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Amyotrophic lateral sclerosis type 21(MPD2, FORMERLY; VCPDM, FORMERLY; ALS2...)

MedGen UID:
813851
Concept ID:
C3807521
Disease or Syndrome
Synonyms: Myopathy, distal, 2; VOCAL CORD AND PHARYNGEAL DYSFUNCTION WITH DISTAL MYOPATHY
 
Gene (location): MATR3 (5q31.2)
 
Monarch Initiative: MONDO:0011632
OMIM®: 606070

Definition

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). [from OMIM]

Additional description

From MedlinePlus Genetics
Distal myopathy 2 is a condition characterized by weakness of specific muscles that begins in adulthood. It is a form of muscular dystrophy that specifically involves muscles in the throat, lower legs, and forearms. Muscles farther from the center of the body, like the muscles of the lower legs and forearms, are known as distal muscles.

Muscle weakness in the ankles is usually the first symptom of distal myopathy 2. The weakness can also affect muscles in the hands, wrists, and shoulders. At first, the muscle weakness may be on only one side of the body, but both sides are eventually involved. This muscle weakness can slowly worsen and make actions like walking and lifting the fingers difficult.

Another characteristic feature of distal myopathy 2 is weakness of the vocal cords and throat. This weakness initially causes the voice to sound weak or breathy (hypophonic). Eventually, the voice becomes gurgling, hoarse, and nasal. The weakness can also cause difficulty swallowing (dysphagia).  https://medlineplus.gov/genetics/condition/distal-myopathy-2

Clinical features

From HPO
Hand muscle weakness
MedGen UID:
66798
Concept ID:
C0239831
Finding
Reduced strength of the musculature of the hand.
Shoulder girdle muscle weakness
MedGen UID:
96533
Concept ID:
C0427063
Finding
The shoulder, or pectoral, girdle is composed of the clavicles and the scapulae. Shoulder-girdle weakness refers to lack of strength of the muscles attaching to these bones, that is, lack of strength of the muscles around the shoulders.
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Bulbar signs
MedGen UID:
347246
Concept ID:
C1856507
Finding
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Abnormal lower motor neuron morphology
MedGen UID:
356272
Concept ID:
C1865412
Finding
Any structural anomaly of the lower motor neuron.
Abnormal upper motor neuron morphology
MedGen UID:
871241
Concept ID:
C4025723
Anatomical Abnormality
Any structural anomaly that affects the upper motor neuron.
Bulbar palsy
MedGen UID:
898626
Concept ID:
C4082299
Disease or Syndrome
Bulbar weakness (or bulbar palsy) refers to bilateral impairment of function of the lower cranial nerves IX, X, XI and XII, which occurs due to lower motor neuron lesion either at nuclear or fascicular level in the medulla or from bilateral lesions of the lower cranial nerves outside the brain-stem. Bulbar weakness is often associated with difficulty in chewing, weakness of the facial muscles, dysarthria, palatal weakness and regurgitation of fluids, dysphagia, and dysphonia.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Centrally nucleated skeletal muscle fibers
MedGen UID:
330782
Concept ID:
C1842170
Finding
An abnormality in which the nuclei of sarcomeres take on an abnormally central localization (or in which this feature is found in an increased proportion of muscle cells).
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Rimmed vacuoles
MedGen UID:
340089
Concept ID:
C1853932
Finding
Presence of abnormal vacuoles (membrane-bound organelles) in the sarcolemma. On histological staining with hematoxylin and eosin, rimmed vacuoles are popcorn-like clear vacuoles with a densely blue rim. The vacuoles are often associated with cytoplasmic and occasionally intranuclear eosinophilic inclusions.
Bowing of the vocal cords
MedGen UID:
96005
Concept ID:
C0396064
Finding
Bowing (abnormal curvature) of the vocal folds.
Aspiration
MedGen UID:
751786
Concept ID:
C2712334
Finding
Inspiration of a foreign object into the airway.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAmyotrophic lateral sclerosis type 21

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 2019 Dec 11;12(12):CD006281. doi: 10.1002/14651858.CD006281.pub5. PMID: 31825542Free PMC Article
Tiigimäe-Saar J, Taba P, Tamme T
Clin Oral Investig 2017 Apr;21(3):795-800. Epub 2016 Apr 26 doi: 10.1007/s00784-016-1826-z. PMID: 27114092

Recent clinical studies

Etiology

Baj J, Flieger W, Barbachowska A, Kowalska B, Flieger M, Forma A, Teresiński G, Portincasa P, Buszewicz G, Radzikowska-Büchner E, Flieger J
Int J Mol Sci 2023 Oct 6;24(19) doi: 10.3390/ijms241914959. PMID: 37834407Free PMC Article
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
López-Gómez JJ, Ballesteros-Pomar MD, Torres-Torres B, De la Maza BP, Penacho-Lázaro MÁ, Palacio-Mures JM, Abreu-Padín C, López-Guzmán A, De Luis-Román DA
Clin Nutr 2021 Jan;40(1):237-244. Epub 2020 May 21 doi: 10.1016/j.clnu.2020.05.014. PMID: 32507583
Gentile F, Doneddu PE, Riva N, Nobile-Orazio E, Quattrini A
Int J Mol Sci 2020 Oct 10;21(20) doi: 10.3390/ijms21207471. PMID: 33050475Free PMC Article

Diagnosis

Henden L, Fearnley LG, Grima N, McCann EP, Dobson-Stone C, Fitzpatrick L, Friend K, Hobson L, Chan Moi Fat S, Rowe DB, D'Silva S, Kwok JB, Halliday GM, Kiernan MC, Mazumder S, Timmins HC, Zoing M, Pamphlett R, Adams L, Bahlo M, Blair IP, Williams KL
Sci Adv 2023 May 5;9(18):eade2044. doi: 10.1126/sciadv.ade2044. PMID: 37146135Free 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
López-Gómez JJ, Ballesteros-Pomar MD, Torres-Torres B, De la Maza BP, Penacho-Lázaro MÁ, Palacio-Mures JM, Abreu-Padín C, López-Guzmán A, De Luis-Román DA
Clin Nutr 2021 Jan;40(1):237-244. Epub 2020 May 21 doi: 10.1016/j.clnu.2020.05.014. PMID: 32507583
Gentile F, Doneddu PE, Riva N, Nobile-Orazio E, Quattrini A
Int J Mol Sci 2020 Oct 10;21(20) doi: 10.3390/ijms21207471. PMID: 33050475Free PMC Article
Bersano E, Sarnelli MF, Solara V, Iazzolino B, Peotta L, De Marchi F, Facchin A, Moglia C, Canosa A, Calvo A, Chiò A, Mazzini L
Amyotroph Lateral Scler Frontotemporal Degener 2020 Aug;21(5-6):373-379. Epub 2020 Jun 2 doi: 10.1080/21678421.2020.1771732. PMID: 32484726

Therapy

Arslan D, Inan B, Kilinc M, Bekircan-Kurt CE, Erdem-Ozdamar S, Tan E
Neurol Sci 2023 Jul;44(7):2393-2400. Epub 2023 Mar 1 doi: 10.1007/s10072-023-06698-9. PMID: 36854931
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
Inoue-Shibui A, Kato M, Suzuki N, Kobayashi J, Takai Y, Izumi R, Kawauchi Y, Kuroda H, Warita H, Aoki M
BMC Neurol 2019 Apr 27;19(1):72. doi: 10.1186/s12883-019-1299-1. PMID: 31029113Free PMC Article
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. PMID: 24986107
Gurney ME, Cutting FB, Zhai P, Andrus PK, Hall ED
Pathol Biol (Paris) 1996 Jan;44(1):51-6. PMID: 8734301

Prognosis

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
Wolff L, Strathmann EA, Müller I, Mählich D, Veltman C, Niehoff A, Wirth B
Cell Mol Life Sci 2021 Jul;78(13):5275-5301. Epub 2021 May 23 doi: 10.1007/s00018-021-03843-5. PMID: 34023917Free PMC Article
López-Gómez JJ, Ballesteros-Pomar MD, Torres-Torres B, De la Maza BP, Penacho-Lázaro MÁ, Palacio-Mures JM, Abreu-Padín C, López-Guzmán A, De Luis-Román DA
Clin Nutr 2021 Jan;40(1):237-244. Epub 2020 May 21 doi: 10.1016/j.clnu.2020.05.014. PMID: 32507583
Palermo G, Mazzucchi S, Della Vecchia A, Siciliano G, Bonuccelli U, Azuar C, Ceravolo R, Lista S, Hampel H, Baldacci F
Mol Neurobiol 2020 Nov;57(11):4667-4691. Epub 2020 Aug 9 doi: 10.1007/s12035-020-02035-9. PMID: 32772223
Bersano E, Sarnelli MF, Solara V, Iazzolino B, Peotta L, De Marchi F, Facchin A, Moglia C, Canosa A, Calvo A, Chiò A, Mazzini L
Amyotroph Lateral Scler Frontotemporal Degener 2020 Aug;21(5-6):373-379. Epub 2020 Jun 2 doi: 10.1080/21678421.2020.1771732. PMID: 32484726

Clinical prediction guides

Baj J, Flieger W, Barbachowska A, Kowalska B, Flieger M, Forma A, Teresiński G, Portincasa P, Buszewicz G, Radzikowska-Büchner E, Flieger J
Int J Mol Sci 2023 Oct 6;24(19) doi: 10.3390/ijms241914959. PMID: 37834407Free PMC Article
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
Kekenadze M, Kvirkvelia N, Beridze M, Vashadze S, Kvaratskhelia E
Georgian Med News 2021 Oct;(319):71-75. PMID: 34749326
López-Gómez JJ, Ballesteros-Pomar MD, Torres-Torres B, De la Maza BP, Penacho-Lázaro MÁ, Palacio-Mures JM, Abreu-Padín C, López-Guzmán A, De Luis-Román DA
Clin Nutr 2021 Jan;40(1):237-244. Epub 2020 May 21 doi: 10.1016/j.clnu.2020.05.014. PMID: 32507583
Bersano E, Sarnelli MF, Solara V, Iazzolino B, Peotta L, De Marchi F, Facchin A, Moglia C, Canosa A, Calvo A, Chiò A, Mazzini L
Amyotroph Lateral Scler Frontotemporal Degener 2020 Aug;21(5-6):373-379. Epub 2020 Jun 2 doi: 10.1080/21678421.2020.1771732. PMID: 32484726

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
Pecoraro V, Mandrioli J, Carone C, Chiò A, Traynor BJ, Trenti T
Eur J Clin Invest 2020 May;50(5):e13228. Epub 2020 May 19 doi: 10.1111/eci.13228. PMID: 32293029Free PMC Article
Wadman RI, van der Pol WL, Bosboom WM, Asselman FL, van den Berg LH, Iannaccone ST, Vrancken AF
Cochrane Database Syst Rev 2019 Dec 11;12(12):CD006281. doi: 10.1002/14651858.CD006281.pub5. PMID: 31825542Free PMC Article

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