Giant axonal neuropathy

review of Giant axonal neuropathy -
pediatric medicine :
dr.mahajna mohammad
Tel-Aviv Uni

1. Giant axonal neuropathy review Mahajna Mohammad Sackler faculty of medicine ,Tel-Aviv Uni.

2. Introduction Peripheral neuropathy  ( PN ) is damage to or disease affecting  nerves , which may impair sensation, movement, gland or organ function, or other aspects of health, depending on the type of nerve affected.

3. Classification Peripheral neuropathy may be classified according to: N umber and distribution of nerves Mononeuropathy (e.g.  compression neuropathy: Carpal tunnel syndrome,  axillary nerve palsy) mononeuritis multiplex : asymmetrical ( e.g cyo ,SLE,parvoB19 , lyme , sarco ) polyneuropathy T ype of nerve fiber predominantly affected motor, sensory autonomic Process affecting the nerves inflammation ( neuritis) compression (compression neuropathy) chemotherapy (chemotherapy-induced peripheral neuropathy).

4. Causes Genetic diseases Friedreich's ataxia, Fabry dis,CMT  hereditary neuropathy with liability to pressure palsy , HMSN Metabolic and endocrine diseases:  diabetes   CRF,  porphyria, amyloidosis, liver failure,  hypothyroidism Toxic  & drugs: Chemo (vincristine), Abx ( metronidazole, phenytoin, nitrofurantoin,  isoniazid )  heavy metals ,excess intake of vitamin B 6  (pyridoxine ). Inflammatory diseases:  Guillain– Barré syndrome, [22]  systemic lupus erythematosus, leprosy, multiple sclerosis, [22]   Sjögren's syndrome,  Babesiosis , Lyme disease, [22] vasculitis, [22]   sarcoidosis Vitamin deficiency states:  Vitamin B 12  ( Methylcobalamin ), [22]  vitamin A, vitamin E, vitamin B 1  (thiamin ) Physical trauma (compression , pinching, cutting) Others :  electric shock, HIV, [22][29]  malignant disease, radiation, shingles, MGUS (Monoclonal gammopathy of undetermined significance). [30]

5. Distribution

6. Axonal Vs demyelinating

7. Giant axonal neuropathy a severe neurodegenerative disorder of the peripheral and central nervous system that becomes clinically apparent in early childhood It is transmitted as an autosomal recessive trait (25% likelihood) mutated GAN gene encodes for a cytoskeletal protein called gigaxonin Abnormal gigaxonin is presumed to be responsible for the generalized disorganization of cytoskeletal intermediate filaments Characterized by abnormal Intermediate Filament Organization Focal axonal enlargements in peripheral and central nervous system myelin sheath is intact

8. Manifestations hair tends to be red and kinky, High forehead Long eyelashes Manifestations of central nervous system cerebellar signs nystagmus Spasticity optic atrophy , opthalmoplegia Babinski's sign may be present  Manifestations of peripheral nervous system Gait disturbance Muscle weakness Atrophy loss of sensation areflexia Treiber -Held, et al. Neuropediatrics 25 (2):89-93 (1994). Maia, et al. Neuropediatrics 19 (1):10-15 (1988).

9. Diagnosis conformation– sural nerve biopsy The pathological hallmark is the disorganization of the intermediate filament network of the cytoskeleton, with axons being predominantly affected . Control GAN diagnosis is established by microscopy of scalp hair MRI MR spectroscopy of the brain ; confirmed by sural nerve biopsy and/or by genetic studies, if available, of the GAN gene

10. Molecular Diagnosis is only available on a research basis. Current diagnosis based on : nerve biopsy showing thinly myelinated, enlarged axons nerve conduction studies showing reduced nerve conduction velocity ( NCV ) severely reduced compound motor action potentials ( CMAP ) absent sensory nerve action potentials ( SNAP ) abnormal visual evoked responses EEG showing increased slow wave activity MRI showing cerebellar and white matter abnormalities : High signals on T 2  sequences in the anterior and posterior periventricular regions as well as the cerebellar white matter Ding, et al. Journal of Cell Biology 158 (3):427-433 (2002). Giant Axonal Neuropathy Gregor Kuhlenbäumer , MD, PhD, Vincent Timmerman, PhD, and Pascale Bomont , PhD. Initial Posting: January 9, 2003; Last Update: October 9, 2014.

11. Demir E, Bomont P, Erdem S, Cavalier L, Demirci M, Kose G, Muftuoglu S, Cakar AN, Tan E, Aysun S, Topcu M, Guicheney P, Koenig M, Topaloglu H. Giant axonal neuropathy: clinical and genetic study in six cases. J Neurol Neurosurg Psychiatry. 2005;76:825–32.

12. Management Treatment of manifestations : goals are to optimize intellectual and physical development A multidisciplinary team :(pediatric) neurologists, orthopedic surgeons, physiotherapists, psychologists, and speech and occupational therapists is recommended; speech therapy to improve communication , occupational therapy to maximize independence in activities of daily living , physiotherapy to preserve mobility as long as possible, early intervention and special education ; orthopedic surgery as needed for foot deformities ; ophthalmologic treatment as needed for diplopia .

13. Management Prevention of secondary complications: For wheelchair-bound or bedridden individuals: prophylaxis and frequent examination for decubitus ulcers . Surveillance :  At least yearly reassessment of intellectual abilities peripheral neuropathy, ataxia, spasticity, and cranial nerve dysfunction.

14. Genetic counseling. GAN is inherited in an  autosomal recessive   manner : At conception: each sib of an  affected  individual has: a 25% chance of being affected , a 50% chance of being an asymptomatic  carrier , a 25% chance of being unaffected and not a carrier . Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the  GAN  pathogenic variants in a family are known . Preimplantation genetic diagnosis (PGD)  may be an option for some families in which the  GAN  pathogenic variants have been identified. Koop O, Schirmacher A, Nelis E, Timmerman V, De Jonghe P, Ringelstein B, Rasic VM, Evrard P, Gärtner J, Claeys KG, Appenzeller S, Rautenstrauss B, Hühne K, Ramos-Arroyo MA, Wörle H, Moilanen JS, Hammans S, Kuhlenbäumer G. Genotype-phenotype analysis in patients with giant axonal neuropathy (GAN).  Neuromuscul Disord . 2007;17:624–30. [ PubMed ]

15. prognosis Most individuals become wheelchair dependent in the second decade of life bedridden with severe polyneuropathy, ataxia, and dementia . Death usually occurs in the third decade.