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Giant axonal neuropathy 2(GAN2)

MedGen UID:
400593
Concept ID:
C1864695
Disease or Syndrome
Synonym: Giant axonal neuropathy 2, autosomal dominant
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): DCAF8 (1q23.2)
 
Monarch Initiative: MONDO:0012411
OMIM®: 610100
Orphanet: ORPHA401964

Definition

Giant axonal neuropathy-2 is an autosomal dominant peripheral axonal neuropathy characterized by onset of distal sensory impairment and lower extremity muscle weakness and atrophy after the second decade. Foot deformities may be present in childhood. More severely affected individuals may develop cardiomyopathy. Sural nerve biopsy shows giant axonal swelling with neurofilament accumulation (summary by Klein et al., 2014). [from OMIM]

Clinical features

From HPO
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).
Hammertoe
MedGen UID:
209712
Concept ID:
C1136179
Anatomical Abnormality
Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Steppage gait
MedGen UID:
98105
Concept ID:
C0427149
Finding
An abnormal gait pattern that arises from weakness of the pretibial and peroneal muscles due to a lower motor neuron lesion. Affected patients have footdrop and are unable to dorsiflex and evert the foot. The leg is lifted high on walking so that the toes clear the ground, and there may be a slapping noise when the foot strikes the ground again.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Peripheral axonal neuropathy
MedGen UID:
266071
Concept ID:
C1263857
Disease or Syndrome
An abnormality characterized by disruption of the normal functioning of peripheral axons.
Onion bulb formation
MedGen UID:
376237
Concept ID:
C1847906
Finding
Repeated episodes of segmental demyelination and remyelination lead to the accumulation of supernumerary Schwann cells around axons, which is referred to as onion bulb formation. This finding affects peripheral nerves.
Impaired distal vibration sensation
MedGen UID:
381262
Concept ID:
C1853767
Finding
A decrease in the ability to perceive vibration in the distal portions of the limbs.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Impaired distal tactile sensation
MedGen UID:
867225
Concept ID:
C4021583
Finding
A reduced sense of touch (tactile sensation) on the skin of the distal limbs. This is usually tested with a wisp of cotton or a fine camel's hair brush, by asking patients to say 'now' each time they feel the stimulus.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
EMG: chronic denervation signs
MedGen UID:
871143
Concept ID:
C4025614
Finding
Evidence of chronic denervation on electromyography.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Giant axonal neuropathy 2 in Orphanet.

Professional guidelines

PubMed

Chakravorty S, Logan R, Elson MJ, Luke RR, Verma S
Sci Rep 2020 Sep 30;10(1):16184. doi: 10.1038/s41598-020-73219-5. PMID: 32999401Free PMC Article
Chen PH, Hu J, Wu J, Huynh DT, Smith TJ, Pan S, Bisnett BJ, Smith AB, Lu A, Condon BM, Chi JT, Boyce M
JCI Insight 2020 Jan 16;5(1) Epub 2019 Nov 26 doi: 10.1172/jci.insight.127751. PMID: 31944090Free PMC Article

Recent clinical studies

Etiology

Bharucha-Goebel DX, Norato G, Saade D, Paredes E, Biancavilla V, Donkervoort S, Kaur R, Lehky T, Fink M, Armao D, Gray SJ, Waite M, Debs S, Averion G, Hu Y, Zein WM, Foley AR, Jain M, Bönnemann CG
Brain 2021 Nov 29;144(10):3239-3250. doi: 10.1093/brain/awab179. PMID: 34114613Free PMC Article
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Echaniz-Laguna A, Cuisset JM, Guyant-Marechal L, Aubourg P, Kremer L, Baaloul N, Verloes A, Beladgham K, Perrot J, Francou B, Latour P
Neurogenetics 2020 Jan;21(1):29-37. Epub 2019 Oct 26 doi: 10.1007/s10048-019-00596-z. PMID: 31655922
Normendez-Martínez MI, Monterde-Cruz L, Martínez R, Marquez-Harper M, Esquitin-Garduño N, Valdes-Flores M, Casas-Avila L, de Leon-Suarez VP, Romero-Díaz VJ, Hidalgo-Bravo A
World J Pediatr 2018 Jun;14(3):298-304. Epub 2018 Jun 6 doi: 10.1007/s12519-018-0140-z. PMID: 29876741
Spencer PS, Kim MS, Sabri MI
Int J Hyg Environ Health 2002 Mar;205(1-2):131-6. doi: 10.1078/1438-4639-00138. PMID: 12018006

Diagnosis

Finsterer J, Löscher WN, Wanschitz J, Iglseder S
J Neuromuscul Dis 2021;8(1):1-23. doi: 10.3233/JND-200518. PMID: 32986679Free PMC Article
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Edem P, Karakaya M, Wirth B, Okur TD, Yiş U
Turk J Pediatr 2019;61(2):275-278. doi: 10.24953/turkjped.2019.02.019. PMID: 31951341
Normendez-Martínez MI, Monterde-Cruz L, Martínez R, Marquez-Harper M, Esquitin-Garduño N, Valdes-Flores M, Casas-Avila L, de Leon-Suarez VP, Romero-Díaz VJ, Hidalgo-Bravo A
World J Pediatr 2018 Jun;14(3):298-304. Epub 2018 Jun 6 doi: 10.1007/s12519-018-0140-z. PMID: 29876741
Spencer PS, Kim MS, Sabri MI
Int J Hyg Environ Health 2002 Mar;205(1-2):131-6. doi: 10.1078/1438-4639-00138. PMID: 12018006

Therapy

Bharucha-Goebel DX, Norato G, Saade D, Paredes E, Biancavilla V, Donkervoort S, Kaur R, Lehky T, Fink M, Armao D, Gray SJ, Waite M, Debs S, Averion G, Hu Y, Zein WM, Foley AR, Jain M, Bönnemann CG
Brain 2021 Nov 29;144(10):3239-3250. doi: 10.1093/brain/awab179. PMID: 34114613Free PMC Article
Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, Goodspeed K, Gray SJ, Kay CN, Boye SL, Boye SE, George LA, Salabarria S, Corti M, Byrne BJ, Tremblay JP
Mol Ther 2021 Feb 3;29(2):464-488. Epub 2020 Dec 10 doi: 10.1016/j.ymthe.2020.12.007. PMID: 33309881Free PMC Article
Mussche S, Devreese B, Nagabhushan Kalburgi S, Bachaboina L, Fox JC, Shih HJ, Van Coster R, Samulski RJ, Gray SJ
Hum Gene Ther 2013 Feb;24(2):209-19. doi: 10.1089/hum.2012.107. PMID: 23316953
Spencer PS, Kim MS, Sabri MI
Int J Hyg Environ Health 2002 Mar;205(1-2):131-6. doi: 10.1078/1438-4639-00138. PMID: 12018006
Takebe Y, Koide N, Takahashi G
Neuropediatrics 1981 Nov;12(4):392-404. doi: 10.1055/s-2008-1059670. PMID: 6801537

Prognosis

Echaniz-Laguna A, Cuisset JM, Guyant-Marechal L, Aubourg P, Kremer L, Baaloul N, Verloes A, Beladgham K, Perrot J, Francou B, Latour P
Neurogenetics 2020 Jan;21(1):29-37. Epub 2019 Oct 26 doi: 10.1007/s10048-019-00596-z. PMID: 31655922
Normendez-Martínez MI, Monterde-Cruz L, Martínez R, Marquez-Harper M, Esquitin-Garduño N, Valdes-Flores M, Casas-Avila L, de Leon-Suarez VP, Romero-Díaz VJ, Hidalgo-Bravo A
World J Pediatr 2018 Jun;14(3):298-304. Epub 2018 Jun 6 doi: 10.1007/s12519-018-0140-z. PMID: 29876741
Aharoni S, Barwick KE, Straussberg R, Harlalka GV, Nevo Y, Chioza BA, McEntagart MM, Mimouni-Bloch A, Weedon M, Crosby AH
BMC Med Genet 2016 Nov 16;17(1):82. doi: 10.1186/s12881-016-0343-x. PMID: 27852232Free PMC Article
Tazir M, Vallat JM, Bomont P, Zemmouri R, Sindou P, Assami S, Nouioua S, Hammadouche T, Grid D, Koenig M
Neuromuscul Disord 2002 Nov;12(9):849-52. doi: 10.1016/s0960-8966(02)00029-9. PMID: 12398836
Ben Hamida C, Cavalier L, Belal S, Sanhaji H, Nadal N, Barhoumi C, M'Rissa N, Marzouki N, Mandel JL, Ben Hamida M, Koenig M, Hentati F
Neurogenetics 1997 Sep;1(2):129-33. doi: 10.1007/s100480050019. PMID: 10732815

Clinical prediction guides

Bharucha-Goebel DX, Norato G, Saade D, Paredes E, Biancavilla V, Donkervoort S, Kaur R, Lehky T, Fink M, Armao D, Gray SJ, Waite M, Debs S, Averion G, Hu Y, Zein WM, Foley AR, Jain M, Bönnemann CG
Brain 2021 Nov 29;144(10):3239-3250. doi: 10.1093/brain/awab179. PMID: 34114613Free PMC Article
Echaniz-Laguna A, Cuisset JM, Guyant-Marechal L, Aubourg P, Kremer L, Baaloul N, Verloes A, Beladgham K, Perrot J, Francou B, Latour P
Neurogenetics 2020 Jan;21(1):29-37. Epub 2019 Oct 26 doi: 10.1007/s10048-019-00596-z. PMID: 31655922
Normendez-Martínez MI, Monterde-Cruz L, Martínez R, Marquez-Harper M, Esquitin-Garduño N, Valdes-Flores M, Casas-Avila L, de Leon-Suarez VP, Romero-Díaz VJ, Hidalgo-Bravo A
World J Pediatr 2018 Jun;14(3):298-304. Epub 2018 Jun 6 doi: 10.1007/s12519-018-0140-z. PMID: 29876741
Fu J, Dai S, Lu Y, Wu R, Wang Z, Yuan Y, Lv H
Neuromuscul Disord 2017 Aug;27(8):760-765. Epub 2017 Apr 20 doi: 10.1016/j.nmd.2017.04.001. PMID: 28495047
Jaffer F, Murphy SM, Scoto M, Healy E, Rossor AM, Brandner S, Phadke R, Selcen D, Jungbluth H, Muntoni F, Reilly MM
J Peripher Nerv Syst 2012 Jun;17(2):210-6. doi: 10.1111/j.1529-8027.2012.00409.x. PMID: 22734908

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