Search

A 38-year-old Brazilian man presented with slowly progressive quadriparesis since age 11 years. He progressed over 15 years with symptoms restricted to the lower limbs, and since then, with a progressive compromise of the upper limbs. His deceased brother had a similar clinical presentation. Examination showed spastic dysarthria, global amyotrophy, brisk tendon reflexes in the lower limbs, symmetrical quadriparesis, and fasciculations in the four limbs. Neurophysiological studies disclosed acute and chronic signs of denervation and chronic reinnervation involving the cervical, thoracic, and lumbosacral myotomes, with normal sensory conduction study. Fibrillation potentials, fasciculations, and positive sharp waves involved mainly the upper limbs. A diagnosis of long-standing juvenile-onset motor neuronopathy was established. Genetic testing identified the possibly pathogenic variant c.3G>T (p.Met1?) in homozygosity in the COQ7 gene. This report highlights the importance of considering a potentially treatable metabolic dysfunction as the primary mechanism in cases of juvenile motor neuron disease.

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.

The aims of this review are to discuss the imaging modalities used to assess muscle changes in myopathies, to provide an overview of the inherited myopathies focusing on their patterns of muscle involvement in magnetic resonance imaging (MR), and to propose up-to-date imaging-based diagnostic algorithms that can help in the diagnostic workup. Familiarization with the most common and specific patterns of muscular involvement in inherited myopathies is very important for radiologists and neurologists, as imaging plays a significant role in diagnosis and follow-up of these patients. • Imaging is an increasingly important tool for diagnosis and follow-up in the setting of inherited myopathies. • Knowledge of the most common imaging patterns of muscle involvement in inherited myopathies is valuable for both radiologists and neurologists. • In this review, we present imaging-based algorithms that can help in the diagnostic workup of myopathies.

Charcot–Marie–Tooth's disease (CMT) represents the most common inherited neuropathy. Most patients are diagnosed during late stages of disease course during adulthood. We performed a review of clinical, neurophysiological, and genetic diagnoses of 32 patients with genetically defined childhood-onset demyelinating CMT under clinical follow-up in a Brazilian Center for Neuromuscular Diseases from January 2015 to December 2019. The current mean age was 33.1 ± 18.3 years (ranging from 7 to 71 years) and mean age at defined genetic diagnosis was 36.1 ± 18.3 years. The mean age at onset was 6.1 ± 4.4 years. The most common initial complaint was bilateral pes cavus. The genetic basis included PMP22 duplication (CMT1A) (n = 18), GJB1 (CMTX1) (n = 5), MPZ (CMT1B) (n = 3), FIG4 (CMT4J) (n = 3), SH3TC2 (CMT4C) (n = 1), PLEKHG5 (CMTRIC) (n = 1), and PRX (CMT4F) (n = 1). Almost all patients (n = 31) presented with moderate or severe compromise in the CMT neuropathy score 2 with the highest values observed in CMT1B. Medical history disclosed obstructive sleep apnea (n = 5), aseptic meningitis (n = 1/MPZ), akinetic-rigid parkinsonism (n = 1/FIG4), and overlapping chronic inflammatory demyelinating polyneuropathy (n = 1/MPZ). Motor conduction block was detected in three individuals (PMP22, FIG4, MPZ). Acute denervation occurred in seven patients. Nonuniform demyelinating patterns were seen in four individuals (two CMT1A, one CMT1B, and one CMTX1). Abnormal cerebral white matter findings were detected in CMT1A and CMTX1, while hypertrophic roots were seen in CMT1A, CMT1B, and CMTX1. Our study emphasizes a relative oligogenic basis in childhood-onset demyelinating CMT and atypical findings may be observed especially in MPZ, PMP22, and GJB1 gene variants.

Background and purpose Spinal muscular atrophy (SMA) is the most important cause of motor neuron disease in childhood, and continues to represent the leading genetic cause of infant death. Adulthood-onset SMA (SMA type 4) is rare, with few isolated cases reported. The objective of the present study was to describe a cohort of patients with SMA type 4. Methods A cross-sectional study was conducted to characterize clinical, genetic, radiological and neurophysiological features of patients with adulthood-onset SMA. Correlation analysis of functional assessment with genetic, radiological and neurophysiological data was performed. Results Twenty patients with SMA type 4 were identified in a Brazilian cohort of 227 patients with SMA. The most common clinical symptom was limb-girdle muscle weakness, observed in 15 patients (75%). The most frequent neurological findings were absent tendon reflexes in 18 (90%) and fasciculations in nine patients (45%). Sixteen patients (80%) had the homozygous deletion of exon 7 in the SMN1 gene, with 12 patients (60%) showing four copies of the SMN2 gene. The functional scales Hammersmith Functional Motor Scale Expanded, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised, Revised Upper Limb Module and Spinal Muscular Atrophy Functional Rating Scale, as well as the six-minute walk and the Time Up and Go tests showed a correlation with duration of disease. Motor Unit Number Index was correlated both with duration of disease and with performance in functional assessment. Radiological studies exhibited a typical pattern, with involvement of biceps femoris short head and gluteus minimus in all patients. Conclusion This study represents the largest cohort of patients with SMA type 4 and provides functional, genetic, radiological and neurophysiological features that can be used as potential biomarkers for the new specific genetic therapies for SMA.

Objective: The description of a new genetic association with late-onset axonal Charcot-Marie-Tooth disease (CMT). Method. A 57-year-old Brazilian woman presented with a slowly progressive history of paresthesia, muscle wasting and weakness in her lower limbs since age 50 years. Examination disclosed peroneal amyotrophy, bilateral pes cavus, mild distal weakness, reduced vibration, pain and temperature sensation in the the lower limbs and brisk tendon reflexes. Results. Neurophysiological studies showed chronic sensorimotor axonal polyneuropathy. Whole-genome sequencing showed compound heterozygous pathogenic variants in the TECPR2 gene (14q32.31). Conclusion. This novel genetic presentation of late-onset axonal CMT with brisk tendon reflexes associated with TECPR2.

Introduction. Inclusion body myositis represents the most common acquired myopathy in clinical practice in patients over 50 years old. Despite classical approach to this myopathy as an inflammatory disorder, a muscle degenerative disorder is now considered the main mechanism linked to these vacuolar myopathies. Hereditary presentations, although quite rare, represent an expanding and underrecognized group in clinical practice. Objective. perform a structured review of the current literature regarding hereditary inclusion body myopathies. Method. review of U.S. NLM PubMed and MEDLINE database of original articles, case reports, case series and review articles including the terms “inclusion body myositis” OR “inclusion body myopathy” AND “genetics” OR “hereditary”. Results. We present in this article a wide review regarding the main clinical, imaging, pathophysiological, genetic and therapeutic aspects related to hereditary myopathies linked to seven different clinical and genetic presentations (GNE, MATR3, VCP, SQSTM1, MYH2, HNRNPA2B1 and HNRNPA1). Conclusion. Hereditary inclusion body myopathy is associated with at least 7 distinct clinic and genetic monogenic forms.

Background: Adult-onset spinal muscular atrophy (SMA) represents an expanding group of inherited neurodegenerative disorders in clinical practice. Objective: This review aims to synthesize the main clinical, genetic, radiological, biochemical, and neurophysiological aspects related to the classical and recently described forms of proximal SMA. Methods: The authors performed a non-systematic critical review summarizing adult-onset proximal SMA presentations. Results: Previously limited to cases of SMN1-related SMA type 4 (adult form), this group has now more than 15 different clinical conditions that have in common the symmetrical and progressive compromise of lower motor neurons starting in adulthood or elderly stage. New clinical and genetic subtypes of adult-onset proximal SMA have been recognized and are currently target of wide neuroradiological, pathological, and genetic studies. Conclusions: This new complex group of rare disorders typically present with lower motor neuron disease in association with other neurological or systemic signs of impairment, which are relatively specific and typical for each genetic subtype. RESUMO Antecedentes: Atrofia muscular espinhal (AME) de início no adulto representa um grupo de doenças neurodegenerativas hereditárias em expansão na prática clínica. Objetivo: Este artigo de revisão sintetiza os principais aspectos clínicos, genéticos, radiológicos, bioquímicos e neurofisiológicos relacionados às formas clássicas e recentemente descritas de AME proximal do adulto. Métodos: Os autores realizaram uma revisão crítica não sistemática descrevendo as principais apresentações de AME proximal de início no adulto. Resultados: Previamente restrito às apresentações de AME tipo 4 associada ao gene SMN1, este grupo atualmente envolve mais de 15 diferentes condições clínicas que compartilham entre si a presença de comprometimento progressivo e simétrico do neurônio motor inferior se iniciando no adulto ou no idoso. Novos subtipos clínicos e genéticos de AME proximal de início no adulto foram reconhecidas e são alvos atuais de estudos direcionados a aspectos neurorradiológicos, patológicos e genéticos. Conclusões: Este novo grupo complexo de doenças raras tipicamente se apresenta com doença do neurônio motor inferior em associação com outros sinais de comprometimento neurológico ou sistêmico, os quais apresentam padrões relativamente específicos para cada subtipo genético.

Acute hepatic porphyria represents a rare, underdiagnosed group of inherited metabolic disorders due to hereditary defects of heme group biosynthesis pathway. Most patients have their definite diagnosis after several years of complex and disabling clinical manifestations and commonly after life-threatening acute neurovisceral episodes or severe motor handicap. Many key studies in the last two decades have been performed and led to the discovery of novel possible diagnostic and prognostic biomarkers and to the development of new therapeutic purposes, including small interfering RNA-based therapy, specifically driven to inhibit selectively delta-aminolevulinic acid synthase production and decrease the recurrence number of severe acute presentation for most patients. Several distinct mechanisms have been identified to contribute to the several neuromuscular signs and symptoms. This review article aims to present the current knowledge regarding the main pathophysiological mechanisms involved with the acute and chronic presentation of acute hepatic porphyria and to highlight the relevance of such content for clinical practice and in decision making about therapeutic options.

Leigh syndrome represents a complex inherited neurometabolic and neurodegenerative disorder associated with different clinical, genetic and neuroimaging findings in the context of bilateral symmetrical lesions involving the brainstem and basal ganglia. Heterogeneous neurological manifestations such as spasticity, cerebellar ataxia, dystonia, choreoathetosis and parkinsonism are associated with multisystemic and ophthalmological abnormalities due to >75 different monogenic causes. Here, we describe the clinical and genetic features of a Brazilian cohort of patients with Leigh Syndrome in which muscle biopsy analysis showed mitochondrial DNA defects and determine the utility of whole exome sequencing for a final genetic diagnostic in this cohort.

Background: Acute hepatic porphyrias represent an expanding group of complex inherited metabolic disorders due to inborn errors of metabolism involving heme biosynthesis. Objective: We aimed to review the main clinical and therapeutic aspects associated with acute hepatic porphyrias. Methods: The authors provided a wide non-systematic review of current concepts and recently acquired knowledge about acute hepatic porphyrias. Results: Acute neurovisceral attacks are the most common and life-threatening presentation of this group and are often considered the main clinical manifestation by clinicians during differential diagnosis and the start of proper diagnostic work-up for acute porphyrias. However, atypical presentations with central nervous system involvement, neuropsychiatric disturbances, and some subtypes with photosensitivity usually make the definite diagnosis difficult and late. Early therapeutic interventions are essential during emergency treatment and intercritical periods to avoid recurrent severe presentations. The availability of new disease-modifying therapeutic proposals based on small interfering RNA (siRNA)-based therapies, complementary to the classic intravenous glucose infusion and hemin-based treatments, emphasizes the importance of early diagnosis and genetic counseling of patients. Conclusions: This review article highlights the main biochemical, pathophysiological, clinical, and therapeutic aspects of acute hepatic porphyrias in clinical practice. RESUMO Introdução: As porfirias hepáticas agudas representam um grupo de doenças metabólicas hereditárias complexas em expansão, decorrentes de erros inatos do metabolismo, envolvendo a via de biossíntese do grupamento heme. Objetivo: realizar revisão dos principais aspectos clínicos e terapêuticos associados com as porfirias hepáticas agudas. Métodos: Os autores realizaram ampla revisão não-sistemática sobre conceitos atuais e conhecimentos recentemente adquiridos. Resultados: Ataques neuroviscerais agudos representam a apresentação clínica mais comum e de maior risco, e são comumente considerados como principal manifestação na prática clínica durante o diagnóstico diferencial e início apropriado da investigação diagnóstica para porfirias agudas. Entretanto, apresentações atípicas com envolvimento do sistema nervoso central, alterações neuropsiquiátricas e alguns subtipos com fotossensibilidade fazem com que o diagnóstico definitivo seja comumente difícil e tardio. As intervenções terapêuticas precoces são essenciais durante o tratamento emergencial e em período intercrítico evitando formas recorrentes graves. A disponibilidade de novas propostas terapêuticas modificadoras de doença baseadas em terapias com pequenas moléculas de RNA de interferência (siRNA) complementares aos clássicos tratamentos com infusão de glicose intravenosa e à base de hemina enfatiza a importância do diagnóstico precoce de tais pacientes e do aconselhamento genético. Conclusões: Este artigo de revisão destaca os principais aspectos bioquímicos, fisiopatológicos, clínicos e terapêuticos das porfirias hepáticas agudas na prática clínica.

Introduction: Motor neuron disease is currently irreversible, and the grave implications of the diagnosis should raise concerns over missing a potencial mimic disorder. The cervical region should be carefully evaluated, since many pitfalls are encounterd there. We present a case of a longitudinal extensive ventral cervical cecerebrospinal fluid leak causing a progressive monomelic amyothrophy associated with intracranial hypotension, mimicking a motor neuron disorder. Objective: To describe the course, clinical manifestations and to raise concern about a rare disorder, potentially treatable that could mimic a motor neuron disease. Methods: A case report seen in the neuromuscular service of the federal university of São Paulo.SP. Results: Cervical pain irradiating to the left shoulder was the first symptom. Pogression to weakness of the bíceps and shoulder girdle with fasciculations happened months after. The patient also complained about severe headache worsening when lowering the head or lyind down. Eletroneuromiography showed chronic denervation. Magnetic ressonance imaging of the cervical spine demonstrated ventral dural displacement with longitudinal extensive cerebrospinal fluid colection. Epidural blood patch procedure was indicated. After the treatment the patient showed complete improvement of the headache, significant decrease in fasciculations and evolutionary strength improvement. Conclusion: We described a rare form of amyothrophy that could be associated or not with intracranial hypotension. Ventral cervical cerebralpinal fluid leak should always be on the list of differential diagnosis and early indentification should be sought, since its a treatable cause.

Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare neurological entity, which consists of an autosomal recessive inherited disorder of bile acid biosynthesis due to CYP27A1 variants, with variable systemic and neurological clinical presentation. Psychiatric signs are also observed at early adulthood and includes behavioral and personality changes, depression and psychosis. However, self-mutilation has not been previously described. Case report: We attend to two sisters with a unique clinical presentation. The first patient, 33 years old, presented epilepsy at 17, in addition to cognitive impairment and tendon xanthomas. A severe depressive condition was established at 25. A year ago, she had frequent bites on his lips and tongue. The second patient, 28 years old, had chronic diarrhea and juvenile cataract in childhood. Axial ataxia has been observed since age 18. After 3 years, she presented psychiatric decline marked by visual, auditory hallucinations and persecutory delirium. Four months ago she showed signs of self-mutilation with a sting in the phalanges of his hands. Both patients had elevated plasma cholestanol and 7-dehydro-cholesterol. The genetic test showed a homozygous c.1183 C>T (p.Arg395Cys) variant in the CYP27A1 gene. Conclusion: The reports illustrate the relevance of self-mutilation in CTX, an unprecedented clinical presentation that should be remembered as another differential diagnosis with this phenomenology.

Introduction: Dysferlinopathies are a group of conditions that are caused by mutations in the dysferlin gene. Objectives: To characterize the clinical phenotypes and genotypic spectrum of dysferlinopathies patients and to estimate the progression of functional and motor decline. Design and setting: Retrospective analysis of the medical records of patients followed up at our institution between 1995 and 2020. Methods: Patients were selected based on the following inclusion criteria:(i) Identification of a mutation defined as pathogenic in homozygosis or compound heterozygosis in the Dysf gene;or (ii)compatible clinical manifestations and decreased expression of dysferlin in immunohistochemistry on muscle biopsy. Classification of the phenotype was based on the first symptoms. Functionality was defined by the Gardner–Medwin & Walton(GMW) scale modified for dysferlinopathy. Results: 23 patients were included in the study. 16 were classified as limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2), 4 as Miyoshi muscular dystrophy, 2 as proximo-distal onset and 1 as asymptomatic hyperCKemia. Thighs adduction was the most affected movement in the first evaluation (mean strength=3). Plantar flexion was the movement with the greatest decline in strength(mean=-0.10 points on MRC/year;pT, Arg2042Cys and c.2643+1G>A, p.?(splicing), found 3 times each. There was no statistical difference in muscle strength in the first evaluation, motor and functional decline between the phenotypes. Conclusion: While LGMDR2 was the most common phenotype at onset, with the exception of asymptomatic hyperCKemia, there were not a clear difference in the pattern of progression between them.

Introduction: Charcot-Marie-Tooth disease (CMT) is a group of inherited sensorymotor neuropathies with variable age of onset, clinical and neurophysiological patterns but often with a chronic slow progression. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy with a relapsing clinical course and typically good response to corticosteroids or other therapies. The distinction between these two conditions can be made with aid of clinical history, neurophysiological studies and genetic testing in the vast majority of cases. However, an overlap between them can occur. Methods: We describe four Brazilian patients under clinical follow-up at our service with genetic diagnosis of CMT and clinical and neurophysiological features compatible with a concurrent CIDP diagnosis. Results: Four cases of different CMT subtypes with co-occurrence of an immunemediated neuropathy compatible with CIDP were reported. The patients were all unrelated, two males and two females, age range from 3 to 45 years. The genetic mutations were the following: hemizygous pathogenic variant c.514C>T (p.Pro172Ser) in GJB1 gene (CMT1X), duplication of PMP22 gene (CMT1A), simple heterozygous pathogenic variant c.188_190delCCT (p.Ser64del) in MPZ gene (CMT1B) and homozygous pathogenic variant c.122T>C (p.Ile41Thr) in FIG4 gene (CMT4J). All four patients presented with relapsing or subacute worsening of neurological symptoms, demyelinating non-uniform features in neurophysiological studies including conduction blocks and elevated cerebrospinal fluid (CSF) protein levels without pleocytosis. Three patients (3/4) improved after treatment with corticosteroids, immunoglobulin or cyclophosphamide with variable clinical response. Conclusion: CMT and CIDP are different conditions involving the peripheral nervous system and the distinction between them usually is possible with the appropriate assessment. The overlap between them is possible and we report four cases with this association.

Background: X-linked Adrenoleukodystrophy (X-ALD) represents a key inherited metabolic disorder in neurological practice, representing an important differential diagnosis in different neurological contexts. Symptomatic female patients have been scarcely studied in large cohorts. Objectives: Evaluation of clinical, laboratory and genetic findings from a Brazilian cohort of women with X-ALD. Methods, design and setting: We performed a retrospective observational study of clinical, biochemical, genetic, neuroimaging and neurophysiological aspects of 10 Brazilian female patients with X-linked Adrenoleukodystrophy under clinical follow-up at the Neurometabolic Unit, Division of Neuromuscular Diseases, Federal University of São Paulo (UNIFESP), São Paulo, Brazil. Results: Mean age at diagnosis was 46.2 years and at symptom-onset was 39 years. Female patients presented with spastic paraparesis and neurogenic bladder (60%), cognitive decline (50%), demyelinating sensorimotor polyneuropathy (40%), cerebellar ataxia (30%), epilepsy (20%), apraxia and psychotic symptoms (10%). The most common misdiagnosis were Primary Progressive Multiple Sclerosis and Hereditary Spastic Paraplegia. The main neuroimaging findings were corticospinal tract hyperintensity and cervical and thoracic spinal cord atrophy (60%), unspecific white matter changes (40%) and typical parieto-occipital leukodystrophy. All patients had abnormal profiles of plasma very-long chain fatty acids, all with elevated C26 levels and 80% with elevated C24 levels, but all with abnormally raised C26:C22 and C26:C24 ratio. The most common pathogenic variant observed was c.311G>A (p.Arg104His) (60%). Conclusions: Female patients with ABCD1 pathogenic variants must be carefully evaluated for neuropsychiatric disturbances and followed-up until elderly due to the common occurrence of variable motor, autonomic and sensory compromise.

Introduction: Lambert-Eaton Myasthenic Syndrome (LEMS) is an ultrarare autoimmune disorder of neuromuscular junction characterized by proximal muscle weakness, arreflexia and autonomic dysfunction due to presynaptic dysfunction caused by autoantibodies against the P/Q-type voltagegated calcium channel with diminished release of acetylcholine. LEMS can occurs as a primary autoimmune disorder or as paraneoplastic disorder with more than half of LEMS cases associated with small cell lung cancer. Objectives: The main objective of this study is described clinical, epidemiological, serological, and neurophysiological findings of a Brazilian cohort with definitive diagnosis of Lambert-Eaton Myasthenic Syndrome (LEMS). Results We identified eight patients with definitive LEMS with a 2:1 male/ female prevalence, all present with proximal muscle weakness with lower limb predominance and the most common autonomic dysfunction were xeropthalmia in 100% of patients, orthostatic hypotension presented in 6 of 9 patients and erectile dysfunction in all male patients. Conclusions: LEMS should always be suspected in patients with proximal muscle weakness associated with autonomic dysfunction and in this Brazilian cohort most cases were seronegative and do not have correlation with small-cell lung cancer in contrast with the current knowledge of disease.

Introduction: Syringomyelia is a chronic disease of the spinal cord that leads to damage to nerve fibers in the spinothalamic tract. The changes in these structures responsible for the thermal and painful sensitivity lead to an abnormal innervation of the joints, which can lead to neuropathic arthropathy, called Charcot arthropathy. Syringomyelia is the main cause of Charcot arthropathy in the upper limbs, and the most involving joints are the shoulder and elbow. It is a rare condition and its recognition allows for early diagnosis and proper management. Case report: A 50-year-old female patient, with a previous history of spinal cord trauma, who has been in a wheelchair since then, started with edema in the left upper limb, mainly in the elbow, evolved with local ulcer and presence of serosanguinolent secretion, weakness and paresthesia in the left hand. Magnetic resonance imaging of the elbow showed signs of neuroarthropathy and the study of the thoracic cervical spine showed enlargement of the cerebrospinal fluid space and tapering of the spinal cord. Conclusions: Charcot’s arthropathy should be considered as a differential diagnosis of pain, edema and limitation of joint movements. When present in the upper limbs, an investigation should be carried out to exclude syringomyelia.

Introduction: Familial Amyotrophic Lateral Sclerosis (fALS) represent 5-10% of ALS patients. Different mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) cause Hereditary Spastic Paraplegia Type 10 (HSP10), Charcot-Marie-Tooth 2 (CMT2), Neonatal Intractable Myoclonus and more recently described fALS Type 25. Previous described phenotypes are very similar to the sporadic type, except from the long course of disease. Methods: We describe four Brazillian patients, under clinical follow-up on two Neuromuscular services with genetic diagnosis of fALS25. Results: Four diferent fALS25 are described. Two brothers and two unrelated patients, with distinct features, three males and one female, age range from 72 to 24; age of onset ranged from 62 to 22. The genetic mutations were the following: simple heterozygous pathogenic variant c.1651C>G (p. Leu551Val), simple heterozygous pathogenic variant c.2953G>A (p. Gly985Ser) and pathogenic variant c.484C>T (p.Arg162Trp); all of KIF5A gene (fALS25). Only one patient presented with similar phenoptype and age of onset as sporadic ALS (sALS), the two brothers presented the symptoms at the ages of 28 and 30, the female patient at 22. All patients still walk without assistence after the diagnosis. All patients showed classic superior and inferior motor neuron involvement signs, but one brother had a mild limb ataxia. The three younger patients had MRI with no specific findings, except from subtle cortical atrophy in one brother, and mild vermis and corpus callosum atrophy on the other brother. Only the female patient had negative familiar history. Conclusions: fALS25 should be suspected in patient with fALS and longer course disease. Mutations KIF5A gene must be remembered either in juvenile form of ALS.

There are three types of autosomal recessive disorders involving pathogenic variants in the ALS2 gene (OMIM*606352), infantile ascending hereditary spastic paraplegia (IAHSP), juvenile primary lateral sclerosis (JPLS) and juvenile amyotrophic lateral sclerosis (JALS), which are rare and related to retrograde degeneration of motor neurons. ALS2 pathogenic variants are distributed widely across the entire coding sequence and mostly result in a loss of protein function. Rarely, patients with JALS have been reported with lower motor neuron involvement. Here, we report the first Brazilian cohort (six patients) of JPLS with novel ALS2 pathogenic variants, and we propose an expanding clinical and genetic spectrum of alsin-related disorders. A review of the literature in PubMed from 2001 to September 2020 allowed us to identify 26 publications about the three different phenotypes caused by ALS2 variants (only case reports or families), encompassing 35 nonrelated families. We compiled data (sex, age, age at onset, first symptoms, atypical clinical features, molecular data, and clinical evolution (improvement or death)) from these studies and analyzed them in a general context on the basis of demographic features.

Introduction: The performance of bariatric surgeries has increased in recente years. Secondary mal- absorptive syndrome is an important cause of acquired copper deficiency, especially after Roux-em-Y gastric by-pass. The clinical manifestation of this deficiency disorder can occur years or decades after the surgery. Objective: To describe the course, clinical manifestations, therapeutic approaches and to raise concern about acquired copper deficiency in patients who underwent bariatric surgery. Methods: A case report seen in the neuromuscular service of the federal university of São Paulo.SP. Results: The patient underwent Roux-en-Y gastrojejunostomy in 2010, 6 years before the initial manifestations of paresthesia on the lower limbs and anemia. The symptons progressed to imbalance and falls. Magnetic resonance image depicted T2 hyperintense signal in the posterior column from C4- T4. A Vitamin B12 deficiency was considered to be the cause but intramuscular therapy was ineffective. The neurological condition deteriorated and the patient was unable to walk without a walker. A severe copper deficiency was diagnosed but oral and intravenous replacement did not improve the clinical picture. Only after reversion of the Roux-em-Y gastric by-pass that the patient improved. Conclusion: Obesity is growing health problem and the incidence of bariatric surgery is increasing. Acquire copper deficiency should always be on mind when facing a patient with myeloneuropathy that underwent these group of surgeries. Rapidly installed therapeutic approach can prevent neurological sequelae.

Background: Neuromuscular involvement has been identified in acute and early stages of severe COVID-19. Guillain-Barre syndrome and variants, rhabdomyolysis and prone position-related neuropathy represent early complications. Mononeuritis multiplex is rarely a post-infectious complication. Objectives: Characterization of patients with mononeuritis multiplex after severe COVID-19. Methods, design and setting: We performed a retrospective observational study of clinical, laboratorial and neurophysiological aspects of nine Brazilian patients with mononeuritis multiplex after severe COVID-19 at the Division of Neuromuscular Diseases, Federal University of São Paulo (UNIFESP), São Paulo, Brazil. Results: Nine patients (4 male, 5 female) had mean age at diagnosis of 60.6 years. 78% had at least one risk factor for severe COVID-19. Dyspnea, cough, fever, headache, anosmia, odynophagia, and myalgia were the most common SARS-CoV-2 symptoms. Most patients had large length of stay in intensive care (35.8 days), with orotracheal intubation and the need of prone positioning and tracheostomy. 44% had venous or arterial thromboembolic complications. Mononeuritis multiplex symptoms started after 45.7 days (23-71) of first COVID-19 symptoms. Sensorimotor multifocal axonal mononeuritis multiplex was the most common pattern (78%) with moderate to severe (89%) and lower limb-dominant compromise (67%). 33% with LANSS pain scale >12 and 67% with high fatigue scores on Fatigue Severity Scale. Two patients developed moderate titles of positive antinuclear antibody for nuclear membrane compounds (titin) during diagnostic work-up. Three patients were treated with oral corticosteroids with moderate disease control. Conclusions: Mononeuritis multiplex may be a late neuromuscular complication after severe COVID-19. Vasculitis and endotheliopathy seem to mediate its pathophysiology.

Context: Hereditary spastic paraplegias (HSPs) represent an expanding group of neurodegenerative diseases characterized mainly by progressive spastic paraparesis of the lower limbs. More than 80 different genetic loci have been associated with HSPs. In 2015, heterozygous pathogenic variants in the CPT1C gene were first associated with SPG73, not yet described in Brazilian patients. Objective: We present clinical, neuroimaging and genetic features of three Brazilian patients with SPG73. Cases reports: We report one male and two female patients, age range 36 to 78 years old. Case 1 presented with a 4-year-history of spasticity, predominantly crural tetraplegia, bladder incontinence, dysphagia and dysphonia. Family history disclosed a sister with epilepsy. Whole-exome sequencing (WES) disclosed a heterozygosis variant c.863G>A (p.Arg288His) in exon 9 of the CPT1C. Cases 2 and 3 are first degree relatives (mother and son). Both presented with long-standing slowly progressive spastic paraplegia. Case 3 presented bladder incontinence, constipation, dysphagia and dysphonia at late stages. Cases 2 and 3 WES disclosed the heterozygosis variant c.196T>G (p.Phe66Val) in exon 4 of the CPT1C. Discussion: Previous literature described six patients from an Italian family with pure HSPs phenotype and the pathogenic variant c.109C>G (p.Arg3. 7Cys) in CPT1C gene. Another group described three patients associated with pure HSPs phenotype and the pathogenic variant (c.226C>T) in the CPT1C gene. All previous reported cases had benign clinical course and bulbar involvement was not described before. One of our cases presented with a de novo variant and rapidly progressive motor and bulbar compromise. Conclusion: our cases expand the current knowledge about SPG73, including a rapidly progressive phenotype with bulbar involvement and cognitive compromise at late stages of disease course.

Introduction: Congenital muscular dystrophies (CMDs) are a group of rare genetic muscle diseases that present at birth or during infancy with hypotonia and weakness. Multiple forms of CMDs are also associated with cerebral and ocular phenotypes. Recently, INPP5K mutations have been described associated with CMD, cataracts and cognitive impairment. The INPP5K gene, encodes SKIP, one of the enzymes that phosphorylate the 5-phosphate position of phosphoinositides and is highly expressed in developing and adult brain, eye and muscle. Methods: We performed a case report of three Brazilian patients with INPP5KCMD with cataracts and intellectual disability under clinical follow-up at our service. Results: Case 1: 39 years old, female, presenting with progressive leg weakness since childhood, mild intellectual disability and bilateral cataracts at 20 years. Her 35-yearold sister (Case 2) had a similar clinical picture with limb-girdle weakness since childhood, cognitive impairment and early- onset bilateral cataracts. Both with myopathic pattern in EMG, elevated creatine phosphokinase (CK) and dystrophic pattern in muscle biopsy. Brain MRI studies disclosed a large megacistern in the elderly and no abnormalities in the younger sister. Genetic testing: c.653_655del(p.(Ser218del) in homozygosity in INPP5K gene. Case 3: 20 years old, female, normal motor development but learning difficulties since childhood. Presented with progressive pelvic girdle weakness in childhood and bilateral cataracts in late adolescence. Exams disclosed elevated CK, brain MRI was normal and genetic testing with the following mutation in INPP5K gene:c.[881_883del];[1088T>C];p.[Ser294del];[Ile363Thr]. Conclusion: We describe patients with CMD, cataracts and intellectual disability, caused by mutation in the INPP5K gene. In literature few cases are reported.

Context: PURA syndrome is a neurodevelopmental disorder characterized by neonatal hypotonia, delayed psychomotor development, early-onset feeding difficulties and an epileptic encephalopathy. Case Report: A 3-month-old Brazilian boy presented with severe neonatal hypotonia associated with feeding difficulties due to serious dysphagia requiring nasoenteral tube feeding. Excessive drowsiness, poor social interaction and repetitive episodes of involuntary abnormal upward eye movements and ocular version with short duration were also reported by parents. Neurological examination revealed severe axial and upper limb hypotonia, orofacial dyskinetic movements and episodes of abnormal eye movements with upward ocular deviation with less than 30 seconds in duration compatible with oculogyric crisis. It was performed Whole-Exome sequencing and it was identified a new pathogenic variant in PURA gene that establisehd the final diagnosis of PURA Syndrome or Autosomal Dominant Mental Retardation type 31, MDR 31 (OMIM #616158). Conclusions: PURA Syndrome emerges as one of the major differential diagnoses of neonatal hypotonia and in addition, we can consider the early manifestation of oculogyric crisis as a phenotypic expansion of the syndrome, making its diagnosis even more challenging, since epileptic encephalopathies and neurotransmitter deficiency-related diseases present with a similar clinical course.

Adult polyglucosan body disease (APBD) represents a complex autosomal recessive inherited neurometabolic disorder due to homozygous or compound heterozygous pathogenic variants in GBE1 gene, resulting in deficiency of glycogen-branching enzyme and secondary storage of glycogen in the form of polyglucosan bodies, involving the skeletal muscle, diaphragm, peripheral nerve (including autonomic fibers), brain white matter, spinal cord, nerve roots, cerebellum, brainstem and to a lesser extent heart, lung, kidney, and liver cells. The diversity of new clinical presentations regarding neuromuscular involvement is astonishing and transformed APBD in a key differential diagnosis of completely different clinical conditions, including axonal and demyelinating sensorimotor polyneuropathy, progressive spastic paraparesis, motor neuronopathy presentations, autonomic disturbances, leukodystrophies or even pure myopathic involvement with limb-girdle pattern of weakness. This review article aims to summarize the main clinical, biochemical, genetic, and diagnostic aspects regarding APBD with special focus on neuromuscular presentations.

The aims of this review are to discuss the imaging modalities used to assess muscle changes in myopathies, to provide an overview of the inherited myopathies focusing on their patterns of muscle involvement in magnetic resonance imaging (MR), and to propose up-to-date imaging-based diagnostic algorithms that can help in the diagnostic workup.Familiarization with the most common and specific patterns of muscular involvement in inherited myopathies is very important for radiologists and neurologists, as imaging plays a significant role in diagnosis and follow-up of these patients.• Imaging is an increasingly important tool for diagnosis and follow-up in the setting of inherited myopathies. • Knowledge of the most common imaging patterns of muscle involvement in inherited myopathies is valuable for both radiologists and neurologists. • In this review, we present imaging-based algorithms that can help in the diagnostic workup of myopathies.