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What is Ataxia?

Ataxia refers to neurological disorders often characterized by uncoordinated motor behavior. These disorders result from abnormalities in the nervous system. (1) 

Symptoms of ataxia include (2):

  • Posture abnormalities 
  • Fine motor incoordination
  • Speech and swallowing disorders
  • Visual abnormalities
  • Increased fatigue

Cerebellar ataxia originates from the cerebellum. People with this condition do not only suffer from motor dysfunctions; they also have cognitive and emotional problems. 

Patients with cerebellar ataxia are also likely to develop anxiety, irritability, and depression.

What Causes Ataxia?

Degeneration (atrophy) of the cells in the cerebellum is the leading cause of the conditions that result in ataxia. The cerebellum is responsible for coordinating voluntary muscle movements and maintaining posture, balance, and equilibrium in the body. (3) 

Atrophy can also affect the spine. This damage may be referred to as spinocerebellar degeneration.

The abnormal genes responsible for ataxia produce proteins that cause nerve cells to function poorly and eventually degenerate. These nerve cells can be found in the cerebellum, spinal cord, and other parts of the brain.

Patients with ataxia experience worsening of balance and coordination. Their muscles also become less responsive to the brain’s commands. (4)

There are two types of ataxia differentiated by their origin:

  • Hereditary ataxia
  • Sporadic ataxia (usually begins in adulthood; patients have no family history of ataxia)

Ataxia Treatment

In treating ataxia, it is best to consult with a neurologist. Usual treatments involve speech and language therapy, occupational therapy, and physical therapy. (5)

Doctors also prescribe medications to treat ataxia and its symptoms.

Can CBD Help with Ataxia?

There have been studies on cannabidiol (CBD) and its promise in helping treat ataxia and related disorders. CBD is the non-psychoactive component of cannabis plants.

A study (6) reveals CBD’s neuroprotective properties because of its antioxidant and anti-inflammatory effects. Researchers conclude that CBD has great potential in managing neurodegenerative diseases, especially since there were no side effects observed in the research.  

Neurodegenerative diseases occur when nerve cells die, often causing mental function problems and ataxia. 

Though there are only a few studies on CBD and ataxia, there are significant studies that show how CBD helps treat dystonia. This disorder has molecular pathways closely related to spinocerebellar ataxia. (7)

Dystonia is characterized by involuntary muscle contractions, resulting in repetitive movements or abnormal posture. 

The 2018 study outlines CBD’s antipsychotic, anxiolytic, anti-inflammatory, and neuroprotective effects. CBD helps alleviate symptoms of movement disorders. These conditions are highly-linked to oxidative stress and neurodegeneration. (8)

Another study concluded that CBD has anti-dystonic properties that help improve dystonia in the test subjects. However, some test subjects’ Parkinsonian symptoms were aggravated, namely hyperkinesia and resting tremors. (9)

Though the U.S. Food and Drug Administration has not approved CBD, it is generally safe to use and has minimal side effects like nausea, fatigue, and irritability. (10)

There is no dosing chart for CBD, but it is recommended that CBD be taken in small amounts. If no adverse effects are observed, the dosage can be gradually increased.

CBD comes in different forms like oils, tinctures (drops), pills, patches, balms, salves, and creams. 

Before administering CBD to patients with ataxia, it is best to consult with a doctor first. 

Conclusion

Ataxia is the collective term for a group of neurological disorders characterized by uncoordinated motor behaviors. It is caused by the degeneration of nerve cells in the cerebellum and sometimes the spinal cord. 

Most symptoms are physical dysfunctions, but patients with cerebellar ataxia develop cognitive and emotional conditions, too, like anxiety, depression, and irritability.

Ataxia is commonly treated through therapy (speech and language, occupational, and physical), although some symptoms can be managed through medications.

CBD is a possible natural alternative that can help treat ataxia’s symptoms. Its neuroprotective, antioxidant, and anti-inflammatory properties are beneficial in neurodegenerative diseases and movement disorders.

CBD use has not been approved by the U.S. Food and Drug Administration. Before using CBD, it is recommended to consult with a doctor first. 

 


  1. “Ataxia Overview.” Ataxia Overview, www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/ataxia/conditions/.
  2. Ibid. 
  3. “Ataxia.” Department of Neurology, www.columbianeurology.org/neurology/staywell/document.php?id=35869.
  4. Ibid.
  5. “What Is Ataxia?” National Ataxia Foundation, 18 Dec. 2019, ataxia.org/what-is-ataxia/.
  6. Iuvone, Teresa, et al. “Cannabidiol: a Promising Drug for Neurodegenerative Disorders?” CNS Neuroscience & Therapeutics, Blackwell Publishing Ltd, 2009, www.ncbi.nlm.nih.gov/pubmed/19228180.
  7. Nibbeling, Esther A R et al. “Using the shared genetics of dystonia and ataxia to unravel their pathogenesis.” Neuroscience and biobehavioral reviews vol. 75 (2017): 22-39. doi:10.1016/j.neubiorev.2017.01.033
  8. Peres, Fernanda F et al. “Cannabidiol as a Promising Strategy to Treat and Prevent Movement Disorders?.” Frontiers in pharmacology vol. 9 482. 11 May. 2018, doi:10.3389/fphar.2018.00482
  9. Consroe, P, et al. “Open-Label Evaluation of Cannabidiol in Dystonic Movement Disorders.” The International Journal of Neuroscience, U.S. National Library of Medicine, Nov. 1986, www.ncbi.nlm.nih.gov/pubmed/3793381.
  10. Grinspoon, Peter. “Cannabidiol (CBD) – What We Know and What We Don’t.” Harvard Health Blog, 24 Aug. 2018, www.health.harvard.edu/blog/cannabidiol-cbd-what-we-know-and-what-we-dont-2018082414476.

 

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International Partnership: Patient Advocacy and Engagement

Julie Greenfield1, Mina Ruggieri2, Barbara Flynn3, Jennifer Farmer4, Jane Larkindale4 1AtaxiaUK, 2GoFar, 3Ataxia Ireland, 4Friedriech’s Ataxia Research Alliance

 

The Friedreich’s Ataxia Research Alliance (FARA), Ataxia UK, Ataxia Ireland, and GoFAR (Italy) partnered to organize and host the largest and most comprehensive International Ataxia Research Conference held to date on March 25-28, 2015 in Windsor, England. The conference highlighted important research advances for hereditary and sporadic ataxias, including Friedreich’s ataxia, spinocerebellar ataxias, ataxia with oculomotor apraxia and episodic ataxia. More than 350 international delegates from academic institutions, from the biopharma industry and from medical, healthcare and advocacy organizations attended and presented the latest research findings from basic, translational and clinical investigations.

People with ataxia are at the heart of everything we do, and four people with ataxia shared their personal experiences with the research community. Giving the research community an opportunity to learn from patient stories related to diagnosis, living with the disease, participation in research and personal experiences is not only motivational and inspiring but truly expands and deepens understanding of the disease. These new insights and shared experiences can also spur new hypotheses or avenues for research, as well as inform researchers about the aspects of disease that patients identify as most important to them.

The ataxias are all rare diseases. Working on each disease individually in individual laboratories or clinics results in slow progress, but by bringing together researchers from around the world from multiple disciplines we can learn from each other and accelerate research. When the global community works together to look at the same problems in different ways new ideas are generated, new concepts are linked and new pathways may be identified that can help move therapies forward in unexpected ways. The International Ataxia Research Conference was a venue where this could happen, and many new partnerships and collaborations were forged.

There are no treatments available commercially for the vast majority of the ataxias. At the Conference, eight different therapeutics in clinical development were presented. This represents the enormous advances in the field in the past years. Furthermore, there was discussion of a range of pathways that may be involved in one or more ataxia, and ways that these could be leveraged for potential therapeutics. There was vigorous discussion of the value of each of these pathways and their therapeutic potential, as well as next steps to prove or disprove their value, and offers of collaboration to complete that work. This suggests that work following the meeting will result in even more progress over the next few years.

Patient advocacy organizations can make meaningful contributions to advancing research, patient engagement and growing the research community by organizing and hosting research conferences. These conferences are the playing field where we assemble and engage all stakeholders; academic investigators, physicians and health care providers, biotech and pharma industry representatives, government and regulatory representatives, and patients, to promote timely dissemination of information, debate and discussion of new research findings and hypotheses, learn from experiences observed in the clinic or living with the disease and network with colleagues to build partnerships and collaborations; all of which advances progress toward treatments. Our advocacy organizations will continue to work together as we believe we are more effective working in partnership rather than isolation and hope that the next international meeting will be even bigger and better – with more new therapies closer to a reality.

 

INTRODUCTION

Hereditary ataxias are progressive, neurodegenerative disorders, associated with degeneration and dysfunction of the cerebellum andƒor sensory pathways. Friedreich’s ataxia (FRDA) is the most common hereditary ataxia, with an estimated prevalence of approximately 1 in 40000 individuals in Caucasian populations [1]. No treatment to prevent or slow the progression of hereditary ataxias has yet been found, with only symptomatic treatments and palliative care currently available for patients. However, research in this field is robust, and as we develop further understanding of the diseases, new therapeutic concepts are being developed.

The International Ataxia Research Conference 2015 covered all aspects of the ataxias from understanding the causes of diseases through to clinical trials testing potential ways to treat them. Sessions covered the discovery of new genes and new diagnostic techniques, new developments in understanding the mechanisms and pathways of the diseases, new models to study the diseases and developments in drug development, as well as the development of tools to support future drug development. Drug development is moving rapidly in this field, with 8 projects discussed that are in the clinic, mostly for Friedreich’s Ataxia or SCA3. Many additional projects are still at a preclinical stage, offering significant hope for patients. This report summarizes some of the conference sessions, focusing on oral presentations. Significant additional work was presented in poster form.

  1. Parkinson, M.H., et al., Clinical features of Friedreich’s ataxia: classical and atypical phenotypes. J Neurochem, 2013. 126 Suppl 1: p. 103-17.

 

NEW GENES AND DEVELOPMENTS IN THE DIAGNOSIS OF ATAXIAS

Matthis Synofzik1,*, Andrea H. Németh2

1 Hertie Institute for Clinical Brain Research, Tübingen; Germany;

2 Nufield Department of Clinical Neurosciences, University of Oxford, UK.

* To whom correspondence should be addressed: Dr. Matthis Synofzik, Center for Neurology and Hertie-Institute for Clinical Brain Research, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany; phone: +49 70712982060, e-mail: [email protected]

MS is currently funded by the Robert Bosch StiGung, Germany, and previously by AtaxiaUK. AHN is currently funded by Action Medical Research and The Henry Smith Charity, and previously by AtaxiaUK.

Unraveling the diagnosis and molecular disease cause in patients with so far unexplained ataxias has been revolutionized by the introduction of next-generation sequencing (NGS) methods like targeted capture of large sets of genes (“gene panels”), whole-exome sequencing (WES) and, more recently, whole-genome sequencing (WGS). As demonstrated by the 10 presentations in the opening session of the ARC International Research Conference (given by Andrea NemethƒOxford, Michel KoenigƒMontpellier, Marie CoutelierƒParis, Marios HadjivassiliouƒShefield, Rebekah JoblingƒToronto, Stefania MagriƒMilano; Rebecca SchüleƒMiami and Tübingen; Matthis SynofzikƒTübingen, Dineke VerbeekƒGroningen, Margit BurmeisterƒMichigan), these NGS methods have led to a rapidly increasing number of newly identified ataxia genes, to new insights into associated molecular pathways and common mechanisms linked to the pathogenesis of degenerative ataxias, and to cost-effective comprehensive diagnostic approaches which now allow to provide a large number of so far unexplained ataxia patients with a molecular diagnosis.

 Novel ataxia genes

NGS enabled the identification of identification of several novel genes in a short time-frame. Within only the last 3 years the following ataxia genes were identified:

  1. recessive mutations in WWOX leading to a broad range of severe infantile onset neurodevelopmental syndromes, reaching from early lethal microcephaly syndrome with epilepsy growth retardation and retinal degeneration in patients with truncating WWOX mutations[1] via epileptic encephalopathies[2] to more benign ataxia-epilepsy syndromes[3] in patients with missense WWOX mutations in hypomorphic alleles[2] (Michel Koenig and team).
  2. recessive missense mutations in SLC9A1, a protein encoding for NHE1 (Na+ƒH+ exchanger family member 1) and involved in pH-regulation at the inner ear, leading to an ataxia-deafness syndrome (Lichtenstein-Knorr syndrome)[4] (Michel Koenig and team)
  3. recessive mutations in PMPCA, encoding the alpha subunit of mitochondrial processing peptidase (a-MPP), leading to a non-progressive cerebellar ataxia syndrome5. Interestingly, a-MPP is the primary enzyme responsible for the maturation of most nuclear-encoded proteins, including the maturation process of frataxin, which is depleted in Friedreich ataxia (Rebekah Jobling and team)[5].
  4. recessive loss-of-function mutations in the BiP co-chaperone DNJAC3, leading to combined cerebellar and peripheral early-onset ataxia with hearing loss and diabetes mellitus (ACPHD; OMIM #616192) as part of a widespread neurodegenerative process (Matthis Synofzik and team)[6].

 

 Novel phenotypic spectra and frequency estimates of ataxia genes

These NGS methods also led to novel insights into the relative frequencies and new phenotypic spectra of known disease genes.

  1. SPG7 mutations are a common cause not only of recessive hereditary spastic paraplegias (HSPs) and spastic ataxias[7,8], but also of pure ataxias and of undiagnosed ataxias in general[8,9].
  2. Similarly, the complicated HSP phenotype (SPG49) caused by recessive PNPLA6 mutations is only one end of a broad spectrum of neurodegenerative diseases caused by PNPLA6. Matthis Synofzik and colleagues have now shown that, along this continuum, PNPLA6 is also a frequent cause of the so-called Boucher-Neuhäuser Syndrome (early onset ataxia plus hypogonadism and chorioretinitis) and Gordon Holmes Syndrome (early onset ataxia plus hypogonadism), which might or might not be accompanied by spastic paraplegia[10-12]. Even more recently, it was shown that on the other end of the spectrum, PNPLA6 can also cause syndromes comprising of trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy (Oliver

-McFarlane syndrome)[13] and even pure ophthalmological phenotypes like Leber congenital amaurosis, photoreceptor degeneration and various other forms of childhood blindness[12,14].

  1. While single heterozygous OPA1 variants have long been acknowledged as common cause of dominant optic atrophy, Matthis Synofzik and colleagues now showed that the combined mutational load of two biallelic OPA1 alleles explains the phenotype of complex optic atrophy-plus phenotypes including severe ataxia, sometimes also dubbed “Behr syndrome” (OMIM %210000)[15]. As one of these two OPA1 alleles might be an OPA1 modifier variant, which does not lead to disease itself, even in a homozygous state (e.g. the p.I382M variant [15]), and as several OPA1 variants have a reduced penetrance, the parental generation of these subjects can be unaffected, despite the fact that the index subjects carry two variants of an, in principle, dominant disease. The pedigree of optic atrophy-plus subjects can thus present as a seemingly “recessive pedigree”, as exemplified by the family presented by Matthis Synofzik[15]. The etiology of OPA1 disease is even more complicated by the fact that deep-intronic mutations – which are not detected by Sanger, panel or WES – are a recurrent finding in both pure optic atrophy syndromes and complex optic atrophy plus syndromes[15].
  2. Non progressive early-onset ataxia phenotypes, frequently (mis-)named “ataxic cerebral palsy”, are usually not caused by injury at birth, as oGen assumed. Nemeth and colleagues have shown that the ataxic subtype of cerebral palsy can be caused by de novo point mutations KCNC3, ITPR1, and SPTBN2[16].
  3. Brown-Vialetto-Van-Laere syndrome type 2 (BVVL2), is known to be caused by recessive mutations in the riboflavin transporter gene SLC52A2, and is characterized by early childhood onset, deafness, bulbar dysfunction, severe diffuse muscle weakness resulting in respiratory insuficiency (+ƒ- optic atrophy). Michel Koenig now showed, by example of an Israeli-Palestinian family, that it can also cause a spinocerebellar ataxia syndrome with blindness and deafness, which had been introduced earlier as SCABD = SCAR3 (OMIM # 271250)[17]. Identifying ataxia patients due to LC52A2 mutations will be important in the future, given that SLC52A2-related syndromes result from a defect in riboflavin metabolism, with some patients benefiting from high-dose riboflavin supplementation[18], as also indicated for the case presented by Michel Koenig.
  4. Recessive loss-of-function mutations in GRID2, encoding the glutamate receptor channel delta-2 subunit, which is largely selectively expressed in cerebellar Purkinje cells, have already been identified as a cause of recessive ataxia[19,20]. Findings from Marie Coutelier and colleagues[21] now indicate that single heterozygous missense mutations in GRID2 might also lead to cerebellar ataxia, with an inheritance pattern that is consistent with semidominant transmission and leading to a putative gain of function mechanism, as supported by findings from Lurcher mice models. The severity of the ataxia thereby ranges from very mild adult onset to congenital onset ataxia, depending on the genotype (heterozygous vs. homozygous GRID2 mutation) and the position of the mutation within the GRID2 gene domains[21].

 

 Novel insights into mechanisms of hereditary ataxias

Given this “explosion” of novel, but all very rare, genes the challenge in ataxia research is now to find common denominators between ataxia genes, which might then allow us to target shared pathways or mechanisms susceptible to treatment interventions. Indeed, the growing list of recessive ataxia genes points to some common themes, as pointed out by Michel Koenig and Andrea Nemeth. Ataxia can result from mutations in genes encoding proteins involved in the following types of pathways [22-25], including:

  • mitochondrial
  • peroxisomal
  • lysosomal
  • ion channel
  • DNA repair
  • ciliopathy
  • cytoskeleton
  • phospholipid metabolism

However, each theme unites only a minor fraction of novel ataxia genes, indicating that the variety of distinct pathways underlying ataxia is large. This fact indicates that ataxia and the corresponding degeneration of the cerebellumƒ spinocerebellar tracts is not the result of disturbances in specific pathways, but rather the common downstream result of an unspecific sensitivity of these neurons to even mild metabolic insults which can result from very different pathway disturbances[22]. Thus, rather than looking for alterations in common metabolic pathways shared between some ataxias, Michel Koenig proposed as an alternative perspective to look for shared genetic mechanisms. He suggested three shared genetic mechanisms leading to ataxia:

  1. i) partial loss of function (in particular in genes of metabolic ataxias, but also e.g. FRDA, SYNE1, POLG, C10orf2/Twinkle, WWOX, SLC9A1)
  2. ii) mutations in specific members of redundant gene families (ATM, APTX, SETX, ADCK3, ABHD12, ANO10)

iii) mutations in detoxifying pathways (TTPA and MTTP in vitamin E deficiency; chaperones in ARSACS and Marinesco Sjögren)

He emphasized that partial loss of function in manifold genes can lead to ataxia, given the assumption that prominent spinocerebellar ataxia occurs only when pathways are mildly affected, whereas compete or near-to-complete loss of function would lead to much more severe lethal andƒor encephalopathic syndromes. He illustrated this hypothesis by examples of WWOX, PEX6 and PEX10.

 State-of-the-art ataxia diagnostics: comprehensive NGS panels and exomes

Exemplified by a consecutive series of 1,288 ataxia patients assessed at the Shefield Ataxia Centre, Marios Hadjivassiliou reported that about 20% (259ƒ1288) of all patients have a positive familial history, 71% of them with an autosomal-dominant history (183ƒ1288). In 48% of the familial patients and in 30% of the total cohort a genetic diagnosis was found by routine selective genetic sequencing of some ataxia genes, yet with numbers still dating from the pre-NGS era. A genetic cause could also be found in sporadic patients, with relative frequencies differing between early versus late onset sporadic ataxia patients: while a genetic diagnosis was found in 46% early-onset cases, a much smaller share of the late-onset cases carried a mutation in an investigated gene.

These numbers are likely to have changed by now, given the advent of NGS procedures to clinical routine diagnostics. NGS panels now covering up to 90-120 ataxia genes and WES covering all coding regions (yet at a variable coverage) can provide a genetic diagnosis in so far unexplained ataxia patients in about 18%[26] by NGS panels and 21%[27]-41%

 

[28] by WES, respectively. Although the high latter estimate of 41% has to be interpreted with caution, given that it largely exceeds all other findings and that some reportedly pathogenic variants might in fact not be causally pathogenic

[29] – exemplifying the problem of over-interpreting NGS findings in ataxia genetics -, these findings nicely demonstrate the power of NGS approaches to diagnose so far unexplained ataxia patients. Similar to these findings, Dineke Verbeek and team identified rare SCA mutations in 7ƒ20 families negative for mutations in the most common SCA genes. In the remaining 13 families, they identified multiple gene candidates (n=39), many of them playing a role in pathways known to involved in cerebellar processing, which are now being functionally validated in the endeavor to identify novel ataxia genes. Stefania Magri and team developed three different ataxia panel approaches (HaloPlex- based gene panel of 127 genes; TrueSeqCustomAmplicon panel of 76 genes; Nextera Rapid Capture Custom Kit of 104 ataxia genes and 100 HSP genes), allowing researchers to identify pathogenic mutations in 25ƒ128 Italian patients (~20%) who were negative for repeat expansion and genes routinely screened by Sanger sequencing. Their NGS panel- based findings included 7 index cases with mutations in the extremely large genes SYNE1 and SACS, where conventional sequencing by Sanger methods is very time consuming and costly. At the same time, the findings from Stefania Magri and Dineke Verbeek also point to a common problem aGer NGS: They demonstrated that the vast majority of patients have variants of unknown significance in more than one disease genes.

WES also leads to changes in the initial diagnosis in a substantial share of patients (up to 10% of subjects with unexplained pediatric-onset neurodevelopmental disease), by unravelling causative genes known to cause a disease different from the initial diagnosis[30], as highlighted by Andrea Nemeth. It thus leads not only improved diagnosis, but also to changes in the patient management, counselling and therapy[30]. For example, Margit Burmeister presented cases of ataxia due to POLR3B mutations where the main phenotypic features had been overlooked on initial referral, but were clinically ascertained aGer variant detection by NGS.

If WES and NGS panels can provide a diagnosis in 20-40% this implies, in turn, that in 60-80% of ataxia patients no genetic cause can be found by these methods. As outlined by Andrea Nemeth, this might be due to non-genetic causes of the respective ataxias, but also due to digenicƒmultigenic causes or mutations not detected by WES and NGS, such as copy number variations (CNVs), repeats, deep-intronic mutations (like the OPA1 mutations exemplified by Matthis Synofzik[15]) or simply mutations in regions with low coverage by these methods.

This share of “missing heritability” in degenerative ataxias might now be substantially reduced by employing whole- genome sequencing (WGS), where costs have come down to $1500-2000 per genome and which can also capture intronic variants and deletions, as described by Andrea Nemeth and Rebecca Schüle. First systematic projects have been started investigating the use of WGS for clinical diagnostics, e.g. the “WGS500 project” launched by the Wellcome Trust Centre for Human Genetics Clinical in collaboration with Illumina, or the “Genomics England” project that aims to produce 100.000 genomes on cancer and rare diseases. First data from the field of intellectual disability indeed indicate that the diagnostic yield by WGS might be up to 50% higher than by WES[31]. Interestingly, however, the vast majority of mutations found by using WGS were found in coding regions, in case of intellectual disability mostly de novo SNPs and CNVs[31].

 The future of analyzing NGS results: trans-national collaborative eßorts

NGS approaches like panel sequencing, WES and WGS inevitably require a new framework of thinking. While classical ataxia genetics could be performed in single centers on a regional or national level, these NGS approaches require large

-scale transnational collaborative efforts and databases, as convincingly argued by Rebecca Schüle. These efforts are not only needed to manage resources eficiently (the sheer size of one genome data-set is 0.1 terabyte, and the analysis and contextual interpretation of variant data for multiple genomes is almost impossible to handle for non- bioinformaticians and for genetic centers without suficient bioinformatic resources). Large-scale collaborative efforts are also needed to produce sustainable results. Given the excess of rare variants in human populations[32], WES commonly produces lists of >250 rare, well conserved heterozygous variants. Rebecca Schüle demonstrated that this can lead to very questionable findings for both dominant and recessive ataxia genes, in particular for large andƒor hypervariable genes. For example, a rare conserved variant in SYNE1 can be found in 7% of all exome data-sets (394 out of 5990 exomes in the database GEM.app[33]). Large-scale collaborative databases here allow to unravel such frequencies and to critically reflect findings on seemingly novel ataxia variants and genes.

Questionable findings might result not only for recessive genes like SYNE1, but even more for dominant genes like TMEM240[34]. Evidence for pathogenicity of this gene in ataxia was taken from several isolated cases with de novo mutations in TMEM240 and then expanded to additional small families with only limited segregation data and without functional proof of the pathogenicity for several variants. Again, large-scale collaborative exome-databases here allow to broaden the perspective and to critically reflect on such variants. For example, an analysis from the 5990 exomes GEM.app reveals that rare (<0.01%) and well conserved TMEM240 variants can be found, inter alia, in 1 patient with spastic ataxia, 2 patients with HSP, 1 patient with a mitochondrial phenotype, 2 patients with deafness, 2 patients with epilepsy, 5 patients with ALS, 7 patients with a neuromuscular phenotype, 1 patient with a brain malformation, 4 patients with cardiomyopathy. These findings show that – although some TMEM240 are likely to cause ataxia – other equally rare, well-conserved TMEM240 variants ubiquitously occur in human disease, and are most likely not linked to ataxia.

In more general and illustrative terms, these findings show that, without access to large-scale multi-phenotype exome databases containing thousands of exomes and without rechecking them to scrutinize target findings, NGS-based gene hunting and variant identification might be mistaken like the blind men in front of the elephant: without having a comprehensive perspective on the different variant frequencies in various neurological and non-neurological exomes, one might be inclined to report a novel gene or variant as a novel ataxia gene, HSP gene, mitochondrial gene, deafness gene, ALS gene, or cardiomyopathy gene, without realizing that it might simply present only a little part of the whole picture.

 

 

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