Referencias científicas Nº 164

 Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function

Natalia Mendoza-Ferreira, Marie Coutelier, Eva Janzen, Seyyedmohsen Hosseinibarkooie, Heiko Löhr, Svenja Schneider, Janine Milbradt, Mert Karakaya, Markus Riessland, Christian Pichlo, Laura Torres-Benito, Andrew Singleton, Stephan Zuchner, Alexis Brice, Alexandra Durr, Matthias Hammerschmidt, Giovanni Stevanin and Brunhilde Wirth


Objective: To ascertain the genetic and functional basis of complex autosomal recessive cerebellar ataxia (ARCA) presented by 2 siblings of a consanguineous family characterized by motor neuropathy, cerebellar atrophy, spastic paraparesis, intellectual disability, and slow ocular saccades.

Methods: Combined whole-genome linkage analysis, whole-exome sequencing, and focused screening for identification of potential causative genes were performed. Assessment of the functional consequences of the mutation on protein function via subcellular fractionation, size-exclusion chromatography, and fluorescence microscopy were done. A zebrafish model, using Morpholinos, was generated to study the pathogenic effect of the mutation in vivo.

Results: We identified a biallelic 3-bp deletion (p.K19del) in CHP1 that cosegregates with the disease. Neither focused screening for CHP1 variants in 2 cohorts (ARCA: N = 319 and NeurOmics: N = 657) nor interrogating GeneMatcher yielded additional variants, thus revealing the scarcity of CHP1mutations. We show that mutant CHP1 fails to integrate into functional protein complexes and is prone to aggregation, thereby leading to diminished levels of soluble CHP1 and reduced membrane targeting of NHE1, a major Na+/H+ exchanger implicated in syndromic ataxia-deafness. Chp1 deficiency in zebrafish, resembling the affected individuals, led to movement defects, cerebellar hypoplasia, and motor axon abnormalities, which were ameliorated by coinjection with wild-type, but not mutant, human CHP1 messenger RNA.

Conclusions: Collectively, our results identified CHP1 as a novel ataxia-causative gene in humans, further expanding the spectrum of ARCA-associated loci, and corroborated the crucial role of NHE1 within the pathogenesis of these disorders.

Targeting potassium channels to treat cerebellar ataxia


·        David D. Bushart,

·        Ravi Chopra,

·        Vikrant Singh,

·        Geoffrey G. Murphy,

·        Heike Wulff,

·        Vikram G. Shakkottai



Purkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice.


Patch-clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice. Additionally, we retrospectively reviewed records of patients with SCA1 and other autosomal-dominant SCAs with prominent Purkinje neuron involvement to determine whether currently approved potassium channel activators were tolerated.


Activating calcium-activated and subthreshold-activated potassium channels improved Purkinje neuron spiking impairment in SCA1 mice (P < 0.05). Additionally, dendritic hyperexcitability was improved by activating subthreshold-activated potassium channels but not calcium-activated potassium channels (P < 0.01). Improving spiking and dendritic hyperexcitability through a combination of chlorzoxazone and baclofen produced sustained improvements in motor dysfunction in SCA1 mice (P < 0.01). Retrospective review of SCA patient records suggests that co-treatment with chlorzoxazone and baclofen is tolerated.


Targeting both altered spiking and dendritic membrane excitability is associated with sustained improvements in motor performance in SCA1 mice, while targeting altered spiking alone produces only short-term improvements in motor dysfunction. Potassium channel activators currently in clinical use are well tolerated and may provide benefit in SCA patients. Future clinical trials with potassium channel activators are warranted in cerebellar ataxia.

Protein YAP in early life influences adult spinocerebellar ataxia pathology

January 25, 2018, Tokyo Medical and Dental University

Black bars indicate durations when YAPdeltaC was expressed. Pre-onset expression of YAPdeltaC, but not post-onset YAPdeltaC, elongates lifespan of SCA1 model mice. The recovery of motor function was also found in pre-onset but not …more

Spinocerebellar ataxia is a group of neurodegenerative diseases characterized by progressive incoordination of gait, and is often associated with poor coordination of hands, speech and eye movements. There are different types of SCA, and these are classified based on the mutated (altered) gene. In spinocerebellar ataxia type 1 (SCA1), the causative gene ATXN1 and its interacting factors were determined over two decades ago. However, SCA1 remains intractable, and no disease-modifying therapy has reached the clinical bedside.

As with other neurodegenerative diseases, the understanding of spinocerebellar ataxias, including SCA1, has changed over time. The types of affected neurons are not as specific as initially believed, the effects of these disorders are not limited to single organs, and SCA might be a developmental disorder that affects cerebellar neurons during embryo formation or in early childhood.

These changes in the conception of neurodegenerative conditions have not deterred researchers at Tokyo Medical and Dental University (TMDU) to delve deep into the underlying mechanisms of these diseases. The researchers previously found the overexpression of YAPdeltaC, the neuronal isoform of the protein YAP which is involved in the regulation of gene expression, prevents transcriptional repression-induced atypical death (TRIAD) of neurons in Huntington’s disease in vitro models. TRIAD is a distinct form of cell death; it is extremely slow in comparison with apoptosis, necrosis, or autophagy.

In a new study, the researchers further tested the therapeutic effect of YAPdeltaC – this time on SCA1 pathology in mice. They published their findings in Nature Communications.

“Unexpectedly, adulthood expression of YAPdeltaC did not ameliorate the pathology andsymptoms of Atxn1-KI mice,” study lead author Kyota Fujita explains. “Instead, YAPdeltaC expression during development markedly rescued the pathology and symptoms in adulthood.”

The researchers also found that YAP/YAPdeltaC functioned as a transcriptional co-activator of RORα, a protein essential for development of cerebellum through direct regulation of genes expressed in Purkinje cells, a class of GABAergic neurons found in the mice cerebellum. The supplementation of YAP/YAPdeltaC successfully overcame the toxic effect of mutant Atxn1 protein and restored thetranscriptional activity of RORα.

“Collectively, our results indicate that functional impairment of YAP/YAPdeltaC by mutant Atxn1 protein during development determines the adult pathology of SCA1,” corresponding author Hitoshi Okazawa says. “We believe certain molecular signatures generated during development significantly influence late-onset phenotypes, and that these signatures act by restoring gene expression to optimal levels. Therefore, identification of these signature genes would enable us to manipulate the late-onset cell death of SCA1 – and even other neurodegenerative diseases – in the future.”


More information: Kyota Fujita et al, Developmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type

Hypertension Therapy Shows Potential to Reverse Friedreich’s Ataxia Symptoms in Mouse Study

JANUARY 18, 2018



Researchers found a 50-year-old hypertension therapy can enhance the amount of frataxin protein in cells from patients with Friedreich’s ataxia and mouse models of the disease.

The finding was reported in the study, “Effect of Diazoxide on Friedreich Ataxia Models,” published in the journal Human Molecular Genetics.

Friedreich’s ataxia is genetic disease caused by a mutation in the FXN gene. The mutations lead to reduced production of its coded protein, frataxin, which is essential for proper functioning of nerve cells and muscles.

With no effective therapies available, scientists are focused on developing new strategies to enhance frataxin production and overcome the effects of FXNmutations.

A group of Italian researchers tested whether the existing drug diazoxide could have therapeutic potential for Friedreich’s ataxia patients by increasing frataxin levels and improving the functional and biochemical features of the disease.

Diazoxide, which is sold under the brand name Proglycem, is a well-known vasodilator drug — which means it helps to relax blood vessels — that has been used for the treatment of acute hypertension for more than five decades.

The researchers started by testing the effects of diazoxide in three cell lines derived from patients with Friedreich’s ataxia. Each cell line represented a different clinical presentation of the disease — a mild, late onset case; a more common presentation; and a severe, early onset case.

After four days of treatment with diazoxide, all cell lines showed a significant changes in frataxin levels, with increases ranging from 80% to 300%.

Next, the team evaluated the activity of the drug in a mouse model of Friedreich’s ataxia. The animals received 3 mg/kg of oral diazoxide or placebo daily for up to three months. The treatment was well tolerated by the animals, and no significant adverse effects were reported.

Treated animals had a significant increase in frataxin levels compared to placebo-treated mice, with 2.6-fold and 1.6-fold increase in the cerebellum (a brain region that controls movement) and the heart, respectively.

Additional analysis revealed that diazoxide treated mice had significantly lower levels of harmful protein oxidation in the brain, pancreas, and liver tissues, with trends to decrease in other tissues.

The treatment was also found to significantly improve the coordination and footprint stride compared to placebo, but the mice still showed a generally reduced locomotor activity.

The researchers believe that these results suggest that “diazoxide is able to induce FXN expression in human cells” with therapeutic potential. Further studies are still needed to “clarify the variable effects concerning functional studies” before the drug is considered for clinical trials, the researchers stated.

Learn More About the MOXIe Clinical Study for Friedreich’s Ataxia

JANUARY 18, 2018



Later this month, Jennifer Farmer, Executive Director of FARA and Dr. Keith Ward, CDO of Reata Pharmaceuticals, will be hosting two meetings to discuss the initial results of the MOXIe clinical study.

The meetings will focus on sharing the data from part one of the study with the patient community, along with providing updates on what’s happening with part two – including information about participation, eligibility, enrollment, and answers to many other frequently asked questions. In addition, participants will have time at the end of each session to ask Farmer and Dr. Ward any questions they may have.

If you’re unable to attend one of the following two sessions live, they will be recorded and will be available online.  Friedreich’s ataxia patients, along with their family members and caregivers are encouraged to attend.

First session: Wednesday, January 31, 2018 – 9am PST/12pm EST
Second session: Thursday, February 1, 2018 – 5pm PST/8pm EST

If you’re interested in attending one of the online meetings (all you need is an internet connection!), please register by emailing Hanh Nguyen at You must register in advance in order to receive the link for the meeting.

MORE: MOXIe trial could lead to first FA treatment

Friedreich’s Ataxia News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

Emotion Perception Seen to Be Impaired in Friedreich’s Ataxia Patients, Study Finds

JANUARY 16, 2018



Patients with Friedreich’s ataxia have impaired emotion recognition that may be secondary to neuropsychological impairment, according to a study published in the journal The Cerebellum.

Expressing and reading emotions are essential social skills necessary for developing relationships, as well as for showing your own feelings. To a great extent, emotions are produced and perceived based on the immediate recognition of facial expression patterns.

“Developmental psychology showed how the quality of nonverbal communications between infants and their caregivers can influence, among others, the development of emotion understanding, attachment relationships, and emotion regulation,” the researchers wrote.

Studies have shown that the frontotemporal lobe and dopaminergic systems of the brain are responsible for both facial processing and facial expression recognition. Diseases that affect these brain regions, such as Alzheimer’s and Parkinson’s, may lead to impaired emotional competence and negative processing of emotions.

The cerebellum, a brain region affected in patients with Friedreich’s ataxia, has been perceived as a main controller of body movement. But some studies have suggested that it may also be involved in the regulation of human behavior, and in computing facial expressions.

In the study, “Emotion Recognition and Psychological Comorbidity in Friedreich’s Ataxia,” a research team from the University Federico II in Naples, Italy, evaluated the ability of patients with Friedreich’s ataxia to recognize emotions using visual and nonverbal auditory hints.

The study included 20 patients previously diagnosed with Friedreich’s ataxiaand 20 healthy volunteers. They underwent an extensive psychological, emotional, and neuropsychological evaluation.

Friedreich’s ataxia patients showed an overall deficit in correctly identifying emotions compared to the healthy individuals, and they required 42 percent more time to respond to an emotion.

They were found to have more difficulties in identifying sadness, interest, amusement, and pleasure.

“Usual Friedreich’s ataxia onset is during adolescence, [a] crucial life period in which the person undergoes biological, psychological, and social changes,” the researchers wrote. “It is possible that pathogenetic changes deriving from Friedreich’s ataxia leave kids unable to integrate social emotions and develop normal emotion recognition abilities.”

An evaluation of global cognitive function revealed that Friedreich’s ataxia patients had a lower score than the control group, which may in part explain the difficulties reported in emotion identification. Cognitive functions are involved in the complex computation process required for emotion recognition.

Overall, patients showed a lower state of anxiety than their healthy counterparts, and no major depressive disorder was detected in either group.

The team reported that three patients had personality disorders: antisocial; avoidant; and obsessive-compulsive disorder (OCD). Additional studies are necessary to understand if the personality disorders were a pre-existing condition or were due to Friedreich’s ataxia.

The researchers believe that Friedreich’s ataxia patients have “impaired emotion recognition that may be secondary to neuropsychological impairment.”

“The impact of the disease on psychological measures is minimal, except for the onset of personality disorders, and should not be considered as part of the clinical picture of Friedreich’s ataxia,” they said.

“These findings should be taken into account when approaching patients both in clinical routine practice, as well as psychological counseling and support,” researchers added.

#IARC2017 (Exclusive Interview) – MOXIe Trial Could Lead to First FA Treatment, Colin Meyer of Reata Says

SEPTEMBER 29, 2017




Dr. Colin Meyer, the chief medical officer and vice president of Reata Pharmaceuticals, spoke Friday in a taped interview with reporter Patricia Inacio about omaveloxolone, an oral therapy in line to possibly become the first FDA-approved treatment for Friedreich’s ataxia.

A Phase 2 clinical trial, called MOXIe (NCT02255435), is moving into a second and possibly pivotal part, testing the effectiveness of omaveloxolone against placebo in about 100 FA patients ages 16 to 40. All enrolled will be randomized to either  omaveloxolone at 150 mg or a placebo. The trial’s main goal is to evaluate changes from baseline in the modified Friedreich Ataxia Rating Scale (mFARS).

Omaveloxolone, also known as omav, is designed to activate the Nrf2 protein within cells to restore mitochondrial energy production, which is depressed in FA, and to dampen inflammation in cells. “This translates,” Meyer said, “to improved organ function in the muscles, in the brain and elsewhere.”

Part one of MOXIe — a dose-escalating phase conducted in 69 FA patients — went well, Meyer said in the interview.

“We were able to show in patients with Friedreich’s ataxia that omav could induce Nrf2 … and improve markers of mitochondrial function. We also demonstrated the drug has activity on many important neurological parameters, such as the modified FARs,” he said, adding that omaveloxolone  “was also well-tolerated with no discontinuations at the optimal dose.”

This trial is a “registrational,” meaning that it is like a Phase 3 trial and — if successful — could lead to a first FA treatment being approved worldwide, Meyer said.

But before that, he added, we have to enroll the patients.

MOXIe is currently recruiting FA patients with mFARS scores from 20 to 80 at study sites across the U.S., and in Austria, Australia and the U.K. More information, including on enrollment and eligibility, is available on its clinical page.

The full interview with Dr. Meyer can be seen here:

The full interview with Dr. Meyer can be seen here: