Heterogeneity of axonal pathology in chinese patients with giant axonal neuropathy

Wang, Lu; Zhao, Danhua; Wang, Zhaoxia; Zhang, Wei; Lv, He; Liu, Xiao; Meng, Lingchao; Yuan, Yun

doi:10.1002/mus.24130

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…Unique kinky or curly hair is another distinctive clinical feature that develops as a result of keratin filament disruption; however, it is not an essential diagnostic feature. (Abu‐Rashid et al, 2013 ; Hentati et al, 2013 ; Normendez‐Martínez et al, 2018 ; Wang et al, 2014 ). The onset of disease could be varied though the majority of patients, it usually presents at 3–4 years of age (Akagi et al, 2012 ; Johnson‐Kerner et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…Magnetic resonance imaging (MRI) reveals several nonspecific abnormal findings such as generalized brain atrophy as well as abnormal signals in cerebellar white matter, middle and superior cerebellar peduncles, posteromedial part of thalamus, internal and external capsules, bilateral periventricular and subcortical white matter, brain stem, and dentate nucleus. Imaging may be normal in the early phases of the disease; however, abnormal findings appear as the disease progresses (Abu‐Rashid et al, 2013 ; Hentati et al, 2013 ; Wang et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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

Ashrafi

Dehnavi

Tavasoli

et al. 2023

Molec Gen & Gen Med

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Background Giant axonal neuropathy (GAN) is a progressive childhood hereditary polyneuropathy that affects both the peripheral and central nervous systems. Disease‐causing variants in the gigaxonin gene (GAN) cause autosomal recessive giant axonal neuropathy. Facial weakness, nystagmus, scoliosis, kinky or curly hair, pyramidal and cerebellar signs, and sensory and motor axonal neuropathy are the main symptoms of this disorder. Here, we report two novel variants in the GAN gene from two unrelated Iranian families. Methods Clinical and imaging data of patients were recorded and evaluated, retrospectively. Whole‐exome sequencing (WES) was undertaken in order to detect disease‐causing variants in participants. Confirmation of a causative variant in all three patients and their parents was carried out using Sanger sequencing and segregation analysis. In addition, for comparing to our cases, we reviewed all relevant clinical data of previously published cases of GAN between the years 2013–2020. Results Three patients from two unrelated families were included. Using WES, we identified a novel nonsense variant [NM_022041.3:c.1162del (p.Leu388Ter)], in a 7‐year‐old boy of family 1, and a likely pathogenic missense variant [NM_022041.3:c.370T>A (p.Phe124Ile)], in two affected siblings of the family 2. Clinical examination revealed typical features of GAN‐1 in all three patients, including walking difficulties, ataxic gait, kinky hair, sensory‐motor polyneuropathy, and nonspecific neuroimaging abnormalities. Review of 63 previously reported cases of GAN indicated unique kinky hair, gait problem, hyporeflexia/areflexia, and sensory impairment were the most commonly reported clinical features. Conclusions One homozygous nonsense variant and one homozygous missense variant in the GAN gene were discovered for the first time in two unrelated Iranian families that expand the mutation spectrum of GAN. Imaging findings are nonspecific, but the electrophysiological study in addition to history is helpful to achieve the diagnosis. The molecular test confirms the diagnosis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ashrafi

Dehnavi

Tavasoli

et al. 2023

Molec Gen & Gen Med

View full text Add to dashboard Cite

show abstract

“…Specifically, gigaxonin plays an important role in the breakdown of neurofilament (NF) [ 8 ], where the cellular hallmark of GAN pathology is the formation of its large aggregates [ 2 , 3 , 5 ]. According to the Leiden Open Variation Database (LOVD) (updated 2022), National Center for Biotechnology Information (NCBI) (updated 2022), and the mutation summary reported by Lescouzères and Bomont, P. (2020), there are 89 variants that lead to manifestation of GAN ( Figure 1 ) [ 5 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic Approaches for the Treatment of Giant Axonal Neuropathy

Shirakaki

Roshmi

Yokota

2022

JPM

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Giant axonal neuropathy (GAN) is a pediatric, hereditary, neurodegenerative disorder that affects both the central and peripheral nervous systems. It is caused by mutations in the GAN gene, which codes for the gigaxonin protein. Gigaxonin plays a role in intermediate filament (IF) turnover hence loss of function of this protein leads to IF aggregates in various types of cells. These aggregates can lead to abnormal cellular function that manifests as a diverse set of symptoms in persons with GAN including nerve degeneration, cognitive issues, skin diseases, vision loss, and muscle weakness. GAN has no cure at this time. Currently, an adeno-associated virus (AAV) 9-mediated gene replacement therapy is being tested in a phase I clinical trial for the treatment of GAN. This review paper aims to provide an overview of giant axonal neuropathy and the current efforts at developing a treatment for this devastating disease.

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Giant axonal neuropathy (GAN) in an 8‐year‐old girl caused by a homozygous pathogenic splicing variant in GAN gene

Guo

Su²,

Zhu

et al. 2021

American J of Med Genetics Pt A

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Giant axonal neuropathy (GAN) is a progressive disease that involves the peripheral and central nervous systems. This neurodegenerative disease is caused by variants in the GAN gene encoding gigaxonin, and is inherited in an autosomal recessive manner. Herein, we performed whole‐exome sequencing on a 8‐year‐old child with dense, curly hair, weakness in both lower limbs, and abnormal MRI. The child was born to consanguineous parents. Our results revealed that the child carried the c.1373+1G>A homozygous pathogenic variant of the GAN gene, while both parents were heterozygous carriers. According to the validation at the cDNA levels, the splicing variant led to the skipping of exon 8 and affected the Kelch domain's formation. Unlike the previously reported cases of GAN, the child's clinical manifestations revealed peripheral nervous system involvement, no vertebral signs, cerebellar signs, and spasticity, but only MRI abnormalities. These results suggested that the patient's central nervous system was mildly involved, which may be related to the genotype. In order to further clarify the correlation between GAN genotype and phenotype, combined with this patient, 54 cases of reported homozygous variants of the GAN gene were merged for the analysis of genotype and phenotype. The results revealed a certain correlation between the GAN gene variant domain and the patient's clinical phenotype, such as central nervous system involvement and age of onset.

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Heterogeneity of axonal pathology in chinese patients with giant axonal neuropathy

Abstract: Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular-like structures appear in the classical type of this neuropathy.

Cited by 6 publications

References 21 publications

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

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

Genetic Approaches for the Treatment of Giant Axonal Neuropathy

Giant axonal neuropathy (GAN) in an 8‐year‐old girl caused by a homozygous pathogenic splicing variant in GAN gene

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