Measuring Disease Progression in Giant Axonal Neuropathy

Roth, Lisa A.; Marra, Jonathan; LaMarca, Nicole Holuba; Sproule, Douglas M.

doi:10.1177/0883073814542946

Cited by 6 publications

(5 citation statements)

References 30 publications

(40 reference statements)

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“…These IF inclusion bodies in lens epithelial cells appear to be unique to GAN, as similar IF inclusion bodies have not been reported previously in experimental animal models or human diseases. Although lens abnormalities have not been reported in clinical or postmortem studies of human GAN [12–16], we confirmed in a specimen obtained at autopsy that similar appearing, intracytoplasmic inclusion bodies are also present in lens epithelial cells in human GAN (Fig. 2e).…”

supporting

confidence: 75%

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

Armao

Bouldin

Bailey

et al. 2019

Orphanet J Rare Dis

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Giant axonal neuropathy (GAN; ORPHA: 643; OMIM# 256850) is a rare, hereditary, pediatric neurodegenerative disorder associated with intracellular accumulations of intermediate filaments (IFs). GAN knockout (KO) mouse models mirror the IF dysregulation and widespread nervous system pathology seen in human GAN. Validation of therapeutic efficacy and viral vector delivery systems with these GAN KO models has provided the springboard for the development of a viral vector being delivered intrathecally in an ongoing Phase I gene therapy clinical trial for the treatment of children with GAN (https://clinicaltrials.gov/ct2/show/NCT02362438). During the course of a comprehensive pathologic characterization of the GAN KO mouse, we discovered the very early and unexpected involvement of the ocular lens. Light microscopy revealed the presence of intracytoplasmic inclusion bodies within lens epithelial cells. The inclusion bodies showed strong immunohistochemical positivity for glial fibrillary acidic protein (GFAP). We confirmed that intracytoplasmic inclusion bodies are also present within lens epithelial cells in human GAN. These IF inclusion bodies in lens epithelial cells are unique to GAN. Similar IF inclusion bodies in lens epithelial cells have not been reported previously in experimental animal models or human diseases. Since current paradigms in drug discovery and drug repurposing for IF-associated disorders are often hindered by lack of validated targets, our findings suggest that lens epithelial cells in the GAN KO mouse may provide a potential target, in vivo and in vitro, for evaluating drug efficacy and alternative therapeutic approaches in promoting the clearance of IF inclusions in GAN and other diseases characterized by intracellular IF accumulations.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0957-5) contains supplementary material, which is available to authorized users.

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supporting

confidence: 75%

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

Armao

Bouldin

Bailey

et al. 2019

Orphanet J Rare Dis

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“…Such observations extend the pathologic characterization of the GAN KO mouse model and may provide an explanation for symptoms suggestive of ANS dysfunction in GAN patients. Further investigation of ANS dysfunction in human GAN may be warranted to (1) augment standardized, clinically meaningful measurements for the rate of unmitigated disease progression in natural history studies [13], (2) promote continued development of alternative outcome measures for therapeutic effect in clinical trials, and (3) expand quality of life (QoL) metrics for GAN patients and their families [14]. …”

Section: Discussionmentioning

confidence: 99%

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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“…Progressive distal motor weakness is the initial symptom in all cases. Diffused muscle atrophy, most predominantly in distal muscles, flaccid, paralysis, severely decreased muscle strength, low muscle tone, and loss of reflexes (areflexia) may be observed as the disease advances ( Table 2 ) [ 3 , 22 , 23 , 24 , 25 , 26 , 37 , 38 ]. Diagnosis of PNS degeneration in early infancy and sensorimotor pathway involvement in teens resemble more commonly inherited peripheral neuropathy called Charcot-Marie-Tooth (CMT) diseases [ 27 ].…”

Section: Clinical Heterogeneity In Persons With Ganmentioning

confidence: 99%

“…Diagnosis of PNS degeneration in early infancy and sensorimotor pathway involvement in teens resemble more commonly inherited peripheral neuropathy called Charcot-Marie-Tooth (CMT) diseases [ 27 ]. Owing to similarities in clinical presentation between patients with GAN and CMT or Friedreich ataxia, CTM Disease Pediatric Scale and Friedreich Ataxia Rating Scale and Gross Motor Function measure may be implemented for physical examination [ 4 , 37 ]. Though, making PNS deterioration unique from some of the other peripheral neuropathies, GAN also leads to proximal motor weakness, evidenced by pectoralis chest-wall muscle wasting, winged scapula, and exhibition of myopathic or “waddling” gait disturbances and positive Gower’s sign during the attempt to achieve erect position, indicative of pelvic girdle and quadriceps muscle weakness [ 2 , 4 , 6 , 25 , 28 ].…”

Section: Clinical Heterogeneity In Persons With Ganmentioning

confidence: 99%

“…GAN also differs from other neuropathies due to CNS involvement including pyramidal signs, positive Babinski signs indicative of deficit in the upper motor neuron, and positive Romberg signs associated with dorsal column lesion ( Table 2 ) [ 2 , 22 ]. Among these, cerebellar involvement is most extensive, including truncal ataxia, incoordination, fine movement impairment, tremor, dysmetria, nystagmus, and oculomotor apraxia [ 25 , 37 , 39 ]. Cranial nerve impairment is also described in patients with GAN, causing facial weakness, ptosis, and ophthalmoplegia, involving facial, oculomotor, trochlear, and abducens nerves [ 6 , 26 , 29 , 30 ].…”

Section: Clinical Heterogeneity In Persons With Ganmentioning

confidence: 99%

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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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Measuring Disease Progression in Giant Axonal Neuropathy

Cited by 6 publications

References 30 publications

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

Advancing the pathologic phenotype of giant axonal neuropathy: early involvement of the ocular lens

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

Genetic Approaches for the Treatment of Giant Axonal Neuropathy

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