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Amyotrophic lateral sclerosis type 5(ALS5)

MedGen UID:
356388
Concept ID:
C1865864
Disease or Syndrome
Synonyms: ALS5; AMYOTROPHIC LATERAL SCLEROSIS 5, JUVENILE
 
Gene (location): SPG11 (15q21.1)
 
Monarch Initiative: MONDO:0011196
OMIM®: 602099

Definition

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). [from OMIM]

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Amyotrophic lateral sclerosis
MedGen UID:
274
Concept ID:
C0002736
Disease or Syndrome
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.
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.
Fasciculations
MedGen UID:
5124
Concept ID:
C0015644
Sign or Symptom
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Bulbar signs
MedGen UID:
347246
Concept ID:
C1856507
Finding
Abnormal lower motor neuron morphology
MedGen UID:
356272
Concept ID:
C1865412
Finding
Any structural anomaly of the lower motor neuron.
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding

Professional guidelines

PubMed

James E, Ellis C, Brassington R, Sathasivam S, Young CA
Cochrane Database Syst Rev 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3. PMID: 35593746Free PMC Article
Wadman RI, van der Pol WL, Bosboom WM, Asselman FL, van den Berg LH, Iannaccone ST, Vrancken AF
Cochrane Database Syst Rev 2020 Jan 6;1(1):CD006282. doi: 10.1002/14651858.CD006282.pub5. PMID: 32006461Free PMC Article
Holecek V, Rokyta R
Neuro Endocrinol Lett 2018 Feb;38(8):528-531. PMID: 29504729

Curated

Orphanet, Amyotrophic lateral sclerosis, 2007

Recent clinical studies

Etiology

Brenner D, Freischmidt A
Curr Opin Neurol 2022 Oct 1;35(5):672-677. Epub 2022 Aug 8 doi: 10.1097/WCO.0000000000001093. PMID: 35942673
James E, Ellis C, Brassington R, Sathasivam S, Young CA
Cochrane Database Syst Rev 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3. PMID: 35593746Free PMC Article
Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, Żekanowski C, Kuźma-Kozakiewicz M
Sci Rep 2022 Jan 7;12(1):103. doi: 10.1038/s41598-021-03891-8. PMID: 34996976Free PMC Article
Zucchi E, Vinceti M, Malagoli C, Fini N, Gessani A, Fasano A, Rizzi R, Sette E, Cavazza S, Fiocchi A, Buja S, Faccioli T, Storani S, Mandrioli J
Ann Clin Transl Neurol 2019 May;6(5):893-901. Epub 2019 Mar 18 doi: 10.1002/acn3.765. PMID: 31139687Free PMC Article
Salminen A, Kaarniranta K, Kauppinen A, Ojala J, Haapasalo A, Soininen H, Hiltunen M
Prog Neurobiol 2013 Jul-Aug;106-107:33-54. Epub 2013 Jul 1 doi: 10.1016/j.pneurobio.2013.06.002. PMID: 23827971

Diagnosis

Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, Żekanowski C, Kuźma-Kozakiewicz M
Sci Rep 2022 Jan 7;12(1):103. doi: 10.1038/s41598-021-03891-8. PMID: 34996976Free PMC Article
Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H
Autophagy 2022 Mar;18(3):496-517. Epub 2021 Aug 19 doi: 10.1080/15548627.2021.1943177. PMID: 34130600Free PMC Article
GBD 2017 US Neurological Disorders Collaborators, Feigin VL, Vos T, Alahdab F, Amit AML, Bärnighausen TW, Beghi E, Beheshti M, Chavan PP, Criqui MH, Desai R, Dhamminda Dharmaratne S, Dorsey ER, Wilder Eagan A, Elgendy IY, Filip I, Giampaoli S, Giussani G, Hafezi-Nejad N, Hole MK, Ikeda T, Owens Johnson C, Kalani R, Khatab K, Khubchandani J, Kim D, Koroshetz WJ, Krishnamoorthy V, Krishnamurthi RV, Liu X, Lo WD, Logroscino G, Mensah GA, Miller TR, Mohammed S, Mokdad AH, Moradi-Lakeh M, Morrison SD, Shivamurthy VKN, Naghavi M, Nichols E, Norrving B, Odell CM, Pupillo E, Radfar A, Roth GA, Shafieesabet A, Sheikh A, Sheikhbahaei S, Shin JI, Singh JA, Steiner TJ, Stovner LJ, Wallin MT, Weiss J, Wu C, Zunt JR, Adelson JD, Murray CJL
JAMA Neurol 2021 Feb 1;78(2):165-176. doi: 10.1001/jamaneurol.2020.4152. PMID: 33136137Free PMC Article
Chatwin M, Simonds AK
Respir Care 2020 Feb;65(2):135-143. Epub 2019 Nov 5 doi: 10.4187/respcare.06882. PMID: 31690614
Finsterer J, Mahjoub SZ
Am J Hosp Palliat Care 2014 Aug;31(5):562-75. Epub 2013 Jul 26 doi: 10.1177/1049909113494748. PMID: 23892338

Therapy

Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF
Lancet Neurol 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094
James E, Ellis C, Brassington R, Sathasivam S, Young CA
Cochrane Database Syst Rev 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3. PMID: 35593746Free PMC Article
Chen H, Zhang J, Wang T, Zhang S, Lai Q, Huang S, Zeng P
J Clin Endocrinol Metab 2021 Oct 21;106(11):e4497-e4508. doi: 10.1210/clinem/dgab465. PMID: 34171091
Cui C, Longinetti E, Larsson H, Andersson J, Pawitan Y, Piehl F, Fang F
Amyotroph Lateral Scler Frontotemporal Degener 2021 May;22(3-4):211-219. Epub 2020 Dec 17 doi: 10.1080/21678421.2020.1861022. PMID: 33331190
Zucchi E, Vinceti M, Malagoli C, Fini N, Gessani A, Fasano A, Rizzi R, Sette E, Cavazza S, Fiocchi A, Buja S, Faccioli T, Storani S, Mandrioli J
Ann Clin Transl Neurol 2019 May;6(5):893-901. Epub 2019 Mar 18 doi: 10.1002/acn3.765. PMID: 31139687Free PMC Article

Prognosis

Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF
Lancet Neurol 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094
Berdyński M, Miszta P, Safranow K, Andersen PM, Morita M, Filipek S, Żekanowski C, Kuźma-Kozakiewicz M
Sci Rep 2022 Jan 7;12(1):103. doi: 10.1038/s41598-021-03891-8. PMID: 34996976Free PMC Article
Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H
Autophagy 2022 Mar;18(3):496-517. Epub 2021 Aug 19 doi: 10.1080/15548627.2021.1943177. PMID: 34130600Free PMC Article
Chatwin M, Simonds AK
Respir Care 2020 Feb;65(2):135-143. Epub 2019 Nov 5 doi: 10.4187/respcare.06882. PMID: 31690614
Holecek V, Rokyta R
Neuro Endocrinol Lett 2018 Feb;38(8):528-531. PMID: 29504729

Clinical prediction guides

Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF
Lancet Neurol 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094
James E, Ellis C, Brassington R, Sathasivam S, Young CA
Cochrane Database Syst Rev 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3. PMID: 35593746Free PMC Article
Chatwin M, Simonds AK
Respir Care 2020 Feb;65(2):135-143. Epub 2019 Nov 5 doi: 10.4187/respcare.06882. PMID: 31690614
Zucchi E, Vinceti M, Malagoli C, Fini N, Gessani A, Fasano A, Rizzi R, Sette E, Cavazza S, Fiocchi A, Buja S, Faccioli T, Storani S, Mandrioli J
Ann Clin Transl Neurol 2019 May;6(5):893-901. Epub 2019 Mar 18 doi: 10.1002/acn3.765. PMID: 31139687Free PMC Article
Finsterer J, Mahjoub SZ
Am J Hosp Palliat Care 2014 Aug;31(5):562-75. Epub 2013 Jul 26 doi: 10.1177/1049909113494748. PMID: 23892338

Recent systematic reviews

James E, Ellis C, Brassington R, Sathasivam S, Young CA
Cochrane Database Syst Rev 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3. PMID: 35593746Free PMC Article
Hurwitz N, Radakovic R, Boyce E, Peryer G
Amyotroph Lateral Scler Frontotemporal Degener 2021 Nov;22(7-8):449-458. Epub 2021 Mar 4 doi: 10.1080/21678421.2021.1892765. PMID: 33661072
GBD 2017 US Neurological Disorders Collaborators, Feigin VL, Vos T, Alahdab F, Amit AML, Bärnighausen TW, Beghi E, Beheshti M, Chavan PP, Criqui MH, Desai R, Dhamminda Dharmaratne S, Dorsey ER, Wilder Eagan A, Elgendy IY, Filip I, Giampaoli S, Giussani G, Hafezi-Nejad N, Hole MK, Ikeda T, Owens Johnson C, Kalani R, Khatab K, Khubchandani J, Kim D, Koroshetz WJ, Krishnamoorthy V, Krishnamurthi RV, Liu X, Lo WD, Logroscino G, Mensah GA, Miller TR, Mohammed S, Mokdad AH, Moradi-Lakeh M, Morrison SD, Shivamurthy VKN, Naghavi M, Nichols E, Norrving B, Odell CM, Pupillo E, Radfar A, Roth GA, Shafieesabet A, Sheikh A, Sheikhbahaei S, Shin JI, Singh JA, Steiner TJ, Stovner LJ, Wallin MT, Weiss J, Wu C, Zunt JR, Adelson JD, Murray CJL
JAMA Neurol 2021 Feb 1;78(2):165-176. doi: 10.1001/jamaneurol.2020.4152. PMID: 33136137Free 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
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

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