In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

2,4-dichlorophenoxyacetic acid (2,4-D) exposure during postnatal development alters the effects of western diet on mouse prostate.

Western diet (WD), abundant in saturated fats and simple carbohydrates, has been associated with the development of prostate diseases. In addition, 2,4-dichlorophenoxyacetic acid (2,4-D), an herbicide used in agricultural and non-agricultural settings, may interfere with the endocrine system impacting reproductive health. The association of both factors is something common in everyday life, however, there are no relevant studies associating them as possible modulators of prostatic diseases. This study evaluated the action of the herbicide 2,4-D on the postnatal development of the prostate in mice fed with WD. Male C57Bl/6J mice received simultaneously a WD and 2,4-D at doses of 0.02, 2.0, or 20.0 mg/kg b.w./day for 6 months. The prolongated WD intake induced obesity and glucose intolerance, increasing body weight and fat. WD induced morphological changes and increased PCNA-positive epithelial cells in prostate. Additionally, the WD increased gene expression of AR, antioxidant targets, inflammation-related cytokines, cell repair and turnover, and targets related to methylation and miRNAs biosynthesis compared to the counterpart (basal diet). 2,4-D (0.02 and 2.0) changed prostate morphology and gene expression evoked by WD. In contrast, the WD group exposed to 20 mg/kg of 2,4-D reduced feed intake and body weight, and increased expression of androgen receptor and genes related to cell repair and DNA methylation compared to the negative control. Our results showed that 2,4-D was able to modulate the effects caused by WD, mainly at lower doses. However, further studies are needed to elucidate the mechanisms of 2,4-D on the obesogenic environment caused by the WD.

Clinical and radiological profile of patients with spinal muscular atrophy type 4.

BACKGROUND AND PURPOSE: Spinal muscular atrophy (SMA) is the most important cause of motor neuron disease in childhood, and continues to represent the leading genetic cause of infant death. Adulthood-onset SMA (SMA type 4) is rare, with few isolated cases reported. The objective of the present study was to describe a cohort of patients with SMA type 4. METHODS: A cross-sectional study was conducted to characterize clinical, genetic, radiological and neurophysiological features of patients with adulthood-onset SMA. Correlation analysis of functional assessment with genetic, radiological and neurophysiological data was performed. RESULTS: Twenty patients with SMA type 4 were identified in a Brazilian cohort of 227 patients with SMA. The most common clinical symptom was limb-girdle muscle weakness, observed in 15 patients (75%). The most frequent neurological findings were absent tendon reflexes in 18 (90%) and fasciculations in nine patients (45%). Sixteen patients (80%) had the homozygous deletion of exon 7 in the SMN1 gene, with 12 patients (60%) showing four copies of the SMN2 gene. The functional scales Hammersmith Functional Motor Scale Expanded, Amyotrophic Lateral Sclerosis Functional Rating Scale Revised, Revised Upper Limb Module and Spinal Muscular Atrophy Functional Rating Scale, as well as the six-minute walk and the Time Up and Go tests showed a correlation with duration of disease. Motor Unit Number Index was correlated both with duration of disease and with performance in functional assessment. Radiological studies exhibited a typical pattern, with involvement of biceps femoris short head and gluteus minimus in all patients. CONCLUSION: This study represents the largest cohort of patients with SMA type 4 and provides functional, genetic, radiological and neurophysiological features that can be used as potential biomarkers for the new specific genetic therapies for SMA.

Leigh syndrome caused by mitochondrial DNA-maintenance defects revealed by whole exome sequencing.

Leigh syndrome represents a complex inherited neurometabolic and neurodegenerative disorder associated with different clinical, genetic and neuroimaging findings in the context of bilateral symmetrical lesions involving the brainstem and basal ganglia. Heterogeneous neurological manifestations such as spasticity, cerebellar ataxia, dystonia, choreoathetosis and parkinsonism are associated with multisystemic and ophthalmological abnormalities due to >75 different monogenic causes. Here, we describe the clinical and genetic features of a Brazilian cohort of patients with Leigh Syndrome in which muscle biopsy analysis showed mitochondrial DNA defects and determine the utility of whole exome sequencing for a final genetic diagnostic in this cohort.

Atypical Motor Neuron Disease variants: Still a diagnostic challenge in Neurology.

Motor neuron disease (MND) represents a wide and heterogeneous expanding group of disorders involving the upper or lower motor neurons, mainly represented by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy. Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Despite its well-known natural history, pathophysiological and clinical characteristics for the most common MND, atypical clinical presentation and neurodegenerative mechanisms are commonly observed in rare clinical entities, so-called atypical variants of MND-ALS, including flail-leg syndrome, flail-arm syndrome, facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus (FEWDON-MND) and long-lasting and juvenile MND-ALS. Herein, we provide a review article presenting clinical, genetic, pathophysiological and neuroimaging findings of atypical variants of MND-ALS in clinical practice.

New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome.

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.

O'Sullivan-McLeod syndrome: Unmasking a rare atypical motor neuron disease.

Atypical motor neuron disease represents a rare heterogeneous group of neurodegenerative disorders with clinical, genetic and neuroimaging features distinct from those of the classic spinal or bulbar-onset amyotrophic lateral sclerosis (ALS). O'Sullivan-McLeod syndrome represents an extremely rare lower motor neuronopathy with early adult-onset distal amyotrophy and weakness in the upper limbs with asymmetrical involvement. To add to the few case series and epidemiological and genetic studies describing this variant syndrome, our team here presents a series of seven unrelated Brazilian patients with O'Sullivan-McLeod syndrome in a detailed review of their clinical, neuroimaging, laboratory and neurophysiological findings. A male-to-female ratio of 2.5 to 1 and a mean age at onset of 34.3years was observed, with a mean time delay of 6.6years between symptom-onset and a definitive diagnosis. A positive family history was observed in one case, yet whole-exome sequencing results were negative. Neuroimaging studies were unremarkable. All cases presented with chronic denervation restricted to cervical myotomes and normal sensory nerve conduction studies. This case series, one of the largest groups of patients with O'Sullivan-McLeod syndrome reported in the literature, confirms the sporadic nature of the condition and the difficulties faced in arriving at a definite diagnosis, and also expands the age limit in late adult-onset cases.

[Brazilian criminal law and genetics]. / El derecho penal brasileño y la genética.

This article analyses the Brasilia criminal regulation on genetic. Act No. 8.974/95 is examined because it regulates some criminal typologies on genetic engineering and assisted reproduction. Moreover, it presents information about the Act Project No. 149/97, on genetic discrimination.