Giant axonal neuropathy

Hentati, Fayçal; Hentati, Emna; Amouri, Rim

doi:10.1016/b978-0-444-52902-2.00052-7

Cited by 13 publications

(10 citation statements)

References 20 publications

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“…The classical form of giant axonal neuropathy [GAN, MIM #256850], is an autosomal recessive progressive neurodegenerative condition of the peripheral and central nervous systems [1]. A distinctive feature of the phenotype is the presence of “kinky” hair (tightly curled lacklustre hair distinctive from that of the parents) and long eyelashes.…”

Section: Introductionmentioning

confidence: 99%

“…A distinctive feature of the phenotype is the presence of “kinky” hair (tightly curled lacklustre hair distinctive from that of the parents) and long eyelashes. Central nervous system (CNS) involvement is variable and includes optic atrophy, nystagmus, intellectual disability and spasticity [1]. GAN is an axonal neuropathy that is typically of infantile onset and diagnosed in early childhood [2, 3] with most affected children becoming wheelchair dependent by the second decade [3, 4].…”

Section: Introductionmentioning

confidence: 99%

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Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel

et al. 2016

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BackgroundCMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of “kinky” hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation.MethodsAn Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair.ResultsHere we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement.ConclusionsOur findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel

et al. 2016

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“…We did not observe major differences in lamin-A/C and B1 expression (Fig.2A) or Lamin B1 localization (Supplemental Fig.3) in the parental line versus the isogenic control cells. However, by immunoblot we observed variable vimentin expression, such that four patient lines (2, 5, 6, 7) expressed detectable levels of vimentin (Vim + ), while the remaining patient lines (1,3,4) did not (Vim - ), similar to the 15CA non-GAN control and the patient 7 isogenic clones (Fig. 2A) .…”

Section: Resultsmentioning

confidence: 77%

Intermediate filament dysregulation and astrocytopathy in the human disease model ofKLHL16mutation in giant axonal neuropathy (GAN)

Battaglia

Faridounnia

Beltran

et al. 2023

Preprint

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Giant Axonal Neuropathy (GAN) is a pediatric neurodegenerative disease caused by KLHL16 mutations. KLHL16 encodes gigaxonin, a regulator of intermediate filament (IF) protein turnover. Previous neuropathological studies and our own examination of postmortem GAN brain tissue in the current study revealed significant involvement of astrocytes in GAN. To study the underlying cellular mechanisms, we generated human models of GAN using induced pluripotent stem cells (iPSCs). Skin fibroblasts from seven GAN patients carrying different KLHL16 mutations were reprogrammed to iPSCs, and isogenic controls were derived via CRISPR/Cas9 editing. Neural progenitor cells (NPCs), astrocytes, and brain organoids were generated through directed differentiation. All GAN iPSC lines were deficient for gigaxonin, which was restored in the isogenic clones. While GAN iPSCs displayed normal organization of lamin B1 and keratin IFs, they exhibited patient-specific increased expression and perinuclear bundling of vimentin. Nestin IF morphology was unaffected, but fewer nestin-positive cells were present in GAN NPCs compared to controls. The most dramatic phenotypes were observed in GAN iPSC-astrocytes and brain organoids, which displayed dense perinuclear IF accumulations and abnormal nuclear morphology. GFAP oligomerization and perinuclear aggregation were strongly potentiated in the presence of vimentin, and GAN cells with large perinuclear vimentin aggregates accumulated nuclear KLHL16 mRNA. As an early effector of KLHL16 mutations, vimentin may be a potential target in GAN.

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“…Giant Axonal Neuropathy (GAN; OMIM #256850) is a rare AR genetic disease affecting both the central and the peripheral nervous system and characterised by the presence of enlarged axons with an accumulation of neurofilaments and progressive axonal loss. Clinically the disorder begins in childhood in most of the cases and presenting symptoms include the variable combination of distal limb weakness, areflexia and gait disturbances [56].…”

Section: Cnvs In Inherited Peripheral Neuropathiesmentioning

confidence: 99%

“…The GAN locus was identified by homozygosity mapping in several consanguineous families at chromosome 16q24.1 and since then more than 40 different compound heterozygous or homozygous mutations ( e.g., missense, nonsense, frameshift) have been identified in the GAN gene [56, 57].…”

Section: Cnvs In Inherited Peripheral Neuropathiesmentioning

confidence: 99%

A Review of Copy Number Variants in Inherited Neuropathies

Salpietro

Manole

Efthymiou

et al. 2018

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The rapid development in the last 10-15 years of microarray technologies, such as oligonucleotide array Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphisms (SNP) genotyping array, has improved the identification of fine chromosomal structural variants, ranging in length from kilobases (kb) to megabases (Mb), as an important cause of genetic differences among healthy individuals and also as disease-susceptibility and/or disease-causing factors. Structural genomic variations due to unbalanced chromosomal rearrangements are known as Copy-Number Variants (CNVs) and these include variably sized deletions, duplications, triplications and translocations. CNVs can significantly contribute to human diseases and rearrangements in several dosage-sensitive genes have been identified as an important causative mechanism in the molecular aetiology of Charcot-Marie-Tooth (CMT) disease and of several CMT-related disorders, a group of inherited neuropathies with a broad range of clinical phenotypes, inheritance patterns and causative genes. Duplications or deletions of the dosage-sensitive gene PMP22 mapped to chromosome 17p12 represent the most frequent causes of CMT type 1A and Hereditary Neuropathy with liability to Pressure Palsies (HNPP), respectively. Additionally, CNVs have been identified in patients with other CMT types (e.g., CMT1X, CMT1B, CMT4D) and different hereditary poly- (e.g., giant axonal neuropathy) and focal- (e.g., hereditary neuralgic amyotrophy) neuropathies, supporting the notion of hereditary peripheral nerve diseases as possible genomic disorders and making crucial the identification of fine chromosomal rearrangements in the molecular assessment of such patients. Notably, the application of advanced computational tools in the analysis of Next-Generation Sequencing (NGS) data has emerged in recent years as a powerful technique for identifying a genome-wide scale complex structural variants (e.g., as the ones resulted from balanced rearrangements) and also smaller pathogenic (intragenic) CNVs that often remain beyond the detection limit of most conventional genomic microarray analyses; in the context of inherited neuropathies where more than 70 disease-causing genes have been identified to date, NGS and particularly Whole-Genome Sequencing (WGS) hold the potential to reduce the number of genomic assays required per patient to reach a diagnosis, analyzing with a single test all the Single Nucleotide Variants (SNVs) and CNVs in the genes possibly implicated in this heterogeneous group of disorders.

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Giant axonal neuropathy

Cited by 13 publications

References 20 publications

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel

Intermediate filament dysregulation and astrocytopathy in the human disease model ofKLHL16mutation in giant axonal neuropathy (GAN)

A Review of Copy Number Variants in Inherited Neuropathies

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