Managing pregnancy in a spinal muscular atrophy type III patient in Indonesia: a case report

Background Spinal muscular atrophy is a genetic disorder characterized by degeneration of lower motor neurons, leading to progressive muscular atrophy and even paralysis. Spinal muscular atrophy usually associated with a defect of the survival motor neuron 1 (SMN-1) gene. Classification of spinal muscular atrophy is based on the age of onset and maximum motor function milestone achieved. Although spinal muscular atrophy can be screened for in newborns, and even confirmed earlier genetically, this remains difficult in Third World countries such as Indonesia. Case presentation A 28-year-old Asian woman in the first trimester of her second pregnancy, was referred to the neurology department from the obstetric department. Her milestone history showed she was developmentally delayed and the ability to walk independently was reached at 26 months old. At 8 years old, she started to stumble and lose balance while walking. At this age, spinal muscular atrophy was suspected because of her clinical presentations, without any molecular genetic testing. She was married at the age of 25 years and was soon pregnant with her first child. At the gestational age of 32 weeks, her first pregnancy was ended by an emergency caesarean section because of premature rupture of the membranes. In this second pregnancy, she was referred early to the general hospital from the district hospital to receive multidisciplinary care. She and her first daughter underwent genetic testing for spinal muscular atrophy, which has been readily available in our institution since 2018, to confirm the diagnosis and prepare for genetic counseling. Conclusions Managing pregnancy in a patient with spinal muscular atrophy should be performed collaboratively. In this case, genetic testing of spinal muscular atrophy and the collaborative management of this patient allowed the clinical decision making and genetic counseling throughout her pregnancy and delivery.

Comprehensive Analysis of Retrotransposon Insertions within the Survival Motor Neuron Genes Involved in Spinal Muscular Atrophy

Transposable elements (TEs) are interspersed repetitive DNA sequences with the ability to mobilize in the genome. The recent development of improved tools for evaluating TE-derived sequences in genomic studies has enabled an increasing attention to the contribution of TEs to human development and disease. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease that is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene. SMN2 gene is a nearly perfect duplication of SMN1. Both genes (collectively known as SMN1/SMN2) are highly enriched in TEs. A comprehensive analysis of TEs insertions in the SMN1/2 loci of SMA carriers, patients and healthy/control individuals was completed to perceive TE dynamics in SMN1/2 and try to establish a link between these elements and SMA.We found an Alu insertion in the promoter region and one L1 element in the 3’UTR that likely play an important role as an alternative promoter and as an alternative terminator to the gene, respectively. Additionally, the several Alu repeats inserted in the genes’ introns influence splicing, giving rise to alternative splicing events that cause RNA circularization and the birth of new alternative exons. These Alu repeats present throughout the genes are also prone to recombination events that can lead to SMN1 exons deletions, that ultimately lead to SMA. The many good and bad implications associated with the presence of TEs inside SMN1/2 make this genomic region ideal for understanding the implications of TEs on genomic evolution as well as on human genomic disease.

Intrafamilial Variability of the R694C Variant in BICD2 Presenting with Lethal Severe Arthrogryposis

Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition comprising congenital multiple joint contractures, and it is secondary to decreased fetal mobility following environmental/genetic abnormalities. BICD2 pathogenic variants have been associated with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). We report the case of a newborn with decreased fetal movements and ventriculomegaly diagnosed in utero, born with severe AMC, multiple bone fractures, congenital hip dislocation, and respiratory insufficiency that led to neonatal death. His mother had AMC diagnosis without established etiology. Her phenotype characterization was key to guide the genetic investigation. A BICD 2 heterozygous variant (NM_001003800.1; c.2080C > T; p. [Arg694Cys]) was detected both in the mother and the newborn. This variant had previously been reported in 3 cases, all having de novo severe SMALED-type 2B (MIM#618291) phenotype. This is the first report of this variant (p. [Arg694Cys]) presenting with an inherited, severe, and lethal phenotype associated to intrafamilial variability, suggesting a more complex phenotype-genotype correlation than previously stated.

Electrical Stimulation Attenuates Disuse Muscular Atrophy by Modulating Endoplasmic Reticulum Stress-induced Parkin-dependent Mitophagy

Background: The aim of this study was to investigate the therapeutic effect of electrical stimulation on disuse muscular atrophy in a rabbit model of knee joint contracture and explore the role of endoplasmic reticulum stress-induced Parkin-dependent mitophagy in this process.Methods: Two sub-experiments were carried out successively in our study. In the first sub-experiment, 24 rabbits were divided into four groups on average based on the immobilization time: Ctrl 1, I-2, I-4, and I-6 groups. In the second sub-experiment, 24 rabbits were also divided into four groups on average in accordance with the process mode: Ctrl2, ES, NR, and EST groups. To test the time-dependent changes of the rectus femoris muscles after immobilization in rabbits, and to evaluate the effect of electrical stimulation on the atrophic rectus femoris muscles, the wet weights of rectus femoris muscles were assessed in this study, along with the protein levels of atrogin-1, p-PERK, Parkin and COXIV.Results: The wet weights of rectus femoris muscles, the protein levels of atrogin-1, p-PERK and Parkin increased after immobilization. It was also revealed that the protein levels of COXIV decreased after immobilization. Electrical stimulation was effective against muscle atrophy, the elevated expression of atrogin-1, p-PERK, Parkin, and the decreased expression of COXIV.Conclusions: Immobilization of unilateral lower limb could induce rectus femoris muscle atrophy, endoplasmic reticulum stress and Parkin mediated mitophagy. Endoplasmic reticulum stress-induced Parkin-dependent mitophagy may be one of the mechanisms by which electrical stimulation can play a significant role.

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

The recent advances in nucleic acid therapeutics demonstrate the potential to treat hereditary neurological disorders by targeting their causative genes. Spinal and bulbar muscular atrophy (SBMA) is an X-linked and adult-onset neurodegenerative disorder caused by the expansion of trinucleotide cytosine-adenine-guanine repeats, which encodes a polyglutamine tract in the androgen receptor gene. SBMA belongs to the family of polyglutamine diseases, in which the use of nucleic acids for silencing a disease-causing gene, such as antisense oligonucleotides and small interfering RNAs, has been intensively studied in animal models and clinical trials. A unique feature of SBMA is that both motor neuron and skeletal muscle pathology contribute to disease manifestations, including progressive muscle weakness and atrophy. As both motor neurons and skeletal muscles can be therapeutic targets in SBMA, nucleic acid-based approaches for other motor neuron diseases and myopathies may further lead to the development of a treatment for SBMA. Here, we review studies of nucleic acid-based therapeutic approaches in SBMA and related neurological disorders and discuss current limitations and perspectives to apply these approaches to patients with SBMA.

Poly-glutamine-dependent self-association as a potential mechanism for regulation of androgen receptor activity

The androgen receptor (AR) plays a central role in prostate cancer. Development of castration resistant prostate cancer (CRPC) requires androgen-independent activation of AR, which involves its large N-terminal domain (NTD) and entails extensive epigenetic changes depending in part on histone lysine demethylases (KDMs) that interact with AR. The AR-NTD is rich in low-complexity sequences, including a polyQ repeat. Longer polyQ sequences were reported to decrease transcriptional activity and to protect against prostate cancer, although they can lead to muscular atrophy. However, the molecular mechanisms underlying these observations are unclear. Using NMR spectroscopy, here we identify weak interactions between the AR-NTD and the KDM4A catalytic domain, and between the AR ligand-binding domain and a central KDM4A region that also contains low-complexity sequences. We also show that the AR-NTD can undergo liquid-liquid phase separation in vitro, with longer polyQ sequences phase separating more readily. Moreover, longer polyQ sequences hinder nuclear localization in the absence of hormone and increase the propensity for formation of AR-containing puncta in the nucleus of cells treated with dihydrotestosterone. These results lead us to hypothesize that polyQ-dependent liquid-liquid phase separation may provide a mechanism to decrease the transcriptional activity of AR, potentially opening new opportunities to design effective therapies against CRPC and muscular atrophy.

Therapy development for spinal muscular atrophy: perspectives for muscular dystrophies and neurodegenerative disorders

Background Major efforts have been made in the last decade to develop and improve therapies for proximal spinal muscular atrophy (SMA). The introduction of Nusinersen/Spinraza™ as an antisense oligonucleotide therapy, Onasemnogene abeparvovec/Zolgensma™ as an AAV9-based gene therapy and Risdiplam/Evrysdi™ as a small molecule modifier of pre-mRNA splicing have set new standards for interference with neurodegeneration. Main body Therapies for SMA are designed to interfere with the cellular basis of the disease by modifying pre-mRNA splicing and enhancing expression of the Survival Motor Neuron (SMN) protein, which is only expressed at low levels in this disorder. The corresponding strategies also can be applied to other disease mechanisms caused by loss of function or toxic gain of function mutations. The development of therapies for SMA was based on the use of cell culture systems and mouse models, as well as innovative clinical trials that included readouts that had originally been introduced and optimized in preclinical studies. This is summarized in the first part of this review. The second part discusses current developments and perspectives for amyotrophic lateral sclerosis, muscular dystrophies, Parkinson's and Alzheimer's disease, as well as the obstacles that need to be overcome to introduce RNA-based therapies and gene therapies for these disorders. Conclusion RNA-based therapies offer chances for therapy development of complex neurodegenerative disorders such as amyotrophic lateral sclerosis, muscular dystrophies, Parkinson’s and Alzheimer’s disease. The experiences made with these new drugs for SMA, and also the experiences in AAV gene therapies could help to broaden the spectrum of current approaches to interfere with pathophysiological mechanisms in neurodegeneration.