mutism, and deficits in complex planning skills. Neurological examination revealed pyramidalism in the lower limbs. Brain imaging showed symmetrical confluent frontal leukoencephalopathy, bilateral frontal calcifications, and thinning of the corpus callosum. The diagnosis was confirmed by the identification of a heterozygous pathogenic variant in the colony-stimulating factor 1 receptor. As far as we know, this is the first documented case in Spain. In this paper, we aim to expand on clinical features and underline the importance of brain imaging for the diagnosis of an entity that we consider to be underdiagnosed.
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Leucoencefalopatias , Fator Estimulador de Colônias de Macrófagos , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Fator Estimulador de Colônias de Macrófagos/genética , Mutação , Fenótipo , Espanha , Masculino , IdosoRESUMO
RATIONALE: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is the most common subtype of mitochondrial encephalopathy. In the past, it was believed that most hereditary white matter lesions were lysosome storage disorders or peroxisome diseases. However, in recent years, white matter lesions have been increasingly regarded as a common feature of patients with mitochondrial diseases. In addition to stroke-like lesions, about half of the patients with MELAS reported white matter lesions in the brain. PATIENT CONCERNS: Herein, we provide a case of A 48-year-old female who presented with episodic loss of consciousness with twitching of extremities. Previous medical history revealed 10 years of history of epilepsy, 10 years of history of diabetes, a history of hearing loss, and unknown etiology. Ancillary findings included brain magnetic fluid-attenuated inversion recovery showed symmetrical lesions in the bilateral parietal lobe with high signal intensity at the edge, and high signal intensity in the bilateral occipital lobe, paraventricular white matter, corona radiata, and the center of semiovale. DIAGNOSES: Mitochondrial deoxyribonucleic acid gene sequencing returned A3243G point mutation and it supports the diagnosis of intracranial hypertension. INTERVENTIONS: Considered the diagnosis of symptomatic epilepsy, the patient was treated with mechanical ventilation, midazolam, and levetiracetam, and the limb twitching symptoms were controlled. The patient was comatose, chronically bedridden, with gastrointestinal dysfunction, and was treated prophylactically with antibiotics against infection, parenteral nutrition, and other supportive measures. B vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone were given, and mechanical ventilation and midazolam were stopped after 8 days. He was discharged from the hospital on 30 days and continued symptomatic treatment with B-vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone, and antiepileptic treatment with levetiracetam, with outpatient follow-up. OUTCOMES: No further seizures were recorded and the patient recovered well. LESSONS: MELAS syndrome without stroke-like episodes of diffuse posterior cerebral white matter lesions is rare in clinical practice, and the possibility of MELAS syndrome should be considered in symmetric posterior cerebral white matter lesions.
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Acidose Láctica , Leucoencefalopatias , Síndrome MELAS , Acidente Vascular Cerebral , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Acidose Láctica/complicações , Síndrome MELAS/complicações , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Levetiracetam/uso terapêutico , Midazolam/uso terapêutico , Acidente Vascular Cerebral/etiologia , Ácido Ascórbico/uso terapêutico , Vitaminas/uso terapêutico , Leucoencefalopatias/complicações , Leucoencefalopatias/diagnóstico , Vitamina E/uso terapêuticoRESUMO
The leukodystrophies (LD) and leukoencephalopathies (LE) are a diverse group of conditions involving the cerebral white and grey matter. There is heterogeneity in the clinical presentations, imaging features, and biochemical dysfunction. Given the number of conditions and varied imaging appearances, this topic can be difficult for non-specialist radiologists who do not routinely work in dedicated paediatric neuroradiology centres. This article will aim to provide a simplified and step-wise approach to assessing suspected LD/LE, focussing on the more common diagnoses you may encounter in the UK. Additionally, it will highlight important non-LD/LE differentials, which if considered early, may significantly alter treatment and prognosis. By the end of this review, we hope the reader will begin to develop an awareness of physiological paediatric brain development in terms of normal myelination; the ability to recognise and categorise the distribution of abnormal signal based on the established diagnostic framework outlined by Schiffmann & Van der Knapp; and be aware of potential non-LD/LE radiological mimics.
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Leucoencefalopatias , Humanos , Criança , Leucoencefalopatias/diagnóstico , Imageamento por Ressonância MagnéticaRESUMO
ABSTRACT: The incidence of 5-Fluorouracil (5FU)- induced leukoencephalopathy is <5% among the patients treated with this agent. It may present with disorientation, confusion, agitation, seizure, and coma. It should be suspected when patients present with any of these symptoms during or immediately after 5FU chemotherapy. Early detection of drug-induced leukoencephalopathy is important as the clinical symptoms can be reversed by early discontinuation of the drug. Therefore, clinicians should be aware of the possibility of this adverse neurologic effect of 5FU. We describe the case of a 35-year-old female with carcinoma esophagus with 5FU-induced leukoencephalopathy.
Assuntos
Carcinoma , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Leucoencefalopatias , Feminino , Humanos , Adulto , Conscientização , Fluoruracila/efeitos adversos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/diagnóstico por imagemRESUMO
BACKGROUND: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive neurological disease. The physiopathology of disease is still little understood, but it seems to involve impairment in maturation of astrocytes; as a consequence white matter is more prone to cellular stress. Disease is caused by mutations in five genes encoding subunits of the translation initiation factor eIF2B. We know five different types of VWM syndrome classified based different ages of onset (prenatal, infantile, childhood, juvenile and adult onset). CASE PRESENTATION: We report the case of a 4-month-old boy with early seizure onset, recurrent hypoglycemia and post mortem diagnosis of vanishing white matter disease (VMD). At the admission he presented suspected critical episodes, resolved after intravenous administration of benzodiazepines. The brain MRI showed total absence of myelination that suggested hypomyelination leukoencephalopathy. The whole exome sequencing (WES) revealed a variant of EIF2B2 gene (p. Val308Met) present in homozygosity. In this case report we also describe the clinical evolution of seizures, in fact the epileptic seizures had a polymorphic aspect, from several complex partial seizures secondarily generalized to status epilepticus. CONCLUSION: Infantile and early childhood onset forms are associated with chronic progressive neurological signs, with episodes of rapid neurological worsening, and poor prognosis, with death in few months or years. Clinical presentation of epilepsy is poorly documented and do not include detailed information about the type, time of onset and severity of seizures. No therapeutic strategies for VWM disease have been reported.
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Epilepsia , Leucoencefalopatias , Substância Branca , Pré-Escolar , Fator de Iniciação 2B em Eucariotos/genética , Humanos , Lactente , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Imageamento por Ressonância Magnética , Masculino , Mutação , Convulsões , Substância Branca/diagnóstico por imagemRESUMO
Abuse of heroin vapour inhalation known as "chasing the dragon" is associated with toxic spongiform leukoencephalopathy. However, similar clinical and imaging findings may occur also after intravenous heroin abuse. We report on a 32-year-old male suffering from extensive toxic spongiform leukoencephalopathy after intravenous heroin abuse resulting in acute impairment of consciousness and a global state of confusion. MRI disclosed broad and nearly symmetrical diffusion restriction of the supratentorial white matter indicating cytotoxic oedema. In an emergency setting, differential diagnosis of acute impairment of consciousness and broad symmetrical white matter lesions in neuroimaging should also include toxic leukoencephalopathy due to intravenous heroin application.
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Dependência de Heroína , Leucoencefalopatias , Masculino , Humanos , Adulto , Heroína/toxicidade , Dependência de Heroína/complicações , Estado de Consciência , Diagnóstico Diferencial , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Several cases of coronavirus disease 2019 (COVID-19)-associated leukoencephalopathy have been reported. Although most cases involve hypoxia, the pathophysiological mechanism and neurologic outcomes of COVID-19-associated leukoencephalopathy remain unclear. CASE PRESENTATION: We report a case of COVID-19-associated leukoencephalopathy without severe hypoxia in a 65-year-old woman diagnosed with pyelonephritis. After the initiation of intravenous ceftriaxone, her fever resolved, but she developed an altered state of consciousness with abnormal behavior and, subsequently, a relapse fever. She was diagnosed with COVID-19 pneumonia and was intubated. Lung-protective ventilation with deep sedation and neuromuscular blockade were used for treatment. After cessation of sedative administration, her mental status remained at a Glasgow Coma Scale score of 3. COVID-19 was assumed to have caused leukoencephalopathy due to the absence of severe hypoxia or other potential causes. She subsequently showed gradual neurologic improvement. Three months after the COVID-19 diagnosis, she regained alertness, with a Glasgow Coma Scale score of 15. CONCLUSION: Clinicians should consider leukoencephalopathy in the differential diagnosis of consciousness disorders in patients with severe COVID-19, even in the absence of severe hypoxia. Gradual neurologic improvement can be expected in such cases.
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COVID-19 , Leucoencefalopatias , Idoso , COVID-19/complicações , COVID-19/diagnóstico , Teste para COVID-19 , Feminino , Humanos , Hipóxia/etiologia , Leucoencefalopatias/diagnóstico , SARS-CoV-2RESUMO
TUBB4A-associated disorder is a rare condition affecting the central nervous system. It displays a wide phenotypic spectrum, ranging from isolated late-onset torsion dystonia to a severe early-onset disease with developmental delay, neurological deficits, and atrophy of the basal ganglia and cerebellum, therefore complicating variant interpretation and phenotype prediction in patients carrying TUBB4A variants. We applied entropy-based normal mode analysis (NMA) to investigate genotype-phenotype correlations in TUBB4A-releated disease and to develop an in-silico approach to assist in variant interpretation and phenotype prediction in this disorder. Variants included in our analysis were those reported prior to the conclusion of data collection for this study in October 2019. All TUBB4A pathogenic missense variants reported in ClinVar and Pubmed, for which associated clinical information was available, and all benign/likely benign TUBB4A missense variants reported in ClinVar, were included in the analysis. Pathogenic variants were divided into five phenotypic subgroups. In-silico point mutagenesis in the wild-type modeled protein structure was performed for each variant. Wild-type and mutated structures were analyzed by coarse-grained NMA to quantify protein stability as entropy difference value (ΔG) for each variant. Pairwise ΔG differences between all variant pairs in each structural cluster were calculated and clustered into dendrograms. Our search yielded 41 TUBB4A pathogenic variants in 126 patients, divided into 11 partially overlapping structural clusters across the TUBB4A protein. ΔG-based cluster analysis of the NMA results revealed a continuum of genotype-phenotype correlation across each structural cluster, as well as in transition areas of partially overlapping structural clusters. Benign/likely benign variants were integrated into the genotype-phenotype continuum as expected and were clearly separated from pathogenic variants. We conclude that our results support the incorporation of the NMA-based approach used in this study in the interpretation of variant pathogenicity and phenotype prediction in TUBB4A-related disease. Moreover, our results suggest that NMA may be of value in variant interpretation in additional monogenic conditions.