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Amyotrophic lateral sclerosis type 10(ALS10)

MedGen UID:
383137
Concept ID:
C2677565
Disease or Syndrome
Synonyms: ALS10; AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS; AMYOTROPHIC LATERAL SCLEROSIS 10 WITHOUT FRONTOTEMPORAL DEMENTIA AND WITH TDP43 INCLUSIONS; TARDBP-Related Amyotrophic Lateral Sclerosis
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
Autosomal dominant inheritance refers to genetic conditions that occur when a mutation is present in one copy of a given gene (i.e., the person is heterozygous).
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): TARDBP (1p36.22)
OMIM®: 612069

Definition

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. [from GeneReviews]

Additional description

From GHR
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.  https://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis

Clinical features

Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
If you have a swallowing disorder, you may have difficulty or pain when swallowing. Some people cannot swallow at all. Others may have trouble swallowing liquids, foods, or saliva. This makes it hard to eat. Often, it can be difficult to take in enough calories and fluids to nourish your body. Anyone can have a swallowing disorder, but it is more likely in the elderly. It often happens because of other conditions, including. - Nervous system disorders, such as Parkinson's disease and cerebral palsy. - Problems with your esophagus, including GERD (gastroesophageal reflux disease). - Stroke. - Head or spinal cord injury. - Cancer of the head, neck, or esophagus. Medicines can help some people, while others may need surgery. Swallowing treatment with a speech-language pathologist can help. You may find it helpful to change your diet or hold your head or neck in a certain way when you eat. In very serious cases, people may need feeding tubes. NIH: National Institute on Deafness and Other Communication Disorders.
Amyotrophic lateral sclerosis
MedGen UID:
274
Concept ID:
C0002736
Disease or Syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
If you have a swallowing disorder, you may have difficulty or pain when swallowing. Some people cannot swallow at all. Others may have trouble swallowing liquids, foods, or saliva. This makes it hard to eat. Often, it can be difficult to take in enough calories and fluids to nourish your body. Anyone can have a swallowing disorder, but it is more likely in the elderly. It often happens because of other conditions, including. - Nervous system disorders, such as Parkinson's disease and cerebral palsy. - Problems with your esophagus, including GERD (gastroesophageal reflux disease). - Stroke. - Head or spinal cord injury. - Cancer of the head, neck, or esophagus. Medicines can help some people, while others may need surgery. Swallowing treatment with a speech-language pathologist can help. You may find it helpful to change your diet or hold your head or neck in a certain way when you eat. In very serious cases, people may need feeding tubes. NIH: National Institute on Deafness and Other Communication Disorders.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Stereotyped routines
MedGen UID:
21318
Concept ID:
C0038271
Mental or Behavioral Dysfunction
A stereotypy is a repetitive, simple movement that can be voluntarily suppressed. Stereotypies are typically simple back-and-forth movements such as waving of flapping the hands or arms, and they do not involve complex sequences or movement fragments. Movement is often but not always rhythmic and may involve fingers, wrists, or more proximal portions of the upper extremity. The lower extremity is not typically involved. Stereotypies are more commonly bilateral than unilateral.
Apathy
MedGen UID:
39083
Concept ID:
C0085632
Mental or Behavioral Dysfunction
An emotional state of indifference characterized by a lack of interest or concern.
Mood swings
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
An exaggeration of emotional affects such as laughing crying, or yawning beyond what the person feels.
Perseveration
MedGen UID:
66686
Concept ID:
C0233651
Mental or Behavioral Dysfunction
Repeats of words that have been previously mentioned on the same trial.
Disinhibition
MedGen UID:
140859
Concept ID:
C0424296
Mental or Behavioral Dysfunction
A lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Skeletal muscle atrophy
MedGen UID:
902598
Concept ID:
C0234958
Disease or Syndrome
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding

Recent clinical studies

Etiology

Vázquez-Costa JF, Máñez I, Alabajos A, Guevara Salazar M, Roda C, Sevilla T
J Neurol 2016 Oct;263(10):1954-60. Epub 2016 Jul 6 doi: 10.1007/s00415-016-8223-z. PMID: 27383643
Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Ikegawa S, Kubo M, Yokoi D, Watanabe H, Ito M, Katsuno M, Izumi Y, Morita M, Kanai K, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Kawata A, Aoki M, Tsuji S, Nakashima K, Kaji R, Sobue G
J Neurol Neurosurg Psychiatry 2016 Aug;87(8):851-8. Epub 2016 Jan 8 doi: 10.1136/jnnp-2015-311541. PMID: 26746183
Di L, Chen H, Da Y, Wang S, Shen XM
J Neurol 2016 Feb;263(2):263-8. Epub 2015 Nov 14 doi: 10.1007/s00415-015-7965-3. PMID: 26566915
Rechtman L, Jordan H, Wagner L, Horton DK, Kaye W
Amyotroph Lateral Scler Frontotemporal Degener 2015 Mar;16(1-2):65-71. Epub 2014 Dec 8 doi: 10.3109/21678421.2014.971813. PMID: 25482100Free PMC Article
Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, Murru MR, Marrosu MG, Marrosu F, Marinou K, Mandrioli J, Sola P, Caponnetto C, Mancardi G, Mandich P, La Bella V, Spataro R, Conte A, Monsurrò MR, Tedeschi G, Pisano F, Bartolomei I, Salvi F, Lauria Pinter G, Simone I, Logroscino G, Gambardella A, Quattrone A, Lunetta C, Volanti P, Zollino M, Penco S, Battistini S; ITALSGEN consortium., Renton AE, Majounie E, Abramzon Y, Conforti FL, Giannini F, Corbo M, Sabatelli M
Brain 2012 Mar;135(Pt 3):784-93. doi: 10.1093/brain/awr366. PMID: 22366794Free PMC Article

Diagnosis

Artemiadis AK, Peppas C, Giannopoulos S, Zouvelou V, Triantafyllou N
J Clin Neuromuscul Dis 2016 Jun;17(4):220-2. doi: 10.1097/CND.0000000000000107. PMID: 27224438
Kaji S, Kawarai T, Miyamoto R, Nodera H, Pedace L, Orlacchio A, Izumi Y, Takahashi R, Kaji R
J Neurol Sci 2016 May 15;364:45-9. Epub 2016 Mar 2 doi: 10.1016/j.jns.2016.03.001. PMID: 27084214
Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Ikegawa S, Kubo M, Yokoi D, Watanabe H, Ito M, Katsuno M, Izumi Y, Morita M, Kanai K, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Kawata A, Aoki M, Tsuji S, Nakashima K, Kaji R, Sobue G
J Neurol Neurosurg Psychiatry 2016 Aug;87(8):851-8. Epub 2016 Jan 8 doi: 10.1136/jnnp-2015-311541. PMID: 26746183
DeLoach A, Cozart M, Kiaei A, Kiaei M
Expert Opin Drug Discov 2015 Oct;10(10):1099-118. Epub 2015 Aug 26 doi: 10.1517/17460441.2015.1067197. PMID: 26307158
Rechtman L, Jordan H, Wagner L, Horton DK, Kaye W
Amyotroph Lateral Scler Frontotemporal Degener 2015 Mar;16(1-2):65-71. Epub 2014 Dec 8 doi: 10.3109/21678421.2014.971813. PMID: 25482100Free PMC Article

Therapy

Vázquez-Costa JF, Máñez I, Alabajos A, Guevara Salazar M, Roda C, Sevilla T
J Neurol 2016 Oct;263(10):1954-60. Epub 2016 Jul 6 doi: 10.1007/s00415-016-8223-z. PMID: 27383643
Fang F, Hållmarker U, James S, Ingre C, Michaëlsson K, Ahlbom A, Feychting M
Eur J Epidemiol 2016 Mar;31(3):247-53. Epub 2015 Jul 29 doi: 10.1007/s10654-015-0077-7. PMID: 26220522
DeLoach A, Cozart M, Kiaei A, Kiaei M
Expert Opin Drug Discov 2015 Oct;10(10):1099-118. Epub 2015 Aug 26 doi: 10.1517/17460441.2015.1067197. PMID: 26307158
Evans MC, Gaillard PJ, de Boer M, Appeldoorn C, Dorland R, Sibson NR, Turner MR, Anthony DC, Stolp HB
Acta Neuropathol Commun 2014 Jun 13;2:66. doi: 10.1186/2051-5960-2-66. PMID: 24923195Free PMC Article
Fang F, Kwee LC, Allen KD, Umbach DM, Ye W, Watson M, Keller J, Oddone EZ, Sandler DP, Schmidt S, Kamel F
Am J Epidemiol 2010 May 15;171(10):1126-33. Epub 2010 Apr 20 doi: 10.1093/aje/kwq063. PMID: 20406759Free PMC Article

Prognosis

Krebs BB, De Mesquita JF
PLoS One 2016;11(7):e0158939. Epub 2016 Jul 14 doi: 10.1371/journal.pone.0158939. PMID: 27414033Free PMC Article
Vázquez-Costa JF, Máñez I, Alabajos A, Guevara Salazar M, Roda C, Sevilla T
J Neurol 2016 Oct;263(10):1954-60. Epub 2016 Jul 6 doi: 10.1007/s00415-016-8223-z. PMID: 27383643
Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Ikegawa S, Kubo M, Yokoi D, Watanabe H, Ito M, Katsuno M, Izumi Y, Morita M, Kanai K, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Kawata A, Aoki M, Tsuji S, Nakashima K, Kaji R, Sobue G
J Neurol Neurosurg Psychiatry 2016 Aug;87(8):851-8. Epub 2016 Jan 8 doi: 10.1136/jnnp-2015-311541. PMID: 26746183
DeLoach A, Cozart M, Kiaei A, Kiaei M
Expert Opin Drug Discov 2015 Oct;10(10):1099-118. Epub 2015 Aug 26 doi: 10.1517/17460441.2015.1067197. PMID: 26307158
Rechtman L, Jordan H, Wagner L, Horton DK, Kaye W
Amyotroph Lateral Scler Frontotemporal Degener 2015 Mar;16(1-2):65-71. Epub 2014 Dec 8 doi: 10.3109/21678421.2014.971813. PMID: 25482100Free PMC Article

Clinical prediction guides

Krebs BB, De Mesquita JF
PLoS One 2016;11(7):e0158939. Epub 2016 Jul 14 doi: 10.1371/journal.pone.0158939. PMID: 27414033Free PMC Article
Watanabe H, Atsuta N, Hirakawa A, Nakamura R, Nakatochi M, Ishigaki S, Iida A, Ikegawa S, Kubo M, Yokoi D, Watanabe H, Ito M, Katsuno M, Izumi Y, Morita M, Kanai K, Taniguchi A, Aiba I, Abe K, Mizoguchi K, Oda M, Kano O, Okamoto K, Kuwabara S, Hasegawa K, Imai T, Kawata A, Aoki M, Tsuji S, Nakashima K, Kaji R, Sobue G
J Neurol Neurosurg Psychiatry 2016 Aug;87(8):851-8. Epub 2016 Jan 8 doi: 10.1136/jnnp-2015-311541. PMID: 26746183
Gorges M, Müller HP, Lulé D, Del Tredici K, Brettschneider J, Keller J, Pfandl K, Ludolph AC, Kassubek J, Pinkhardt EH
PLoS One 2015;10(11):e0142546. Epub 2015 Nov 11 doi: 10.1371/journal.pone.0142546. PMID: 26559944Free PMC Article
DeLoach A, Cozart M, Kiaei A, Kiaei M
Expert Opin Drug Discov 2015 Oct;10(10):1099-118. Epub 2015 Aug 26 doi: 10.1517/17460441.2015.1067197. PMID: 26307158
Roudeau S, Chevreux S, Carmona A, Ortega R
Electrophoresis 2015 Oct;36(19):2482-8. Epub 2015 Aug 18 doi: 10.1002/elps.201500187. PMID: 26084641

Recent systematic reviews

Roet KC, Verhaagen J
Exp Neurol 2014 Nov;261:594-609. Epub 2014 May 17 doi: 10.1016/j.expneurol.2014.05.007. PMID: 24842489
Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, McLaughlin R, Hardiman O
J Neurol Neurosurg Psychiatry 2011 Jun;82(6):623-7. Epub 2010 Nov 3 doi: 10.1136/jnnp.2010.224501. PMID: 21047878
Chiò A, Logroscino G, Hardiman O, Swingler R, Mitchell D, Beghi E, Traynor BG; Eurals Consortium.
Amyotroph Lateral Scler 2009 Oct-Dec;10(5-6):310-23. doi: 10.3109/17482960802566824. PMID: 19922118Free PMC Article
Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG
Hepatology 2007 Oct;46(4):1071-80. doi: 10.1002/hep.21885. PMID: 17828789

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