A severe form of autosomal recessive spinocerebellar ataxia associated with novel PMPCA variants

Yoko Takahashi, Masaya Kubota, Rika Kosaki, Kenjiro Kosaki, Akira Ishiguro; Brain and Development, Volume 43, Issue 3, 2021, Pages 464-469, doi:10.1016/j.braindev.2020.11.008. 

Spinocerebellar ataxia, autosomal recessive 2 (SCAR2) [MIM:213200] is a rare autosomal recessive disease of spinocerebellar ataxia associated with degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR2 is characterized by onset of impaired motor development and ataxic gait in early childhood. Recently, several PMPCA gene variants have been reported in SCAR2 patients with mild and non-progressive symptoms. PMPCA codes frataxin, which is crucial for iron biosynthesis in cells. 

**Evidences showed that MPP ( Mitochondrial-processing peptidase subunit alpha) is an enzyme that in humans is encoded by the PMPCA gene, it's involved in the proteolytic maturation of Frataxin, a protein responsible for iron homeostasis. Accordingly, MPP deficiency was shown to be involved in Friedreich ataxia, an autossomic recessive neurodegenerative disorder.

Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study

Prof Kathrin Reetz, MD, Imis Dogan, PhD, Prof Ralf-Dieter Hilgers, PhD, Prof Paola Giunti, MD, Michael H Parkinson, MBBS, Caterina Mariotti, MD, Lorenzo Nanetti, MD, Prof Alexandra Durr, MD, Claire Ewenczyk, MD, Sylvia Boesch, MDWolfgang Nachbauer, MD, Thomas Klopstock, MD,, Claudia Stendel, MD, Francisco Javier Rodríguez de Rivera Garrido, MD, Christian Rummey, PhD, Prof Ludger Schöls, MD, Stefanie N Hayer, PhD Prof Thomas Klockgether, MD, Ilaria Giordano, MD, Claire Didszun, PhD, Myriam Rai, PhD, Prof Massimo Pandolfo, MD, Prof Jörg B Schulz on behalf of theEFACTS study group; The Lancet Neurology, Published:March 23, 2021 DOI:10.1016/S1474-4422(21)00027-2 

The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia.

The Role of Serum Levels of Neurofilament Light (NfL) Chain as a Biomarker in Friedreich Ataxia

Bernice Frempong, Robert B. Wilson, Kimberly Schadt and David R. Lynch; Front. Neurosci., 02 March 2021, doi:10.3389/fnins.2021.653241 

A deeper understanding of the mechanisms of NfL elevation in serum in FRDA is needed to make it a useful biomarker in FRDA.

The responsiveness of gait and balance outcomes to disease progression in Friedreich ataxia

Sarah C Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli, Eppie M Yiu, Nellie Georgiou-Karistianis, Geneieve Tai, Zesiewicz Zesiewicz, Martin B Delatycki, Louise A Corben; doi: 10.1101/2021.03.18.434657 

The FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

In vivo survival and differentiation of Friedreich ataxia iPSC-derived sensory neurons transplanted in the adult dorsal root ganglia

Viventi S, Frausin S, Howden SE, Lim SY, Finol-Urdaneta RK, McArthur JR, Abu-Bonsrah KD, Ng W, Ivanusic J, Thompson L, Dottori M.; Stem Cells Transl Med. 2021 Mar 18. doi: 10.1002/sctm.20-0334. Epub ahead of print. 

 Our data showed survival and differentiation of hESC and FRDA iPSC-derived progenitors in the DRG 2 and 8 weeks post-transplantation, respectively. Donor cells expressed neuronal markers, including sensory and glial markers, demonstrating differentiation to these lineages. These results are novel and a highly significant first step in showing the possibility of using stem cells as a cell replacement therapy to treat DRG neurodegeneration in FRDA as well as other peripheral neuropathies.

Research priorities for rare neurological diseases: a representative view of patient representatives and healthcare professionals from the European Reference Network for Rare Neurological Diseases

Annemarie E. M. Post, Thomas Klockgether, G. Bernhard Landwehrmeyer, Massimo Pandolfo, Astri Arnesen, Carola Reinhard & Holm Graessner. Orphanet J Rare Dis 16, 135 (2021). doi:10.1186/s13023-020-01641-z 

Patient involvement in research increases the impact of research and the likelihood of adoption in clinical practice. A first step is to know which research themes are important for patients. We distributed a survey on research priorities to ERN-RND members, both patient representatives and healthcare professionals, asking them to prioritize five research themes for rare neurological diseases on a scale ranging from 1 (most important) to 5 (least important). A follow-up e-mail interview was conducted with patient representatives and professionals to assess potential reasons for differences in opinions between these two groups.

Evaluation of the Effects of Calcitriol's in the Neurological Symptoms of Friedreich's Ataxia Patients (Calcitriol-FA)

ClinicalTrials.gov Identifier: NCT04801303. 

Recruitment Status : Not yet recruiting, First Posted : March 17, 2021, Last Update Posted : March 17, 2021 

 Description of the trial: to assess the effect of Calcitriol 0.25mcg/24h for a year in the neurological function of FA patients. Main objective of the trial: to evaluate the effects of Calcitriol in the neurological symptoms of patients with FA. The second objectives of the trial are: To evaluate the safety and the risk of hypercalcemia with the treatment with low dosis of Calcitriol (0.25mcg of Calcitriol every 24h) in patients with FA. To measure de change in the Frataxin's levels during the treatment with Calcitriol. To evaluate the effects of Calcitriol in the daily life activities and the life quality of the patients with FA. Sample size: The number of participants needed to compleat the trial is 20. 

Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)

Duration: The duration of the trial is one year 

Locations: Spain, Hospital Santa Caterina/Parc Martí i Julià, Salt, Spain, 17190

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice

ural, A., Şimşir, G., Tekgül, Ş., Koçoğlu, C., Akçimen, F., Kartal, E., Şen, N.E., Lahut, S., Ömür, Ö., Saner, N., Gül, T., Bayraktar, E., Palvadeau, R., Tunca, C., Pirkevi Çetinkaya, C., Gündoğdu Eken, A., Şahbaz, I., Kovancılar Koç, M., Öztop Çakmak, Ö., Hanağası, H., Bilgiç, B., Eraksoy, M., Gündüz, A., Apaydın, H., Kızıltan, G., Özekmekçi, S., Siva, A., Altıntaş, A., Kaya Güleç, Z.E., Parman, Y., Oflazer, P., Deymeer, F., Durmuş, H., Şahin, E., Çakar, A., Tüfekçioğlu, Z., Tektürk, P., Çorbalı, M.O., Tireli, H., Akdal, G., Yiş, U., Hız, S., Şengün, İ., Bora, E., Serdaroğlu, G., Erer Özbek, S., Ağan, K., İnce Günal, D., Us, Ö., Kurt, S.G., Aksoy, D., Bora Tokçaer, A., Elmas, M., Gültekin, M., Kumandaş, S., Acer, H., Kaya Özçora, G.D., Yayla, V., Soysal, A., Genç, G., Güllüoğlu, H., Kotan, D., Özözen Ayas, Z., Şahin, H.A., Tan, E., Topçu, M., Topçuoğlu, E.S., Akbostancı, C., Koç, F., Ertan, S., Elibol, B. and Başak, A.N. (2021), Mov Disord. doi.:10.1002/mds.28518 

Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix–Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole‐exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty‐eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data.

Early onset ataxia with Marfanoid features a new varient of Friedreich s ataxia

Khichar S.; IP Indian J Neurosci 2021;7(1):95-96, doi:10.18231/j.ijn.2021.015

A young male with ataxia since early childhood with Marfanoid features, normal intellect and no biochemical abnormality is reported. The syndrome has partial resemblance with previously described syndrome of arachnodactyle, cerebellar ataxia and other features, what has been named as "Bhaskar Syndrome". The documentation of such rare entities is worth for future research.

Design Therapeutics, Inc. (DSGN)

12/3/21. Design Therapeutics is a preclinical-stage biopharmaceutical company pioneering novel small-molecule therapeutic candidates, called gene targeted chimeras (GeneTACs), that are designed to be disease-modifying and target the underlying cause of inherited nucleotide repeat expansion diseases, of which there are more than 40 debilitating degenerative diseases. 

 In preclinical studies for our lead program, we have observed restoration of frataxin (FXN) levels in cells from Friedreich ataxia (FA) patients using our FA GeneTACs. 

 We plan to initiate clinical trials with our lead product candidate in FA patients to evaluate its safety, pharmacokinetics (PK) and effect on FXN levels by the first half of 2022, subject to receiving regulatory clearance to proceed into clinical trials.