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.

Cardiomyopathy of Friedreich's Disease. Modern Methods of Diagnostic

Fomicheva E.I., Myasnikov R.P., Selivyorstov Y.A., Illarioshkin S.N., Dadali E.L., Drapkina O.M. ; Rational Pharmacotherapy in Cardiology. 2021;17(1):105-110. doi:10.20996/1819-6446-2021-01-05 

The basis of the clinical picture of Friedreich's disease is ataxia of a mixed (sensitive and cerebellar) nature. The steady and gradual progression of neurological symptoms significantly affects the quality of life of patients and is most often the leading reason for seeking medical attention. However, the prognosis is primarily due to the involvement of cardiac tissue in the pathological process. The main causes of death in patients with Friedreich's ataxia are severe heart failure and sudden cardiac death due to cardiomyopathy. The overwhelming majority of foreign and domestic publications on Friedreich's ataxia are devoted to the neurological manifestations of this disease, and little attention is paid to this problem in the cardiological scientific and practical society. The purpose of this review is to provide up-to-date information on modern methods of diagnosing myocardial damage at various stages of Friedreich's disease.

Coenzyme Q10 Analogues: Benefits and Challenges for Therapeutics

Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Munuera-Cabeza M, Suárez-Carrillo A, Talaverón-Rey M, Sánchez-Alcázar JA.; Antioxidants. 2021; 10(2):236. doi:10.3390/antiox10020236

  Over the past few years, a wide variety of CoQ10 analogues with improved properties have been developed. These analogues conserve the antioxidant features of CoQ10 but present upgraded characteristics such as water solubility or enhanced mitochondrial accumulation. Moreover, recent studies have proven that some of these analogues might even outperform CoQ10 in the treatment of certain specific diseases. The aim of this review is to provide detailed information about these Coenzyme Q10 analogues, as well as their functionality and medical applications.

This synthetic quinone stands out for its efficacy as a treatment for Friedreich ataxia (FRDA). From 1990 and up to the present, several clinical trials have tested the impact of Idebenone supplementation on patients of FRDA. These studies have proven that the quinone ameliorates patients’ conditions through the improvement of neurological function (reduced general weakness, improvement in fine movement and speech, and decreased difficulty in swallowing) [49] and cardiac hypertrophy (reduction in interventricular septal wall thickness, left ventricular posterior wall thickness, or left ventricular mass index) [50,51]. Idebenone has been widely tested in clinical trials for several years. Its main relevance is in FRDA

Friedreich ataxia in a family from Mali, West Africa

heick Abdel Kader Cissé,Lassana Cissé,Hamidou O Bah,Oumar Samassékou,Assiatou Simaga,Abdoulaye Tamega,Salimata Diarra,Seybou Hassane Diallo,Thomas Coulibaly,Salimata Diallo,Abdoulaye Yalcouye,Alassane Baneye Maiga,Mohamed Kéita,Kenneth Fischbeck,Sekou Fantamady Traore,Cheick Guinto,Guida Landouré; West Africa. Authorea. February 24, 2021. DOI: 10.22541/au.161414432.28217723/v1 

Cissé, CAK, Cissé, L, Ba, HO, et al; from the H3Africa Consortium. Friedreich ataxia in a family from Mali, West Africa/Friedreich ataxia in a Malian family. Clin Case Rep. 2021; 9:e04065.  doi: 10.1002/ccr3.4065

 Friedreich ataxia is the most common inherited ataxia in the world, but yet to be reported in black African. We report the first genetically confirmed case in a West African family. Studying genetic diseases in populations with diverse backgrounds may give new insights into their pathophysiology for future therapeutic targets.

Crosstalk between nucleus and mitochondria in human disease: Mitochondrial iron and calcium homeostasis in Friedreich ataxia

Jordi Tamarit, Elena Britti, Fabien Delaspre, Marta Medina‐Carbonero, Arabela Sanz‐Alcázar, Elisa Cabiscol, Joaquim Ros; IUBMB Life. 2021; 1– 11. https://doi.org/10.1002/iub.2457

 Friedreich Ataxia is a neuro‐cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.

Preclinical autoimmune disease biotech Design Therapeutics files for a $100 million IPO

March 5, 2021, 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. The GeneTACs are designed to selectively bind to genetic repeat sequences, modulate gene expression either by restoring or blocking transcription, and restore cellular health. As a platform, the company believes that GeneTACs have broad applicability across monogenic nucleotide repeat expansion diseases. Design plans to initiate clinical trials with its lead product candidate in Friedreich ataxia patients to evaluate its safety, pharmacokinetics, and effect on frataxin levels by the first half of 2022, subject to receiving regulatory clearance to proceed into clinical trials.

Ectopic Burden via Holter Monitors in Friedreich Ataxia.

Erika Mejia,Abigail Lynch,Patrick Hearle,Oluwatimilehin Okunowo,Heather Griffis,Maully Shah,David Lynch,Kimberly Y Lin; Physician's Weekly; Mar 4, 2021

Using a natural history study of patients with Friedreich ataxia at a single center, we analyzed portable heart rhythm monitors (Holters). Ectopic burden was defined as the proportion of atrial or ventricular ectopic beats over total beats.
Of 456 patients, 131 had Holters. Sixty-eight (52.0%) were male, median age of symptom onset was 8.0 years (5.0 to 13.0, n = 111), median age at time of Holter was 17.3 years (interquartile range [IQR] 12.9 to 22.8, n = 129), and median duration of illness was 8.7 years (IQR 5.3 to 11.6, n = 110). Median GAA length on the shorter FXN allele was 706.0 (IQR 550.0 to 840.0, n = 112). Eight (7.8%, n = 103) had diminished cardiac function, and 74 (74.0%, n = 100) had ventricular hypertrophy. Ninety patients (83.0%) had atrial ectopy (supraventricular ectopy [SVE]): 85 (78.0%) with rare SVE (>0% to 5%) and five (5.0%) with frequent SVE (>10%). Twenty-five (19.0%) had supraventricular runs, and one (0.8%) had atrial fibrillation/flutter. Forty-five (41.0%) had ventricular ectopy (VE): 43 (39.0%) with rare VE (0% to 5%) and two (2.0%) with moderate VE (5% to 10%). Compared with patients with none and rare SVE, patients with frequent SVE had longer disease duration (18.3 versus 4.6 versus 9.0 years, P = 0.0005).
Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification; however, longitudinal analysis is needed.

Larimar Therapeutics Reports Fourth Quarter and Full Year 2020 Operating and Financial Results

BioSpace.com, Published: Mar 04, 2021​. 

 

Reported preliminary Phase 1 findings from a Single Ascending Dose (SAD) trial that suggest single subcutaneous injections of CTI-1601 were well tolerated at doses up to 100 mg in Friedreich'sataxia (FA) patients Placebo-controlled Phase 1 trials in FA patients remain on track for topline data in Q2 2021