Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis

Johnson-Kerner, Bethany L.; Roth, Lisa A.; Greene, J. P.; Wichterle, Hynek; Sproule, Douglas M.

doi:10.1002/mus.24321

Cited by 54 publications

(60 citation statements)

References 65 publications

(100 reference statements)

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“…Most notably, the signature ultrastructural feature of human GAN, giant axonal swellings packed with accumulations of IFs [1], is very prominent in the GAN KO mouse. The GAN KO mouse also shows the involvement of both peripheral nerves and the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…There is one published case report of a young child with GAN in whom ultrastructural examination of a rectal biopsy revealed abnormal neurons with perikaryal IFs “arranged into interwoven bundles” in the myenteric plexus [8]. Gastrointestinal symptoms, including lactose intolerance, constipation, obstipation, and reflux and regurgitation, are prominent and present in early childhood in GAN patients [1]. Additional signs and symptoms pointing to disturbances in autonomic regulation, such as reduction or loss of sweating ability, blood pressure instability with orthostatic hypotension, and heat intolerance are reported by GAN patient advocacy groups and professional organizations (http://www.hannahshopefund.org).…”

Section: Discussionmentioning

confidence: 99%

“…Giant axonal neuropathy (GAN, OMIM# 256850) is a rare, hereditary, severe motor and sensory axonal neuropathy with central nervous system (CNS) involvement [1]. Onset of symptoms is typically at 3–4 years of age and commonly heralded by clumsiness of gait.…”

Section: Introductionmentioning

confidence: 99%

“…From a clinical standpoint, GAN is characterized by a distally predominant peripheral neuropathy manifested by hypotonia, muscle atrophy, tendon contractures, and areflexia [1]. CNS features include prominent cerebellar dysfunction, reflected in nystagmus, dysarthria, dysmetria and ataxia.…”

Section: Introductionmentioning

confidence: 99%

“…GAN is caused by autosomal recessive loss-of-function mutations in the GAN gene that encodes the protein gigaxonin [1]. Gigaxonin plays a pivotal role in cytoskeletal organization and degradation of intermediate filaments (IFs).…”

Section: Introductionmentioning

confidence: 99%

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Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

et al. 2016

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PURPOSE Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood. METHODS Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice. RESULTS Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice. CONCLUSIONS For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

et al. 2016

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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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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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Giant axonal neuropathy: An updated perspective on its pathology and pathogenesis

Cited by 54 publications

References 65 publications

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease

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

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

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