MRI Features in a Rat Model of H-ABC Tubulinopathy

Garduno-Robles, Angeles; Alata, Milvia; Piazza, Valeria; Cortes, Carmen; Eguibar, José R.; Pantano, Sergio; Hernández, Victor H.

doi:10.3389/fnins.2020.00555

Cited by 11 publications

(17 citation statements)

References 41 publications

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“…Here, we report the hearing deficit in a patient with a D249N mutation in the TUBB4A gene and the correlation with morphological and physiological analysis in the taiep murine model that carries a point mutation in TUBB4A (A302T) (Garduno‐Robles et al, 2020). In the patient, AEP recordings for both ears showed only Waves I and II at 80 dB nHL.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we report a case of a patient with H‐ABC with severe hearing impairment. We also analyze the effects of this neurodegenerative disease on hearing function in the taiep (Holmgren, Urbá‐Holmgren, Riboni, & Vega‐SaenzdeMiera, 1989) murine model of H‐ABC which carries a mutation in TUBB4A (A302T) (Garduno‐Robles et al, 2020). This study is relevant because as far as we know, our rat model of tubulinopathy is the only one that shares most of the characteristics of human H‐ABC, including that, as in humans, the mutation appeared spontaneously, even though as a recessive trait (Holmgren et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

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Auditory impairment in H‐ABC tubulinopathy

López-Juárez

Vega

Kleinert‐Altamirano³

et al. 2020

J of Comparative Neurology

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Hypomyelination with atrophy of the basal ganglia and cerebellum (H‐ABC) is a neurodegenerative disease due to mutations in TUBB4A. Patients suffer from extrapyramidal movements, spasticity, ataxia, and cognitive deficits. Magnetic resonance imaging features are hypomyelination and atrophy of the striatum and cerebellum. A correlation between the mutations and their cellular, tissue and organic effects is largely missing. The effects of these mutations on sensory functions have not been described so far. We have previously reported a rat carrying a TUBB4A (A302T) mutation and sharing most of the clinical and radiological signs with H‐ABC patients. Here, for the first time, we did a comparative study of the hearing function in an H‐ABC patient and in this mutant model. By analyzing hearing function, we found that there are no significant differences in the auditory brainstem response (ABR) thresholds between mutant rats and WT controls. Nevertheless, ABRs show longer latencies in central waves (II–IV) that in some cases disappear when compared to WT. The patient also shows abnormal AEPs presenting only Waves I and II. Distortion product of otoacoustic emissions and immunohistochemistry in the rat show that the peripheral hearing function and morphology of the organ of Corti are normal. We conclude that the tubulin mutation severely impairs the central hearing pathway most probably by progressive central white matter degeneration. Hearing function might be affected in a significant fraction of patients with H‐ABC; therefore, screening for auditory function should be done on patients with tubulinopathies to evaluate hearing support therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Auditory impairment in H‐ABC tubulinopathy

López-Juárez

Vega

Kleinert‐Altamirano³

et al. 2020

J of Comparative Neurology

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“…For these reasons, an animal model is invaluable to investigate the disease's mechanisms and essential for the proposal of therapeutics. The taiep is a tubulin mutant that shares clinical and radiological signs with human patients (18).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we analyzed by MRI segmentation the longitudinal changes of the affected structures in the central nervous system of the aforementioned patient and in the taiep rat, the only model of this disease that, as well as the patients, carries a spontaneous tubulin mutation (18). We used immunocytochemistry to correlate MRI findings to histological damage and analyzed physiological gait motor pattern and tremor signs.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model

et al. 2021

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Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

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“…The decrease in TGF-β 1 expression in 6-month-old taiep and SD rats might also be a sign of CNS aging and demyelination in the former and only the first component in the second. It is probably that the alteration in microtubule proteins in the taiep rats was recently had been proposed as a tubulinopathy with a point mutation in the beta tubulin 4A (TUBB4A) similar to human hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) one of the leukodystrophies [31], and myelin decrease could cause protection against the infection with the human nematode Trichinella spiralis.…”

Section: Plos Onementioning

confidence: 99%

The deficiency of myelin in the mutant taiep rat induces a differential immune response related to protection from the human parasite Trichinella spiralis

et al. 2020

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Taiep rat is a myelin mutant with a progressive motor syndrome characterized by tremor, ataxia, immobility episodes, epilepsy and paralysis of the hindlimbs. Taiep had an initial hypomyelination followed by a progressive demyelination associated with an increased expression of some interleukins and their receptors. The pathology correlated with an increase in nitric oxide activity and lipoperoxidation. In base of the above evidences taiep rat is an appropriate model to study neuroimmune interactions. The aim of this study was to analyze the immune responses in male taiep rats after acute infection with Trichinella spiralis. Our results show that there is an important decrease in the number of intestinal larvae in the taiep rat with respect to Sprague-Dawley control rats. We also found differences in the percentage of innate and adaptive immune cell profile in the mesenteric lymphatic nodes and the spleen that correlated with the demyelination process that took place on taiep subjects. Finally, a clear pro-inflammatory cytokine pattern was seen on infected taiep rats, that could be responsible of the decrement in the number of larvae number. These results sustain the theory that neuroimmune interaction is a fundamental process capable of modulating the immune response, particularly against the parasite Trichinella spiralis in an animal model of progressive demyelination due to tubulinopathy, that could be an important mechanism for the clinical course of autoimmune diseases associated with parasite infection.

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MRI Features in a Rat Model of H-ABC Tubulinopathy

Cited by 11 publications

References 41 publications

Auditory impairment in H‐ABC tubulinopathy

Auditory impairment in H‐ABC tubulinopathy

Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model

The deficiency of myelin in the mutant taiep rat induces a differential immune response related to protection from the human parasite Trichinella spiralis

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