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Amyotrophic lateral sclerosis type 4(ALS4)

MedGen UID:
355983
Concept ID:
C1865409
Disease or Syndrome
Synonyms: ALS4; Amyotrophic lateral sclerosis 4; AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE; NEURONOPATHY, DISTAL HEREDITARY MOTOR, WITH PYRAMIDAL FEATURES; SETX-Related Amyotrophic Lateral Sclerosis
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
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).
 
Gene (location): SETX (9q34.13)
OMIM®: 602433
Orphanet: ORPHA357043

Disease characteristics

Excerpted from the GeneReview: Amyotrophic Lateral Sclerosis Overview
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. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Definition  |  Causes  |  Evaluation Strategy  |  Genetic Counseling  |  Resources  |  Management  |  References  |  Chapter Notes
Authors:
Lisa Kinsley  |  Teepu Siddique   view full author information

Additional descriptions

From OMIM
Childhood- and adolescent-onset forms of familial ALS (see ALS1, 105400) carry the designation 'juvenile ALS.' Several forms of autosomal recessive juvenile ALS have been identified; see ALS2 (205100) and ALS5 (602099).  http://www.omim.org/entry/602433
From GHR
Amyotrophic lateral sclerosis (ALS) is a progressive disease that affects motor neurons, which are specialized nerve cells that are important for controlling muscle movement and strength. These nerve cells are found in the spinal cord and the brain. In ALS, motor neurons die over time, leading to problems with muscle control and 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 the condition. 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 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 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 wastes away (atrophies). Individuals with ALS lose their strength and the ability to walk. Affected individuals eventually become wheelchair-dependent. 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 a condition called frontotemporal dementia (FTD), which is a progressive brain disorder that affects personality, behavior, and language. Changes in personality and behavior may make it difficult for affected individuals to interact with others in a socially appropriate manner. People with FTD increasingly require help with personal care and other activities of daily living. 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.  http://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis

Clinical features

Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex found in normal infants consisting of dorsiflexion of the HALLUX and abduction of the other TOES in response to cutaneous stimulation of the plantar surface of the FOOT. In adults, it is used as a diagnostic criterion, and if present is a NEUROLOGIC MANIFESTATION of dysfunction in the CENTRAL NERVOUS SYSTEM.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
We walk thousands of steps each day. We walk to do our daily activities, get around, and exercise. Having a problem with walking can make daily life more difficult. . The pattern of how you walk is called your gait. A variety of problems can cause an abnormal gait and lead to problems with walking. These include: : -Injuries, diseases, or abnormal development of the muscles or bones of your legs or feet. -Movement disorders such as Parkinson's disease. -Diseases such as arthritis or multiple sclerosis. -Vision or balance problems. Treatment of walking problems depends on the cause. Physical therapy, surgery, or mobility aids may help.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Degeneration of anterior horn cells
MedGen UID:
340270
Concept ID:
C1854647
Finding
Pallor of dorsal columns of the spinal cord
MedGen UID:
355986
Concept ID:
C1865416
Finding
Diffuse axonal swelling
MedGen UID:
356274
Concept ID:
C1865417
Finding
Abnormal upper motor neuron morphology
MedGen UID:
446436
Concept ID:
CN001927
Finding
Any structural anomaly that affects the upper motor neuron.
Clonus
MedGen UID:
505137
Concept ID:
CN001966
Finding
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
Abnormal lower motor neuron morphology
MedGen UID:
505213
Concept ID:
CN002149
Finding
Any structural anomaly of the lower motor neuron.
Amyotrophic lateral sclerosis
MedGen UID:
506059
Concept ID:
CN006437
Finding
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
We walk thousands of steps each day. We walk to do our daily activities, get around, and exercise. Having a problem with walking can make daily life more difficult. . The pattern of how you walk is called your gait. A variety of problems can cause an abnormal gait and lead to problems with walking. These include: : -Injuries, diseases, or abnormal development of the muscles or bones of your legs or feet. -Movement disorders such as Parkinson's disease. -Diseases such as arthritis or multiple sclerosis. -Vision or balance problems. Treatment of walking problems depends on the cause. Physical therapy, surgery, or mobility aids may help.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Pes cavus
MedGen UID:
425071
Concept ID:
CN001601
Finding
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.

Recent clinical studies

Etiology

Neuenschwander AG, Thai KK, Figueroa KP, Pulst SM
JAMA Neurol 2014 Dec;71(12):1529-34. doi: 10.1001/jamaneurol.2014.2082. PMID: 25285812
Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, Baloh RH, Ravits J, Simpson E, Appel SH, Pestronk A, Goate AM, Miller TM, Cruchaga C, Harms MB
JAMA Neurol 2014 Apr;71(4):449-53. doi: 10.1001/jamaneurol.2013.6237. PMID: 24535663Free PMC Article
Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, Belzil VV, Dion PA, Higasa K, Doi K, Ishiura H, Mitsui J, Date H, Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T, Ikoma M, Hashimoto T, Kimura F, Murayama S, Onodera O, Nishizawa M, Yoshida M, Atsuta N, Sobue G; JaCALS, Fifita JA, Williams KL, Blair IP, Nicholson GA, Gonzalez-Perez P, Brown RH Jr, Nomoto M, Elenius K, Rouleau GA, Fujiyama A, Morishita S, Goto J, Tsuji S
Am J Hum Genet 2013 Nov 7;93(5):900-5. Epub 2013 Oct 10 doi: 10.1016/j.ajhg.2013.09.008. [Epub ahead of print] PMID: 24119685Free PMC Article
Kano O, Iwamoto K, Ito H, Kawase Y, Cridebring D, Ikeda K, Iwasaki Y
BMC Neurol 2013 Feb 9;13:19. doi: 10.1186/1471-2377-13-19. [Epub ahead of print] PMID: 23394455Free PMC Article
Farg MA, Soo KY, Warraich ST, Sundaramoorthy V, Blair IP, Atkin JD
Hum Mol Genet 2013 Feb 15;22(4):717-28. Epub 2012 Nov 19 doi: 10.1093/hmg/dds479. [Epub ahead of print] PMID: 23172909

Diagnosis

Quartuccio N, Van Weehaeghe D, Cistaro A, Jonsson C, Van Laere K, Pagani M
Q J Nucl Med Mol Imaging 2014 Dec;58(4):344-54. Epub 2014 Nov 6 [Epub ahead of print] PMID: 25375229
Al-Chalabi A, Calvo A, Chio A, Colville S, Ellis CM, Hardiman O, Heverin M, Howard RS, Huisman MH, Keren N, Leigh PN, Mazzini L, Mora G, Orrell RW, Rooney J, Scott KM, Scotton WJ, Seelen M, Shaw CE, Sidle KS, Swingler R, Tsuda M, Veldink JH, Visser AE, van den Berg LH, Pearce N
Lancet Neurol 2014 Nov;13(11):1108-13. Epub 2014 Oct 7 doi: 10.1016/S1474-4422(14)70219-4. [Epub ahead of print] PMID: 25300936Free PMC Article
Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P, Baloh RH, Ravits J, Simpson E, Appel SH, Pestronk A, Goate AM, Miller TM, Cruchaga C, Harms MB
JAMA Neurol 2014 Apr;71(4):449-53. doi: 10.1001/jamaneurol.2013.6237. PMID: 24535663Free PMC Article
Kano O, Iwamoto K, Ito H, Kawase Y, Cridebring D, Ikeda K, Iwasaki Y
BMC Neurol 2013 Feb 9;13:19. doi: 10.1186/1471-2377-13-19. [Epub ahead of print] PMID: 23394455Free PMC Article
Pupillo E, Messina P, Logroscino G, Zoccolella S, Chiò A, Calvo A, Corbo M, Lunetta C, Micheli A, Millul A, Vitelli E, Beghi E; EURALS Consortium
Eur J Neurol 2012 Dec;19(12):1509-17. Epub 2012 Apr 27 doi: 10.1111/j.1468-1331.2012.03723.x. [Epub ahead of print] PMID: 22537412

Therapy

Jawaid A, Paganoni S, Hauser C, Schulz PE
Neurodegener Dis 2014;13(4):205-8. Epub 2013 Oct 2 doi: 10.1159/000353158. [Epub ahead of print] PMID: 24107404Free PMC Article
Ashworth NL, Satkunam LE, Deforge D
Cochrane Database Syst Rev 2012 Feb 15;2:CD004156. doi: 10.1002/14651858.CD004156.pub4. PMID: 22336799
Fanos JH, Gronka S, Wuu J, Stanislaw C, Andersen PM, Benatar M
Genet Med 2011 Apr;13(4):342-8. doi: 10.1097/GIM.0b013e318204d004. PMID: 21285887Free PMC Article
Guidubaldi A, Fasano A, Ialongo T, Piano C, Pompili M, Mascianà R, Siciliani L, Sabatelli M, Bentivoglio AR
Mov Disord 2011 Feb 1;26(2):313-9. Epub 2011 Jan 21 doi: 10.1002/mds.23473. [Epub ahead of print] PMID: 21259343
Gilio F, Iacovelli E, Frasca V, Gabriele M, Giacomelli E, Picchiori F, Soldo P, Cipriani AM, Ruoppolo G, Inghilleri M
Amyotroph Lateral Scler 2010 Aug;11(4):359-63. doi: 10.3109/17482960903264998. PMID: 19929745

Prognosis

Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, Belzil VV, Dion PA, Higasa K, Doi K, Ishiura H, Mitsui J, Date H, Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T, Ikoma M, Hashimoto T, Kimura F, Murayama S, Onodera O, Nishizawa M, Yoshida M, Atsuta N, Sobue G; JaCALS, Fifita JA, Williams KL, Blair IP, Nicholson GA, Gonzalez-Perez P, Brown RH Jr, Nomoto M, Elenius K, Rouleau GA, Fujiyama A, Morishita S, Goto J, Tsuji S
Am J Hum Genet 2013 Nov 7;93(5):900-5. Epub 2013 Oct 10 doi: 10.1016/j.ajhg.2013.09.008. [Epub ahead of print] PMID: 24119685Free PMC Article
Pugliatti M, Parish LD, Cossu P, Leoni S, Ticca A, Saddi MV, Ortu E, Traccis S, Borghero G, Puddu R, Chiò A, Pirina P
J Neurol 2013 Feb;260(2):572-9. Epub 2012 Sep 30 doi: 10.1007/s00415-012-6681-5. [Epub ahead of print] PMID: 23052600
Chandrasoma B, Balfe D, Naik T, Elsayegh A, Lewis M, Mosenifar Z
Monaldi Arch Chest Dis 2012 Sep-Dec;77(3-4):129-33. PMID: 23461249
Blauw HM, van Rheenen W, Koppers M, Van Damme P, Waibel S, Lemmens R, van Vught PW, Meyer T, Schulte C, Gasser T, Cuppen E, Pasterkamp RJ, Robberecht W, Ludolph AC, Veldink JH, van den Berg LH
Hum Mol Genet 2012 Jun 1;21(11):2497-502. Epub 2012 Feb 28 doi: 10.1093/hmg/dds064. [Epub ahead of print] PMID: 22378146
Park JH, Kang SW, Won JY, Uhm CW
JPEN J Parenter Enteral Nutr 2010 Jul-Aug;34(4):421-5. doi: 10.1177/0148607110362528. PMID: 20631388

Clinical prediction guides

Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, Belzil VV, Dion PA, Higasa K, Doi K, Ishiura H, Mitsui J, Date H, Ahsan B, Matsukawa T, Ichikawa Y, Moritoyo T, Ikoma M, Hashimoto T, Kimura F, Murayama S, Onodera O, Nishizawa M, Yoshida M, Atsuta N, Sobue G; JaCALS, Fifita JA, Williams KL, Blair IP, Nicholson GA, Gonzalez-Perez P, Brown RH Jr, Nomoto M, Elenius K, Rouleau GA, Fujiyama A, Morishita S, Goto J, Tsuji S
Am J Hum Genet 2013 Nov 7;93(5):900-5. Epub 2013 Oct 10 doi: 10.1016/j.ajhg.2013.09.008. [Epub ahead of print] PMID: 24119685Free PMC Article
Akamatsu M, Takuma H, Yamashita T, Okada T, Keino-Masu K, Ishii K, Kwak S, Masu M, Tamaoka A
Neurosci Res 2013 Dec;77(4):234-41. Epub 2013 Sep 27 doi: 10.1016/j.neures.2013.09.009. [Epub ahead of print] PMID: 24080146
Kano O, Iwamoto K, Ito H, Kawase Y, Cridebring D, Ikeda K, Iwasaki Y
BMC Neurol 2013 Feb 9;13:19. doi: 10.1186/1471-2377-13-19. [Epub ahead of print] PMID: 23394455Free PMC Article
Dobson-Stone C, Luty AA, Thompson EM, Blumbergs P, Brooks WS, Short CL, Field CD, Panegyres PK, Hecker J, Solski JA, Blair IP, Fullerton JM, Halliday GM, Schofield PR, Kwok JB
Acta Neuropathol 2013 Apr;125(4):523-33. Epub 2013 Jan 22 doi: 10.1007/s00401-013-1078-9. [Epub ahead of print] PMID: 23338750Free PMC Article
Beers DR, Henkel JS, Zhao W, Wang J, Huang A, Wen S, Liao B, Appel SH
Brain 2011 May;134(Pt 5):1293-314. doi: 10.1093/brain/awr074. PMID: 21596768Free PMC Article

Recent systematic reviews

Neuenschwander AG, Thai KK, Figueroa KP, Pulst SM
JAMA Neurol 2014 Dec;71(12):1529-34. doi: 10.1001/jamaneurol.2014.2082. PMID: 25285812
Hamidou B, Couratier P, Besançon C, Nicol M, Preux PM, Marin B
Eur J Epidemiol 2014 Jul;29(7):459-75. Epub 2014 Jul 2 doi: 10.1007/s10654-014-9923-2. [Epub ahead of print] PMID: 24986107
Ashworth NL, Satkunam LE, Deforge D
Cochrane Database Syst Rev 2012 Feb 15;2:CD004156. doi: 10.1002/14651858.CD004156.pub4. PMID: 22336799
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. [Epub ahead of print] PMID: 21047878
Ng L, Khan F, Mathers S
Cochrane Database Syst Rev 2009 Oct 7;(4):CD007425. doi: 10.1002/14651858.CD007425.pub2. PMID: 19821416

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