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Amyotrophic lateral sclerosis(ALS)

MedGen UID:
274
Concept ID:
C0002736
Disease or Syndrome
Synonyms: ALS; Charcot disease; Lou Gehrig disease; Lou gehrig's disease
SNOMED CT: Amyotrophic lateral sclerosis (86044005); Bulbar motor neuron disease (86044005); Lou Gehrig's disease (86044005); ALS - Amyotrophic lateral sclerosis (86044005)
 
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
OMIM® Phenotypic series: PS105400
Orphanet: ORPHA803

Definition

A neurodegenerative disease characterized by progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. [from ORDO]

Additional descriptions

From MedlinePlus Genetics
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.\n\nThere 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.\n\nThe 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.\n\nA 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.\n\nApproximately 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.  https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis
From MedlinePlus Genetics
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.\n\nThere 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.\n\nThe 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.\n\nApproximately 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.\n\nA 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.  https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis

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
An autosomal dominant form of amyotrophic lateral sclerosis caused by mutation(s) in the VAPB gene, encoding vesicle-associated membrane protein-associated protein B/C.
Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia
MedGen UID:
374989
Concept ID:
C1842675
Disease or Syndrome
A form of amyotrophic lateral sclerosis caused by heterozygous mutation(s) in the FUS gene, encoding RNA-binding protein FUS.
Amyotrophic lateral sclerosis with polyglucosan bodies
MedGen UID:
347953
Concept ID:
C1859805
Disease or Syndrome
Amyotrophic lateral sclerosis, juvenile, 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 neurodegenerastaion. 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; and ALS26 (619133) is caused by mutation in the TIA1 gene (603518) on chromosome 2p13. 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 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
TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is characterized by upper motor neuron (UMN) and lower motor neuron (LMN) disease that appears indistinguishable from ALS of other known and unknown causes based on gender ratio, age of onset, symptom distribution, and severity of disease. The male-to-female ratio is 1.6 to 1. Mean age of onset is 54 ± 12 years. UMN manifestations can include stiffness, spasticity, hyperreflexia, and pseudobulbar affect; LMN manifestations often include weakness accompanied by muscle atrophy, fasciculations, and cramping. Limb onset occurs in 80% and bulbar onset in 20%. Affected individuals typically succumb to respiratory failure when phrenic and thoracic motor neurons become severely involved.
Amyotrophic lateral sclerosis type 9
MedGen UID:
395629
Concept ID:
C2678468
Disease or Syndrome
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 15, with or without frontotemporal dementia
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 16, juvenile
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 18
MedGen UID:
766633
Concept ID:
C3553719
Disease or Syndrome
Amyotrophic lateral sclerosis 19
MedGen UID:
811607
Concept ID:
C3715155
Disease or Syndrome
Amyotrophic lateral sclerosis 20
MedGen UID:
811608
Concept ID:
C3715156
Disease or Syndrome
Amyotrophic lateral sclerosis 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).
Amyotrophic lateral sclerosis and/or frontotemporal dementia 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 22 with or without frontotemporal dementia
MedGen UID:
863949
Concept ID:
C4015512
Disease or Syndrome
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).
Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1
MedGen UID:
1641069
Concept ID:
C4551951
Disease or Syndrome
Inclusion body myopathy associated with Paget disease of bone (PDB) and/or frontotemporal dementia (IBMPFD) is characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset PDB, and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occur on occasion. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, and paraphasic errors, with minimal impairment of episodic memory; later stages are characterized by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 56 years. Dilated cardiomyopathy, amyotrophic lateral sclerosis, and Parkinson disease are now known to be part of the spectrum of findings associated with IBMPFD.
Amyotrophic lateral sclerosis type 23
MedGen UID:
1645924
Concept ID:
C4693381
Disease or Syndrome
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).
Amyotrophic lateral sclerosis 14, with or without frontotemporal dementia
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

EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis:., Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chio A, Van Damme P, Hardiman O, Kollewe K, Morrison KE, Petri S, Pradat PF, Silani V, Tomik B, Wasner M, Weber M
Eur J Neurol 2012 Mar;19(3):360-75. Epub 2011 Sep 14 doi: 10.1111/j.1468-1331.2011.03501.x. PMID: 21914052

External

Orphanet, Amyotrophic lateral sclerosis, 2007

Recent clinical studies

Etiology

Bueno APA, de Souza LC, Pinaya WHL, Teixeira AL, de Prado LGR, Caramelli P, Hornberger M, Sato JR
Brain Imaging Behav 2021 Apr;15(2):996-1006. doi: 10.1007/s11682-020-00307-5. PMID: 32734436
Zhang QQ, Jiang H, Li CY, Liu YL, Tian XY
J Integr Neurosci 2020 Sep 30;19(3):495-499. doi: 10.31083/j.jin.2020.03.131. PMID: 33070529
Kornitzer J, Abdulrazeq HF, Zaidi M, Bach JR, Kazi A, Feinstein E, Sander HW, Souayah N
Am J Phys Med Rehabil 2020 Oct;99(10):895-901. doi: 10.1097/PHM.0000000000001438. PMID: 32251109
Guo W, Vandoorne T, Steyaert J, Staats KA, Van Den Bosch L
Brain 2020 Jun 1;143(6):1651-1673. doi: 10.1093/brain/awaa022. PMID: 32206784Free PMC Article
Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M
J Neurol 2019 Dec;266(12):2952-2961. Epub 2019 Aug 27 doi: 10.1007/s00415-019-09507-6. PMID: 31456060

Diagnosis

Sarraf P, Bitarafan S, Nafissi S, Fathi D, Abaj F, Asl Motallebnejad Z, Teimouri R, Vahedi K
J Clin Neurosci 2021 Jul;89:232-236. Epub 2021 May 13 doi: 10.1016/j.jocn.2021.05.017. PMID: 34119273
Lisiecka D, Kelly H, Jackson J
Palliat Med 2020 Sep;34(8):1097-1107. Epub 2020 Jun 17 doi: 10.1177/0269216320932754. PMID: 32552499
Kornitzer J, Abdulrazeq HF, Zaidi M, Bach JR, Kazi A, Feinstein E, Sander HW, Souayah N
Am J Phys Med Rehabil 2020 Oct;99(10):895-901. doi: 10.1097/PHM.0000000000001438. PMID: 32251109
Ingre C, Chen L, Zhan Y, Termorshuizen J, Yin L, Fang F
Neurology 2020 Apr 28;94(17):e1835-e1844. Epub 2020 Mar 27 doi: 10.1212/WNL.0000000000009322. PMID: 32221024Free PMC Article
Sako W, Abe T, Izumi Y, Harada M, Kaji R
Clin Neurol Neurosurg 2019 Jun;181:73-75. Epub 2019 Apr 15 doi: 10.1016/j.clineuro.2019.04.015. PMID: 31009854

Therapy

Zhang QQ, Jiang H, Li CY, Liu YL, Tian XY
J Integr Neurosci 2020 Sep 30;19(3):495-499. doi: 10.31083/j.jin.2020.03.131. PMID: 33070529
Barczewska M, Maksymowicz S, Zdolińska-Malinowska I, Siwek T, Grudniak M
Stem Cell Rev Rep 2020 Oct;16(5):922-932. doi: 10.1007/s12015-020-10016-7. PMID: 32725316Free PMC Article
Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Kirby J, Suehs C, Saker S, Masseguin C, De Vos J, Zetterberg H, Shaw PJ, Al-Chalabi A, Leigh PN, Tree T, Bensimon G
EBioMedicine 2020 Sep;59:102844. Epub 2020 Jul 7 doi: 10.1016/j.ebiom.2020.102844. PMID: 32651161Free PMC Article
Vergonjeanne M, Fayemendy P, Marin B, Penoty M, Lautrette G, Sourisseau H, Preux PM, Desport JC, Couratier P, Jésus P
Clin Nutr 2020 Oct;39(10):3112-3118. Epub 2020 Jan 31 doi: 10.1016/j.clnu.2020.01.018. PMID: 32063408
Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M
J Neurol 2019 Dec;266(12):2952-2961. Epub 2019 Aug 27 doi: 10.1007/s00415-019-09507-6. PMID: 31456060

Prognosis

Ferri L, Ajdinaj P, Rispoli MG, Carrarini C, Barbone F, D'Ardes D, Capasso M, Muzio AD, Cipollone F, Onofrj M, Bonanni L
Biomolecules 2021 Jun 10;11(6) doi: 10.3390/biom11060867. PMID: 34200812Free PMC Article
Kornitzer J, Abdulrazeq HF, Zaidi M, Bach JR, Kazi A, Feinstein E, Sander HW, Souayah N
Am J Phys Med Rehabil 2020 Oct;99(10):895-901. doi: 10.1097/PHM.0000000000001438. PMID: 32251109
Ingre C, Chen L, Zhan Y, Termorshuizen J, Yin L, Fang F
Neurology 2020 Apr 28;94(17):e1835-e1844. Epub 2020 Mar 27 doi: 10.1212/WNL.0000000000009322. PMID: 32221024Free PMC Article
Chiaramonte R, Bonfiglio M
Logoped Phoniatr Vocol 2020 Dec;45(4):151-163. Epub 2019 Nov 25 doi: 10.1080/14015439.2019.1687748. PMID: 31760837
Sako W, Abe T, Izumi Y, Harada M, Kaji R
Clin Neurol Neurosurg 2019 Jun;181:73-75. Epub 2019 Apr 15 doi: 10.1016/j.clineuro.2019.04.015. PMID: 31009854

Clinical prediction guides

Sarraf P, Bitarafan S, Nafissi S, Fathi D, Abaj F, Asl Motallebnejad Z, Teimouri R, Vahedi K
J Clin Neurosci 2021 Jul;89:232-236. Epub 2021 May 13 doi: 10.1016/j.jocn.2021.05.017. PMID: 34119273
Lisiecka D, Kelly H, Jackson J
Palliat Med 2020 Sep;34(8):1097-1107. Epub 2020 Jun 17 doi: 10.1177/0269216320932754. PMID: 32552499
Violi F, Solovyev N, Vinceti M, Mandrioli J, Lucio M, Michalke B
Metallomics 2020 May 27;12(5):668-681. doi: 10.1039/d0mt00051e. PMID: 32373852
Kornitzer J, Abdulrazeq HF, Zaidi M, Bach JR, Kazi A, Feinstein E, Sander HW, Souayah N
Am J Phys Med Rehabil 2020 Oct;99(10):895-901. doi: 10.1097/PHM.0000000000001438. PMID: 32251109
Ingre C, Chen L, Zhan Y, Termorshuizen J, Yin L, Fang F
Neurology 2020 Apr 28;94(17):e1835-e1844. Epub 2020 Mar 27 doi: 10.1212/WNL.0000000000009322. PMID: 32221024Free PMC Article

Recent systematic reviews

Ferri L, Ajdinaj P, Rispoli MG, Carrarini C, Barbone F, D'Ardes D, Capasso M, Muzio AD, Cipollone F, Onofrj M, Bonanni L
Biomolecules 2021 Jun 10;11(6) doi: 10.3390/biom11060867. PMID: 34200812Free 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
McKay KA, Smith KA, Smertinaite L, Fang F, Ingre C, Taube F
Acta Neurol Scand 2021 Jan;143(1):39-50. Epub 2020 Oct 12 doi: 10.1111/ane.13345. PMID: 32905613Free PMC Article
Chiaramonte R, Bonfiglio M
Logoped Phoniatr Vocol 2020 Dec;45(4):151-163. Epub 2019 Nov 25 doi: 10.1080/14015439.2019.1687748. PMID: 31760837
Luo L, Song Z, Li X, Huiwang, Zeng Y, Qinwang, Meiqi, He J
Neurol Sci 2019 Feb;40(2):235-241. Epub 2018 Nov 27 doi: 10.1007/s10072-018-3653-2. PMID: 30483992

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