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Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.
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Complexo 4 de Proteínas Adaptadoras , Proteínas Relacionadas a Receptor de LDL , Paraplegia Espástica Hereditária , Animais , Humanos , Camundongos , Complexo 4 de Proteínas Adaptadoras/genética , Complexo 4 de Proteínas Adaptadoras/metabolismo , Células HeLa , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas Relacionadas a Receptor de LDL/metabolismo , Receptores de Superfície Celular , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismoRESUMO
ABSTRACT Introduction: Hereditary spastic paraplegia (HSP) is the term for a group of neurological disorders characterized by progressive spasticity and muscle weakness in the lower limbs. Its etiology is genetic and has been associated with mutations in more than 60 genes. HSP is rare and may be useful in the differential diagnosis of cerebral palsy. Case presentation: 16-year-old male with a diagnosis of HSP due to mutation of the NIPAi gene:c.316G>A (p. Gly106arg), which corresponds to HSP type 6 (SPG6). The patient presented with clinical signs of progressive upper motor neuron syndrome in the lower limbs, such as spasticity, hyperreflexia and paraparesis, associated with focal onset seizures diagnosed at age 11 and successfully treated with valproic acid. Spasticity treatment was complex and included oral baclofen, intraoperative botulinum toxin, physical therapy, and multilevel orthopedic surgery for the management of musculoskeletal deformities. Conclusion: This is a rare case of complex HSP, associated with epilepsy, due to the mutation of the NIPAi gene (SPG6), the most common pathogenic variant within this type of mutation. The present case demonstrates the importance of making an early diagnosis of GSP6 to perform timely interventions in these patients, prevent complications, and avoid a higher level of disability.
RESUMEN Introducción. La paraplejía espástica hereditaria (PEH) es un grupo de trastornos neurológicos caracterizados por espasticidad progresiva y debilidad muscular de miembros inferiores. Su etiología es genética y se ha asociado con mutaciones en más de 60 genes. La PEH es poco frecuente y puede ser útil en el diagnóstico diferencial de la parálisis cerebral. Presentación de caso. Adolescente masculino de 16 años con diagnóstico de PEH por mutación del gen NIPAi: c. 316G>A (p. Gly106arg), correspondiente a una PEH tipo 6 (SPG6). El paciente presentó signos clínicos de síndrome de motoneurona superior progresivos en miembros inferiores como espasticidad, hiperreflexia y paraparesia, asociados a epilepsia de inicio focal diagnosticada a los 11 años y tratada satisfactoriamente con ácido valproico. El manejo de la espasticidad fue complejo e incluyó baclofeno oral, toxina botulínica intraoperatoria, terapia física y cirugía ortopédica multinivel para manejo de deformidades musculoesqueléticas en miembros inferiores. Conclusión. El presente caso demuestra la importancia de realizar un diagnóstico temprano de la SPG6 (variante más común de la PEH) para realizar intervenciones oportunas en estos pacientes, prevenir complicaciones y evitar un mayor nivel de discapacidad.
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The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.
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Homocistinúria , Paraplegia Espástica Hereditária , Humanos , Espasticidade Muscular , Qualidade de Vida , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo , Deficiência de Vitamina B 12/congênitoRESUMO
Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.
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Deficiência Intelectual , Atrofia Óptica , Paraplegia Espástica Hereditária , Ataxias Espinocerebelares , Humanos , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Atrofia Óptica/genética , Deficiência Intelectual/genética , Paraplegia Espástica Hereditária/genética , Síndrome , MutaçãoRESUMO
Spastic paraplegia type 7 (SPG7) is one of the most common forms of autosomal recessive hereditary spastic paraplegia, which can lead to a hybrid spastic-ataxic phenotype. Recently, novel complicated forms of SPG7, including cognitive and social impairment phenotypes, have been reported. We present a SPG7 case with two pathogenic variants in compound heterozygosity in the SPG7 gene, featuring a cerebellar cognitive affective syndrome with psychosis not yet described in the literature.
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Disfunção Cognitiva , Transtornos Psicóticos , ATPases Associadas a Diversas Atividades Celulares/genética , Disfunção Cognitiva/genética , Humanos , Metaloendopeptidases/genética , Mutação , Fenótipo , Transtornos Psicóticos/complicações , Transtornos Psicóticos/genéticaRESUMO
BACKGROUND: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes. OBJECTIVE: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates. METHODS: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum. RESULTS: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum. CONCLUSIONS: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease. © 2021 International Parkinson and Movement Disorder Society.
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Paraplegia Espástica Hereditária , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Estudos Transversais , Expressão Gênica , Humanos , Mutação , Proteínas/genética , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genética , EspastinaRESUMO
BACKGROUND: Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS: This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS: We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.
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Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Paraplegia Espástica Hereditária , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Paraplegia Espástica Hereditária/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Hereditary spastic paraplegia is a heterogeneous group of genetic disorders characterized by degeneration of the corticospinal tracts, coursing with progressive weakness and spasticity of the lower limbs. To date, there are no effective treatments for progressive deficits or disease-modifying therapy for those patients. We report encouraging results for spastic paraparesis after spinal cord stimulation. METHODS: A 51-year-old woman suffering from progressive weakness and spasticity in lower limbs related to hereditary spastic paraplegia type 4 underwent spinal cord stimulation (SCS) and experienced also significant improvement in motor function. Maximum ballistic voluntary isometric contraction test, continuous passive motion test and gait analysis using a motion-capture system were performed in ON and OFF SCS conditions. Neurophysiologic assessment consisted of obtaining motor evoked potentials in both conditions. RESULTS: Presurgical Spastic Paraplegia Rating Scale (SPRS) score was 26. One month after effective SCS was initiated, SPRS went down to 15. At 12 months follow up, she experienced substantial improvement in motor function and in gait performance, with SPRS scores 23 (OFF) and down to 20 (ON). There was an increased isometric muscle strength (knee extension, OFF: 41 N m; ON: 71 N m), lower knee extension and flexion torque values in continuous passive motion test (decrease in spastic tone) and improvement in gait (for example, step length increase). CONCLUSION: Despite being a case study, our findings suggest innovative lines of research for the treatment of spastic paraplegia.
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Transtornos Neurológicos da Marcha/reabilitação , Atividade Motora , Paraplegia/reabilitação , Paraplegia Espástica Hereditária/reabilitação , Estimulação da Medula Espinal , Feminino , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Paraplegia/complicações , Paraplegia/fisiopatologia , Índice de Gravidade de Doença , Paraplegia Espástica Hereditária/complicações , Paraplegia Espástica Hereditária/fisiopatologiaRESUMO
Hereditary spastic paraplegias are an uncommon group of monogenic diseases that include 79 types of genetic disorders. The most frequent cause of recessive hereditary spastic paraplegia is a mutation in the spastic paraplegia gene type 11 followed by type 15. This group is usually associated with non-specific clinical features like cognitive decline and may precede the progressive weakness and spasticity of lower limbs. The magnetic resonance imaging hallmark of hereditary spastic paraplegia is thinning of the spinal cord. However, brain magnetic resonance imaging may provide relevant clues for specific hereditary spastic paraplegia subtypes, and thinning of the corpus callosum has been described as the most frequent abnormality in almost one-third of recessive hereditary spastic paraplegias. Moreover, a characteristic abnormality affecting the forceps minor of the corpus callosum has been recently reported as the "ears of the lynx" sign and is highly suggestive of type 11 and 15 hereditary spastic paraplegias. We report a patient who was diagnosed with hereditary spastic paraplegia type 11 by exome genetic testing, presenting the ears of the lynx sign in the first magnetic resonance imaging assessment.
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Imageamento por Ressonância Magnética/métodos , Paraplegia Espástica Hereditária/diagnóstico por imagem , Adolescente , Diagnóstico Diferencial , Humanos , Paraplegia Espástica Hereditária/patologiaRESUMO
SPG11 mutations lead to heterogeneous neurological phenotypes, but metabolic abnormalities have not yet been explored in this disease. In this study, we investigate whether SPG11 pathogenic variants might affect metabolic regulation, leading to weight changes and if this could relate to hypothalamic damage. In this cross-sectional case-control study, we selected a group of individuals with confirmed SPG11 mutations (nâ¯=â¯20), paired with healthy controls - both groups underwent brain MRI, from which we performed manual hypothalamic segmentation - and patients with Friedreich Ataxia (FRDA), having collected weight and height data for BMI-comparison. In the SPG11 group, we found significantly higher BMI compared to FRDA (pâ¯=â¯.034), as well as hypothalamic atrophy compared to controls (pâ¯=â¯.030). Volumetric changes were not associated with BMI, age, disease duration or SPRS amongst subjects with SPG11. Therefore, this study presents a new feature in SPG11 by characterizing a higher obesity rate in these patients, that could be associated with the hypothalamic atrophy found in this population.
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Paraplegia Espástica Hereditária , Estudos de Casos e Controles , Estudos Transversais , Humanos , Mutação , Obesidade/complicações , Obesidade/genética , Proteínas/genética , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genéticaRESUMO
Ophthalmological abnormalities may occur in specific subtypes of hereditary spastic paraplegia (HSP) and in genetic diseases that present with spastic paraplegia mimicking HSP. These ophthalmological changes may precede the motor symptoms and include pigmentary retinal degeneration, ophthalmoplegia, optic atrophy, cataracts and nystagmus. Some ophthalmological abnormalities are more prevalent in specific forms of HSP. Considering that the diagnosis of HSP is usually difficult and complex, specific ophthalmological changes may guide the genetic testing. There are other genetic diseases such as autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), X-linked adrenoleukodystrophy and spastic paraplegia, optic atrophy and neuropathy (SPOAN) that may mimic HSP and also may present with specific ophthalmological changes. In this article, we review the main ophthalmological changes observed in patients with HSP and HSP-like disorders.
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Técnicas de Diagnóstico Oftalmológico , Oftalmopatias/diagnóstico por imagem , Oftalmopatias/genética , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/genética , Oftalmopatias/epidemiologia , Humanos , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/epidemiologia , Espasticidade Muscular/genética , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/epidemiologia , Atrofia Óptica/genética , Paraplegia/diagnóstico por imagem , Paraplegia/epidemiologia , Paraplegia/genética , Paraplegia Espástica Hereditária/epidemiologia , Ataxias Espinocerebelares/congênito , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genéticaRESUMO
Background: Little is known about the cognitive profile of Hereditary Spastic Paraplegias (HSP), where most scientific attention has been given to motor features related to corticospinal tract degeneration. Objectives: We aimed to perform a broad characterization of the cognitive functions of patients with pure and complicated HSP as well as to determine the frequency of abnormal cognitive performances in the studied subtypes. Methods: A two-center cross-sectional case-control study was performed. All individuals underwent cognitive assessment through screening tests (Mini Mental State Examination-MEEM and Montreal Cognitive Assessment-MOCA) and tests to assess specific cognitive functions (Verbal fluency with phonological restriction-FAS; Verbal categorical fluency-FAS-cat and Rey's Verbal Auditory Learning Test -RAVLT). Results: Fifty four patients with genetically confirmed HSP diagnosis, 36 with spastic paraplegia type 4 (SPG4), 5 SPG11, 4 SPG5, 4 cerebrotendinous xanthomatosis (CTX), 3 SPG7 and 2 SPG3A, and 10 healthy, unrelated control subjects, with similar age, sex, and education participated in the study. SPG4 patients had worse performances in MOCA, FAS, FAS-cat, and RAVLT when compared to controls. Most SPG4 patients presented cognitive changes not compatible with dementia, performing poorly in memory, attention and executive functions. SPG5 patients scored lower in executive functions and memory, and SPG7 patients performed poorly on memory tasks. All evaluated cognitive functions were markedly altered in CTX and SPG11 patients. Conclusions: Cognitive abnormalities are frequent in HSP, being more severe in complicated forms. However, cognitive impairments of pure HSPs might impact patients' lives, decreasing families' socioeconomic status and contributing to the overall disease burden.
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BACKGROUND AND PURPOSE: SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4-HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non-motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4-HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. METHODS: Thirty-four molecularly confirmed SPG4 patients were recruited in a multicenter cross-sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease - Autonomic Questionnaire (SCOPA-AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age- and gender-matched healthy controls using non-parametric tests. P values <0.05 were considered significant. RESULTS: In the SPG4-HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA-AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4-HSP group. CONCLUSION: Our results indicate that SPG4-HSP patients have sudomotor dysfunction caused by damaged small post-ganglionic cholinergic fibers. Damage in SPG4-HSP extends to the peripheral nervous system.
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Sistema Nervoso Autônomo/fisiopatologia , Mutação , Paraplegia/fisiopatologia , Paraplegia Espástica Hereditária/fisiopatologia , Espastina/genética , Adenosina Trifosfatases/genética , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paraplegia/genética , Paraplegia Espástica Hereditária/genéticaRESUMO
BACKGROUND: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. OBJECTIVES: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. METHODS: Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. RESULTS: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. CONCLUSION: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.
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Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Mutação/genética , Transtornos Parkinsonianos , Proteínas/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Estudos de Coortes , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Compostos de Organotecnécio/farmacocinética , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Método Simples-Cego , Estatísticas não Paramétricas , Tomógrafos Computadorizados , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/farmacocinética , Adulto JovemRESUMO
SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3â¯T MRI scan. Mean age and disease duration were 29 and 13.2â¯years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.
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Gânglios da Base/diagnóstico por imagem , Mutação , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Paraplegia Espástica Hereditária/diagnóstico por imagem , Adulto JovemRESUMO
Hereditary spastic paraplegias (HSP) are a large group of genetic diseases characterized by progressive degeneration of the long tracts of the spinal cord, namely the corticospinal tracts and dorsal columns. Genotypic and phenotypic heterogeneity is a hallmark of this group of diseases, which makes proper diagnosis and management often challenging. In this scenario, magnetic resonance imaging (MRI) emerges as a valuable tool to assist in the exclusion of mimicking disorders and in the detailed phenotypic characterization. Some neuroradiological signs have been reported in specific subtypes of HSP and are therefore helpful to guide genetic testing/interpretation. In addition, advanced MRI techniques enable detection of subtle structural abnormalities not visible on routine scans in the spinal cord and brain of subjects with HSP. In particular, quantitative spinal cord morphometry and diffusion tensor imaging look promising tools to uncover the pathophysiology and to track progression of these diseases. In the current review article, we discuss the current use and future perspectives of MRI in the context of HSP.
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BACKGROUND: Molecular diagnosis of hereditary spastic paraplegias (HSP) is a difficult task due to great clinical and genetic heterogeneity. We aimed to characterize clinical and molecular findings of HSP families from Rio Grande do Sul, Brazil; and to evaluate the diagnostic yield of a next-generation sequencing (NGS) panel with twelve HSP-related genes. METHODS: A consecutive series of HSP index cases with familial recurrence of spasticity, consanguinity or thin corpus callosum (TCC) were included in this cross-sectional study. RESULTS: Among the 29 index cases, 51.7% (15/29) received at least a likely molecular diagnosis, and 48.3% (14/29) a defined diagnosis. NGS panel diagnostic yield was 60% for autosomal dominant HSP (6/10, all SPG4), 47.4% for autosomal recessive HSP (9/19: 5 SPG11, 2 SPG7, 1 SPG5 and 1 cerebrotendinous xanthomatosis), and 50% for patients with TCC (3/6, all SPG11). Remarkably, 2/6 SPG11 patients presented keratoconus, and tendon xanthomas were absent in the patient with cerebrotendinous xanthomatosis. CONCLUSION: A likely molecular diagnosis was obtained for more than half of families with the NGS panel, indicating that this approach could be employed as a first-line investigation for HSP. SPG4 is the most frequent form of autosomal dominant and SPG11 of autosomal recessive HSP in Southern Brazil.
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Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Paraplegia Espástica Hereditária/genética , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/fisiopatologia , Consanguinidade , Estudos Transversais , Diagnóstico Diferencial , Família , Feminino , Humanos , Masculino , Mutação , Paraplegia Espástica Hereditária/fisiopatologiaRESUMO
ABSTRACT The authors have constructed a brief timeline of major clinical research related to hereditary spastic paraplegia (HSP). This timeline summarizes the evolution of HSP research, from the first clinical descriptions by Adolf von Strümpell in 1880 to the present day, with the transformation of these diseases into a rapidly-growing and heterogeneous group of neurogenetic diseases.
RESUMO Os autores constroem uma breve linha do tempo com as principais pesquisas clinicas relacionadas as paraplegias espásticas hereditárias. Desde a descrição clínica inicial em 1880, feita por Adolf von Strümpell, até os dias atuais com a transformação dessas doenças em um grupo de doenças neurogenéticas com grande variabilidade na apresentação fenotípica e genotípica.
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Humanos , História do Século XIX , História do Século XX , História do Século XXI , Paraplegia Espástica Hereditária/históriaRESUMO
INTRODUCTION: Hereditary Spastic Paraplegia (HSP) represents a complex and heterogeneous group of rare neurodegenerative disorders that share a common clinical feature of weakness and lower limb spasticity that can occur alone or in combination with a constellation of other neurological or systemic signs and symptoms. Although the core clinical feature of weakness and lower limb spasticity is virtually universal, the genetic heterogeneity is almost uncountable with more than 70 genetic forms described so far. We performed review of medical records from twenty-one patients from seventeen Brazilian families with complex phenotype of HSP. All cases have previously negative mutations in SPG11/KIAA1840 and SPG7 gene and were evaluated by whole-exome sequencing. An extensive description of systemic and neurological signs has been described. RESULTS: Whole-exome sequencing was unremarkable in eight patients and established a definite genetic diagnosis in thirteen patients of twelve non-related families. Mutations were found in genes previously implicated in other neurodegenerative disorders such as Amyotrophic Lateral Sclerosis, Hereditary Neuropathy, Spastic Ataxias, Neurodegeneration with Brain Iron Accumulation, Glycogen Metabolism, Congenital Lipodystrophy and aminoacyl-tRNA synthetases disorders. CONCLUSIONS: We report thirteen new genetically-proven cases of complex HSP, expanding the clinical spectrum of presentations of HSP, providing new pathophysiological mechanisms and disclosing new potential therapeutic targets.