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Amyotrophic lateral sclerosis(ALS)

MedGen UID:
274
Concept ID:
C0002736
Disease or Syndrome
Synonyms: ALS; Charcot disease; Lou Gehrig disease
SNOMED CT: Amyotrophic lateral sclerosis (86044005); Bulbar motor neuron disease (86044005); Lou Gehrig's disease (86044005); ALS - Amyotrophic lateral sclerosis (86044005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Genes (locations): C9orf72 (9p21.2); OPTN (10p13); UBQLN2 (Xp11.21); VCP (9p13.3)
Related genes: SPG11, ALS2, TARDBP, SETX, SIGMAR1, FIG4, VAPB, SOD1, PRPH, NEFH, FUS, DCTN1, ANG
 
HPO: HP:0007354
Monarch Initiative: MONDO:0004976
Orphanet: ORPHA803

Definition

Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons, which are specialized nerve cells that control muscle movement. These nerve cells are found in the spinal cord and the brain. In ALS, motor neurons die (atrophy) over time, leading to muscle weakness, a loss of muscle mass, and an inability to control movement.

There are many different types of ALS; these types are distinguished by their signs and symptoms and their genetic cause or lack of clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. People with sporadic ALS usually first develop features of the condition in their late fifties or early sixties. A small proportion of people with ALS, estimated at 5 to 10 percent, have a family history of ALS or a related condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. The signs and symptoms of familial ALS typically first appear in one's late forties or early fifties. Rarely, people with familial ALS develop symptoms in childhood or their teenage years. These individuals have a rare form of the disorder known as juvenile ALS.

The first signs and symptoms of ALS may be so subtle that they are overlooked. The earliest symptoms include muscle twitching, cramping, stiffness, or weakness. Affected individuals may develop slurred speech (dysarthria) and, later, difficulty chewing or swallowing (dysphagia). Many people with ALS experience malnutrition because of reduced food intake due to dysphagia and an increase in their body's energy demands (metabolism) due to prolonged illness. Muscles become weaker as the disease progresses, and arms and legs begin to look thinner as muscle tissue atrophies. Individuals with ALS eventually lose muscle strength and the ability to walk. Affected individuals eventually become wheelchair-dependent and increasingly require help with personal care and other activities of daily living. Over time, muscle weakness causes affected individuals to lose the use of their hands and arms. Breathing becomes difficult because the muscles of the respiratory system weaken. Most people with ALS die from respiratory failure within 2 to 10 years after the signs and symptoms of ALS first appear; however, disease progression varies widely among affected individuals.

Approximately 20 percent of individuals with ALS also develop FTD. Changes in personality and behavior may make it difficult for affected individuals to interact with others in a socially appropriate manner. Communication skills worsen as the disease progresses. It is unclear how the development of ALS and FTD are related. Individuals who develop both conditions are diagnosed as having ALS-FTD.

A rare form of ALS that often runs in families is known as ALS-parkinsonism-dementia complex (ALS-PDC). This disorder is characterized by the signs and symptoms of ALS, in addition to a pattern of movement abnormalities known as parkinsonism, and a progressive loss of intellectual function (dementia). Signs of parkinsonism include unusually slow movements (bradykinesia), stiffness, and tremors. Affected members of the same family can have different combinations of signs and symptoms. [from MedlinePlus Genetics]

Term Hierarchy

Follow this link to review classifications for Amyotrophic lateral sclerosis in Orphanet.

Conditions with this feature

Frontotemporal dementia
MedGen UID:
83266
Concept ID:
C0338451
Disease or Syndrome
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration (FTLD). FTD, the most common subtype of FTLD, is a behavioral variant characterized by changes in social and personal conduct with loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output. A second clinical subtype of FTLD is 'semantic dementia,' characterized by specific loss of comprehension of language and impaired facial and object recognition. A third clinical subtype of FTLD is 'primary progressive aphasia' (PPA), characterized by a reduction in speech production, speech errors, and word retrieval difficulties resulting in mutism and an inability to communicate. All subtypes have relative preservation of memory, at least in the early stages. FTLD is often associated with parkinsonism or motor neuron disease (MND) resembling amyotrophic lateral sclerosis (ALS; 105400) (reviews by Tolnay and Probst, 2002 and Mackenzie and Rademakers, 2007). Mackenzie et al. (2009, 2010) provided a classification of FTLD subtypes according to the neuropathologic findings (see PATHOGENESIS below). Clinical Variability of Tauopathies Tauopathies comprise a clinically variable group of neurodegenerative diseases characterized neuropathologically by accumulation of abnormal MAPT-positive inclusions in nerve and/or glial cells. In addition to frontotemporal dementia, semantic dementia, and PPA, different clinical syndromes with overlapping features have been described, leading to confusion in the terminology (Tolnay and Probst, 2002). Other terms used historically include parkinsonism and dementia with pallidopontonigral degeneration (PPND) (Wszolek et al., 1992); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994); frontotemporal dementia with parkinsonism (FLDEM) (Yamaoka et al., 1996); and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997). These disorders are characterized by variable degrees of frontal lobe dementia, parkinsonism, motor neuron disease, and amyotrophy. Other neurodegenerative associated with mutations in the MAPT gene include Pick disease (172700) and progressive supranuclear palsy (PSP; 601104), Inherited neurodegenerative tauopathies linked to chromosome 17 and caused by mutation in the MAPT gene have also been collectively termed 'FTDP17' (Lee et al., 2001). Kertesz (2003) suggested the term 'Pick complex' to represent the overlapping syndromes of FTD, primary progressive aphasia (PPA), corticobasal degeneration (CBD), PSP, and FTD with motor neuron disease. He noted that frontotemporal dementia may also be referred to as 'clinical Pick disease' and that the term 'Pick disease' should be restricted to the pathologic finding of Pick bodies. Genetic Heterogeneity of Frontotemporal Lobar Degeneration Mutations in several different genes can cause frontotemporal dementia and frontotemporal lobar degeneration, with or without motor neuron disease. See FTLD with TDP43 inclusions (607485), caused by mutation in the GRN gene (138945) on chromosome 17q21; FTLALS7 (600795), caused by mutation in the CHMP2B gene (609512) on chromosome 3p11; inclusion body myopathy with Paget disease and FTD (IBMPFD; 167320), caused by mutation in the VCP gene (601023) on chromosome 9p13; ALS6 (608030), caused by mutation in the FUS gene (137070) on 16p11; ALS10 (612069), caused by mutation in the TARDBP gene (605078) on 1p36; and FTDALS1 (105550), caused by mutation in the C9ORF72 gene (614260) on 9p21. In 1 family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1; 104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3; 607822).
Amyotrophic lateral sclerosis-parkinsonism-dementia complex
MedGen UID:
107775
Concept ID:
C0543859
Disease or Syndrome
Amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam is a neurodegenerative disorder with unusually high incidence among the Chamorro people of Guam. Both ALS and parkinsonism-dementia are chronic, progressive, and uniformly fatal disorders in this population. Both diseases are known to occur in the same kindred, the same sibship, and even the same individual.
Amyotrophic lateral sclerosis type 8
MedGen UID:
325237
Concept ID:
C1837728
Disease or Syndrome
A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the VAPB gene on chromosome 20q13.
Amyotrophic lateral sclerosis with polyglucosan bodies
MedGen UID:
347953
Concept ID:
C1859805
Disease or Syndrome
Juvenile amyotrophic lateral sclerosis with dementia
MedGen UID:
395347
Concept ID:
C1859806
Disease or Syndrome
A juvenile amyotrophic lateral sclerosis that is slowly progressive with concomitantly progressive dementia.
Amyotrophic lateral sclerosis type 2, juvenile
MedGen UID:
349246
Concept ID:
C1859807
Disease or Syndrome
ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts and comprises a clinical continuum of the following three phenotypes: Infantile ascending hereditary spastic paraplegia (IAHSP), characterized by onset of spasticity with increased reflexes and sustained clonus of the lower limbs within the first two years of life, progressive weakness and spasticity of the upper limbs by age seven to eight years, and wheelchair dependence in the second decade with progression toward severe spastic tetraparesis and a pseudobulbar syndrome caused by progressive cranial nerve involvement. Juvenile primary lateral sclerosis (JPLS), characterized by upper motor neuron findings of pseudobulbar palsy and spastic quadriplegia without dementia or cerebellar, extrapyramidal, or sensory signs. Juvenile amyotrophic lateral sclerosis (JALS or ALS2), characterized by onset between ages three and 20 years. All affected individuals show a spastic pseudobulbar syndrome (spasticity of speech and swallowing) together with spastic paraplegia. Some individuals are bedridden by age 12 to 50 years.
Amyotrophic lateral sclerosis type 1
MedGen UID:
400169
Concept ID:
C1862939
Disease or Syndrome
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. Some forms of ALS occur with frontotemporal dementia (FTD); see 105500. Ranganathan et al. (2020) provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration. Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture. Genetic Heterogeneity of Amyotrophic Lateral Sclerosis ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. ALS6 (608030) is caused by mutation in the FUS gene (137070) on chromosome 16p11; ALS8 (608627) is caused by mutation in the VAPB gene (605704) on chromosome 13; ALS9 (611895) is caused by mutation in the ANG gene (105850) on chromosome 14q11; ALS10 (612069) is caused by mutation in the TARDBP gene (605078) on 1p36; ALS11 (612577) is caused by mutation in the FIG4 gene (609390) on chromosome 6q21; ALS12 (613435) is caused by mutation in the OPTN gene (602432) on chromosome 10p13; ALS15 (300857) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11; ALS18 (614808) is caused by mutation in the PFN1 gene (176610) on chromosome 17p13; ALS19 (615515) is caused by mutation in the ERBB4 gene (600543) on chromosome 2q34; ALS20 (615426) is caused by mutation in the HNRNPA1 gene (164017) on chromosome 12q13; ALS21 (606070) is caused by mutation in the MATR3 gene (164015) on chromosome 5q31; ALS22 (616208) is caused by mutation in the TUBA4A gene (191110) on chromosome 2q35; ALS23 (617839) is caused by mutation in the ANXA11 gene (602572) on chromosome 10q23; ALS26 (619133) is caused by mutation in the TIA1 gene (603518) on chromosome 2p13; ALS27 (620285) is caused by mutation in the SPTLC1 gene (605712) on chromosome 9q22; and ALS28 (620452) is caused by mutation in the LRP12 gene (618299) on chromosome 8q22. Loci associated with ALS have been found on chromosomes 18q21 (ALS3; 606640) and 20p13 (ALS7; 608031). Intermediate-length polyglutamine repeat expansions in the ATXN2 gene (601517) contribute to susceptibility to ALS (ALS13; 183090). Susceptibility to ALS24 (617892) is conferred by mutation in the NEK1 gene (604588) on chromosome 4q33, and susceptibility to ALS25 (617921) is conferred by mutation in the KIF5A gene (602821) on chromosome 12q13. Susceptibility to ALS has been associated with mutations in other genes, including deletions or insertions in the gene encoding the heavy neurofilament subunit (NEFH; 162230); deletions in the gene encoding peripherin (PRPH; 170710); and mutations in the dynactin gene (DCTN1; 601143). Some forms of ALS show juvenile onset. See juvenile-onset ALS2 (205100), caused by mutation in the alsin (606352) gene on 2q33; ALS4 (602433), caused by mutation in the senataxin gene (SETX; 608465) on 9q34; ALS5 (602099), caused by mutation in the SPG11 gene (610844) on 15q21; and ALS16 (614373), caused by mutation in the SIGMAR1 gene (601978) on 9p13.
Amyotrophic lateral sclerosis type 4
MedGen UID:
355983
Concept ID:
C1865409
Disease or Syndrome
Juvenile amyotrophic lateral sclerosis-4 (ALS4) is an autosomal dominant disorder characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs, with onset of symptoms before the age of 25 years, a slow rate of progression, and a normal life span (summary by Chen et al., 2004). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Amyotrophic lateral sclerosis type 5
MedGen UID:
356388
Concept ID:
C1865864
Disease or Syndrome
Autosomal recessive juvenile amyotrophic lateral sclerosis-5 (ALS5) is a neurodegenerative disorder characterized by onset of upper and lower motor neuron signs before age 25. Affected individuals have progressive spasticity of limb and facial muscles associated with distal amyotrophy. The disorder is slowly progressive, with cases of prolonged survival of more than 3 decades (summary by Orlacchio et al., 2010). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
Amyotrophic lateral sclerosis type 11
MedGen UID:
393399
Concept ID:
C2675491
Disease or Syndrome
An autosomal dominant form of amyotrophic lateral sclerosis caused by mutation(s) in the FIG4 gene, encoding polyphosphoinositide phosphatase.
Amyotrophic lateral sclerosis type 10
MedGen UID:
383137
Concept ID:
C2677565
Disease or Syndrome
A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. There is evidence this disease is caused by heterozygous mutation in the TARDBP gene that encodes the TDP43 protein on chromosome 1p36.
Amyotrophic lateral sclerosis type 9
MedGen UID:
395629
Concept ID:
C2678468
Disease or Syndrome
A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the angiogenin gene (ANG) on chromosome 14q11.
Amyotrophic lateral sclerosis type 6
MedGen UID:
419901
Concept ID:
C2931786
Disease or Syndrome
A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the FUS gene on chromosome 16p11.
Amyotrophic lateral sclerosis type 12
MedGen UID:
462042
Concept ID:
C3150692
Disease or Syndrome
Amyotrophic lateral sclerosis-12 with or without frontotemporal dementia (ALS12) is a neurodegenerative disorder characterized by onset of ALS in adulthood. Rare patients may also develop frontotemporal dementia (FTD). Autosomal dominant and autosomal recessive inheritance patterns have been reported; there is also sporadic occurrence (summary by Maruyama et al., 2010 and Feng et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Amyotrophic lateral sclerosis type 15
MedGen UID:
477090
Concept ID:
C3275459
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the UBQLN2 gene.
Amyotrophic lateral sclerosis type 16
MedGen UID:
482217
Concept ID:
C3280587
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the SIGMAR1 gene.
Amyotrophic lateral sclerosis type 18
MedGen UID:
766633
Concept ID:
C3553719
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the PFN1 gene.
Amyotrophic lateral sclerosis type 19
MedGen UID:
811607
Concept ID:
C3715155
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the ERBB4 gene.
Amyotrophic lateral sclerosis type 20
MedGen UID:
811608
Concept ID:
C3715156
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the HNRNPA1 gene.
Amyotrophic lateral sclerosis type 21
MedGen UID:
813851
Concept ID:
C3807521
Disease or Syndrome
Amyotrophic lateral sclerosis-21 (ALS21) is an autosomal dominant neurodegenerative disorder affecting upper and lower motor neurons, resulting in muscle weakness and respiratory failure. Some patients may develop myopathic features or dementia (summary by Johnson et al., 2014). For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Frontotemporal dementia and/or amyotrophic lateral sclerosis 1
MedGen UID:
854771
Concept ID:
C3888102
Disease or Syndrome
C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis (C9orf72-FTD/ALS) is characterized most often by frontotemporal dementia (FTD) and upper and lower motor neuron disease (MND); however, atypical presentations also occur. Age at onset is usually between 50 and 64 years (range: 20-91 years) irrespective of the presenting manifestations, which may be pure FTD, pure amyotrophic lateral sclerosis (ALS), or a combination of the two phenotypes. The clinical presentation is highly heterogeneous and may differ between and within families, causing an unpredictable pattern and age of onset of clinical manifestations. The presence of MND correlates with an earlier age of onset and a worse overall prognosis.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2
MedGen UID:
863085
Concept ID:
C4014648
Disease or Syndrome
CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include: Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance. Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons. Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs. Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia. Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities. Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder. Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.
Amyotrophic lateral sclerosis type 22
MedGen UID:
863949
Concept ID:
C4015512
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the TUBA4A gene.
Frontotemporal dementia and/or amyotrophic lateral sclerosis 4
MedGen UID:
902979
Concept ID:
C4225325
Disease or Syndrome
Frontotemporal dementia and/or amyotrophic lateral sclerosis-4 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. The phenotype is highly variable (summary by Freischmidt et al., 2015). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Frontotemporal dementia and/or amyotrophic lateral sclerosis 3
MedGen UID:
897127
Concept ID:
C4225326
Disease or Syndrome
Frontotemporal dementia and/or amyotrophic lateral sclerosis-3 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. Some patients may also develop Paget disease of bone. The phenotype is highly variable, even within families (summary by Rea et al., 2014). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Amyotrophic lateral sclerosis type 23
MedGen UID:
1645924
Concept ID:
C4693381
Disease or Syndrome
An autosomal dominant subtype of amyotrophic lateral sclerosis caused by mutation(s) in the ANXA11 gene, encoding annexin A11.
Amyotrophic lateral sclerosis, susceptibility to, 24
MedGen UID:
1632999
Concept ID:
C4693523
Finding
Amyotrophic lateral sclerosis-24 (ALS24) is a fatal neurodegenerative disease characterized by adult-onset loss of motor neurons (Brenner et al., 2016).
Amyotrophic lateral sclerosis, susceptibility to, 25
MedGen UID:
1633917
Concept ID:
C4693609
Finding
Amyotrophic lateral sclerosis is a neurodegenerative disorder clinically characterized by rapidly progressive muscle weakness and death due to respiratory failure. ALS25 may have a lower median age at onset (46.5 years) and longer median survival (10 years) than that found in epidemiologic studies (62.5 years and 20 to 30 months, respectively) (Nicolas et al., 2018).
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6
MedGen UID:
1759760
Concept ID:
C5436279
Disease or Syndrome
Frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6) is an autosomal dominant neurodegenerative disorder with highly variable manifestations. Some patients present in adulthood with progressive FTD, often classified as the 'behavioral variant,' which is characterized by reduced empathy, impulsive behavior, personality changes, and reduced verbal output. Other patients present with features of amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. The pathologic hallmarks of this disease include pallor of the corticospinal tract due to loss of motor neurons (in ALS). In both ALS and FTD, there are ubiquitin-positive inclusions within surviving neurons as well as deposition of pathologic TDP43 (TARDBP; 605078) or p62 (SQSTM1; 601530) aggregates. Patients with a D395G mutation (601023.0014) have been shown to develop pathologic tau (MAPT; 157140) aggregates. Some patients with the disorder may have features of both diseases, and there is significant interfamilial and intrafamilial phenotypic variability (summary by Johnson et al., 2010; Wong et al., 2018; Al-Obeidi et al., 2018; Darwich et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Frontotemporal dementia and/or amyotrophic lateral sclerosis 8
MedGen UID:
1728824
Concept ID:
C5436881
Disease or Syndrome
Frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8) is an autosomal dominant neurodegenerative disorder characterized by adult-onset dementia manifest as memory impairment, executive dysfunction, and behavioral or personality changes. Some patients may develop ALS or parkinsonism. Neuropathologic studies show frontotemporal lobar degeneration (FTLD) with tau (MAPT; 157140)- and TDP43 (605078)-immunoreactive inclusions (summary by Dobson-Stone et al., 2020). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Amyotrophic lateral sclerosis 26 with or without frontotemporal dementia
MedGen UID:
1771903
Concept ID:
C5436882
Disease or Syndrome
Amyotrophic lateral sclerosis-26 with or without frontotemporal dementia (ALS26) is an autosomal dominant neurodegenerative disorder characterized by adult onset of upper and low motor neuron disease causing bulbar dysfunction and limb weakness (ALS). Patients may also develop frontotemporal dementia (FTD) manifest as primary progressive aphasia, memory impairment, executive dysfunction, and behavioral or personality changes. Although patients may present with 1 or the other diseases, all eventually develop ALS. Neuropathologic studies of the brain and spinal cord show TDP43 (605078)-immunoreactive cytoplasmic inclusions that correlate with clinical features and Lewy body-like cytoplasmic inclusions in lower motor neurons (summary by Mackenzie et al., 2017). For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Frontotemporal dementia and/or amyotrophic lateral sclerosis 5
MedGen UID:
1756201
Concept ID:
C5436884
Disease or Syndrome
Frontotemporal dementia and/or amyotrophic lateral sclerosis-5 (FTDALS5) is an autosomal dominant neurodegenerative disorder characterized by onset of ALS or FTD symptoms in adulthood. The disease is progressive, and some patients may develop both diseases, although ALS seems to be more prevalent than FTD. The disorder usually results in premature death (summary by Williams et al., 2016). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

Professional guidelines

PubMed

Larson ST, Wilbur J
Am Fam Physician 2020 Jan 15;101(2):95-108. PMID: 31939642
Foster LA, Salajegheh MK
Am J Med 2019 Jan;132(1):32-37. Epub 2018 Aug 1 doi: 10.1016/j.amjmed.2018.07.012. PMID: 30075105
Burgos R, Bretón I, Cereda E, Desport JC, Dziewas R, Genton L, Gomes F, Jésus P, Leischker A, Muscaritoli M, Poulia KA, Preiser JC, Van der Marck M, Wirth R, Singer P, Bischoff SC
Clin Nutr 2018 Feb;37(1):354-396. Epub 2017 Sep 22 doi: 10.1016/j.clnu.2017.09.003. PMID: 29274834

Curated

Orphanet, Amyotrophic lateral sclerosis, 2007

Recent clinical studies

Etiology

Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G
Lancet 2022 Oct 15;400(10360):1363-1380. Epub 2022 Sep 15 doi: 10.1016/S0140-6736(22)01272-7. PMID: 36116464Free PMC Article
Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, Feldman EL
Lancet Neurol 2022 May;21(5):465-479. Epub 2022 Mar 22 doi: 10.1016/S1474-4422(21)00414-2. PMID: 35334234Free PMC Article
Ortega-Hombrados L, Molina-Torres G, Galán-Mercant A, Sánchez-Guerrero E, González-Sánchez M, Ruiz-Muñoz M
Int J Environ Res Public Health 2021 Jan 26;18(3) doi: 10.3390/ijerph18031074. PMID: 33530383Free PMC Article
Abati E, Bresolin N, Comi G, Corti S
Expert Opin Ther Targets 2020 Apr;24(4):295-310. Epub 2020 Mar 14 doi: 10.1080/14728222.2020.1738390. PMID: 32125907
Talbott EO, Malek AM, Lacomis D
Handb Clin Neurol 2016;138:225-38. doi: 10.1016/B978-0-12-802973-2.00013-6. PMID: 27637961

Diagnosis

Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G
Lancet 2022 Oct 15;400(10360):1363-1380. Epub 2022 Sep 15 doi: 10.1016/S0140-6736(22)01272-7. PMID: 36116464Free PMC Article
Hulisz D
Am J Manag Care 2018 Aug;24(15 Suppl):S320-S326. PMID: 30207670
Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH
Nat Rev Dis Primers 2017 Oct 5;3:17071. doi: 10.1038/nrdp.2017.71. PMID: 28980624
Talbott EO, Malek AM, Lacomis D
Handb Clin Neurol 2016;138:225-38. doi: 10.1016/B978-0-12-802973-2.00013-6. PMID: 27637961
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC
Lancet 2011 Mar 12;377(9769):942-55. Epub 2011 Feb 4 doi: 10.1016/S0140-6736(10)61156-7. PMID: 21296405

Therapy

Johnson SA, Fang T, De Marchi F, Neel D, Van Weehaeghe D, Berry JD, Paganoni S
Drugs 2022 Sep;82(13):1367-1388. Epub 2022 Sep 19 doi: 10.1007/s40265-022-01769-1. PMID: 36121612
Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME
N Engl J Med 2020 Sep 3;383(10):919-930. doi: 10.1056/NEJMoa1916945. PMID: 32877582Free PMC Article
Chiò A, Mazzini L, Mora G
Neuropharmacology 2020 May 1;167:107986. Epub 2020 Feb 3 doi: 10.1016/j.neuropharm.2020.107986. PMID: 32062193
Jaiswal MK
Med Res Rev 2019 Mar;39(2):733-748. Epub 2018 Aug 12 doi: 10.1002/med.21528. PMID: 30101496
Mazzini L, Vescovi A, Cantello R, Gelati M, Vercelli A
Expert Opin Biol Ther 2016;16(2):187-99. Epub 2016 Jan 9 doi: 10.1517/14712598.2016.1116516. PMID: 26558293

Prognosis

Brown CA, Lally C, Kupelian V, Flanders WD
Neuroepidemiology 2021;55(5):342-353. Epub 2021 Jul 9 doi: 10.1159/000516752. PMID: 34247168
Xu L, Liu T, Liu L, Yao X, Chen L, Fan D, Zhan S, Wang S
J Neurol 2020 Apr;267(4):944-953. Epub 2019 Dec 3 doi: 10.1007/s00415-019-09652-y. PMID: 31797084
Longinetti E, Fang F
Curr Opin Neurol 2019 Oct;32(5):771-776. doi: 10.1097/WCO.0000000000000730. PMID: 31361627Free PMC Article
Westeneng HJ, Debray TPA, Visser AE, van Eijk RPA, Rooney JPK, Calvo A, Martin S, McDermott CJ, Thompson AG, Pinto S, Kobeleva X, Rosenbohm A, Stubendorff B, Sommer H, Middelkoop BM, Dekker AM, van Vugt JJFA, van Rheenen W, Vajda A, Heverin M, Kazoka M, Hollinger H, Gromicho M, Körner S, Ringer TM, Rödiger A, Gunkel A, Shaw CE, Bredenoord AL, van Es MA, Corcia P, Couratier P, Weber M, Grosskreutz J, Ludolph AC, Petri S, de Carvalho M, Van Damme P, Talbot K, Turner MR, Shaw PJ, Al-Chalabi A, Chiò A, Hardiman O, Moons KGM, Veldink JH, van den Berg LH
Lancet Neurol 2018 May;17(5):423-433. Epub 2018 Mar 26 doi: 10.1016/S1474-4422(18)30089-9. PMID: 29598923
van Es MA, Hardiman O, Chio A, Al-Chalabi A, Pasterkamp RJ, Veldink JH, van den Berg LH
Lancet 2017 Nov 4;390(10107):2084-2098. Epub 2017 May 25 doi: 10.1016/S0140-6736(17)31287-4. PMID: 28552366

Clinical prediction guides

Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G
Lancet 2022 Oct 15;400(10360):1363-1380. Epub 2022 Sep 15 doi: 10.1016/S0140-6736(22)01272-7. PMID: 36116464Free PMC Article
Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, Feldman EL
Lancet Neurol 2022 May;21(5):480-493. Epub 2022 Mar 22 doi: 10.1016/S1474-4422(21)00465-8. PMID: 35334233Free PMC Article
Meng L, Li X, Li C, Tsang RCC, Chen Y, Ge Y, Gao Q
Am J Phys Med Rehabil 2020 Sep;99(9):801-810. doi: 10.1097/PHM.0000000000001419. PMID: 32452880
Matilla-Dueñas A, Corral-Juan M, Rodríguez-Palmero Seuma A, Vilas D, Ispierto L, Morais S, Sequeiros J, Alonso I, Volpini V, Serrano-Munuera C, Pintos-Morell G, Álvarez R, Sánchez I
Adv Exp Med Biol 2017;1031:443-496. doi: 10.1007/978-3-319-67144-4_25. PMID: 29214587
Hardiman O, van den Berg LH, Kiernan MC
Nat Rev Neurol 2011 Oct 11;7(11):639-49. doi: 10.1038/nrneurol.2011.153. PMID: 21989247

Recent systematic reviews

Ortega-Hombrados L, Molina-Torres G, Galán-Mercant A, Sánchez-Guerrero E, González-Sánchez M, Ruiz-Muñoz M
Int J Environ Res Public Health 2021 Jan 26;18(3) doi: 10.3390/ijerph18031074. PMID: 33530383Free PMC Article
Bianchi VE, Herrera PF, Laura R
Nutr Neurosci 2021 Oct;24(10):810-834. Epub 2019 Nov 4 doi: 10.1080/1028415X.2019.1681088. PMID: 31684843
Meng L, Li X, Li C, Tsang RCC, Chen Y, Ge Y, Gao Q
Am J Phys Med Rehabil 2020 Sep;99(9):801-810. doi: 10.1097/PHM.0000000000001419. PMID: 32452880
Gibbons C, Pagnini F, Friede T, Young CA
Cochrane Database Syst Rev 2018 Jan 2;1(1):CD011005. doi: 10.1002/14651858.CD011005.pub2. PMID: 29293261Free PMC Article
Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP
J Neurol Neurosurg Psychiatry 2017 Jul;88(7):540-549. Epub 2017 Jan 5 doi: 10.1136/jnnp-2016-315018. PMID: 28057713

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    Clinical resources

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