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Charcot-Marie-Tooth disease, axonal, mitochondrial form, 1(CMTMA1)

MedGen UID:
1731194
Concept ID:
C5435765
Disease or Syndrome
Synonyms: CHARCOT-MARIE-TOOTH DISEASE, AXONAL, MITOCHONDRIAL FORM, 1; CMTMA1
 
Monarch Initiative: MONDO:0025622
OMIM®: 500013

Definition

Mitochondrial form of axonal Charcot-Marie-Tooth disease-1 (CMTMA1) is inherited only through the maternal line. The disorder is characterized by onset of distal muscle weakness and atrophy mainly affecting the lower limbs and resulting in difficulty walking in the second decade of life, although both earlier and later onset can occur. Upper limb involvement often develops with time, and affected individuals have weakness and atrophy of the intrinsic hand muscles. Other features may include distal sensory impairment, foot deformities, scoliosis, hypo- or hyperreflexia, spastic paraparesis, and neurogenic bladder. Electrophysiologic studies are compatible with an axonal sensorimotor peripheral neuropathy, and muscle and nerve biopsy show evidence of mitochondrial dysfunction with decreased activities of respiratory complexes, mtDNA deletions, and mitochondrial hyperplasia (summary by Fay et al., 2020). [from OMIM]

Clinical features

From HPO
Neurogenic bladder
MedGen UID:
595
Concept ID:
C0005697
Disease or Syndrome
A type of bladder dysfunction caused by neurologic damage. Neurogenic bladder can be flaccid or spastic. Common manifestatios of neurogenic bladder are overflow incontinence, frequency, urgency, urge incontinence, and retention.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Distal upper limb muscle weakness
MedGen UID:
461970
Concept ID:
C3150620
Finding
Reduced strength of the distal musculature of the arms.
Equinovarus deformity
MedGen UID:
1636532
Concept ID:
C4551566
Anatomical Abnormality
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.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Sensory ataxia
MedGen UID:
66020
Concept ID:
C0240991
Sign or Symptom
Incoordination of movement caused by a deficit in the sensory nervous system. Sensory ataxia can be distinguished from cerebellar ataxia by asking the patient to close his or her eyes. Persons with cerebellar ataxia show only a minimal worsening of symptoms, whereas persons with sensory ataxia show a marked worsening of symptoms.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Impaired vibratory sensation
MedGen UID:
220959
Concept ID:
C1295585
Finding
A decrease in the ability to perceive vibration. Clinically, this is usually tested with a tuning fork which vibrates at 128 Hz and is applied to bony prominences such as the malleoli at the ankles or the metacarpal-phalangeal joints. There is a slow decay of vibration from the tuning fork. The degree of vibratory sense loss can be crudely estimated by counting the number of seconds that the examiner can perceive the vibration longer than the patient.
Impaired proprioception
MedGen UID:
346424
Concept ID:
C1856691
Finding
A loss or impairment of the sensation of the relative position of parts of the body and joint position.
Distal lower limb amyotrophy
MedGen UID:
324515
Concept ID:
C1836451
Disease or Syndrome
Muscular atrophy of distal leg muscles.
Interosseus muscle atrophy
MedGen UID:
339618
Concept ID:
C1846829
Finding
Atrophy of the interosseus muscles (including the palmar interossei that lie on the anterior aspect of the metacarpals, the dorsal interosseus muscles of the hand, which lie between the intercarpals, the plantar interosseus muscles, which lie underneath the metatarsal bones, and the dorsal interossei, which are located between the metatarsal bones.
Thenar muscle atrophy
MedGen UID:
355274
Concept ID:
C1864715
Finding
Wasting of thenar muscles, which are located on palm of the hand at the base of the thumb.
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.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex III
MedGen UID:
460434
Concept ID:
C3149083
Finding
A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex IV
MedGen UID:
866520
Concept ID:
C4020800
Finding
A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria.
Mitochondrial hypertrophy
MedGen UID:
1740956
Concept ID:
C5435767
Finding
Enlargement of mitochondria. Mitochondrial hypertrophy is not discernible by light microscopy. By electron microscopy (EM), hypertrophic mitochondria have normal cristae and normal matrix density. In contrast, swollen mitochondria display swollen cristae and irregular matrix densities in EM.

Recent clinical studies

Etiology

Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN)
Brain 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323. PMID: 33415332Free PMC Article
Perez-Siles G, Cutrupi A, Ellis M, Screnci R, Mao D, Uesugi M, Yiu EM, Ryan MM, Choi BO, Nicholson G, Kennerson ML
Sci Rep 2020 Jun 5;10(1):9262. doi: 10.1038/s41598-020-66266-5. PMID: 32504000Free PMC Article
Tucci A, Liu YT, Preza E, Pitceathly RD, Chalasani A, Plagnol V, Land JM, Trabzuni D, Ryten M; UKBEC, Jaunmuktane Z, Reilly MM, Brandner S, Hargreaves I, Hardy J, Singleton AB, Abramov AY, Houlden H
J Neurol Neurosurg Psychiatry 2014 May;85(5):486-92. Epub 2013 Nov 6 doi: 10.1136/jnnp-2013-306387. PMID: 24198383Free PMC Article
Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, Dubas F, Amati-Bonneau P, Reynier P, Bonneau D, Procaccio V
Exp Neurol 2011 Jan;227(1):31-41. Epub 2010 Sep 21 doi: 10.1016/j.expneurol.2010.09.006. PMID: 20849849
Benedetti S, Previtali SC, Coviello S, Scarlato M, Cerri F, Di Pierri E, Piantoni L, Spiga I, Fazio R, Riva N, Natali Sora MG, Dacci P, Malaguti MC, Munerati E, Grimaldi LM, Marrosu MG, De Pellegrin M, Ferrari M, Comi G, Quattrini A, Bolino A
Arch Neurol 2010 Dec;67(12):1498-505. doi: 10.1001/archneurol.2010.303. PMID: 21149811

Diagnosis

Khani M, Taheri H, Shamshiri H, Moazzeni H, Hardy J, Bras JT, InanlooRahatloo K, Alavi A, Nafissi S, Elahi E
J Neurol 2021 Feb;268(2):640-650. Epub 2020 Sep 8 doi: 10.1007/s00415-020-10171-4. PMID: 32897397
Cassereau J, Chevrollier A, Codron P, Goizet C, Gueguen N, Verny C, Reynier P, Bonneau D, Lenaers G, Procaccio V
Exp Neurol 2020 Jan;323:113069. Epub 2019 Oct 23 doi: 10.1016/j.expneurol.2019.113069. PMID: 31655048
Stojkovic T
Rev Neurol (Paris) 2016 Dec;172(12):775-778. Epub 2016 Nov 17 doi: 10.1016/j.neurol.2016.06.007. PMID: 27866730
Bergamin G, Boaretto F, Briani C, Pegoraro E, Cacciavillani M, Martinuzzi A, Muglia M, Vettori A, Vazza G, Mostacciuolo ML
Neuromolecular Med 2014 Sep;16(3):540-50. Epub 2014 May 13 doi: 10.1007/s12017-014-8307-9. PMID: 24819634
Benedetti S, Previtali SC, Coviello S, Scarlato M, Cerri F, Di Pierri E, Piantoni L, Spiga I, Fazio R, Riva N, Natali Sora MG, Dacci P, Malaguti MC, Munerati E, Grimaldi LM, Marrosu MG, De Pellegrin M, Ferrari M, Comi G, Quattrini A, Bolino A
Arch Neurol 2010 Dec;67(12):1498-505. doi: 10.1001/archneurol.2010.303. PMID: 21149811

Therapy

Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN)
Brain 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323. PMID: 33415332Free PMC Article

Prognosis

Berti B, Longo G, Mari F, Doccini S, Piccolo I, Donati MA, Moro F, Guerrini R, Santorelli FM, Petruzzella V
BMC Med Genomics 2021 Jun 12;14(1):157. doi: 10.1186/s12920-021-01001-1. PMID: 34118926Free PMC Article
Khani M, Taheri H, Shamshiri H, Moazzeni H, Hardy J, Bras JT, InanlooRahatloo K, Alavi A, Nafissi S, Elahi E
J Neurol 2021 Feb;268(2):640-650. Epub 2020 Sep 8 doi: 10.1007/s00415-020-10171-4. PMID: 32897397
Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN)
Brain 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323. PMID: 33415332Free PMC Article
Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S, Larcher K, Amati-Bonneau P, Latour P, Vignal O, Cazeneuve C, Brice A, Leguern E
JAMA Neurol 2014 Aug;71(8):1036-42. doi: 10.1001/jamaneurol.2014.629. PMID: 24957169
Kabzińska D, Niemann A, Drac H, Huber N, Potulska-Chromik A, Hausmanowa-Petrusewicz I, Suter U, Kochański A
Neurogenetics 2011 May;12(2):145-53. Epub 2011 Mar 2 doi: 10.1007/s10048-011-0276-7. PMID: 21365284

Clinical prediction guides

Narayanan RK, Brewer MH, Perez-Siles G, Ellis M, Ly C, Burgess A, Neumann B, Nicholson GA, Vucic S, Kennerson ML
Hum Mol Genet 2021 Dec 17;31(1):133-145. doi: 10.1093/hmg/ddab228. PMID: 34387338Free PMC Article
Berti B, Longo G, Mari F, Doccini S, Piccolo I, Donati MA, Moro F, Guerrini R, Santorelli FM, Petruzzella V
BMC Med Genomics 2021 Jun 12;14(1):157. doi: 10.1186/s12920-021-01001-1. PMID: 34118926Free PMC Article
Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN)
Brain 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323. PMID: 33415332Free PMC Article
Tamiya G, Makino S, Hayashi M, Abe A, Numakura C, Ueki M, Tanaka A, Ito C, Toshimori K, Ogawa N, Terashima T, Maegawa H, Yanagisawa D, Tooyama I, Tada M, Onodera O, Hayasaka K
Am J Hum Genet 2014 Sep 4;95(3):294-300. Epub 2014 Aug 21 doi: 10.1016/j.ajhg.2014.07.013. PMID: 25152455Free PMC Article
Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S, Larcher K, Amati-Bonneau P, Latour P, Vignal O, Cazeneuve C, Brice A, Leguern E
JAMA Neurol 2014 Aug;71(8):1036-42. doi: 10.1001/jamaneurol.2014.629. PMID: 24957169

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