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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, JUVENILE; NEURONOPATHY, DISTAL HEREDITARY MOTOR, WITH PYRAMIDAL FEATURES; SETX-Related Amyotrophic Lateral Sclerosis
SNOMED CT: Amyotrophic lateral sclerosis type 4 (784341001); ALS4 - amyotrophic lateral sclerosis type 4 (784341001); dHMN (distal hereditary motor neuropathy) with upper motor neuron signs (784341001)
Modes of inheritance:
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.
 
Gene (location): SETX (9q34.13)
 
Monarch Initiative: MONDO:0011223
OMIM®: 602433
Orphanet: ORPHA357043

Definition

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). [from OMIM]

Clinical features

From HPO
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.
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
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.
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.
Muscle fibrillation
MedGen UID:
65418
Concept ID:
C0231531
Finding
Fine, rapid twitching of individual muscle fibers with little or no movement of the muscle as a whole. If a motor neuron or its axon is destroyed, the muscle fibers it innervates undergo denervation atrophy. This leads to hypersensitivity of individual muscle fibers to acetyl choline so that they may contract spontaneously. Isolated activity of individual muscle fibers is generally so fine it cannot be seen through the intact skin, although it can be recorded as a short-duration spike in the EMG.
Atrophy of the spinal cord
MedGen UID:
235592
Concept ID:
C1389102
Disease or Syndrome
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Degeneration of anterior horn cells
MedGen UID:
375215
Concept ID:
C1843505
Finding
Abnormal lower motor neuron morphology
MedGen UID:
356272
Concept ID:
C1865412
Finding
Any structural anomaly of the lower motor neuron.
Pallor of dorsal columns of the spinal cord
MedGen UID:
355986
Concept ID:
C1865416
Finding
An abnormally pale appearance of the dorsal portion of the gray substance of the spinal cord. This finding can be observed by histological examination.
Diffuse axonal swelling
MedGen UID:
356274
Concept ID:
C1865417
Finding
Peripheral axonal degeneration
MedGen UID:
871339
Concept ID:
C4025830
Finding
Progressive deterioration of peripheral axons.
Decreased compound muscle action potential amplitude
MedGen UID:
908357
Concept ID:
C4230625
Finding
Reduced level of the compound muscle action potential (CMAP), which is recorded following electrical stimulation of a nerve from surface electrodes overlying a muscle supplied by that nerve.
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
EMG: positive sharp waves
MedGen UID:
607215
Concept ID:
C0429349
Finding
These are spontaneous firing action potentials stimulated by needle movement of an injured muscle fiber. There is propagation to, but not past, the needle tip. This inhibits the display of the negative deflection of the waveform.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.

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
Ashworth NL, Satkunam LE, Deforge D
Cochrane Database Syst Rev 2012 Feb 15;(2):CD004156. doi: 10.1002/14651858.CD004156.pub4. PMID: 22336799

Curated

Orphanet, Amyotrophic lateral sclerosis, 2007

Recent clinical studies

Etiology

Lei L, Chen H, Lu Y, Zhu W, Ouyang Y, Duo J, Chen Z, Da Y
J Neurol 2021 Mar;268(3):1050-1058. Epub 2020 Sep 30 doi: 10.1007/s00415-020-10246-2. PMID: 32997296

Diagnosis

Bennett CL, La Spada AR
Mol Genet Genomic Med 2021 Dec;9(12):e1745. Epub 2021 Jul 14 doi: 10.1002/mgg3.1745. PMID: 34263556Free PMC Article
Vantaggiato C, Bondioni S, Airoldi G, Bozzato A, Borsani G, Rugarli EI, Bresolin N, Clementi E, Bassi MT
Brain 2011 Jun;134(Pt 6):1808-28. Epub 2011 May 15 doi: 10.1093/brain/awr084. PMID: 21576111

Prognosis

Lei L, Chen H, Lu Y, Zhu W, Ouyang Y, Duo J, Chen Z, Da Y
J Neurol 2021 Mar;268(3):1050-1058. Epub 2020 Sep 30 doi: 10.1007/s00415-020-10246-2. PMID: 32997296
Vantaggiato C, Bondioni S, Airoldi G, Bozzato A, Borsani G, Rugarli EI, Bresolin N, Clementi E, Bassi MT
Brain 2011 Jun;134(Pt 6):1808-28. Epub 2011 May 15 doi: 10.1093/brain/awr084. PMID: 21576111

Clinical prediction guides

Pourshafie N, Masati E, Lopez A, Bunker E, Snyder A, Edwards NA, Winkelsas AM, Fischbeck KH, Grunseich C
Neurobiol Dis 2022 Oct 1;172:105832. Epub 2022 Jul 27 doi: 10.1016/j.nbd.2022.105832. PMID: 35907632
Lei L, Chen H, Lu Y, Zhu W, Ouyang Y, Duo J, Chen Z, Da Y
J Neurol 2021 Mar;268(3):1050-1058. Epub 2020 Sep 30 doi: 10.1007/s00415-020-10246-2. PMID: 32997296
Richard P, Feng S, Tsai YL, Li W, Rinchetti P, Muhith U, Irizarry-Cole J, Stolz K, Sanz LA, Hartono S, Hoque M, Tadesse S, Seitz H, Lotti F, Hirano M, Chédin F, Tian B, Manley JL
Autophagy 2021 Aug;17(8):1889-1906. Epub 2020 Aug 7 doi: 10.1080/15548627.2020.1796292. PMID: 32686621Free PMC Article
Bennett CL, Dastidar SG, Ling SC, Malik B, Ashe T, Wadhwa M, Miller DB, Lee C, Mitchell MB, van Es MA, Grunseich C, Chen Y, Sopher BL, Greensmith L, Cleveland DW, La Spada AR
Acta Neuropathol 2018 Sep;136(3):425-443. Epub 2018 May 3 doi: 10.1007/s00401-018-1852-9. PMID: 29725819Free PMC Article
Vantaggiato C, Bondioni S, Airoldi G, Bozzato A, Borsani G, Rugarli EI, Bresolin N, Clementi E, Bassi MT
Brain 2011 Jun;134(Pt 6):1808-28. Epub 2011 May 15 doi: 10.1093/brain/awr084. PMID: 21576111

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