Paulo Victor Sgobbi de Souza

Hereditary Spastic Paraplegia: Clinical and Genetic Hallmarks

Hereditary spastic paraplegia comprises a wide and heterogeneous group of inherited neurodegenerative and neurodevelopmental disorders resulting from primary retrograde dysfunction of the long descending fibers of the corticospinal tract. Although spastic paraparesis and urinary dysfunction represent the most common clinical presentation, a complex group of different neurological and systemic compromise has been recognized recently and a growing number of new genetic subtypes were described in the last decade. Clinical characterization of individual and familial history represents the main step during diagnostic workup; however, frequently, few and unspecific data allows a low rate of definite diagnosis based solely in clinical and neuroimaging basis. Likewise, a wide group of neurological acquired and inherited disorders should be included in the differential diagnosis and properly excluded after a complete laboratorial, neuroimaging, and genetic evaluation. The aim of this review article is to provide an extensive overview regarding the main clinical and genetic features of the classical and recently described subtypes of hereditary spastic paraplegia (HSP).

C9orf72-related disorders: expanding the clinical and genetic spectrum of neurodegenerative diseases

Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC) of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.

Complex movement disorders in fatal familial insomnia: A clinical and genetic discussion

Fatal familial insomnia (FFI) represents a rare neurodegenerative autosomal dominant prion disease, usually affecting patients between the fifth and sixth decades, evolving rapidly to death.1,2 FFI results from a missense mutation at codon 178 (D178N) of the PRNP gene (located on chromosome 20p13) linked with methionine at codon 129 of the mutated allele. Its major neuropathologic features include severe neuronal loss with astrogliosis of mediodorsal and ventral anterior thalamic nuclei and inferior olivary nuclei, with variable degrees of spongiosis, especially in subiculum entorhinal cortex.3

SCA1 patients may present as hereditary spastic paraplegia and must be included in spastic-ataxias group.

INTRODUCTION The combination of cerebellar ataxia and spasticity is common. However, autosomal dominant genetic diseases presenting with spastic-ataxia are a smaller group. Pyramidal signs have been frequently observed in several SCA subtypes, particularly in spinocerebellar ataxia type 1. METHODS We prospectively evaluated the pyramidal signs and spasticity in SCA1 patients, and correlated the data with genetic and clinical features. RESULTS In this study, we observed that spasticity may be an early and presenting feature of SCA1, since 3 patients had pyramidal signs and spasticity as the first neurological sign. SCA1 patients with spasticity were significantly younger. CONCLUSION SCA1 may rarely present with pure spastic paraplegia, resembling hereditary spastic paraplegia, before the appearance of cerebellar signs. This observation may confuse the neurologist when a genetic testing is requested for an autosomal dominant spastic paraplegia, directing research to hereditary spastic paraplegia group.

Normal muscle structure, growth, development, and regeneration

Knowledge about biochemical, structural and physiological aspects, and properties regarding the skeletal muscle has been widely obtained in the last decades. Muscle disorders, mainly represented in neuromuscular clinical practice by acquired and hereditary myopathies, are well-recognized and frequently diagnosed in practice. Most clinical complaints and biochemical characterizations of each myopathy depends on the appropriate knowledge and interpretation of pathological findings and their comparison with normal muscle findings. Great improvement has been obtained in the last decades mainly involving the mechanisms of normal muscle architecture and physiological function in the healthy individuals. Genetic mechanisms have also been widely studied. We provide an extensive literature review involving current knowledge regarding muscle cell structure and function and embryological and regenerative processes linked to muscle lesion. An updated comprehensive description involving the main nuclear genomic regulatory mechanisms of muscle regeneration and embryogenesis is provided in this review.

Clinical and genetic basis of familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis represents the most common neurodegenerative disease leading to upper and lower motor neuron compromise. Although the vast majority of cases are sporadic, substantial gain has been observed in the knowledge of the genetic forms of the disease, especially of familial forms. There is a direct correlation between the profile of the mutated genes in sporadic and familial forms, highlighting the main role of C9orf72 gene in the clinical forms associated with frontotemporal dementia spectrum. The different genes related to familial and sporadic forms represent an important advance on the pathophysiology of the disease and genetic therapeutic perspectives, such as antisense therapy. The objective of this review is to signal and summarize clinical and genetic data related to familial forms of amyotrophic lateral sclerosis.

Early‐onset epilepsy as the main neurological manifestation of cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder, which usually presents with diverse systemic manifestations (ophthalmologic, cardiac, and dermatologic symptoms), and neurological dysfunction, such as neuropsychiatric symptoms, cognitive decline, and ataxia. Epilepsy is rarely seen as the main neurological manifestation of CTX. Herein, we describe a middle-aged woman with epilepsy since childhood as the only neurological symptom associated with the classical systemic manifestations of CTX.

Early-onset familial Alzheimer’s disease related to presenilin 1 mutation resembling autosomal dominant spinocerebellar ataxia

Dear Sirs,Early-onset familial Alzheimer’s disease (EOFAD) is acondition characterized by early onset dementia associ-ated with a positive family history [1]. Presenilin 1 (PS1)mutations account for the majority cases and comprise anenormous phenotype variability. In special cases, ataxiahas also been reported during the course of the disease, butnot as a major symptom [2].The spinocerebellar ataxias (SCA) are a group of auto-somal dominant inherited neurological disorders, charac-terized by heterogeneous clinical presentations and a broadcombination of cerebellar signs [3]. Cognitive and neuro-psychological deficits have been described in some SCAsubtypes over the last years [4].Herein, we describe a family whose predominant neu-rological features were cerebellar ataxia and memoryimpairment. Bearing in mind that ataxia was one of thepredominant symptoms, genetic investigation was focusedon SCA. In this report, we call attention for atypical pre-sentation of presenilin 1 mutation that might mimick SCA.In Table 1, we summarize the main clinical, demographic,neuroimaging and neuropsychological features of thepatients evaluated.A 37-year-old-man (patient IV.4) presented to our clinicwith a 5-year history of progressive gait disturbances. Onneurological examination, there was axial and appendicularataxia, spasticity and brisk tendon reflexes. The Mini-Mental State Examination (MMSE) score was 13. Brainmagnetic resonance imaging (MRI) disclosed moderatecortical and cerebellar atrophy. His family history wasremarkable, since other family members were affected.Considering cerebellar symptoms as the most relevant,SCA subtypes 1, 2, 3, 6, 10, 17 and dentato-rubro-pallido-luysian (DRPLA) were investigated, and all genetic testsresulted in a negative. Huntington’s disease also was ruledout. For the following 2 years, he developed progressivememory impairment with disorientation in time. Hedeveloped mutism, and his communication is incompre-hensible for no relation to people. Severe stage of dementia(Clinical Dementia Rating-CDR = 3) and neuropsychiatricsymptoms (Neuropsychiatric Inventory-NPI = 45), asaggressiveness, irritability and sleep disturbance, indicate ahigh degree of dependence of daily activities and beingunwieldy for caregivers. Cognitive functions rapidlyworsened and he could not be evaluated by our neuro-psychological battery.A 35-year-old-man (patient IV.11), a cousin of patient 1,came to our hospital with progressive memory impairmentfor the last 6 years and gait instability and dysarthria forthe last 4 years. Neurological examination showed axialand appendicular ataxia, brisk tendon reflexes, and pyra-midal signs. Brain MRI disclosed moderate cortical andcerebellar atrophy. He presented a rapid worsening, and isnow confined to bed. Cognitive functions could not beevaluated, indicating a severe stage of dementia.(CDR = 3; MMSE not testable).A 33-year-old-woman (patient IV.13), a cousin ofpatients 1 and sister of patient 2, complained of progressivememory impairment for the last 4 years and gait instabilityfor the last 3 years. Neurological examination revealed

The cerebellum in Parkinson’s disease and parkinsonism in cerebellar disorders

Sir, We have read with great interest the article by Wu and Hallett (2013) entitled ‘The cerebellum in Parkinson’s disease’. These authors reviewed related anatomical, clinical and neurophysiological findings, and discuss the possible roles of the cerebellum in the pathophysiology of Parkinson’s disease. They pointed out that Parkinson’s disease is associated with pathological and structural changes in the cerebellum, and also stated that functional neuroimaging has demonstrated increased activation of the cerebellum in Parkinson’s disease. Furthermore, tremor and cerebellar involvement is discussed in Parkinson’s disease, and a primary dysfunction in the cerebello-thalamo-cortical circuit, particularly the vermis/paravermis region, is thought to be responsible for the occurrence of resting tremor. Another assumption is that functional or structural changes in the cerebellum may contribute to non-motor symptoms …

Clinical and genetic basis of congenital myasthenic syndromes

Neuromuscular junction disorders represent a wide group of neurological diseases characterized by weakness, fatigability and variable degrees of appendicular, ocular and bulbar musculature involvement. Its main group of disorders includes autoimmune conditions, such as autoimmune acquired myasthenia gravis and Lambert-Eaton syndrome. However, an important group of diseases include congenital myasthenic syndromes with a genetic and sometimes hereditary basis that resemble and mimick many of the classic myasthenia neurological manifestations, but also have different presentations, which makes them a complex clinical, therapeutic and diagnostic challenge for most clinicians. We conducted a wide review of congenital myasthenic syndromes in their clinical, genetic and therapeutic aspects.