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Axonal loss

MedGen UID:
316962
Concept ID:
C1832338
Finding
HPO: HP:0003447

Definition

A reduction in the number of axons in the peripheral nervous system. [from HPO]

Conditions with this feature

Charcot-Marie-Tooth disease type 4D
MedGen UID:
371304
Concept ID:
C1832334
Disease or Syndrome
Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive disorder of the peripheral nervous system characterized by early-onset distal muscle weakness and atrophy, foot deformities, and sensory loss affecting all modalities. Affected individuals develop deafness by the third decade of life (summary by Okamoto et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive Charcot-Marie-Tooth disease, see CMT4A (214400).
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type A
MedGen UID:
381530
Concept ID:
C1854988
Disease or Syndrome
Molybdenum cofactor deficiency (MoCD) represents a spectrum, with some individuals experiencing significant signs and symptoms in the neonatal period and early infancy (termed early-onset or severe MoCD) and others developing signs and symptoms in childhood or adulthood (termed late-onset or mild MoCD). Individuals with early-onset MoCD typically present in the first days of life with severe encephalopathy, including refractory seizures, opisthotonos, axial and appendicular hypotonia, feeding difficulties, and apnea. Head imaging may demonstrate loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of focal lesional injury within the sulci), diffusely elevated T2-weighted signal, and panlobar diffusion restriction throughout the forebrain and midbrain with relative sparring of the brain stem. Prognosis for early-onset MoCD is poor, with about 75% succumbing in infancy to secondary complications of their neurologic disability (i.e., pneumonia). Late-onset MoCD is typically characterized by milder symptoms, such as acute neurologic decompensation in the setting of infection. Episodes vary in nature but commonly consist of altered mental status, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia. These features may improve after resolution of the inciting infection or progress in a gradual or stochastic manner over the lifetime. Brain imaging may be normal or may demonstrate T2-weighted hyperintense or cystic lesions in the globus pallidus, thinning of the corpus callosum, and cerebellar atrophy.
Sulfite oxidase deficiency due to molybdenum cofactor deficiency type B
MedGen UID:
340760
Concept ID:
C1854989
Disease or Syndrome
Molybdenum cofactor deficiency (MoCD) represents a spectrum, with some individuals experiencing significant signs and symptoms in the neonatal period and early infancy (termed early-onset or severe MoCD) and others developing signs and symptoms in childhood or adulthood (termed late-onset or mild MoCD). Individuals with early-onset MoCD typically present in the first days of life with severe encephalopathy, including refractory seizures, opisthotonos, axial and appendicular hypotonia, feeding difficulties, and apnea. Head imaging may demonstrate loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of focal lesional injury within the sulci), diffusely elevated T2-weighted signal, and panlobar diffusion restriction throughout the forebrain and midbrain with relative sparring of the brain stem. Prognosis for early-onset MoCD is poor, with about 75% succumbing in infancy to secondary complications of their neurologic disability (i.e., pneumonia). Late-onset MoCD is typically characterized by milder symptoms, such as acute neurologic decompensation in the setting of infection. Episodes vary in nature but commonly consist of altered mental status, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia. These features may improve after resolution of the inciting infection or progress in a gradual or stochastic manner over the lifetime. Brain imaging may be normal or may demonstrate T2-weighted hyperintense or cystic lesions in the globus pallidus, thinning of the corpus callosum, and cerebellar atrophy.
Cerebellar ataxia, benign, with thermoanalgesia
MedGen UID:
349136
Concept ID:
C1859303
Disease or Syndrome
Charcot-Marie-Tooth disease type 4J
MedGen UID:
370808
Concept ID:
C1970011
Disease or Syndrome
Charcot-Marie-Tooth disease type 4J is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from early childhood to adulthood. Most patients have both proximal and distal asymmetric muscle weakness of the upper and lower limbs. There is significant motor dysfunction, followed by variably progressive sensory loss, which may be mild. Nerve conduction studies and nerve biopsies indicate demyelination as well as axonal loss (summary by Nicholson et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Myofibrillar myopathy 6
MedGen UID:
414119
Concept ID:
C2751831
Disease or Syndrome
Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).
Amyotrophic lateral sclerosis type 15
MedGen UID:
477090
Concept ID:
C3275459
Disease or Syndrome
Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the UBQLN2 gene.
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome
MedGen UID:
482853
Concept ID:
C3281223
Disease or Syndrome
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive adult-onset, slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia, impaired vestibular function bilaterally, and non-length-dependent sensory neuropathy (summary by Szmulewicz et al., 2011).
Charcot-Marie-Tooth disease type 1E
MedGen UID:
501212
Concept ID:
C3495591
Disease or Syndrome
A rare subtype of CMT1 characterized by a variable clinical presentation. Onset within the first two years of life with a delay in walking is not uncommon; however, onset may occur later. CMT1E is caused by point mutations in the <i>PMP22</i> (17p12) gene. The disease severity depends on the particular <i>PMP22</i> mutation, with some cases being very mild and even resembling hereditary neuropathy with liability to pressure palsies, while others having an earlier onset with a more severe phenotype (reminiscent of Dejerine-Sottas syndrome) than that seen in CMT1A, caused by gene duplication. These severe cases may also report deafness and much slower motor nerve conduction velocities compared to CMT1A patients.
Spinal muscular atrophy with congenital bone fractures 2
MedGen UID:
907910
Concept ID:
C4225176
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). For a discussion of genetic heterogeneity of spinal muscular atrophy with congenital bone fractures, see SMABF1 (616866).
Spinal muscular atrophy with congenital bone fractures 1
MedGen UID:
896011
Concept ID:
C4225177
Disease or Syndrome
Spinal muscular atrophy with congenital bone fractures is an autosomal recessive severe neuromuscular disorder characterized by onset of severe hypotonia with fetal hypokinesia in utero. This results in congenital contractures, consistent with arthrogryposis multiplex congenita, and increased incidence of prenatal fracture of the long bones. Affected infants have difficulty breathing and feeding and often die in the first days or months of life (summary by Knierim et al., 2016). Genetic Heterogeneity of Spinal Muscular Atrophy With Congenital Bone Fractures See also SMABF2 (616867), caused by mutation in the ASCC1 gene (614215) on chromosome 10q22.
Charcot-Marie-Tooth disease type 4K
MedGen UID:
895560
Concept ID:
C4225246
Disease or Syndrome
Charcot-Marie-Tooth disease type 4K is an autosomal recessive demyelinating peripheral neuropathy characterized by onset in the first decade of distal muscle weakness and atrophy associated with impaired distal sensation. Both upper and lower limbs are affected. Affected individuals may also have nystagmus and late-onset cerebellar ataxia. Laboratory studies show increased serum lactate and isolated mitochondrial complex IV deficiency (summary by Echaniz-Laguna et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).
Charcot-Marie-Tooth disease dominant intermediate E
MedGen UID:
928336
Concept ID:
C4302667
Disease or Syndrome
Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy (summary by Boyer et al., 2011). Isolated focal segmental glomerulosclerosis-5 (FSGS5; 613237) is also caused by heterozygous mutation in the INF2 gene. For a discussion of genetic heterogeneity of CMTDI, see 606482.
Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder
MedGen UID:
1626007
Concept ID:
C4540086
Disease or Syndrome
Childhood-onset neurodegeneration with brain atrophy (CONDBA) is a severe progressive neurodegenerative disorder characterized by loss of motor and cognitive skills between ages 2 and 7 years. Affected individuals may have normal development or mild developmental delay, but all eventually lose all motor skills, resulting in inability to walk, absence of language, and profound intellectual disability. Brain imaging shows progressive cerebral and cerebellar atrophy (summary by Edvardson et al., 2017).
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1
MedGen UID:
1648386
Concept ID:
C4721893
Disease or Syndrome
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. The clinical course of PLOSL can be divided into four stages: 1. The latent stage is characterized by normal early development. 2. The osseous stage (3rd decade of life) is characterized by pain and tenderness, mostly in ankles and feet, usually following strain or injury. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities. 3. In the early neurologic stage (4th decade of life), a change of personality begins to develop insidiously. Affected individuals show a frontal lobe syndrome (loss of judgment, euphoria, loss of social inhibitions, disturbance of concentration, and lack of insight, libido, and motor persistence) leading to serious social problems. 4. The late neurologic stage is characterized by progressive dementia and loss of mobility. Death usually occurs before age 50 years.
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
MedGen UID:
1648391
Concept ID:
C4748527
Disease or Syndrome
Stress-induced childhood-onset neurodegeneration with variable ataxia and seizures (CONDSIAS) is an autosomal recessive neurodegenerative disorder with onset in the first years of life following normal early development. Patient have cyclic episodic deterioration in response to stress, such as infection or febrile illness. The severity is highly variable: some patients develop seizures early in life that are associated with loss of developmental milestones and early sudden death in childhood, whereas others present at a later age with muscle weakness, gait ataxia, impaired speech, more subtle clinical deterioration, and cognitive decline. Neurologic involvement includes gait ataxia, cerebellar signs associated with cerebellar atrophy, generalized brain atrophy, impaired intellectual development, hearing loss, and peripheral neuropathy (summary by Ghosh et al., 2018).
Charcot-Marie-Tooth disease, axonal, IIa 2II
MedGen UID:
1824000
Concept ID:
C5774227
Disease or Syndrome
Axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is an autosomal dominant neurologic disorder characterized by a slowly progressive sensorimotor peripheral neuropathy affecting mainly the lower limbs, resulting in distal muscle weakness and atrophy and subsequent walking difficulties. Some patients may have upper limb involvement with atrophy of the intrinsic hand muscles. The age at onset is highly variable, ranging from infancy to adulthood. Electrophysiologic studies are usually consistent with an axonal process, although some may show intermediate or even demyelinating values (Park et al., 2020; Ando et al., 2022). One family with possible autosomal recessive inheritance has been reported (Bogdanova-Mihaylova et al., 2021). For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Professional guidelines

PubMed

Correale J, Gaitán MI, Ysrraelit MC, Fiol MP
Brain 2017 Mar 1;140(3):527-546. doi: 10.1093/brain/aww258. PMID: 27794524
Goodman AD, Gyang T, Smith AD 3rd
Expert Opin Investig Drugs 2016 Oct;25(10):1231-7. Epub 2016 Aug 22 doi: 10.1080/13543784.2016.1221924. PMID: 27501293
Dalakas MC; Medscape
Nat Rev Neurol 2011 Aug 16;7(9):507-17. doi: 10.1038/nrneurol.2011.121. PMID: 21844897

Recent clinical studies

Etiology

Traub R, Chaudhry V
Semin Neurol 2023 Oct;43(5):791-798. Epub 2023 Oct 3 doi: 10.1055/s-0043-1775750. PMID: 37788681
Liu B, Zhou L, Sun C, Wang L, Zheng Y, Hu B, Qiao K, Zhao C, Lu J, Lin J
Ann Clin Transl Neurol 2023 Jun;10(6):944-952. Epub 2023 Apr 14 doi: 10.1002/acn3.51775. PMID: 37060203Free PMC Article
McKee AC, Daneshvar DH, Alvarez VE, Stein TD
Acta Neuropathol 2014 Jan;127(1):29-51. Epub 2013 Dec 24 doi: 10.1007/s00401-013-1230-6. PMID: 24366527Free PMC Article
Graus F, Dalmau J
Curr Opin Neurol 2013 Oct;26(5):489-95. doi: 10.1097/WCO.0b013e328364c020. PMID: 23892629
Compston A, Coles A
Lancet 2008 Oct 25;372(9648):1502-17. doi: 10.1016/S0140-6736(08)61620-7. PMID: 18970977

Diagnosis

Chang MC, Yang S
Ann Palliat Med 2023 Mar;12(2):390-398. Epub 2023 Feb 8 doi: 10.21037/apm-22-693. PMID: 36786097
Correale J, Gaitán MI, Ysrraelit MC, Fiol MP
Brain 2017 Mar 1;140(3):527-546. doi: 10.1093/brain/aww258. PMID: 27794524
McKee AC, Daneshvar DH, Alvarez VE, Stein TD
Acta Neuropathol 2014 Jan;127(1):29-51. Epub 2013 Dec 24 doi: 10.1007/s00401-013-1230-6. PMID: 24366527Free PMC Article
Toosy AT, Mason DF, Miller DH
Lancet Neurol 2014 Jan;13(1):83-99. doi: 10.1016/S1474-4422(13)70259-X. PMID: 24331795
Compston A, Coles A
Lancet 2008 Oct 25;372(9648):1502-17. doi: 10.1016/S0140-6736(08)61620-7. PMID: 18970977

Therapy

Dalakas MC
Neurotherapeutics 2021 Oct;18(4):2397-2418. Epub 2021 Nov 11 doi: 10.1007/s13311-021-01108-4. PMID: 34766257Free PMC Article
Fumagalli G, Monza L, Cavaletti G, Rigolio R, Meregalli C
Front Immunol 2020;11:626687. Epub 2021 Feb 4 doi: 10.3389/fimmu.2020.626687. PMID: 33613570Free PMC Article
Nally FK, De Santi C, McCoy CE
Cells 2019 Jun 5;8(6) doi: 10.3390/cells8060543. PMID: 31195710Free PMC Article
Graus F, Dalmau J
Curr Opin Neurol 2013 Oct;26(5):489-95. doi: 10.1097/WCO.0b013e328364c020. PMID: 23892629
Sättler MB, Bähr M
Exp Neurol 2010 Sep;225(1):40-7. Epub 2009 Aug 27 doi: 10.1016/j.expneurol.2009.08.016. PMID: 19716365

Prognosis

Traub R, Chaudhry V
Semin Neurol 2023 Oct;43(5):791-798. Epub 2023 Oct 3 doi: 10.1055/s-0043-1775750. PMID: 37788681
Uncini A, Santoro L
Clin Neurophysiol 2020 Oct;131(10):2367-2374. Epub 2020 Aug 10 doi: 10.1016/j.clinph.2020.07.014. PMID: 32828039
McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee HS, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC
Brain 2013 Jan;136(Pt 1):43-64. Epub 2012 Dec 2 doi: 10.1093/brain/aws307. PMID: 23208308Free PMC Article
Miller E
Adv Exp Med Biol 2012;724:222-38. doi: 10.1007/978-1-4614-0653-2_17. PMID: 22411246
Compston A, Coles A
Lancet 2008 Oct 25;372(9648):1502-17. doi: 10.1016/S0140-6736(08)61620-7. PMID: 18970977

Clinical prediction guides

Traub R, Chaudhry V
Semin Neurol 2023 Oct;43(5):791-798. Epub 2023 Oct 3 doi: 10.1055/s-0043-1775750. PMID: 37788681
Liu B, Zhou L, Sun C, Wang L, Zheng Y, Hu B, Qiao K, Zhao C, Lu J, Lin J
Ann Clin Transl Neurol 2023 Jun;10(6):944-952. Epub 2023 Apr 14 doi: 10.1002/acn3.51775. PMID: 37060203Free PMC Article
Uncini A, Santoro L
Clin Neurophysiol 2020 Oct;131(10):2367-2374. Epub 2020 Aug 10 doi: 10.1016/j.clinph.2020.07.014. PMID: 32828039
McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, Lee HS, Wojtowicz SM, Hall G, Baugh CM, Riley DO, Kubilus CA, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC
Brain 2013 Jan;136(Pt 1):43-64. Epub 2012 Dec 2 doi: 10.1093/brain/aws307. PMID: 23208308Free PMC Article
Miller DH, Chard DT, Ciccarelli O
Lancet Neurol 2012 Feb;11(2):157-69. doi: 10.1016/S1474-4422(11)70274-5. PMID: 22265211

Recent systematic reviews

Christodoulou MV, Petkou E, Atzemoglou N, Gkorla E, Karamitrou A, Simos YV, Bellos S, Bekiari C, Kouklis P, Konitsiotis S, Vezyraki P, Peschos D, Tsamis KI
Hum Cell 2024 Jan;37(1):9-53. Epub 2023 Nov 21 doi: 10.1007/s13577-023-01006-1. PMID: 37985645Free PMC Article
Clement Freiberg J, von Spreckelsen A, Kolko M, Azuara-Blanco A, Virgili G
Cochrane Database Syst Rev 2022 Jun 10;6(6):CD013817. doi: 10.1002/14651858.CD013817.pub2. PMID: 35686679Free PMC Article
Lopez-Escamez JA, Attyé A
J Vestib Res 2019;29(2-3):121-129. doi: 10.3233/VES-180646. PMID: 31356219
Zare-Shahabadi A, Rashidian A, Sahraian MA, Rezaei N
Expert Rev Clin Immunol 2015;11(12):1291-5. Epub 2015 Oct 21 doi: 10.1586/1744666X.2015.1102059. PMID: 26488634
Gouw AA, Seewann A, van der Flier WM, Barkhof F, Rozemuller AM, Scheltens P, Geurts JJ
J Neurol Neurosurg Psychiatry 2011 Feb;82(2):126-35. Epub 2010 Oct 9 doi: 10.1136/jnnp.2009.204685. PMID: 20935330

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