Assessing Chitinases and Neurofilament Light Chain as Biomarkers for Adult-Onset Leukodystrophies.

Leukodystrophies represent a large and complex group of inherited disorders affecting the white matter of the central nervous system. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare leukodystrophy which still needs the proper identification of diagnostic, prognostic, and monitoring biomarkers. The aim of this study was to determine the diagnostic and prognostic value of chitinases and neurofilament light chain as biomarkers for ALSP. A cross-sectional study was performed to analyze cerebrospinal fluid levels of chitinases (chitotriosidase and chitinase 3-like 2) and neurofilament light chain in five different groups: (i) normal health individuals; (ii) patients with definitive diagnosis of ALSP and genetic confirmation; (iii) asymptomatic patients with CSF1R variants; (iv) patients with other adult-onset leukodystrophies; and (v) patients with amyotrophic lateral sclerosis (external control group). Chitinase levels showed a statistical correlation with clinical assessment parameters in ALSP patients. Chitinase levels were also distinct between ALSP and the other leukodystrophies. Significant differences were noted in the levels of chitinases and neurofilament light chain comparing symptomatic (ALSP) and asymptomatic individuals with CSF1R variants. This study is the first to establish chitinases as a potential biomarker for ALSP and confirms neurofilament light chain as a good biomarker for primary microgliopathies.

Neurofilament light chain as a biomarker for acute hepatic porphyrias.

Background: Acute hepatic porphyrias (AHP) represent a rare group of inherited metabolic disorders of heme biosynthesis pathway. This study aims to determine the diagnostic and prognostic value of serum neurofilament light chain (NfL) as potential biomarker for AHP. Methods: We conducted a cross-sectional observational study to evaluate NfL levels in patients with AHP. They were divided in different groups: normal health individuals; patients with definitive diagnosis of AHP during acute episodes; patients with AHP and infrequent attacks; patients with AHP and recurrent attacks; asymptomatic individuals with positive genetic testing and urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels elevated 4 or more times ("high excretors"); asymptomatic individuals with exclusive positive genetic test; control group with Hereditary Amyloidosis related to Transthyretin with Polyneuropathy (ATTRv-PN). Results: During acute attacks, serum NfL levels were 68 times higher compared to normal controls and disclosed a strong correlation with ALA and PBG levels; also exhibited elevated levels in patients with chronic symptoms regardless of the number of disease attacks compared to healthy controls, and at similar levels to patients with ATTRv-PN, which is a model of progressive neuropathy. Conclusion: This study represents the first to establish NfL as a biomarker for AHP, disclosing NfL as a sensitive biomarker for axonal damage and chronic symptom occurrence. This study not only underscores that neurological damage associated with the disease in any patient, irrespective of the number of attacks, but also reinforces the progressive and profoundly debilitating nature of acute and chronic symptoms observed in individuals with AHP.

Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges.

Juvenile Amyotrophic Lateral Sclerosis is a genetically heterogeneous neurodegenerative disorder, which is frequently misdiagnosed due to low clinical suspicion and little knowledge about disease characteristics. More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally. Despite several upper motor neuron-dominant forms being generally associated with long-standing motor symptoms and slowly progressive course, certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap. For some monogenic forms, there is a well-established genotypic-phenotypic correlation. There are no specific biochemical and neuroimaging biomarkers for the diagnosis of juvenile Amyotrophic Lateral Sclerosis. There are several inherited neurodegenerative and neurometabolic disorders which can lead to the signs of motor neuron impairment. This review emphasizes the importance of high clinical suspicion, assessment, and proper diagnostic work-up for juvenile Amyotrophic Lateral Sclerosis.

Brazilian registry of patients with porphyria: REBRAPPO study.

BACKGROUND: Porphyrias are a rare group of disease due to inherited defects of heme synthesis with important systemic manifestations and great burden of disease for patients and families due to the exceptional course of disease with disabling chronic symptoms interposed by life-threatening acute attacks. Unfortunately, the porphyrias are usually underrecognized reflecting a lack of medical and disease awareness as well as few studies about natural history in large cohorts of patients. The main aim of this article is present consistent data about natural history and burden of disease in a large Brazilian cohort. METHODS: We conducted a national cross-sectional registry with retrospective clinical data of Brazilian patients with porphyria collected with Brazilian patients Association with Porphyria in collaboration with a tertiary care center for rare diseases. RESULTS: A cohort of 172 patients was analyzed in which 148 (86%) patients had the diagnosis of acute hepatic porphyria [AHP] that needed a mean of 62.04 medical visits and 9.6 years to achieve a definitive diagnosis. About AHP cohort, the most common first clinical manifestation were abdominal pain in 77 (52%) patients and acute muscle weakness in 23 (15.5%) with 73 (49.3%) patients presenting only one attack during disease course and 37 (25%) exhibiting 4 or more attacks in the last year. Of note, 105 patients with AHP reported chronic manifestations and the scores for quality of life are lower when compared with general healthy population. CONCLUSIONS: Brazilian patients with AHP had a higher prevalence of chronic disabling manifestations and a poor quality of life like other cohorts and a higher proportion of patients with recurrent attacks than previously reported.

Myasthenia gravis in the complex scenario of LRBA-related immune dysregulation / Miastenia gravis no cenário clínico complexo das imunodesregulações relacionadas ao gene LRBA

Autoimmune diseases have been progressively recognized as a potential complication of primary immunodeficiency, especially for some genetic subtypes of common variable immunodeficiency. Although often associated with other autoimmune disorders, autoimmune myasthenia gravis is occasionally identified as a neuromuscular complication of primary immunodeficiency. We report the case of a Brazilian woman with common variable immunodeficiency-8 due to an LRBA variant, in which myasthenia gravis was identified in association with anti-acetylcholine receptor antibody. Marked clinical improvement occurred after intravenous immunoglobulin therapy.

Doenças autoimunes foram progressivamente reconhecidas como complicações potenciais das imunodeficiências primárias, especialmente para alguns subtipos genéticos das imunodeficiências comuns variáveis. Embora se associe comumente a outras doenças autoimunes, a Miastenia gravis autoimune adquirida foi raramente associada como complicação neuromuscular de imunodeficiências primárias. É descrito neste artigo o caso de paciente brasileira do sexo feminino com diagnóstico de Imunodeficiência Comum Variável tipo 8 por variante no gene LRBA, na qual foi identificada Miastenia gravis em associação a anticorpos antirreceptor de acetilcolina. Ela evoluiu com marcante melhora clínica após a introdução de terapêutica com imunoglobulina endovenosa.

Olfactory nerve: from ugly duckling to swan.

BACKGROUND: The olfactory nerve has never been the shining star of neurological examination. Quite the contrary, examining the first cranial nerve is often an overlooked step. As cases of anosmia secondary to COVID-19 infection continue to rise, the 2020 pandemic has shed new light on this much-forgotten nerve, its value as an aid to diagnosis of several diseases and its central role in our daily lives. OBJECTIVE: We aimed to emphasize how essential and simple clinical examination of the olfactory system can be by highlighting practical techniques and clinical tips for its assessment. We also share pearls and pitfalls in localization and differential diagnosis, which may prove valuable to busy clinicians. METHODS: A broad review of the literature was conducted by searching PubMed, Cochrane and Google Scholar for articles and books containing topics regarding examination of the olfactory nerve and its anatomy, physiology and pathology. No particular inclusion or exclusion criteria were used. RESULTS: Forty different works were found, between books and articles, from which 20 were selected after careful analysis. CONCLUSIONS: Despite the tragedy and adversity that followed the COVID-19 pandemic, its legacy has taught us a crystal-clear lesson: olfaction should no longer be neglected in clinical practice.

Olfactory nerve: from ugly duckling to swan / Nervo olfatório: de patinho feio a cisne

ABSTRACT Background: The olfactory nerve has never been the shining star of neurological examination. Quite the contrary, examining the first cranial nerve is often an overlooked step. As cases of anosmia secondary to COVID-19 infection continue to rise, the 2020 pandemic has shed new light on this much-forgotten nerve, its value as an aid to diagnosis of several diseases and its central role in our daily lives. Objective: We aimed to emphasize how essential and simple clinical examination of the olfactory system can be by highlighting practical techniques and clinical tips for its assessment. We also share pearls and pitfalls in localization and differential diagnosis, which may prove valuable to busy clinicians. Methods: A broad review of the literature was conducted by searching PubMed, Cochrane and Google Scholar for articles and books containing topics regarding examination of the olfactory nerve and its anatomy, physiology and pathology. No particular inclusion or exclusion criteria were used. Results: Forty different works were found, between books and articles, from which 20 were selected after careful analysis. Conclusions: Despite the tragedy and adversity that followed the COVID-19 pandemic, its legacy has taught us a crystal-clear lesson: olfaction should no longer be neglected in clinical practice.

RESUMO Antecedentes: O nervo olfatório nunca foi a estrela do exame neurológico. Pelo contrário, o exame desse nervo craniano é um passo frequentemente ignorado. No entanto, o aumento exponencial de casos de anosmia secundária a COVID-19 o colocou sob os holofotes, tanto em relação á sua função para o ser humano em sociedade, como seu papel no auxílio do diagnóstico de diversas patologias. Objetivos: Enfatizar quão importante é examinar o nervo olfatório e compreender as desordens do seu sistema. Ressaltamos pérolas clínicas e erros comuns no exame deste nervo, além dicas que possam auxiliar no diagnóstico de uma série de doenças neurológicas e sistêmicas. Métodos: Uma ampla revisão da literatura foi conduzida por meio de busca no PubMed, Cochrane e Google Acadêmico por artigos e livros relacionados aos tópicos do exame físico, fisiologia, anatomia e patologia do nervo olfatório. Não foram utilizados critérios específicos de inclusão ou exclusão. Resultados: Foram encontrados 40 artigos itens relacionados na língua inglesa, dentre os quais livros e artigos, tendo sido analisados e selecionados um a um até o total de 20 referências. Conclusões: Apesar da tragédia e adversidade trazidas pela pandemia de COVID-19, uma lição clara permanece: o olfato não deve mais ser negligenciado na prática clínica.

Progressive spastic tetraplegia and axial hypotonia (STAHP) due to SOD1 deficiency: is it really a new entity?

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and fatal neurodegenerative disease due to upper and lower motor neuron involvement with symptoms classically occurring in adulthood with an increasing recognition of juvenile presentations and childhood neurodegenerative disorders caused by genetic variants in genes related to Amyotrophic Lateral Sclerosis. The main objective of this study is detail clinical, radiological, neurophysiological, and genetic findings of a Brazilian cohort of patients with a recent described condition known as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency and compare with other cases described in the literature and discuss whether the clinical picture related to SOD1 protein deficiency is a new entity or may be represent a very early-onset form of Amyotrophic Lateral Sclerosis. METHODS: We conducted a case series report which included retrospective data from five Brazilian patients with SOD1 protein deficiency of a Brazilian reference center for Neuromuscular Disorders. Clinical data were obtained from a review of the medical records and descriptive statistics and variables were summarized using counts and percentages of the total population. RESULTS: All 5 patients presented with a childhood-onset neurodegenerative disorders characterized by spastic tetraplegia with axial hypotonia in all cases, with gestational history showing polyhydramnios in 4/5 and intrauterine growth restriction in 3/5 patients, with most patients initially presenting a normal motor development until the six month of life or during the first year followed by a rapidly progressive motor decline with severe dysphagia and respiratory insufficiency in all patients accompanied by cognitive impairment in 3/5 patients. All patients were homozygous for the c.335dupG (p.Cys112Trpfs*11) mutation in the SOD1 gene with completely decreased enzyme activity. CONCLUSIONS: This case series is the biggest data collection of the new recent clinical entity described as Spastic Tetraplegia and Axial Hypotonia (STAHP) due to SOD1 deficiency.

Endarterectomia de carótida sob anestesia local: evolução de 104 pacientes / Carotid endarterectomy under regional anesthesia: follow-up of 104 patients

A estenose carotídea cervical é uma das causas mais freqüentes de acidente vascular cerebral isquêmico. A endarterectomia de carótida é um tratamento eficaz para lesões estenóticas moderadas e graves, tanto sintomáticas quanto assintomáticas. A endarterectomia realizada sob anestesia local permite a monitorização neurológica do paciente durante o ato cirúrgico. O objetivo deste trabalho foi avaliar as complicações cirúrgicas e acompanhar a evolução dos pacientes submetidos a endarterectomia sob anestesia local em nossa instituição, comparando os resultados com outras publicações. 104 pacientes foram submetidos a 110 procedimentos no período de abril de 1996 a maio de 2002. 64 pacientes eram sintomáticos (61,54 por cento) e 40 assintomáticos (38,46 por cento). Todos possuíam grau de estenose carotídea igual ou superior a 70 por cento. Os pacientes foram avaliados retrospectivamente. O tempo de evolução variou de um a 72 meses (média: 29,5). Três pacientes apresentaram hematoma cervical necessitando drenagem cirúrgica. Dois pacientes (1,92 por cento) tiveram acidente vascular cerebral do mesmo lado da endarterectomia no pós-operatório e outros dois durante o seguimento. Dois pacientes faleceram em decorrência da cirurgia (1,92 por cento). Os resultados desta série, comparados com a literatura, permitem concluir que a endarterectomia é uma forma segura de tratamento para as estenoses carotídeas moderadas e graves.

[Carotid endarterectomy under regional anesthesia: follow-up of 104 patients]. / Endarterectomia de carótida sob anestesia local: evolução de 104 pacientes.

Cervical carotid stenosis is one of the main causes of ischemic stroke. Carotid endarterectomy is a safe procedure for treatment of moderate and severe symptomatic and asymptomatic carotid stenosis. Regional anesthesia allows neurological evaluation of the patient during the surgery. We reviewed the results of 104 patients operated on at our institution under regional anesthesia during the period of April 1996 and May 2002. 64 patients were symptomatic (61.54%) and 40 asymptomatic (38.46%). All patients had carotid stenosis over 70%. The patients were followed from one to 72 months (Mean: 29.5). Three patients had cervical hematoma, that required surgical drainage. Two patients had minor stroke at the same side of the endarterectomy at the post-operative period and another two during the follow-up (1.92%). Two patients died due to complications related to the surgery (1.92%). Our results, compared with the literature, show that endarterectomy is a safe procedure to treat moderate or severe carotid artery stenosis.