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Amyotrophic lateral sclerosis 28(ALS28)

MedGen UID:
1841278
Concept ID:
C5830642
Disease or Syndrome
Synonym: ALS28
 
Gene (location): LRP12 (8q22.3)
 
Monarch Initiative: MONDO:0957538
OMIM®: 620452

Definition

Amyotrophic lateral sclerosis-28 (ALS28) is an autosomal dominant neurodegenerative disorder characterized by adult onset of slowly progressive limb muscle weakness and atrophy resulting in gait difficulties, loss of ambulation, and distal upper limb weakness. Facial involvement is rare, but some patients may have respiratory insufficiency. EMG and muscle biopsy show active and chronic denervation. Patient-derived motor neurons show accumulation of TDP43 (605078) and toxic intranuclear RNA accumulation (Kume et al., 2023). For discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400). [from OMIM]

Clinical features

From HPO
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Upper limb muscle weakness
MedGen UID:
305607
Concept ID:
C1698196
Finding
Weakness of the muscles of the arms.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
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.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Chaddock reflex
MedGen UID:
451083
Concept ID:
C1531651
Finding
A diagnostic reflex elicited by stimulation of the skin over the surface of the lateral malleolus of the foot. The Chaddock refelx is present if there is extension of one or more or all of the toes with or without fanning of them when the external inframalleolar skin is stimulated. The Chaddock sign, similar to the Babinski sign, is taken to be an indication of disease of the spinocortical (pyramidal) tract.
Reduced tendon reflexes
MedGen UID:
356648
Concept ID:
C1866934
Finding
Diminution of tendon reflexes, which is an invariable sign of peripheral nerve disease.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Difficulty standing
MedGen UID:
69136
Concept ID:
C0241237
Sign or Symptom
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
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.
Fiber type grouping
MedGen UID:
478824
Concept ID:
C3277194
Finding
An abnormal distribution of muscle fiber types in muscle tissue. Human skeletal muscle contains at least two fiber types recognizable by histochemical techniques. In transverse sections of normal skeletal muscle, type 1 and type 2 fibers are distributed in a random fashion. Grouping of fibers of the same type can be seen in certain peripheral neuropathies, thought to be due to reinnervation of denervated muscle fibers by sprouting axons. With grouping, motor units enlarge. The fibers of a motor unit, which are normally scattered, come to lie adjacent to one another. Histochemical examination shows groups of muscle fibers of the same histochemical type.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.

Professional guidelines

PubMed

Oliveira Santos M, de Carvalho M
Expert Rev Neurother 2024 Jun;24(6):549-553. Epub 2024 May 17 doi: 10.1080/14737175.2024.2355983. PMID: 38758193
Kacem I, Sghaier I, Peverelli S, Souissi E, Ticozzi N, Gharbi A, Ratti A, Berrechid AG, Silani V, Gouider R
Neurobiol Aging 2022 Dec;120:27-33. Epub 2022 Aug 14 doi: 10.1016/j.neurobiolaging.2022.08.002. PMID: 36108486
Greenwood DI
Nutr Clin Pract 2013 Jun;28(3):392-9. Epub 2013 Mar 6 doi: 10.1177/0884533613476554. PMID: 23466470

Recent clinical studies

Etiology

Li D, Zhou L, Cao Z, Wang J, Yang H, Lyu M, Zhang Y, Yang R, Wang J, Bian Y, Xu W, Wang Y
Ageing Res Rev 2024 Mar;95:102254. Epub 2024 Feb 29 doi: 10.1016/j.arr.2024.102254. PMID: 38430933
Cao W, Cao Z, Tian Y, Zhang L, Wang W, Tang L, Xu C, Fan D
Ann Neurol 2023 Nov;94(5):942-954. Epub 2023 Aug 28 doi: 10.1002/ana.26760. PMID: 37554051
Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group
N Engl J Med 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705. PMID: 36129998
Lotti F, Przedborski S
Adv Neurobiol 2022;28:323-352. doi: 10.1007/978-3-031-07167-6_13. PMID: 36066831
Writing Group; Edaravone (MCI-186) ALS 19 Study Group
Lancet Neurol 2017 Jul;16(7):505-512. Epub 2017 May 15 doi: 10.1016/S1474-4422(17)30115-1. PMID: 28522181

Diagnosis

Baloh RH, Johnson JP, Avalos P, Allred P, Svendsen S, Gowing G, Roxas K, Wu A, Donahue B, Osborne S, Lawless G, Shelley B, Wheeler K, Prina C, Fine D, Kendra-Romito T, Stokes H, Manoukian V, Muthukumaran A, Garcia L, Bañuelos MG, Godoy M, Bresee C, Yu H, Drazin D, Ross L, Naruse R, Babu H, Macklin EA, Vo A, Elsayegh A, Tourtellotte W, Maya M, Burford M, Diaz F, Patil CG, Lewis RA, Svendsen CN
Nat Med 2022 Sep;28(9):1813-1822. Epub 2022 Sep 5 doi: 10.1038/s41591-022-01956-3. PMID: 36064599Free PMC Article
Cudkowicz ME, Lindborg SR, Goyal NA, Miller RG, Burford MJ, Berry JD, Nicholson KA, Mozaffar T, Katz JS, Jenkins LJ, Baloh RH, Lewis RA, Staff NP, Owegi MA, Berry DA, Gothelf Y, Levy YS, Aricha R, Kern RZ, Windebank AJ, Brown RH Jr
Muscle Nerve 2022 Mar;65(3):291-302. Epub 2022 Jan 5 doi: 10.1002/mus.27472. PMID: 34890069Free PMC Article
Zuo X, Zhou J, Li Y, Wu K, Chen Z, Luo Z, Zhang X, Liang Y, Esteban MA, Zhou Y, Fu XD
Nat Struct Mol Biol 2021 Feb;28(2):132-142. Epub 2021 Jan 4 doi: 10.1038/s41594-020-00537-7. PMID: 33398173
Writing Group; Edaravone (MCI-186) ALS 19 Study Group
Lancet Neurol 2017 Jul;16(7):505-512. Epub 2017 May 15 doi: 10.1016/S1474-4422(17)30115-1. PMID: 28522181
Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP
J Neurol Neurosurg Psychiatry 2017 Jul;88(7):540-549. Epub 2017 Jan 5 doi: 10.1136/jnnp-2016-315018. PMID: 28057713

Therapy

Duan QQ, Wang H, Su WM, Gu XJ, Shen XF, Jiang Z, Ren YL, Cao B, Li GB, Wang Y, Chen YP
BMC Med 2024 Mar 5;22(1):96. doi: 10.1186/s12916-024-03314-1. PMID: 38443977Free PMC Article
Li D, Zhou L, Cao Z, Wang J, Yang H, Lyu M, Zhang Y, Yang R, Wang J, Bian Y, Xu W, Wang Y
Ageing Res Rev 2024 Mar;95:102254. Epub 2024 Feb 29 doi: 10.1016/j.arr.2024.102254. PMID: 38430933
Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group
N Engl J Med 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705. PMID: 36129998
Skrzypczak-Wiercioch A, Sałat K
Molecules 2022 Aug 26;27(17) doi: 10.3390/molecules27175481. PMID: 36080253Free PMC Article
Writing Group; Edaravone (MCI-186) ALS 19 Study Group
Lancet Neurol 2017 Jul;16(7):505-512. Epub 2017 May 15 doi: 10.1016/S1474-4422(17)30115-1. PMID: 28522181

Prognosis

Cao W, Cao Z, Tian Y, Zhang L, Wang W, Tang L, Xu C, Fan D
Ann Neurol 2023 Nov;94(5):942-954. Epub 2023 Aug 28 doi: 10.1002/ana.26760. PMID: 37554051
Hanhisuanto M, Solje E, Jokela M, Sipilä JOT
Neuroepidemiology 2023;57(4):238-245. Epub 2023 Jul 3 doi: 10.1159/000531238. PMID: 37399804
de Luna N, Carbayo Á, Dols-Icardo O, Turon-Sans J, Reyes-Leiva D, Illan-Gala I, Jericó I, Pagola-Lorz I, Lleixà C, Querol L, Rubio-Guerra S, Alcolea D, Fortea J, Lleó A, Cortés-Vicente E, Rojas-Garcia R
Neurol Neuroimmunol Neuroinflamm 2023 Mar;10(2) Epub 2022 Dec 2 doi: 10.1212/NXI.0000000000200072. PMID: 36460480Free PMC Article
Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group
N Engl J Med 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705. PMID: 36129998
Tay YT, H Chai JY, Shekh Jabin KB, Ang K
Singapore Med J 2022 Jul;63(7):371-375. Epub 2021 Jan 21 doi: 10.11622/smedj.2021001. PMID: 33472335Free PMC Article

Clinical prediction guides

Moda F, Ciullini A, Dellarole IL, Lombardo A, Campanella N, Bufano G, Cazzaniga FA, Giaccone G
Front Biosci (Landmark Ed) 2023 Oct 20;28(10):255. doi: 10.31083/j.fbl2810255. PMID: 37919089
Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chiò A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group
N Engl J Med 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705. PMID: 36129998
Cudkowicz ME, Lindborg SR, Goyal NA, Miller RG, Burford MJ, Berry JD, Nicholson KA, Mozaffar T, Katz JS, Jenkins LJ, Baloh RH, Lewis RA, Staff NP, Owegi MA, Berry DA, Gothelf Y, Levy YS, Aricha R, Kern RZ, Windebank AJ, Brown RH Jr
Muscle Nerve 2022 Mar;65(3):291-302. Epub 2022 Jan 5 doi: 10.1002/mus.27472. PMID: 34890069Free PMC Article
Moujalled D, Strasser A, Liddell JR
Cell Death Differ 2021 Jul;28(7):2029-2044. Epub 2021 Jun 7 doi: 10.1038/s41418-021-00814-y. PMID: 34099897Free PMC Article
Writing Group; Edaravone (MCI-186) ALS 19 Study Group
Lancet Neurol 2017 Jul;16(7):505-512. Epub 2017 May 15 doi: 10.1016/S1474-4422(17)30115-1. PMID: 28522181

Recent systematic reviews

Zheng X, Wang S, Huang J, Lin J, Yang T, Xiao Y, Jiang Q, Huang R, Li C, Shang H
J Neurol 2023 May;270(5):2438-2450. Epub 2023 Jan 21 doi: 10.1007/s00415-022-11555-4. PMID: 36670248
Ramos-Martínez E, Ramos-Martínez I, Sánchez-Betancourt I, Ramos-Martínez JC, Peña-Corona SI, Valencia J, Saucedo R, Almeida-Aguirre EKP, Cerbón M
Biomolecules 2022 Jul 31;12(8) doi: 10.3390/biom12081062. PMID: 36008956Free PMC Article
Xu L, He B, Zhang Y, Chen L, Fan D, Zhan S, Wang S
J Neurol 2021 Sep;268(9):3361-3370. Epub 2021 Mar 10 doi: 10.1007/s00415-021-10508-7. PMID: 33694050
Gu D, Ou S, Tang M, Yin Z, Wang Z, Liu G
Amyotroph Lateral Scler Frontotemporal Degener 2021 May;22(3-4):170-185. Epub 2021 Jan 11 doi: 10.1080/21678421.2020.1861024. PMID: 33423565
Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP
J Neurol Neurosurg Psychiatry 2017 Jul;88(7):540-549. Epub 2017 Jan 5 doi: 10.1136/jnnp-2016-315018. PMID: 28057713

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