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Giant axonal neuropathy(GAN1)

MedGen UID:
376775
Concept ID:
C1850386
Disease or Syndrome
Synonyms: GAN1; Giant axonal neuropathy 1; GIANT AXONAL NEUROPATHY 1, AUTOSOMAL RECESSIVE
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Giant axonal neuropathy (128207002)
 
Gene (location): GAN (16q23.2)
OMIM®: 256850
Orphanet: ORPHA643

Definition

Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. [from GTR]

Additional descriptions

From GeneReviews
Giant axonal neuropathy (GAN) is an early-onset fatal neurodegenerative disorder. GAN starts as severe peripheral motor and sensory neuropathy during infancy and evolves into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade.  https://www.ncbi.nlm.nih.gov/books/NBK1136
From OMIM
Giant axonal neuropathy is a chronic polyneuropathy of childhood that affects both the peripheral and central nervous systems and is accompanied by characteristically kinky hair and unique posture of legs (see illustrations by Berg et al., 1972; Igisu et al., 1975; Carpenter et al., 1974). Axonal loss and the presence of giant axonal swellings filled with neurofilaments on nerve biopsy are the pathologic hallmark of this neurodegenerative disorder (Tazir et al., 2009). Genetic Heterogeneity of Giant Axonal Neuropathy See also GAN2 (610100), caused by mutation in the DCAF8 gene (615820) on chromosome 1q23.  http://www.omim.org/entry/256850
From GHR
Giant axonal neuropathy is an inherited condition characterized by abnormally large and dysfunctional axons called giant axons. Axons are specialized extensions of nerve cells (neurons) that transmit nerve impulses. Symptoms of the disorder first become apparent in the peripheral nervous system, in which long axons connect the brain and spinal cord (central nervous system) to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. However, axons in the central nervous system are affected as well.The signs and symptoms of giant axonal neuropathy generally begin in early childhood and get worse over time. Most affected individuals first have problems with walking. Later they may lose sensation, strength, and reflexes in their limbs; experience difficulty coordinating movements (ataxia); and require wheelchair assistance. Visual and hearing problems may also occur. Many individuals with this condition have extremely kinky hair as compared to others in their family.Giant axonal neuropathy can also impact the autonomic nervous system, which controls involuntary body processes. Affected individuals may experience problems with the release of urine (neurogenic bladder), constipation, heat intolerance, and reduction in or loss of the ability to sweat.As the disorder worsens, paralysis, seizures, and a gradual decline in mental function (dementia) can also occur. Most people with giant axonal neuropathy do not survive past their twenties.  https://ghr.nlm.nih.gov/condition/giant-axonal-neuropathy

Clinical features

Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Talipes equinovarus
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot anomaly in which one or more of the arches of the foot have flattened out.
Abnormality of the hand
MedGen UID:
6715
Concept ID:
C0018564
Anatomical Abnormality
Alterations or deviations from normal shape or size which result in a disfigurement of the hand.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
The presence of an unusually high plantar arch. Also called high instep, pes cavus refers to a distinctly hollow form of the sole of the foot when it is bearing weight.
Hyporeflexia of lower limbs
MedGen UID:
371881
Concept ID:
C1834696
Finding
Reduced intensity of muscle tendon reflexes in the lower limbs. Reflexes are elicited by stretching the tendon of a muscle, e.g., by tapping.
Areflexia of lower limbs
MedGen UID:
347285
Concept ID:
C1856694
Finding
Inability to elicit tendon reflexes in the lower limbs.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Abnormal pyramidal signs
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Facial paralysis
MedGen UID:
98103
Concept ID:
C0427055
Sign or Symptom
A reduction in the strength of the facial muscles.
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 of lower limbs
MedGen UID:
371881
Concept ID:
C1834696
Finding
Reduced intensity of muscle tendon reflexes in the lower limbs. Reflexes are elicited by stretching the tendon of a muscle, e.g., by tapping.
Sensory axonal neuropathy
MedGen UID:
334116
Concept ID:
C1842587
Finding
An axonal neuropathy of peripheral sensory nerves.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Distal motor neuropathy
MedGen UID:
344318
Concept ID:
C1854570
Finding
Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg.
Areflexia of lower limbs
MedGen UID:
347285
Concept ID:
C1856694
Finding
Inability to elicit tendon reflexes in the lower limbs.
Decreased number of peripheral myelinated nerve fibers
MedGen UID:
346872
Concept ID:
C1858285
Finding
A loss of myelinated nerve fibers in the peripheral nervous system (in general, this finding can be observed on nerve biopsy).
Abnormality of the cerebellum
MedGen UID:
400925
Concept ID:
C1866129
Finding
An abnormality of the cerebellum.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Morphological abnormality of the pyramidal tract
MedGen UID:
892809
Concept ID:
C4021761
Anatomical Abnormality
Any structural abnormality of the pyramidal tract, whose chief element, the corticospinal tract, is the only direct connection between the brain and the spinal cord. In addition to the corticospinal tract, the pyramidal system includes the corticobulbar, corticomesencephalic, and corticopontine tracts.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Facial paralysis
MedGen UID:
98103
Concept ID:
C0427055
Sign or Symptom
A reduction in the strength of the facial muscles.
Proximal muscle weakness
MedGen UID:
325534
Concept ID:
C1838869
Sign or Symptom
A lack of strength of the proximal muscles.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Distal muscle weakness
MedGen UID:
355271
Concept ID:
C1864696
Finding
Reduced strength of the musculature of the distal extremities.
Scoliosis
MedGen UID:
21278
Concept ID:
C0037932
Finding
Deformities of the SPINE characterized by abnormal bending or flexure in the vertebral column. They may be bending forward (KYPHOSIS), backward (LORDOSIS), or sideway (SCOLIOSIS).
Facial paralysis
MedGen UID:
98103
Concept ID:
C0427055
Sign or Symptom
A reduction in the strength of the facial muscles.
Curly hair
MedGen UID:
488919
Concept ID:
C0558165
Finding

Term Hierarchy

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

Professional guidelines

PubMed

Aretz S, Rautenstrauss B, Timmerman V
Eur J Hum Genet 2010 Sep;18(9) Epub 2010 May 26 doi: 10.1038/ejhg.2010.75. PMID: 20512157Free PMC Article

Recent clinical studies

Etiology

Incecik F, Herguner OM, Ceylaner S, Zorludemir S, Altunbasak S
Brain Dev 2015 Sep;37(8):803-7. Epub 2014 Dec 19 doi: 10.1016/j.braindev.2014.12.002. PMID: 25533284
Sharma A, Gokulchandran N, Kulkarni P, Chopra G
Indian J Med Sci 2010 Jan;64(1):41-4. doi: 10.4103/0019-5359.92487. PMID: 22301809
Zhang LP, Zou LP
J Child Neurol 2009 Dec;24(12):1552-6. Epub 2009 Mar 18 doi: 10.1177/0883073809332703. PMID: 19295179
Brenner C, Speck-Martins CE, Farage L, Barker PB
J Magn Reson Imaging 2008 Jul;28(1):236-41. doi: 10.1002/jmri.21425. PMID: 18581347Free PMC Article
Yang Y, Allen E, Ding J, Wang W
Cell Mol Life Sci 2007 Mar;64(5):601-9. doi: 10.1007/s00018-007-6396-4. PMID: 17256086

Diagnosis

Vijaykumar K, Bindu PS, Taly AB, Mahadevan A, Bharath RD, Gayathri N, Nagappa M, Sinha S
J Child Neurol 2015 Jun;30(7):912-5. Epub 2014 Sep 11 doi: 10.1177/0883073814547721. PMID: 25213662
Roth LA, Marra JD, LaMarca NH, Sproule DM
J Child Neurol 2015 May;30(6):741-8. Epub 2014 Sep 3 doi: 10.1177/0883073814542946. PMID: 25186661
Wang L, Zhao D, Wang Z, Zhang W, Lv H, Liu X, Meng L, Yuan Y
Muscle Nerve 2014 Aug;50(2):200-5. Epub 2014 May 17 doi: 10.1002/mus.24130. PMID: 24273072
Roth LA, Johnson-Kerner BL, Marra JD, LaMarca NH, Sproule DM
Neuromuscul Disord 2014 Jan;24(1):48-55. Epub 2013 Jul 24 doi: 10.1016/j.nmd.2013.06.007. PMID: 23890932
Xu M, Da YW, Liu L, Wang F, Jia JP
J Child Neurol 2013 Oct;28(10):1316-9. Epub 2012 Dec 17 doi: 10.1177/0883073812467688. PMID: 23248352

Therapy

Babar MU, Hakeem H, Khan S
BMJ Case Rep 2017 Mar 27;2017 doi: 10.1136/bcr-2016-219105. PMID: 28348263
Roth LA, Marra JD, LaMarca NH, Sproule DM
J Child Neurol 2015 May;30(6):741-8. Epub 2014 Sep 3 doi: 10.1177/0883073814542946. PMID: 25186661
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
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. PMID: 12398836
Mitchell A, Moskovits PE
Anaesthesia 1991 Jun;46(6):469-70. PMID: 2048666

Prognosis

Almeida HL Jr, Garcias G, Silva RM, Batista SL, Pasetto F
An Bras Dermatol 2016 Sep-Oct;91(5 suppl 1):125-127. doi: 10.1590/abd1806-4841.20164677. PMID: 28300918Free PMC Article
Koichihara R, Saito T, Ishiyama A, Komaki H, Yuasa S, Saito Y, Nakagawa E, Sugai K, Shiihara T, Shioya A, Saito Y, Higuchi Y, Hashiguchi A, Takashima H, Sasaki M
Brain Dev 2016 Mar;38(3):350-3. Epub 2015 Sep 14 doi: 10.1016/j.braindev.2015.09.001. PMID: 26381321
Roth LA, Marra JD, LaMarca NH, Sproule DM
J Child Neurol 2015 May;30(6):741-8. Epub 2014 Sep 3 doi: 10.1177/0883073814542946. PMID: 25186661
Hentati F, Hentati E, Amouri R
Handb Clin Neurol 2013;115:933-8. doi: 10.1016/B978-0-444-52902-2.00052-7. PMID: 23931822
Abu-Rashid M, Mahajnah M, Jaber L, Kornreich L, Bar-On E, Basel-Vanagaite L, Soffer D, Koenig M, Straussberg R
Eur J Paediatr Neurol 2013 May;17(3):259-64. Epub 2013 Jan 16 doi: 10.1016/j.ejpn.2012.10.012. PMID: 23332420

Clinical prediction guides

Koichihara R, Saito T, Ishiyama A, Komaki H, Yuasa S, Saito Y, Nakagawa E, Sugai K, Shiihara T, Shioya A, Saito Y, Higuchi Y, Hashiguchi A, Takashima H, Sasaki M
Brain Dev 2016 Mar;38(3):350-3. Epub 2015 Sep 14 doi: 10.1016/j.braindev.2015.09.001. PMID: 26381321
Johnson-Kerner BL, Ahmad FS, Diaz AG, Greene JP, Gray SJ, Samulski RJ, Chung WK, Van Coster R, Maertens P, Noggle SA, Henderson CE, Wichterle H
Hum Mol Genet 2015 Mar 1;24(5):1420-31. Epub 2014 Nov 4 doi: 10.1093/hmg/ddu556. PMID: 25398950Free PMC Article
Roth LA, Marra JD, LaMarca NH, Sproule DM
J Child Neurol 2015 May;30(6):741-8. Epub 2014 Sep 3 doi: 10.1177/0883073814542946. PMID: 25186661
Mahammad S, Murthy SN, Didonna A, Grin B, Israeli E, Perrot R, Bomont P, Julien JP, Kuczmarski E, Opal P, Goldman RD
J Clin Invest 2013 May;123(5):1964-75. Epub 2013 Apr 15 doi: 10.1172/JCI66387. PMID: 23585478Free PMC Article
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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