Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Theresa A. Zesiewicz, George Wilmot, Sheng-Han Kuo, Susan Perlman, Patricia E. Greenstein, Sarah H. Ying, Tetsuo Ashizawa, S.H. Subramony, Jeremy D. Schmahmann, K.P. Figueroa, Hidehiro Mizusawa, Ludger Schöls, Jessica D. Shaw, Richard M. Dubinsky, Melissa J. Armstrong, Gary S. Gronseth and Kelly L. Sullivan. Neurology published online February 9, 2018 doi:10.1212/WNL.0000000000005055

Objective To systematically review evidence regarding ataxia treatment.

Methods A comprehensive systematic review was performed according to American Academy of Neurology methodology.

Conclusions For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis–associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Interactions of Frataxin with ISCU and Ferredoxin on the Cysteine Desulfurase Complex Leading to Fe-S Cluster Assembly

Kai Cai. Volume 114, Issue 3, Supplement 1, 2 February 2018, Pages 571a, doi:10.1016/j.bpj.2017.11.3123

Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry, chemical cross-linking with analysis by LC/MS/MS, multinuclear NMR spectroscopy, and biochemical assays to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. We have constructed a structural model of the core of this machine by combining homology modeling with docking constraints derived from NMR chemical shift perturbations and chemical cross-linking studies. We show that the machinery operates through dynamic interactions among its components and have identified interactions relevant to the cysteine desulfurase reaction, which generates S, and iron transfer from FXN, which leads to iron-sulfur cluster assembly. We also have elucidated the mechanism by which the variant ISCU(M108I) bypasses the requirement for FXN.

RNA–DNA hybrids promote the expansion of Friedreich's ataxia (GAA)n repeats via break-induced replication

Alexander J Neil Miranda U Liang Alexandra N Khristich Kartik A Shah Sergei M Mirkin; Nucleic Acids Research, , gky099, doi:10.1093/nar/gky099

Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA–DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich’s ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA–DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed. Unexpectedly, we observed a similar increase in repeat instability in RNase H-deficient cells when we either changed the direction of transcription-replication collisions, or flipped the repeat sequence such that the (UUC)n run occurred in the transcript. The increase in repeat expansions in RNase H-deficient strains was dependent on Rad52 and Pol32 proteins, suggesting that break-induced replication (BIR) is responsible for this effect. We conclude that expansions of (GAA)n repeats are induced by the formation of RNA–DNA hybrids that trigger BIR. Since this stimulation is independent of which strand of the repeat (homopurine or homopyrimidine) is in the RNA transcript, we hypothesize that triplex H-DNA structures stabilized by an RNA–DNA hybrid (H-loops), rather than conventional R-loops, could be responsible.

Restless legs syndrome and periodic leg movements in patients with movement disorders: Specific considerations

Högl, B. and Stefani, A. (2017), Mov. Disord., 32: 669–681. doi: 10.1002/mds.26929

The diagnostic criteria for restless legs syndrome (RLS) have been continuously updated in recent years, considerably facilitating both an accurate diagnosis and appropriate management of RLS.
Periodic leg or limb movements during sleep (PLMS) are present in patients with and without RLS and can be seen as biomarkers of genetic susceptibility to RLS.
Restless legs syndrome, and eriodic leg movements during wakefulness (PLMW) were significantly higher in Friedrich’s ataxia patients with RLS than in those without. Interestingly, in most of them RLS onset was after Friedreich’s ataxia onset, and Friedreich’s ataxia patients with RLS had significantly lower ferritin levels than those without.
Substantia nigra echogenicity correlated inversely with disease severity of Friedrich’s ataxia and was significantly associated with RLS. In contrast, few Friedreich’s ataxia patients fulfilled RLS criteria.
Although the large variation of RLS frequencies reported in these patients could indicate diagnostic difficulties because of confounding symptoms, the apparent high frequency of RLS in Frie-
dreich’s ataxia and the association with disturbed brain iron metabolism is interesting and requires further study.

New Approaches to Exciting Exergame-Experiences for People with Motor Function Impairments

Eckert, M.; Gómez-Martinho, I.; Meneses, J.; Martínez, J.-F.; Sensors 2017, 17, 354. doi:10.3390/s17020354             
OPEN ACCESS

The work presented here suggests new ways to tackle exergames for physical rehabilitation and to improve the players’ immersion and involvement. The primary (but not exclusive) purpose is to increase the motivation of children and adolescents with severe physical impairments, for doing their required exercises while playing. The proposed gaming environment is based on the Kinect sensor and the Blender Game Engine. A middleware has been implemented that efficiently transmits the data from the sensor to the game. Inside the game, different newly proposed mechanisms have been developed to distinguish pure exercise-gestures from other movements used to control the game (e.g., opening a menu). The main contribution is the amplification of weak movements, which allows the physically impaired to have similar gaming experiences as the average population. To test the feasibility of the proposed methods, four mini-games were implemented and tested by a group of 11 volunteers with different disabilities, most of them bound to a wheelchair. Their performance has also been compared to that of a healthy control group. Results are generally positive and motivating, although there is much to do to improve the functionalities. There is a major demand for applications that help to include disabled people in society and to improve their life conditions. This work will contribute towards providing them with more fun during exercise.

ISCU(M108I) and ISCU(D39V) differ from wild type ISCU in their failure to form cysteine desulfurase complexes containing both frataxin and ferredoxin

Kai Cai, Ronnie O. Frederick, Marco Tonelli, and John L. Markley; Biochemistry, Just Accepted Manuscript DOI: 10.1021/acs.biochem.7b01234

Whereas iron-sulfur (Fe-S) cluster assembly on the wild-type scaffold protein ISCU, as catalyzed by the human cysteine desulfurase complex (SDA), exhibits a requirement for frataxin (FXN), assembly on variant ISCU(M108I) has been shown to bypass the FXN requirement. Wild-type ISCU populates two interconverting conformational states: one structured and one dynamically disordered. We show here that ISCU(M108I) populates only the structured state as does another variant ISCU(D39V). We have compared the properties ISCU, ISCU(M108I), and ISCU(D39V), with and without FXN, in both the cysteine desulfurase step of Fe-S cluster assembly and in the overall Fe-S cluster assembly reaction. In the cysteine desulfurase step with DTT as the reductant, FXN was found to stimulate cluster assembly with both the wild-type and structured variants, although the effect was less prominent with ISCU(D39V) than with wild-type or ISCU(M108I). In overall Fe-S cluster assembly, frataxin was found to stimulate cluster assembly with both the wild-type and structured variants when the reductant was DTT; however, with the physiological reductant, reduced ferredoxin 2 (rdFDX2), frataxin stimulated the reaction with wild-type ISCU but not with the fully-structured variants. Through NMR titration experiments, we discovered that, wild-type ISCU, frataxin, and rdFDX2 all bind to SDA. However, when ISCU was replaced by the fully-structured variant ISCU(M108I), the addition of rdFDX2 to the SDA-ISCU(M108I)-FXN complex led to the release of FXN. Thus, the displacement of FXN by rdFDX2 explains the failure of FXN to stimulate Fe-S cluster assembly on ISCU(M108I).

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

Lucia Montenegro, Rita Turnaturi, Carmela Parenti and Lorella Pasquinucci; Nanomaterials 2018, 8(2), 87; doi:10.3390/nano8020087

The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE’s unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives.

Jotrol IND Application Submission for MPS and Friedrich's Ataxia Imminent

Mathew Shanley, Rare Disease Report. FEBRUARY 05, 2018

Jupiter Orphan Therapeutics, Inc. (JOT) announced this morning that it intends to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for Jotrol in mucopolysaccharidosis type 1 (MPS I), among other indications, within the next few weeks.
"We will initiate the IND in MPS I and plan to cross-reference PK and safety data in follow-on indications. We are well prepared to gear up for a study in Friedreich's Ataxia (FA) and will thereafter determine if Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) or Leber's Hereditary Optic Neuropathy (LHON) will be the 3rd indication we approach. An IND submission for FA is planned for quarter 2 of 2018, and for MELAS and/or LHON no later than quarter 4," stated JOT Chief Security Officer Dr. Marshall Hayward in a press release.
JOT has used an isomer of the resveratrol to develop a pharmaceutical grade compound that can be properly tested in clinical trials, and successful pre-clinical data have shown that it can increase levels of frataxin.

To study the genotype - phenotype correlation of Friedreich’s Ataxia (FRDA) patients in Indian population

I. Ahmad, A. Kumar Srivastava, M. Faruq, V. Padma Srivastava M., Parkinsonism & Related Disorders, Volume 46, Supplement 2, January 2018, Page e7, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.11.023.

This is the largest genotype and phenotype series on FRDA in Indian population. This study showed GAA1 size affects the cerebellar atrophy, muscles twisting and tremor.

Paediatric genomics: diagnosing rare disease in children

Caroline F. Wright, David R. FitzPatrick & Helen V. Firth, Nature Reviews Genetics, Published online:05 February 2018, doi:10.1038/nrg.2017.116

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition. However, making a molecular diagnosis with current technologies and knowledge is often still a challenge. Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows. This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease. Importantly, for affected families, a better understanding of the genetic basis of rare disease translates to more accurate prognosis, management, surveillance and genetic advice; stimulates research into new therapies; andenables provision of better support.

Ethical, legal and social implications of paediatric genomics:
Paediatric genomics has many of the same ethical, legal and social issues that clinical genetics has been dealing with for decades, such as reproductive autonomy, informed consent for research, misattributed parentage and implications for family members. Issues which are more complicated for paediatric testing: the reduced capacity of the child to consent to testing and/or research means that parents and clinicians have an increased role in deciding what may be in the best interests of the child. Most of the novel ethical issues in the era of genomics relate to the storage, interpretation and access of data.


Data storage: it is not clear who should have access to that data and when they should be allowed access to it. Should access be limited to clinicians involved in the direct care of the family or opened to researchers in industry and/or academia?
Confidentiality versus data access: Parents are often asked to make decisions about their child’s data that may have irreversible repercussions. Should these decisions be revisited when the child approaches and passes the age of majority?
Duty of care: For clinicians, the issue of data access is linked to the question of whether their duty of care is limited to finding a diagnosis for the child’s immediate problems or whether it extends beyond the scope of the initial investigation. The duty of care could also extend to looking for incidental predispositions to adult-onset conditions or to adverse drug reactions either in the child or their parents. In general, investigating children for adult-onset conditions for which there is no early treatment is not recommended.