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Review Article

Tale of two diseases: Amyotrophic lateral sclerosis and frontotemporal dementia Ashok Verma Department of Neurology, Miller School of Medicine, University of Miami, Miami, Florida, USA

Abstract

Address for correspondence: Dr. Ashok Verma, Professor of Neurology, Clinical Research Building, 1120 NW 14 Street, Suite 1317, Miami, Florida 3313, USA. E‑mail: [email protected] Received : 28‑05‑2014 Review completed : 24-08-2014 Accepted : 24‑08‑2014

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were independently described in clinical and pathological details more than a century ago. Recent breakthrough discoveries identifying common genes that are causal to either ALS or FTD or an overlapping ALS‑FTD syndrome have dramatically transformed our view regarding their pathogenesis. Most recently, a massive hexanucleotide (GGGGCC) repeat expansion mutation in C9orf72 gene has been linked to the majority of familial ALS, FTD and mixed ALS‑FTD cases. C9orf72 and other genes causal to ALS and FTD are consistently associated with the formation of cellular RNA inclusions and protein aggregates. This article summarizes the recently reported ALS‑FTD‑linked genes and the emerging common unifying mechanism in the pathogenesis of ALS‑FTD spectrum disorders along with a comment on the potential new therapeutic targets in these hitherto incurable diseases. Key words: Amyotrophic lateral sclerosis, C9orf72, frontotemporal dementia, Protein

aggregates, TAR DNA binding protein‑43

Introduction In a series of case demonstrations, lectures and publications in 1860s, Jean‑Martin Charcot of La Salpêtrière hospital in Paris described the clinicopathological entity of progressive muscular atrophy (amyotrophy) and pyramidal tract degeneration (lateral sclerosis), and named it amyotrophic lateral sclerosis (ALS), also called Charcot’s disease or motor neuron disease.[1] Thirty years later in 1892, Arnold Pick, a psychiatrist at the Viennese hospital in Prague, published a case report under the title ‘on the relationship between senile cerebral atrophy and aphasia’, describing specifically behavioral symptoms and speech difficulty in conjunction with gross frontotemporal lobe atrophy. [2] Familiar with Carl Wernicke’s opinion Access this article online Quick Response Code:

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(with whom Pick had previously worked in Berlin) that ‘General Paralysis of the Insane’ can be associated with focal neuropsychological deficits, Pick affirmed his thesis that prominent neuropsychiatric symptoms could emanate also from focal cerebral atrophy in senile dementia. What particularly drew Pick’s attention in his case, in addition to dementia, was the unusually severe language disorder, now widely recognized as the first description of primary progressive aphasia (PPA).[3] Pick did not perform microscopic study in this and other cases that he his colleagues subsequently reported.[3,4] In 1911, Alois Alzheimer described the pathological findings in patients with frontotemporal lobe degeneration (FTLD),[3] specifically pointing the absence of senile plaques and neurofibrillary tangles that he had described in a disease in 1907 that bears his name. Alzheimer reported instead the presence of argyrophilic neural inclusions and swollen cells in FTLD, later called Pick bodies and Pick cells, respectively.[4] Although motor cortex (pyramidal tracts) can be potentially involved in FTLD, a clear connection between frontotemporal dementia (FTD) and ALS remained unknown for almost a century. 347

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Two major research groups from Lund in Sweden and Manchester in England[6] in 1990s proposed clinic and neuropathological criteria of FTD which later Neary et al.,[7] in 1998 refined as consensus diagnostic criteria of FTLD in the American Academy of Neurology practice guidelines. FTLD is characterized by progressive atrophy with neuronal loss in the frontal and temporal cortices and is characterized clinically by behavior changes (bvFTD) as well as gradual impairment of language skills, PPA. PPA phenotype of FTLD is further subclassified into three subtypes: The common nonfluent variant (nfvPPA) and rare logopenic (lvPPA) and semantic dementia (sdvPPA) variants.[8] FTD is the second most common cause of degenerative dementia after Alzheimer’s disease.[8‑10] As the clinical FTD syndrome became widely recognized, it also became evident in ALS community that bvFTD was particularly common in ALS. Up to half of ALS patients have cognitive behavioral or linguistic impairment attributable to FTLD.[9‑11] Recent discovery of mutation in chromosome 9 open reading frame 72 (C9orf72) as a major cause of familial ALS, FTD and mixed ALS‑FTD syndrome closes the clear relationship between ALS and FTD and provides new insight in the pathogenesis of these related disorders.[12,13] Convergence of genetic causes of ALS and FTD Similar in clinical details, familial (10%) and sporadic (90%) ALS (familiarly known as Lou Gehrig’s disease in the United States) is characterized by premature degeneration of upper and lower motor neurons. ALS is a progressive disease and patients with ALS generally survive 3-5 years after the disease‑onset. Mutations in four genes (C9orf72, SOD1, TDP‑43, and FUS) account for approximately 65% of the familial ALS cases. [12‑17] Other rare genes causal to familial ALS include microtubule‑associated protein tau (MAPT),[18] progranulin (PGRN),[19] valosin containing protein (VCP),[20] ubiquilin2 (UBQLN2),[21] and charged multivesicular protein 2B (CHMP2B).[22]

Clinically indistinguishable, familial (50%) and sporadic FTD is characterized by progressive loss of neuronal cells in frontal and temporal lobes. The typical clinical picture in FTD and Pick’s FTLD is a slowly progressive dementia dominated at early stage by prominent personality and behavior changes, [23] lack of insight, disinhibition, and at later stage by psychomotor slowing, stereotype and apathy. [7,8] There can also be progressive impairment of speech, often ending in mutism. Memory and visuospatial functions are generally spared, although elements of Klϋver‑Bucy syndrome (blunt affect, hyperorality and hypersexuality, likely from the medial frontal and temporal lobe degeneration) can be other recognizable features in FTD.[8] Mutations in first two identified causal genes encoding the MAPT and PGRN account for 10%-20% of familial FTD [Table 1]. Mutations in TDP‑43, FUS, UBQLN2, VCP and CHMP2B are causal for a small proportion of familial FTD. Most recently, hexanucleotide (GGGGCC, G4C2) expansion mutation in C9orf72 gene is linked to most genetic as well as some sporadic forms of FTD[12,13,24‑26] [Table 1]. Although MAPT‑ and PGRN‑gene‑associated FTD were reported on occasion to show ALS features, the real breakthrough linking ALS and FTD disease mechanisms came with the identification of TDP‑43 as the major ubiquitinated protein in both sporadic and non‑SOD1 familial ALS and in most pathological forms of FTD.[24,27] This finding was followed soon thereafter by the discovery of mutations in the gene encoding the TDP‑43 in patients with ALS as well as FTD.[15] Recognition that mutation in RNA‑binding protein (TDP‑43) was causal to ALS and FTD was quickly expanded to screen for other RNA binding proteins. Mutations in the FUS gene (another RNA binding protein) are now shown to account for an additional 5% of familial ALS and some cases of FTD.[16] Recently, the most convincing direct molecular link between ALS and FTD has been the identification of a large intronic hexanucleotide expansion (few hundreds to thousands of G 4 C 2 repeats) in the previously

Table 1: Genes associated with the ALS‑FTD spectrum disorders

Gene C9orf72 TDP‑43 FUS UBQLN2 VCP CHMP2B MAPT PGRN

Chromosome

Proportion of affected patients with ALS, %

Proportion of affected patients with FTD, %

9p 1p 16 Xp 9p 3p 17q 17q

~60 ~100 ~100 ~100 ~1 Rare Rare ~5

~65

Tale of two diseases: amyotrophic lateral sclerosis and frontotemporal dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were independently described in clinical and pathological details more than a ce...
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