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Congenital myasthenic syndrome 14(CMSTA3; CMS14)

MedGen UID:
864034
Concept ID:
C4015597
Disease or Syndrome
Synonym: Myasthenic syndrome, congenital, 14, with tubular aggregates
 
Gene (location): ALG2 (9q22.33)
 
Monarch Initiative: MONDO:0014543
OMIM®: 616228

Definition

Congenital myasthenic syndrome-14 is an autosomal recessive neuromuscular disorder characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. There is no respiratory or cardiac involvement. Treatment with anticholinesterase medication may be beneficial (summary by Cossins et al., 2013). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). [from OMIM]

Clinical features

From HPO
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
Knee flexion contracture
MedGen UID:
98042
Concept ID:
C0409355
Finding
A type of knee joint contracture in which the knee is in a fixed bent (flexed) configuration such that it cannot be straightened actively or passively.
Limb-girdle muscle weakness
MedGen UID:
347625
Concept ID:
C1858127
Finding
Weakness of the limb-girdle muscles (also known as the pelvic and shoulder girdles), that is, lack of strength of the muscles around the shoulders and the pelvis.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Fatigable weakness
MedGen UID:
451076
Concept ID:
C0947912
Disease or Syndrome
A type of weakness that occurs after a muscle group is used and lessens if the muscle group has some rest. That is, there is diminution of strength with repetitive muscle actions.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Weakness of facial musculature
MedGen UID:
98103
Concept ID:
C0427055
Disease or Syndrome
Reduced strength of one or more muscles innervated by the facial nerve (the seventh cranial nerve).
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.
Distal joint hypermobility
MedGen UID:
376894
Concept ID:
C1850851
Finding
Lack of stability of a distal joint (e.g., finger).
Type 1 muscle fiber predominance
MedGen UID:
344274
Concept ID:
C1854387
Finding
An abnormal predominance of type I muscle fibers (in general, this feature can only be observed on muscle biopsy).
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Muscle fiber tubular inclusions
MedGen UID:
866677
Concept ID:
C4021024
Anatomical Abnormality
Unusual regions of densely packed membranous tubules known as tubular aggregates which present as membranous inclusions, derived from membranes of sarcoplasmic reticulum and mitochondria, containing miscellaneous proteins with a variety of enzymatic activities.
EMG: decremental response of compound muscle action potential to repetitive nerve stimulation
MedGen UID:
892749
Concept ID:
C4021728
Finding
A compound muscle action potential (CMAP) is a type of electromyography (EMG). CMAP refers to a group of almost simultaneous action potentials from several muscle fibers in the same area evoked by stimulation of the supplying motor nerve and are recorded as one multipeaked summated action potential. This abnormality refers to a greater than normal decrease in the amplitude during the course of the investigation.
Mildly elevated creatine kinase
MedGen UID:
342469
Concept ID:
C1850309
Finding
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

Professional guidelines

PubMed

Zhang Z, Zhang X, Xue H, Chu L, Hu L, Bi X, Zhu P, Zhang D, Chen J, Cui X, Kong L, Liang B, Wu X
Mol Genet Genomic Med 2024 Mar;12(3):e2409. doi: 10.1002/mgg3.2409. PMID: 38511267Free PMC Article
Engel AG, Shen XM, Selcen D, Sine SM
Lancet Neurol 2015 Apr;14(4):420-34. doi: 10.1016/S1474-4422(14)70201-7. PMID: 25792100Free PMC Article
Kinali M, Beeson D, Pitt MC, Jungbluth H, Simonds AK, Aloysius A, Cockerill H, Davis T, Palace J, Manzur AY, Jimenez-Mallebrera C, Sewry C, Muntoni F, Robb SA
J Neuroimmunol 2008 Sep 15;201-202:6-12. Epub 2008 Aug 15 doi: 10.1016/j.jneuroim.2008.06.026. PMID: 18707767

Recent clinical studies

Etiology

Polavarapu K, Sunitha B, Töpf A, Preethish-Kumar V, Thompson R, Vengalil S, Nashi S, Bardhan M, Sanka SB, Huddar A, Unnikrishnan G, Arunachal G, Girija MS, Porter A, Azuma Y, Lorenzoni PJ, Baskar D, Anjanappa RM, Keertipriya M, Padmanabh H, Harikrishna GV, Laurie S, Matalonga L, Horvath R, Nalini A, Lochmüller H
Brain 2024 Jan 4;147(1):281-296. doi: 10.1093/brain/awad315. PMID: 37721175Free PMC Article
Ohno K, Ohkawara B, Shen XM, Selcen D, Engel AG
Int J Mol Sci 2023 Feb 13;24(4) doi: 10.3390/ijms24043730. PMID: 36835142Free PMC Article
Yoganathan K, Stevenson A, Tahir A, Sadler R, Radunovic A, Malek N
J Neurol 2022 Jun;269(6):3372-3384. Epub 2022 Feb 10 doi: 10.1007/s00415-022-10986-3. PMID: 35142871Free PMC Article
Finsterer J
Orphanet J Rare Dis 2019 Feb 26;14(1):57. doi: 10.1186/s13023-019-1025-5. PMID: 30808424Free PMC Article
Engel AG, Shen XM, Selcen D, Sine SM
Lancet Neurol 2015 Apr;14(4):420-34. doi: 10.1016/S1474-4422(14)70201-7. PMID: 25792100Free PMC Article

Diagnosis

Polavarapu K, Sunitha B, Töpf A, Preethish-Kumar V, Thompson R, Vengalil S, Nashi S, Bardhan M, Sanka SB, Huddar A, Unnikrishnan G, Arunachal G, Girija MS, Porter A, Azuma Y, Lorenzoni PJ, Baskar D, Anjanappa RM, Keertipriya M, Padmanabh H, Harikrishna GV, Laurie S, Matalonga L, Horvath R, Nalini A, Lochmüller H
Brain 2024 Jan 4;147(1):281-296. doi: 10.1093/brain/awad315. PMID: 37721175Free PMC Article
Ohno K, Ohkawara B, Shen XM, Selcen D, Engel AG
Int J Mol Sci 2023 Feb 13;24(4) doi: 10.3390/ijms24043730. PMID: 36835142Free PMC Article
Yoganathan K, Stevenson A, Tahir A, Sadler R, Radunovic A, Malek N
J Neurol 2022 Jun;269(6):3372-3384. Epub 2022 Feb 10 doi: 10.1007/s00415-022-10986-3. PMID: 35142871Free PMC Article
Finsterer J
Orphanet J Rare Dis 2019 Feb 26;14(1):57. doi: 10.1186/s13023-019-1025-5. PMID: 30808424Free PMC Article
Engel AG, Shen XM, Selcen D, Sine SM
Lancet Neurol 2015 Apr;14(4):420-34. doi: 10.1016/S1474-4422(14)70201-7. PMID: 25792100Free PMC Article

Therapy

Hesami O, Ramezani M, Ghasemi A, Fatehi F, Okhovat AA, Ziaadini B, Kariminejad A, Nafissi S
Orphanet J Rare Dis 2024 Mar 12;19(1):113. doi: 10.1186/s13023-024-03116-x. PMID: 38475910Free PMC Article
Eshaghian T, Rabbani B, Badv RS, Mikaeeli S, Gharib B, Iyadurai S, Mahdieh N
Neurogenetics 2023 Jul;24(3):189-200. Epub 2023 May 25 doi: 10.1007/s10048-023-00719-7. PMID: 37231228
Finsterer J
Orphanet J Rare Dis 2019 Feb 26;14(1):57. doi: 10.1186/s13023-019-1025-5. PMID: 30808424Free PMC Article
Visser AC, Laughlin RS, Litchy WJ, Benarroch EE, Milone M
Muscle Nerve 2017 Jan;55(1):131-135. Epub 2016 Aug 10 doi: 10.1002/mus.25244. PMID: 27397848
Engel AG, Shen XM, Selcen D, Sine SM
Lancet Neurol 2015 Apr;14(4):420-34. doi: 10.1016/S1474-4422(14)70201-7. PMID: 25792100Free PMC Article

Prognosis

Ma Y, Xiong T, Lei G, Ding J, Yang R, Li Z, Guo J, Shen D
Neurol Sci 2021 Aug;42(8):3485-3490. Epub 2021 Jan 13 doi: 10.1007/s10072-020-05021-0. PMID: 33438142
Parr JR, Andrew MJ, Finnis M, Beeson D, Vincent A, Jayawant S
Arch Dis Child 2014 Jun;99(6):539-42. Epub 2014 Feb 5 doi: 10.1136/archdischild-2013-304788. PMID: 24500997
Schara U, Della Marina A, Abicht A
Neuropediatrics 2012 Aug;43(4):184-93. Epub 2012 Aug 21 doi: 10.1055/s-0032-1323850. PMID: 22911480
Engel AG, Ohno K, Sine SM
J Neurocytol 2003 Jun-Sep;32(5-8):1017-37. doi: 10.1023/B:NEUR.0000020639.22895.28. PMID: 15034283
Szobor A, Máttyus A, Molnár J
Acta Paediatr Hung 1988-1989;29(3-4):299-312. PMID: 3077607

Clinical prediction guides

McMacken G, Whittaker RG, Evangelista T, Abicht A, Dusl M, Lochmüller H
J Neurol 2018 Jan;265(1):194-203. Epub 2017 Nov 30 doi: 10.1007/s00415-017-8689-3. PMID: 29189923Free PMC Article
Engel AG
Curr Neurol Neurosci Rep 2012 Feb;12(1):92-101. doi: 10.1007/s11910-011-0234-7. PMID: 21997714Free PMC Article
Engel AG, Shen XM, Selcen D, Sine SM
Ann N Y Acad Sci 2008;1132:104-13. doi: 10.1196/annals.1405.039. PMID: 18567859Free PMC Article
Engel AG, Sine SM
Curr Opin Pharmacol 2005 Jun;5(3):308-21. doi: 10.1016/j.coph.2004.12.007. PMID: 15907919
Engel AG, Ohno K, Sine SM
J Neurocytol 2003 Jun-Sep;32(5-8):1017-37. doi: 10.1023/B:NEUR.0000020639.22895.28. PMID: 15034283

Recent systematic reviews

Finsterer J
Orphanet J Rare Dis 2019 Feb 26;14(1):57. doi: 10.1186/s13023-019-1025-5. PMID: 30808424Free PMC Article

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