Spinal Muscular Atrophy Type IIIb Complicated by Moyamoya Syndrome: A Case Report and Literature Review

Li, Jing; Li, Xin; Wang, Liqun; Wu, Gaofeng

doi:10.3389/fncel.2022.811596

Cited by 5 publications

(4 citation statements)

References 28 publications

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“…Notably, a small number of SMA patients present with a deletion in one copy of SMN1 and a missense mutation in the other copy [42, 45]. Patients bearing zero copies of SMN2 together with a homozygous missense mutation in SMN1 are even more exceptional [46]. Thus, disease presentation in humans varies dramatically, depending on the SMN1 allele, and the number of SMN2 gene copies present in the background (which can vary from 0 to 6,).…”

Section: Resultsmentioning

confidence: 99%

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

Matera,

Steiner,

Mills

et al. 2024

Preprint

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Molecular chaperones and co-chaperones are highly conserved cellular components that perform variety of duties related to the proper three-dimensional folding of the proteome. The web of factors that carries out this essential task is called the proteostasis network (PN). Ribonucleoproteins (RNPs) represent an underexplored area in terms of the connections they make with the PN. The Survival Motor Neuron (SMN) complex is an RNP assembly chaperone and serves as a paradigm for studying how specific small nuclear (sn)RNAs are identified and paired with their client substrate proteins. SMN protein is the eponymous component of a large complex required for the biogenesis of uridine-rich small nuclear ribonucleoproteins (U-snRNPs) and localizes to distinct membraneless organelles in both the nucleus and cytoplasm of animal cells. SMN forms the oligomeric core of this complex, and missense mutations in its YG box self-interaction domain are known to cause Spinal Muscular Atrophy (SMA). The basic framework for understanding how snRNAs are assembled into U-snRNPs is known, the pathways and mechanisms used by cells to regulate their biogenesis are poorly understood. Given the importance of these processes to normal development as well as neurodegenerative disease, we set out to identify and characterize novel SMN binding partners. Here, we carried out affinity purification mass spectrometry (AP-MS) of SMN using stable fly lines exclusively expressing either wildtype or SMA-causing missense alleles. Bioinformatic analyses of the pulldown data, along with comparisons to proximity labeling studies carried out in human cells, revealed conserved connections to at least two other major chaperone systems including heat shock folding chaperones (HSPs) and histone/nucleosome assembly chaperones. Notably, we found that heat shock cognate protein Hsc70-4 and other HspA family members preferentially interacted with SMA-causing alleles of SMN. Hsc70-4 is particularly interesting because its mRNA is aberrantly sequestered by a mutant form of TDP-43 in mouse and Drosophila ALS (Amyotrophic Lateral Sclerosis) disease models. Most important, a missense allele of Hsc70-4 (HspA8 in mammals) was recently identified as a bypass suppressor of the SMA phenotype in mice. Collectively, these findings suggest that chaperone-related dysfunction lies at the etiological root of both ALS and SMA.

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Section: Resultsmentioning

confidence: 99%

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

Matera,

Steiner,

Mills

et al. 2024

Preprint

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“…The vast majority of severe SMA cases are caused by homozygous deletions of SMN1 (Prior et al, 1993;Alias et al, 2009;Keinath et al, 2021;Wirth, 2021;Li et al, 2022;Mercuri et al, 2022). We report a case in which the patient carries a homozygous missense variant (c.796T>C) on SMN1 that clinically presents as Type 0 SMA.…”

Section: Discussionmentioning

confidence: 97%

A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization

Li,

Perera,

Varghese

et al. 2023

Front. Cell. Neurosci.

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The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions of survival motor neuron 1 (SMN1). We report a case in which the patient has two copies of SMN1 but clinically presents as Type 0 SMA. The patient is an African American male carrying a homozygous maternally inherited missense variant (c.796T>C) in a cis-oriented SMN1 duplication on one chromosome and an SMN1 deletion on the other chromosome (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used in the initial testing for SMA also failed to detect SMA as the patient has two copies of SMN1. Because of high clinical suspicion, SMA diagnosis was finally confirmed based on full-length SMN1 sequencing. The patient was initially treated with risdiplam and later gene therapy with onasemnogene abeparvovec at 5 months without complications. The patient’s muscular weakness has stabilized with mild improvement. The patient is now 28 months old and remains stable and diffusely weak, with stable respiratory ventilatory support. This case highlights challenges in the diagnosis of SMA with a non-deletion genotype and provides a clinical example demonstrating that disruption of functional SMN protein polymerization through an amino acid change in the YG-box domain represents a little known but important pathogenic mechanism for SMA. Clinicians need to be mindful about the limitations of the current diagnostic approach for SMA in detecting non-deletion genotypes.

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“…SMA is a neuromuscular disorder characterized by progressive and irreversible loss of anterior horn cells in the spinal cord that essentially results in muscle weakness and atrophy. The clinical manifestations of SMA are quite heterogeneous [ 10 ]. Furthermore, SMA can be classified into four types according to the age of the onset of symptoms.…”

Section: Discussionmentioning

confidence: 99%

An Insightful Observation Leading to a Late Diagnosis of Spinal Muscular Atrophy: A Case Report

Rivera Troia,

Ocasio Villa

2024

Cureus

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Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder characterized by the loss of motor neurons in the spinal cord that results in progressive muscle weakness and atrophy. Most often, the gene involved in this disorder is the survival motor neuron (SMN1) gene, located on the telomeric regions of chromosome 5q13. This gene is involved in the processing of pre-mRNA required for the formation of dendrites and axons. Here we present the case of a 47-year-old female with an extensive past medical history of progressive muscle weakness who, after numerous specialist evaluations, was sent for germline mutation panel sequencing and analysis and was incidentally found to have a pathogenic heterozygous deletion encompassing the exon 8 region of the SMN1 gene. This case report aims to highlight the importance of timely identification and management for individuals who present with early clinical signs of the disease to reduce the morbidity and mortality associated with it.

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Spinal Muscular Atrophy Type IIIb Complicated by Moyamoya Syndrome: A Case Report and Literature Review

Cited by 5 publications

References 28 publications

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

Chaperoning the chaperones: Proteomic analysis of the SMN complex reveals conserved and etiologic connections to the proteostasis network

A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization

An Insightful Observation Leading to a Late Diagnosis of Spinal Muscular Atrophy: A Case Report

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