Clinical trials for genetic diseases in Latin America Poswar, Fabiano de Oliveira; da Silva, Larissa Pozzebon; Zambrano, Marina Bauer ...
American journal of medical genetics. Part C, Seminars in medical genetics,
09/2021, Letnik:
187, Številka:
3
Journal Article
Latin American geneticists have been contributing to the scientific development of Human and Medical Genetics fields since the early 1950s. In the last decades, as Medical Genetics is moving toward a ...new era of innovative therapies for previously untreatable conditions, the participation of Latin America in clinical trials is also increasing. This review discusses the particularities regarding funding, regulatory, and ethical aspects of conducting clinical trials for genetic diseases in Latin America, with an especial focus on Brazil, the largest country with the highest number of studies. Although there are still several barriers to overcome, the recent development of orphan drug legislation and policies for rare diseases in many Latin American countries indicates a growing opportunity for the participation of the region in international efforts for the development of new therapies for genetic diseases.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset, neurodegenerative disorder caused by mutations in SACS, firstly reported in Quebec, Canada. The disorder is ...typically characterized by childhood onset ataxia, spasticity, neuropathy and retinal hypermyelination. The clinical picture of patients born outside Quebec, however, is often atypical. In the present article, the authors describe clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil. We present a review on the neuroimaging, ophthalmologic and neurophysiologic clues for ARSACS diagnosis. The early-onset, slowly progressive, spastic-ataxia phenotype of reported patients was similar to ARSACS patients from Quebec. The SACS sequencing revealed the novel homozygous c.5150_5151insA frameshift mutation confirming the ARSACS diagnosis. ARSACS is a frequent cause of early onset ataxia/spastic-ataxia worldwide, with unknown frequency in Brazil.
Genetic testing is being considered the first-step in the investigation of hereditary myopathies. However, the performance of the different testing approaches is little known. The aims of the present ...study were to evaluate the diagnostic yield of a next-generation sequencing panel comprising 39 genes as the first-tier test for genetic myopathies diagnosis and to characterize clinical and molecular findings of families from southern Brazil. Fifty-one consecutive index cases with clinical suspicion of genetic myopathies were recruited from October 2014 to March 2018 in a cross-sectional study. The overall diagnostic yield of the next-generation sequencing panel was 52.9%, increasing to 60.8% when including cases with candidate variants. Multi-gene panel solved the diagnosis of 12/25 (48%) probands with limb-girdle muscular dystrophies, of 7/14 (50%) with congenital muscular diseases, and of 7/10 (70%) with muscular dystrophy with prominent joint contractures. The most frequent diagnosis for limb-girdle muscular dystrophies were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related; for congenital muscular diseases,
RYR1
-related-disorders; and for muscular dystrophy with prominent joint contractures, Emery-Dreifuss-muscular-dystrophy-type-1 and
COL6A1
-related-disorders. In summary, the customized next-generation sequencing panel when applied in the initial investigation of genetic myopathies results in high diagnostic yield, likely reducing patient’s diagnostic odyssey and providing important information for genetic counseling and participation in disease-specific clinical trials.
Although it is predominantly a muscular disease, impairments in the central nervous system in patients with facioscapulohumeral muscular dystrophy (FSHD) have been described in the literature.
To ...describe the cognitive profile of patients with FSHD and to correlate the impairments found with clinical variables and quality of life.
Cross-sectional and case-control study that evaluated FSHD patients using a series of cognitive assessments (Mini-Mental State Examination - MMSE, Montreal Cognitive Assessment - MoCA, verbal fluency with phonological restriction - FAS, categorical verbal fluency - FAS-cat, trail-making test - TMT, and Rey's Verbal Auditory Learning Test); a neurological severity scale (Gardner-Medwin-Walton - GMWS); and a quality of life measurement tool (Medical Outcomes Study 36-Item Short-Form Health Survey).
Individuals with FSHD (13) and healthy controls (26) were paired by gender and age. Significant differences between case and control groups were found in MMSE, TMT A, and A7 (p≤0.05) and MOCA (p≤0.001) performances. A positive correlation was verified in long-term memory impairments and the age in which symptoms appear (r=-0.593, p=0.033). Regarding quality of life assessment, the emotional domain correlated to MEEM (r=0.657, p=0.015), TMT A (r=-0.601, p=0.030), and A7 (r=0.617, p=0.025) performances.
Individuals with FSHD presented mild impairments in the performance of tasks that involve attention, planning, and long-term memory functions. Those impairments were associated neither with the disease duration nor with its neurological severity.
Spinocerebellar ataxia 3 is an untreatable CAG repeat expansion disorder whose natural history is not completely understood. Our aims were to describe the progression of neurological manifestations ...in a long-term cohort of spinocerebellar ataxia 3, and to verify if CAG expanded repeat, gender, and age at onset were associated with the rate of progression. Patients entered the study between 1998 and 2005 and were seen until 2007. On each visit, the validated NESSCA scale, an inventory of 18 neurological manifestations, was applied. Scores observed in each year of disease duration produced a Growth Curve, which was analyzed through the random coefficients model. Scores obtained in some individual items were described through multi-state Markov models. One hundred fifty-six patients (78 families) were recruited; 28 were lost, and 23 died. Mean (sd) ages at onset and at baseline were 32.8 (10.6) and 40.7 (12.8) years; median (range) expanded CAGn was 74 (67–85). Three hundred fifteen NESSCA evaluations were performed, comprising disease durations from zero to 34 years. The 105 patients who completed the study were seen over 5 (sd = 2.4) years at intervals of 2.5 (sd = 1.5) years. The trajectory of NESSCA obtained for the overall group increased by 1.26 points per year. This slope increased by 0.15 points per each additional CAG in the expanded repeat (
p
< 0.0002) and decreased by 0.03 points per each additional year of age at onset (
p
= 0.005). NESSCA worsened steadily, producing linear trajectories, which were faster among patients with longer expanded repeats (>74) and with lower ages at onset (<34 years).
To describe survival and neurological outcomes after HSCT for these disorders.
Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic ...resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated.
Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT.
Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.
Spinal muscular atrophy linked to chromosome 5 (SMA-5q) is an autosomal recessive genetic disease caused by mutations in the
. SMA-5q is characterized by progressive degeneration of the spinal cord ...and bulbar motor neurons, causing severe motor and respiratory impairment with reduced survival, especially in its more severe clinical forms. In recent years, highly effective disease-modifying therapies have emerged, either acting by regulating the splicing of exon 7 of the
gene or adding a copy of the
gene through gene therapy, providing a drastic change in the natural history of the disease. In this way, developing therapeutic guides and expert consensus becomes essential to direct the use of these therapies in clinical practice. This consensus, prepared by Brazilian experts, aimed to review the main available disease-modifying therapies, critically analyze the results of clinical studies, and provide recommendations for their use in clinical practice for patients with SMA-5q. This consensus also addresses aspects related to diagnosis, genetic counseling, and follow-up of patients under drug treatment. Thus, this consensus provides valuable information regarding the current management of SMA-5q, helping therapeutic decisions in clinical practice and promoting additional gains in outcomes.
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