Amyotrophic Lateral Sclerosis: Its Natural History

Caroscio, James T.; Mulvihill, Michael; Sterling, Robert C.; Abrams, Bruce

doi:10.1016/s0733-8619(18)30931-9

Cited by 157 publications

(88 citation statements)

References 7 publications

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“…The next symptoms frequently occur in the contralateral limb at the same spinal level and at contiguous spinal levels (26). Alternatively, spread may occur up and down the motor neuron system through the primary motor neurons directly connected to muscles and those neurons that feed into the primary motor system (27).…”

Section: Risk Of Neurodegenerative Diseasementioning

confidence: 99%

Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration

Frank

2010

Proc. Natl. Acad. Sci. U.S.A.

161

129

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Somatic mutations must happen often during development because of the large number of cell divisions to expand from a single-cell zygote to a full organism. A mutation in development carries forward to all descendant cells, causing genetic mosaicism. Widespread genetic mosaicism may influence diseases that derive from a few genetically altered cells, such as cancer. I show how to predict the expected amount of mosaicism and the variation in mosaicism between individuals. I then calculate the predicted risk of cancer derived from developmental mutations. The calculations show that a significant fraction of cancer in later life likely arises from developmental mutations in early life. In addition, much of the variation in the risk of cancer between individuals may arise from variation in the degree of genetic mosaicism set in early life. I also suggest that certain types of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), may derive from a small focus of genetically altered cells. If so, then the risk of ALS would be influenced by developmental mutations and the consequent variation in genetic mosaicism. New technologies promise the ability to measure genetic mosaicism by sampling a large number of cellular genomes within an individual. The sampling of many genomes within an individual will eventually allow one to reconstruct the cell lineage history of genetic change in a single body. Somatic evolutionary genomics will follow from this technology, providing new insight into the origin and progression of disease with increasing age.

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Section: Risk Of Neurodegenerative Diseasementioning

confidence: 99%

Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration

Frank

2010

Proc. Natl. Acad. Sci. U.S.A.

161

129

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“…It is now well established that ALS with SOD1 mutations is caused by a gain of toxic properties associated with the propensity of mutant SOD1 to misfold (11,12), but what elicits the progressive aggregation of mutant SOD1 in ALS is unknown. The onset of motor symptoms is variable, but always focal, and subsequently spreads to contiguous areas (14). Although primarily cytosolic, SOD1 can be secreted (15,16) and has been detected in cerebrospinal fluid of ALS patients (17).…”

mentioning

confidence: 99%

Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells

Münch

O’Brien

Bertolotti

2011

Proc. Natl. Acad. Sci. U.S.A.

427

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Deposition of proteins of aberrant conformation is the hallmark of many neurodegenerative diseases. Misfolding of the normally globular mutant superoxide dismutase-1 (SOD1) is a central, early, but poorly understood event in the pathogenic cascade leading to familial forms of ALS. Here we report that aggregates composed of an ALS-causing SOD1 mutant penetrate inside cells by macropinocytosis and rapidly exit the macropinocytic compartment to nucleate aggregation of the cytosolic, otherwise soluble, mutant SOD1 protein. Once initiated, mutant SOD1 aggregation is selfperpetuating. Mutant SOD1 aggregates transfer from cell to cell with remarkable efficiency, a process that does not require contacts between cells but depends on the extracellular release of aggregates. This study reveals that SOD1 aggregates, propagate in a prion-like manner in neuronal cells and sheds light on the mechanisms underlying aggregate uptake and cell-to-cell transfer.amyotrophic lateral sclerosis | amyloid | transmission | protein folding | endocytosis

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“…As to their age, it is surprising a percentage of 21.1% of sporadic juvenile cases in this region of Brazil, in comparison with northern areas of the world, where the percentage of those cases reaches only 0.5 to 2.3% 10,11 . The sporadic juvenile ALS is considered to be rare [12][13][14] , and in Brazil, excepting for an indirect report on some cases 15 , no established analysis of this occurrence has been carried out up to now.…”

Section: Discussionmentioning

confidence: 83%

Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

Castro-Costa

Oriá

Machado-Filho

et al. 1999

Arq. Neuro-Psiquiatr.

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-We report on the clinical characteristics of amyotrophic lateral sclerosis (ALS) in Fortaleza (Northeastern Brazil). For this, we analyzed retrospectively (from 1980 to 1999) 78 cases of ALS from the Service of Neurology of the University Hospital of Fortaleza diagnosed clinically and laboratorially (EMG, muscle biopsy, myelography, blood biochemistry, muscle enzymes and cranio-cervical X-ray). The results showed that they were mostly sporadic ALS (76/78), and they were divided into definite (n= 36), probable (n= 20), possible (n= 15) and suspected (n= 7), according to the level of diagnostic certainty. They were also subdivided into juvenile (n= 17), early-onset adult (n= 18), age-specific (n= 39) and late-onset (n= 4) groups. Clinically, they presented as initials symptoms, principally, asymmetrical (30/78) and symmetrical (24/78) weakness of extremities, besides bulbar signs, fasciculations, and atrophy. Curiously, pain as first symptom occurred in an expressive fashion (17/78). The predominant initial anatomic site, in this series, was the spinal cord, and mainly affecting the arms. As to the symptom accrual from region to region, this occurs more quickly in contiguous areas, and fasciculations are predominant when bulbar region was associated.KEY WORDS: ALS, sporadic, early-onset, pain, anatomy, symptom accrual, fasciculations. Esclerose lateral amiotrófica: análise clínica de 78 casos de Fortaleza (Nordeste Brasileiro)RESUMO -Descrevemos as características clínicas da esclerose lateral amiotrófica (ELA) em Fortaleza (Nordeste Brasileiro). Para isso, fizemos uma análise retrospectiva (de 1980 a 1999) de 78 casos de ELA do Serviço de Neurologia do Hospital Universitário de Fortaleza, diagnosticados do ponto de vista clínico e laboratorial (EMG, biópsia de músculo, mielografia, análises hematológica e bioquímica, e raio X da junção crânio-cervical). Os resultados mostraram que esses casos eram principalmente da forma esporádica (76/78), e estes foram divididos, de acordo com o nível de certeza diagnóstica, em definidos (n= 36), prováveis (n= 20), possíveis (n= 15) e suspeitos (n= 7). Eles foram também subdivididos nos grupos juvenil (n= 17), adulto jovem (n= 18), idadeespecífico (n= 39) e tardio (n= 4). Clinicamente, os principais sintomas iniciais foram fraqueza assimétrica (38/ 78) e simétrica (24/78) das extremidades, além de sinais bulbares, fasciculações e atrofia. Curiosamente, dor como sintoma inicial ocorria de maneira expressiva (17/78). O local anatômico inicial predominante foi, nessa série, a medula espinhal, afetando principalmente os braços. O avanço regional de sintomas ocorreu mais rapidamente em áreas contíguas, e as fasciculações eram predominantes quando a região bulbar estava associada. PALAVRAS-CHAVE: ELA, esporádica, início precoce, dor, anatomia, avanço dos sintomas, fasciculações.Amyotrophic lateral sclerosis (ALS) is a condition of undetermined cause, which affects the anterior horn cells and the corticospinal tract.The etiology is manifold so that different causes have been...

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Amyotrophic Lateral Sclerosis: Its Natural History

Cited by 157 publications

References 7 publications

Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration

Somatic evolutionary genomics: Mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration

Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells

Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (Northeastern Brazil)

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