2.5.1 Epidemiology
The incidence of ALS in population based studies ranges from 1:100 000 in Europe and North America, and 0.5:100 000 in Asia (Cronin, Hardiman & Traynor, 2007). The incidence might be lower in some populations such as the African population (Cronin, Hardiman & Traynor, 2007).
There is also some variation in the incidence within and between countries. For example, there has been a significantly higher incidence of ALS in Guam, an island in the western Pacific Ocean (Arnold, Edgren & Palladino, 1953, Koerner, 1952, Mulder, Kurland & Iriarte, 1954). The
geographical variation is evident also in Finland as there is a regional clustering of ALS in Southeast Finland (Murros, Fogeholm, 1983). The incidence of ALS is higher in males than females (Ingre et al., 2015). ALS incidence increases after age 40, the peak age for the incidence is 65-74 and declines in older age groups (Chio et al., 2011).
2.5.2 Clinical features
ALS is a motor neuron disease that affects both the upper and lower motor neurons. Aside from genetic ALS, there is no single diagnostic laboratory test currently in use for the disease and therefore the diagnosis is most often based on clinical features and EMG results. The El Escorial criteria are the most widely used consensus clinical criteria in the diagnosis of ALS (Brooks, 1994).
The El Escorial criteria has categories for the certainty of a diagnosis ranging from suspected to definitive based on motor neuron signs (Brooks, 1994). Autopsy studies have shown that the diagnosis of definite ALS was confirmed pathologically in 100% of cases whereas only 33% of suspected ALS was confirmed pathologically (Chaudhuri et al., 1995). Suspected ALS has been removed from the revised El Escorial criteria (Brooks et al., 2000). The issue with clinical diagnostic criteria is that the diagnosis requires evidence of a progressive disease, which often delays diagnosis and therefore could potentially delay treatment (Traynor et al., 2000). 90% of ALS patients meet the clinical criteria of definite or probable ALS during their lifetime (Traynor et al., 2000).
ALS is classically divided into a bulbar and limb onset disease, depending on the site of first symptoms. Bulbar ALS usually starts with dysarthria. Limb onset ALS is further defined to lower or upper limb onset. Usually the symptoms start in the distal rather than the proximal muscles of the limbs. ALS causes weakness and atrophy of the muscles. Most patients have fasciculations. Upper motor neuron signs (i.e. Babinski and Hoffman signs, the jaw jerk) may be difficult to detect as lower motor neuron dysfunction can mask them (Brooks et al., 2000).
The duration of the disease varies, but is usually 3-5 years (del Aguila et al., 2003). The cause of death is usually related to respiration as ventilation muscles deteriorate (del Aguila et al., 2003).
Approximately 50% of patients have some cognitive issues and a significant portion of those have cognitive decline that reaches the level of dementia, which is usually FTLD type (Lomen-Hoerth et al., 2003).
2.5.3 Neuropathology
The neuropathology of genetic and sporadic ALS is usually quite similar. The brain is fairly unaffected if there is no dementia, while the anterior horns of the spinal cord are atrophic.
Histopathologically there is a loss of neurons in the motor cortex and in the anterior horn of the spinal cord, and in the hypoglossal nucleus. There is also a loss of myelinated axons in the anterior and lateral columns of the spinal cord. Intracellular TDP43 positive inclusions are usually present in the anterior horn cells of the spinal cord (Al-Chalabi et al., 2012, Arai et al., 2006, Brettschneider et al., 2013, Kato et al., 2000, Tan et al., 2007). In some genetic forms this is not the case, for example ALS caused by SOD1 mutations is TDP43 negative (Mackenzie, I. R. et al., 2007). C9ORF72 related ALS patients have p62 positive and TDP43 negative inclusions in the neurons of the cerebellum (Al-Sarraj et al., 2011).
2.5.4 Genetics
Approximately 5-10% of ALS is genetic. ALS is generally considered to be familial if there are two or more ALS patients in a family. Studies have revealed that 10% of apparently sporadic ALS has a
genetic etiology (Kenna et al., 2013). Most mutations are inherited in an autosomal dominant pattern (Marangi, Traynor, 2015).
The C9ORF72 hexanucleotide repeat expansion mutation is the most common genetic cause of ALS in most Western populations, explaining about 27% of familial ALS and 3% of apparently sporadic ALS (Garcia-Redondo et al., 2013). As the C9ORF72 repeat expansion mutation is also the most common cause of genetic FTLD, it indicates a strong connection between the pathogenesis of these two diseases (Byrne et al., 2012).
The second most common cause of familial ALS are SOD1 mutations (Zou et al., 2017). SOD1 was the first gene whose mutations were found to cause ALS (Rosen, D. R. et al., 1993). Although most of them are inherited in an autosomal dominant manner, the recessive p.Asp91Ala mutation is more common among Finnish patients due to a founder effect (Andersen et al., 1995, Andersen et al., 1996). SOD1 encodes a cytoplasmic antioxidant enzyme superoxide dismutase-1 (Rosen, D. R.
et al., 1993). The enzyme works against oxygen toxicity by metabolizing superoxide radicals into molecular oxygen and hydrogen peroxide (Rosen, D. R. et al., 1993). SOD1 mutations have been considered to cause ALS by a toxic gain of function, although loss of function has also been proposed (Baskoylu et al., 2018).
There are several other genes whose mutations cause ALS (TABLE 4). As genetic studies of several genes in a gene panel test, and whole exome and genome sequencing have become available it has become apparent that some patients harbor mutations in multiple genes and ALS has an oligogenic inheritance pattern. It could explain the incomplete penetrance of many mutations such as the C9ORF72 hexanucleotide expansion mutation (Cooper-Knock et al., 2017, Giannoccaro et al., 2017, Pang et al., 2017)
TABLE 4 Genes associated with ALS. Data from Marangi, Traynor, 2015 and original publications. GENE (HGNC) MIM#Genomic location (GRCh38) Inferitance patternClinical phenotypes (OMIM) Reference C9ORF726142609:27546545-27573865 ADFrontotemporal dementia and/or amyotrophic lateral sclerosis 1 (MIM 105550)
(Renton, Alan E et al., 2011, DeJesus-Hernandez et al., 2011) SOD1147450 21:31659692-31668930 AD, ARAmyotrophic lateral sclerosis 1 (MIM105400), Spastic tetraplegia and axial hypotonia, progressive (MIM618598) (Rosen, D. R. et al., 1993) SETX6084659:132261355-132356725 AD,AR
Amyotrophic lateral sclerosis 4, juvenile (MIM602433), Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (MIM606002)
(Chen et al., 2004) SPG1161084415:44562695-44663677AR
Amyotrophic lateral sclerosis 5, juvenile (MIM602099), Charcot-Marie-Tooth disease, axonal, type 2X (MIM616668), Spastic paraplegia 11, autosomal recessive (MIM604360) (Orlacchio et al., 2010, Daoud et al., 2012) FUS13707016:31180109-31194870AD
Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia (MIM608030), Essential tremor, hereditary, 4 (MIM614782)
(Vance et al., 2009, Kwiatkowski et al., 2009) VAPB60570420:58389210-58451100ADAmyotrophic lateral sclerosis 8 (MIM608627), Spinal muscular atrophy, late- onset, Finkel type (MIM182980)(Nishimura et al., 2004) ANG10585014:20684176-20694185ADAmyotrophic lateral sclerosis 9 (MIM611895) (Greenway et al., 2006) TARDBP605078 1:11012653-11030527 AD
Amyotrophic lateral sclerosis 10, with or without FTD (MIM612069), Frontotemporal lobar degeneration, TARDBP-related (MIM612069) (Gitcho et al., 2009, Kabashi et al., 2008, Sreedharan et al., 2008)
FIG46093906:109691295-109825430 AD, AR Amyotrophic lateral sclerosis 11 (MIM612577), Polymicrogyria, bilateral temporooccipital(MIM612691), Charcot- Marie-Tooth disease, type 4J (MIM611228), Yunis-Varon syndrome (MIM216340)
(Chow, C. Y. et al., 2009) OPTN60243210:13100081-13138307AD
Amyotrophic lateral sclerosis 12 (MIM613435), Glaucoma 1, open angle, E(MIM137760), Glaucoma, normal tension, susceptibility to (MIM606657)
(Maruyama et al., 2010) VCP6010239:35056063-35072667 AD
Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia (MIM613954), Charcot-Marie-Tooth disease, type 2Y(MIM616687), Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 (MIM167320)
(Johnson et al., 2010) UBQLN2300264X:56563592-56567009 XLDAmyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MIM300857) (Deng et al., 2011) SIGMAR1601978 9:34634721-34637825ARAmyotrophic lateral sclerosis 16, juvenile (MIM614373), Spinal muscular atrophy, distal, autosomal recessive, 2 (MIM605726)
(Al-Saif, Al-Mohanna & Bohlega, 2011) CHMP2B6095123:87227308-87255555 ADAmyotrophic lateral sclerosis 17(MIM614696), Dementia, familial, nonspecific (MIM600795) (Parkinson et al., 2006) PFN117661017:4945651-4948529 ADAmyotrophic lateral sclerosis 18 (MIM614808) (Wu et al., 2012) MATR31640155:139273751-139331676 ADAmyotrophic lateral sclerosis 21 (MIM606070) (Johnson et al., 2014)
CHCHD1061590322:23765833-23767971AD Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (MIM615911), Spinal muscular atrophy, Jokela type (MIM615048), Myopathy, isolated mitochondrial, autosomal dominant (MIM616209)
(Bannwarth et al., 2014, Chaussenot et al., 2014) SQSTM1601530 5:179806392-179838077AD, AR
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (MIM616437), Myopathy, distal, with rimmed vacuoles (MIM617158), Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood- onset(MIM617145), Paget disease of bone 3 (MIM167250)
(Fecto et al., 2011) TAF1560157417:35809483-35847241ADChondrosarcoma, extraskeletal myxoid (MIM612237) (Couthouis et al., 2011) EWSR113345022:29268253-29300522ADNeuroepithelioma (MIM612219), Ewing sarcoma (MIM612219) (Couthouis et al., 2012) HNRNPA116401712:54280725-54287086AD
Amyotrophic lateral sclerosis 20 (MIM615426), Inclusion body myopathy with early-onset Paget disease without frontotemporal dementia 3 (MIM615424)
(Kim et al., 2013) HNRNPA2B1 6001247:26189919-26200774 ADInclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia (MIM615422) (Kim et al., 2013) SPAST6042772:32063550-32157636 ADSpastic paraplegia 4, autosomal dominant (MIM182601) (Meyer et al., 2005) PRPH17071012:49295143-49298697 AD,ARAmyotrophic lateral sclerosis, susceptibility to (MIM105400) (Leung et al., 2004)
DCTN16011432:74361153-74392086 AD, AR Perry syndrome (MIM168605), Neuropathy, distal hereditary motor, type VIIB (MIM607641), Amyotrophic lateral sclerosis, susceptibility to (MIM105400)
(Puls et al., 2003) ERLIN26116058:37736626-37758421 ARSpastic paraplegia 18, autosomal recessive (MIM611225) (Al-Saif, Bohlega & Al- Mohanna, 2012) SS18L160647220:62,143,764-62,182,513AD NA (Chesi et al., 2013) DAO12405012:108880029-108901042 AD NA (Mitchell et al., 2010) PNPLA660319719:7534163-7561766 AR
Spastic paraplegia 39, autosomal recessive (MIM612020), Oliver-McFarlane syndrome (MIM275400), Boucher-Neuhauser syndrome (MIM215470), Laurence-Moon syndrome (MIM245800)
(Rainier et al., 2008) TUBA4A191110 2:219249709-219254607 ADAmyotrophic lateral sclerosis 22 with or without frontotemporal dementia (MIM616208) (Smith et al., 2014) KIF5A60282112:57550038-57586632AD
Spastic paraplegia 10, autosomal dominant (MIM604187), Myoclonus, intractable, neonatal (MIM617235), Amyotrophic lateral sclerosis, susceptibility to, 25 (MIM617921)
(Nicolas et al., 2018) NA: not in OMIM.
2.5.5 Hypotheses on pathogenesis
Smoking has been concluded to be a risk factor for ALS based on several studies (Ingre et al., 2015). Physical activity has been concluded to be a minor risk factor in some studies although this has also been refuted (Chio et al., 2005, Pupillo et al., 2014). The association of several
autoimmune diseases and the development of ALS has also been studied (McCauley, Baloh, 2019).
It has been theorized that the pathogenesis of ALS is in some way relates to autoimmune diseases because ALS patients have been shown to have autoimmune diseases such as asthma more than the general population (Turner et al., 2013). However, standard immune suppression therapies have not shown to be effective in treating ALS patients (Baumann, 1965, Brown et al., 1986).
Microglial cells are the immune system cells in the nervous system and their dysfunction or abnormal activation has been suggested to be a factor in neuronal degeneration, for example microglial cells with wild type SOD1 have been shown to protect neurons with mutant SOD1 (Clement et al., 2003).
Glutamate excitotoxicity, which is caused by impaired glutamate intake by astrocytes, causes motor neuron damage in ALS (Bruijn et al., 1997). C9ORF72 mutations may cause altered RNA metabolism, along with SOD1 and TARDBP mutations (Alami et al., 2014, Lee et al., 2013, Gitcho et al., 2009). Altered RNA metabolism in turn causes among other things, altered protein translation and protein aggregates in motor neurons. The pathogenicity of this pathway is in part supported by the fact that most patients have protein aggregates in motor neurons (Mackenzie, I. R. et al., 2007, Da Cruz et al., 2017). SOD1 mutations also cause mitochondrial dysfunction and oxidative stress (Harraz et al., 2008). Impaired axonal transport has also been discovered (Williamson, Cleveland, 1999). The pathogenic pathways are presented in FIGURE 3.
FIGURE 3 Pathogenic pathways in ALS. Modified from van den Bos et al., 2019.
C9orf72, TARDBP, FUS, SOD1
SOD1