Jonas Alex Morales Saute

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by bi-allelic pathogenic variants in SMN1, leading to motor neuron degeneration, muscle atrophy and progressive weakness. Although disease-modifying therapies have recently become available, reliable biomarkers for disease monitoring remain limited. This study aimed to identify potential biomarkers of disease severity and monitoring in SMA using an unbiased approach based on differential gene expression datasets. A meta-analysis of datasets from 15 studies in SMA mouse models identified genes differentially expressed in at least three studies. Of the 134 differentially expressed genes, 122 had human orthologs, with only two being CNS-specific and consistently altered across studies, including glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity. Candidate gene expression was subsequently evaluated in two human datasets. GFAP and neurofilament light chain (NfL) serum levels were then measured in a case–control study including 25 SMA patients (11 type 1, 14 types 2/3) and 24 matched controls, followed by a 12-month cohort study of the SMA patients. GFAP levels in cerebrospinal fluid (CSF) were assessed in 14 patients before and up to 14 months after initiation of disease-modifying therapies. Serum GFAP levels were lower in SMA patients compared with controls (P = 0.014), but higher in those with SMA type 1 (P = 0.028) and in patients with two SMN2 copies (P = 0.03). Patients under disease-modifying treatment exhibited higher baseline GFAP levels (P = 0.01). CSF GFAP levels decreased after 14 months of treatment in SMA type 1 and in pre-symptomatic patients predicted to develop type 1 (P = 0.045). NfL levels were elevated in SMA patients, correlating with disease severity and SMN2 genotype, and further increased over 12 months. Taken together, this study, employing an unbiased biomarker discovery strategy, identified GFAP as a candidate biomarker for SMA. Clinical validation demonstrated reduced serum GFAP levels, which correlated with disease type, SMN2 copy number and treatment status. In SMA type 1, CSF GFAP levels declined over time with treatment. These findings implicate astrocytes in SMA-related neurodegeneration and support GFAP as a potential biomarker for the disease.

Spinal muscular atrophy (SMA) is considered one of the most common autosomal recessive disorders, with an estimated incidence of 1 in 10,000 live births. Testing for SMA has been recommended for inclusion in neonatal screening (NBS) panels since there are several therapies available and there is evidence of greater efficacy when introduced in the pre/early symptomatic phases. In the present study, dried blood spot samples collected by the Reference Services of Neonatal Screening of the Brazilian states of Rio Grande do Sul, Sao Paulo, Mato Grosso and Bahia to perform the routine NBS panel were also screened for 5q-SMA, using real-time PCR (SALSA MC002 technique). In this study, samples from 80,000 newborns were analyzed, enabling the identification of 7 5q-SMA cases, which were confirmed by multiplex ligation-dependent probe amplification (MLPA). Considering our findings, Brazil has an incidence of 5q-SMA of 1 in 11,428 live births. This work expands regional knowledge about the incidence of SMA and is fundamental for planning the implementation of screening for this condition in Brazil.

Many countries lack their guidelines for best practices in genomic medicine, whether for clinical practice or research. For the construction of these national guidelines or institutional policies in human genomics research several key criteria must be observed. The determination of variant pathogenicity has become more refined, with specific global recommendations being adopted. A well-conducted consent process, managed by qualified professionals, ensures the protection of research participants’ rights. Pre-established sequencing and data analysis parameters are crucial for ensuring reliable results, and clear guidelines must be provided on whether or not to disclose findings to participants. Data storage remains a challenge due to both the size and sensitivity of the generated files. This work discusses these critical aspects and represents an initiative to propose the best practice recommendations for genomic medicine in human research. These recommendations were developed by a working group of experts and were further refined through discussions with members of the scientific community in genetics and genomic medicine.

Introduction: Hereditary Spastic Paraplegias (HSP) are a group of genetic disorders leading to the degeneration of long motor and sensory tracts in a progressive course. Clinician-reported outcomes (ClinROs) are the most commonly used endpoints for monitoring these diseases, but they have low sensitivity to detect progression. Therefore, identifying new monitoring biomarkers with higher sensitivity to change is crucial. Our objective was to compare the progression of Somatosensory Evoked Potential (SSEP) latencies over time with ClinROs in HSP. Methods: A longitudinal study was conducted on 22 individuals with a genetic diagnosis (13 SPG4, 3 SPG5, 3 SPG7, 2 SPG10, and 1 cerebrotendinous xanthomatosis), with two evaluations over a 4-year interval of upper limb (UL) and lower limb (LL) SSEPs and the Spastic Paraplegia Rating Scale (SPRS) total score and motor items only (mSPRS). Results: In the follow-up time analysis, progression after 4 years was observed only for SPRS and mSPRS, with an annual progression of 1.12 points and 1.02 points, respectively. No statistically significant progression was observed for SSEPs. Disease progression modeled according to disease duration showed worsening in all outcomes. For each additional year of disease, the SPRS worsened by 0.834 points (95% CI 0.62 to 1.04, p < 0.001), mSPRS by 0.758 points (95% CI 0.55 to 0.96, p < 0.001), SSEP-UL latency by 0.164 ms (95% CI 0.03 to 0.3, p < 0.001), and SSEP-LL latency by 1.343 ms (95% CI 0.74 to 1.93, p < 0.001). Results for the SPG4 subgroup were similar to those for the overall HSP group. Conclusion: The neurophysiological progression of sensory long tract dysfunction is even slower than the progression of motor findings measured by COAs in HSP. The low sensitivity to change of SSEPs identified suggests that they should not be used as primary endpoints in future clinical trials for disease-modifying drugs.

Over the last decade, whole-exome sequencing (WES) has become a standard diagnostic tool, significantly transforming the landscape of clinical genetics and playing a pivotal role in the diagnosis of neurogenetic diseases. This revolutionary shift has left a lasting impact on the field of neurology in Brazil. The current review article examines key developments and milestones achieved in Brazil through the application of WES in neurology and discusses forthcoming challenges and essential steps to advance molecular diagnosis. Several studies report the use of WES to diagnose genetic disorders with neurological manifestations in Brazil, underscoring the growing importance of molecular diagnosis in neurogenetics. These studies often provide detailed phenotypic analyses and clinical descriptions, offering valuable insights into the genetic underpinnings of several neurological conditions. Many reports highlight the use of WES in the investigation of complex neurological conditions in Brazil, such as neurodevelopmental disorders, hereditary spastic paraplegia, movement disorders, and ataxia. The discovery of new genes implicated in monogenic diseases with neurological manifestations through WES was a significant breakthrough. Despite these advances, the availability of large cohort studies on rare diseases in Brazil remains limited, hindering the ability to generalize findings and explore the full spectrum of genetic diversity. However, a few larger cohort studies have substantially contributed to our understanding of rare diseases and specific neurological disorders.While WES has limitations and may eventually be supplanted by more advanced diagnostic tools, it left a permanent mark on the neurology field in Brazil. The field of neurogenetics is set to become increasingly important in the future.