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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. Autosomal dominant inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	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).

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Hammertoe

MedGen UID:: 209712
•Concept ID:: C1136179
•: Anatomical Abnormality

Hyperextension of the metatarsal-phalangeal joint with hyperflexion of the proximal interphalangeal (PIP) joint.

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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.

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Areflexia

MedGen UID:: 115943
•Concept ID:: C0234146
•: Finding

Absence of neurologic reflexes such as the knee-jerk reaction.

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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.

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Hyporeflexia

MedGen UID:: 195967
•Concept ID:: C0700078
•: Finding

Reduction of neurologic reflexes such as the knee-jerk reaction.

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Peripheral axonal neuropathy

MedGen UID:: 266071
•Concept ID:: C1263857
•: Disease or Syndrome

An abnormality characterized by disruption of the normal functioning of peripheral axons.

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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.

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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.

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Decreased motor nerve conduction velocity

MedGen UID:: 388130
•Concept ID:: C1858729
•: Finding

A type of decreased nerve conduction velocity that affects the motor neuron.

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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.

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Distal muscle weakness

MedGen UID:: 140883
•Concept ID:: C0427065
•: Finding

Reduced strength of the musculature of the distal extremities.

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Distal amyotrophy

MedGen UID:: 338530
•Concept ID:: C1848736
•: Disease or Syndrome

Muscular atrophy affecting muscles in the distal portions of the extremities.

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EMG: chronic denervation signs

MedGen UID:: 871143
•Concept ID:: C4025614
•: Finding

Evidence of chronic denervation on electromyography.

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Abnormality of limbs
- Hammertoe
- Pes cavus
Abnormality of the cardiovascular system
- Cardiomyopathy
Abnormality of the musculoskeletal system
Abnormality of the nervous system

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVGiant axonal neuropathy
- CROGVGiant axonal neuropathy 1
- CROGVGiant axonal neuropathy 2

Fetal anomaly
- Congenital Systemic Disorder
  - Abnormality of the nervous system
    - Hereditary motor and sensory neuropathy
      - Charcot-Marie-Tooth disease
        Charcot-Marie-Tooth disease type 2
        Giant axonal neuropathy 2

Follow this link to review classifications for Giant axonal neuropathy 2 in Orphanet.

Professional guidelines

PubMed

Expanding the genotype-phenotype correlation of childhood sensory polyneuropathy of genetic origin.

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: 32999401 Free PMC Article

Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment.

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: 31944090 Free PMC Article

See all (2)

Recent clinical studies

Etiology

Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Zielen S, Crawford T, Benatti L, Magnani M, Kieslich M, Ryan M, Meyts I, Gulati S, Borgohain R, Yadav R, Pal P, Hegde A, Kumar S, Venkateswar A, Udani V, Vinayan KP, Nissenkorn A, Fazzi E, Leuzzi V, Stray-Pedersen A, Pietrucha B, Pascual SI, Gouider R, Koenig MK, Wu S, Perlman S, Thye D, Janhofer G, Horn B, Whitehouse W, Lederman H
Lancet Neurol 2024 Sep;23(9):871-882. doi: 10.1016/S1474-4422(24)00220-5. PMID: 39152028

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families.

Ashrafi MR, Dehnavi AZ, Tavasoli AR, Heidari M, Ghahvechi Akbari M, Ronagh AR, Ghafouri M, Mahdieh N, Mohammadi P, Rezaei Z
Mol Genet Genomic Med 2023 Jun;11(6):e2159. Epub 2023 Mar 3 doi: 10.1002/mgg3.2159. PMID: 36866531 Free PMC Article

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

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: 34114613 Free PMC Article

An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.

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

Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion.

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

See all (16)

Diagnosis

Expanding the genetic spectrum of giant axonal neuropathy: Two novel variants in Iranian families.

Orphan Peripheral Neuropathies.

Finsterer J, Löscher WN, Wanschitz J, Iglseder S
J Neuromuscul Dis 2021;8(1):1-23. doi: 10.3233/JND-200518. PMID: 32986679 Free PMC Article

An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.

Giant axonal neuropathy: A differential diagnosis of consideration.

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

Two novel mutations in the GAN gene causing giant axonal neuropathy.

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

See all (28)

Therapy

Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Intrathecal Gene Therapy for Giant Axonal Neuropathy.

Bharucha-Goebel DX, Todd JJ, Saade D, Norato G, Jain M, Lehky T, Bailey RM, Chichester JA, Calcedo R, Armao D, Foley AR, Mohassel P, Tesfaye E, Carlin BP, Seremula B, Waite M, Zein WM, Huryn LA, Crawford TO, Sumner CJ, Hoke A, Heiss JD, Charnas L, Hooper JE, Bouldin TW, Kang EM, Rybin D, Gray SJ, Bönnemann CG; GAN Trial Team
N Engl J Med 2024 Mar 21;390(12):1092-1104. doi: 10.1056/NEJMoa2307952. PMID: 38507752

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Current Clinical Applications of In Vivo Gene Therapy with AAVs.

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: 33309881 Free PMC Article

Aromatic as well as aliphatic hydrocarbon solvent axonopathy.

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

See all (13)

Prognosis

Giant axonal neuropathy: a multicenter retrospective study with genotypic spectrum expansion.

Two novel mutations in the GAN gene causing giant axonal neuropathy.

Genetic heterogeneity in giant axonal neuropathy: an Algerian family not linked to chromosome 16q24.1.

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

Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1.

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

Giant cell hepatitis associated with systemic lupus erythematosus.

Cairns A, McMahon RF
J Clin Pathol 1996 Feb;49(2):183-4. doi: 10.1136/jcp.49.2.183. PMID: 8655694 Free PMC Article

See all (7)