Childhood Spinal Muscular Atrophy Research Articles

Spinal Muscle Atrophy (SMA) in a 5 Years Old Girl from Macedonia: Case Report

Spinal muscular atrophies are inherited diseases in which nerve cells in the spinal cord and brainstem regress, causing progressive muscle weakness and wasting. There are five main types of spinal muscular atrophy, which are classified according to the severity of muscle weakness and wasting. Depending on the type, one may be confined to a wheelchair, and life expectancy may also be limited. Based on symptoms, the diagnosis can be proven through family history, muscle and nerve function studies, and blood tests to determine the location of the defective gene. Spinal muscular atrophies are usually inherited in an autosomal recessive manner. Thus, for a person to inherit the disease, two genes are necessary, one from each parent. The group of SMA disease in childhood can affect the brain and spinal cord as well as the peripheral nerves. We present a case of a 5 years old girl with spinal muscle atrophy and analyze the different new therapeutical options and future research in the field of spinal muscular atrophy in childhood.

Long-term efficacy of nusinersen and its evaluation in adolescent and adult patients with spinal muscular atrophy types 1 and 2

BackgroundsThe efficacy of nusinersen and its evaluation in patients with spinal muscular atrophy (SMA) has been established in clinical trials only for pediatric patients, not for adolescent and adult patients who developed SMA in infancy or early childhood. We report a long-term follow-up in adolescent and adult patients with SMA types 1 and 2. MethodsNusinersen-treated patients with SMA types 1 and 2 between 2017 and 2022 were retrospectively reviewed. We compared baseline motor function tests with those after the final treatment. Physical and occupational therapists performed Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Functional Motor Scale-Expanded (HFMSE), and Revised Upper Limb Module (RULM). The Landau and Galant reflexes were not performed in CHOP-INTEND. Meaningful improvement was defined as CHOP-INTEND, 4; HFSME, 3; and RULM, 2. ResultsSeven patients with SMA (type 1, 1; type 2, 6) with a median age of 23 (range, 12–40)years were treated with nusinersen for 3.55 (1.78–4.53)years. Improvement was detected in CHOP-INTEND (pre, 5 [0–31]; post, 21 [0–39]; difference, 5 [0–26]; p = 0.100) without significance, although not in HFMSE (pre, 0 [0–3]; post, 0 [0–5]; difference, 0 [0–2]; p = 0.346) and RULM (pre, 1 [0–20]; post, 3 [0–21]; difference, 1 [0–2]; p = 0.089). Owing to prolonged treatment intervals with the COVID-19 pandemic, RULM worsened in two patients. ConclusionNusinersen was effective in long-term follow-up. Only CHOP-INTEND showed meaningful improvement. The interval between doses of nusinersen should not be prolonged even with the COVID-19 pandemic.

Relationship between respiratory function and need for NIV in childhood SMA.

BackgroundSpinal muscular atrophy (SMA) causes progressive respiratory muscle weakness but respiratory function (RF) in those using noninvasive ventilation (NIV) is not well described.ObjectiveTo describe RF in childhood SMA and assess differences between those using and not using NIV.MethodsA cross‐sectional study of childhood SMA assessed polysomnography (PSG), spirometry, forced oscillation technique (FOT), lung clearance index (LCI), sniff nasal inspiratory pressures, peak cough flow, maximal inspiratory and expiratory pressure, and NIV use and indication.ResultsTwenty‐five children (median age [interquartile range], 8.96 [5.63] years; 10 F) with SMA 1 (n = 3), 2 (n = 15), and 3 (n = 7) were recruited. Spirometry and FOT testing was feasible in children as young as 3 years. Ten (40%) required NIV, 5 for sleep‐disordered breathing (SDB), and 5 initiated during lower respiratory tract infection (LRTI). Children requiring NIV were older (median, 10.52 vs 5.67 years; P < .02) with more abnormal forced vital capacity (FVC) z‐score (−5.70 vs −1.39, P < .02), Rsr8 z‐score (1.97 vs 0.50, P = .04), and LCI (8.84 vs 7.34, P = .01). Two had normal RF and SDB. For FVC z‐score less than −2.5 and LCI greater than 7.5, the odds ratio for NIV was 10.70 (95% confidence interval [CI], 1.39‐82.03) and 2 (95% CI, 0.40‐10.31), respectively. All children with LCI greater than 8 used NIV. FVC z‐score and LCI are associated with maximum transcutaneous carbon dioxide on PSG (r = 0.43, P < .001).ConclusionNIV is common in SMA. Normal RF does not exclude SDB. Children with more abnormal FVC and LCI should be considered at risk of starting NIV during/following an LRTI.

Another milestone in childhood spinal muscular atrophy

Another milestone in childhood spinal muscular atrophy

Correlation between deletion patterns of SMN1 and NAIP genes and clinical subtypes of spinal muscular atrophy in Iranian Azeri Turk ethnic patients

The childhood spinal muscular atrophy (SMA) is classified into three groups based on the age of onset and clinical course. The aim of this study was to define the correlation between genotype and phenotype in Iranian patients with SMA. Molecular analysis was carried out on two candidate genes of survival motor neuron one (SMN1), and neuronal apoptosis in- hibitory protein (NAIP) in 189 patients with SMA (130 patients with SMA type I, 32 patients with type II and 27 patients with type III) and the phenotypic features of SMA were compared with the deletion pattern of these genes. Polymerase chain reaction along with restriction fragment length polymorphism analysis were used to detect the deletion of exons 7 and 8 of SMN1 gene, as well as multiplex polymerase chain reaction for exon 5 of NAIP gene. Deletion in exon 7 was detected in 167 patients (88.4%); deletion in exon 8 was detected in 162 patients (85.7%) and deletion in exon 5 of NIAP gene was detected in 95 patients (50.3%). Deletion of exons 7 and/or 8 of SMN1 were detected in 90%, 84.4%, and 88.9% in patients with types I, II and III SMA, re- spectively. The prevalence rates of exon 5 deletion in NAIP gene was 66.9%, 12.5%, and 14.8% in types I, II and III SMA patients, respectively (P < 0.001). Combined homozygous deletion in both SMN1 and NAIP genes was found in 65.4% SMA type I, 12.5% SMA type II and 14.8% SMA type III (P < 0.001).There was a significant correlation between combined deletion of both SMN1 and NAIP genes and clinical subtypes of SMA patients.

A mixed methods exploration of families' experiences of the diagnosis of childhood spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with a carrier frequency of 1 in 41 in Australia. Childhood SMA is classified into three types based on the age at which children present with symptoms and the clinical severity. Families' experiences leading up to the diagnosis have not been described, but are important when considering the potential for a diagnostic odyssey. Using a mixed methods approach, data were collected from interviews and a national survey of families of children with SMA to explore their experiences of this journey. The combined findings (n=28) revealed that the journey to receiving a diagnosis was protracted. The time from first noticing symptoms to finally receiving a diagnosis was emotional and frustrating. Once parents or other family members became aware of symptoms, almost all had consulted with multiple different health professionals before the diagnosis was ultimately made. Not surprisingly, receiving the diagnosis was devastating to the families. The nature of the information and the way it was given to them was not always optimal, particularly because of the difficulties predicting clinical severity. Most felt that their child could have been diagnosed earlier and, although there were mixed views around the benefit of this for their child, they felt it may have reduced the emotional impact on families. Overall, families were more in favour of population carrier screening for SMA when compared with newborn screening of the population. Despite an increasing awareness of SMA, the diagnostic delay continues to have negative impacts on families.

Defects of RNA metabolism in the pathogenesis of spinal muscular atrophy

Childhood spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous group of inherited neuromuscular disorders characterized by degeneration of motor neurons of the spinal cord leading to progressive atrophy of skeletal muscles and paralysis. The most frequent form is inherited as an autosomal recessive trait and is due to mutations of the survival motor neuron 1, telomeric ( SMN1 )1 gene manifesting with a proximal distribution of weakness of legs and arms. The other forms of SMAs are rare disorders differing by their mode of inheritance, the topography of the muscle deficit, or the association with other neurologic abnormalities.

Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.

Synaptic defects in type I spinal muscular atrophy in human development

Childhood spinal muscular atrophy is an autosomal recessive neuromuscular disorder caused by alterations in the Survival Motor Neuron 1 gene that triggers degeneration of motor neurons within the spinal cord. Spinal muscular atrophy is the second most common severe hereditary disease of infancy and early childhood. In the most severe cases (type I), the disease appears in the first months of life, suggesting defects in fetal development. However, it is not yet known how motor neurons, neuromuscular junctions, and muscle interact in the neuropathology of the disease. We report the structure of presynaptic and postsynaptic apparatus of the neuromuscular junctions in control and spinal muscular atrophy prenatal and postnatal human samples. Qualitative and quantitative data from confocal and electron microscopy studies revealed changes in acetylcholine receptor clustering, abnormal preterminal accumulation of vesicles, and aberrant ultrastructure of nerve terminals in the motor endplates of prenatal type I spinal muscular atrophy samples. Fetuses predicted to develop milder type II disease had a similar appearance to controls. Postnatal muscle of type I spinal muscular atrophy patients showed persistence of the fetal subunit of acetylcholine receptors, suggesting a delay in maturation of neuromuscular junctions. We observed that pathology in the severe form of the disease starts in fetal development and that a defect in maintaining the initial innervation is an early finding of neuromuscular dysfunction. These results will improve our understanding of the spinal muscular atrophy pathogenesis and help to define targets for possible presymptomatic therapy for this disease.

Molecular prenatal diagnosis of autosomal recessive childhood spinal muscular atrophies (SMAs)

Autosomal recessive childhood spinal muscular atrophy (SMAs) is the second most common neuromuscular disorder and a common cause of infant disability and mortality. SMA patients are classified into three clinical types based on age of onset, and severity of symptoms. About 94% of patients have homozygous deletion of exon 7 in survival motor neuron (SMN1) gene. The neuronal apoptosis inhibitory protein (NAIP) gene was found to be more frequently deleted in the severest form of the disease. This study aimed to comment on the implementation of genetic counseling and prenatal diagnosis of SMAs for 85 fetuses from 75 Egyptian couples at risk of having an affected child. The homozygous deletion of exon 7 in SMN1 gene and the deletion of exon 5 of the NAIP gene were detected using PCR-REFLP and multiplex PCR methods respectively. Eighteen fetuses showed homozygous deletion of exon 7 in SMN1 gene and deletion of exon 5 in NAIP gene. In conclusion prenatal diagnosis is an important tool for accurate diagnosis and genetic counseling that help decision making in high risk families.

Modification of phenotype by SMN2 copy numbers in two Chinese families with SMN1 deletion in two continuous generations

BackgroundAs a lethal autosomal recessive hereditary disorder, childhood spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene. Most of the patients died at early stage or were seriously disabled, which accounts partly for the scarcity of two continuous generations with SMA. Increasing evidence indicated that SMN2 copy number was a modifier of SMA, but in majority of sporadic patients, the bias of phenotype judgments may largely reduce the accuracy of genotype–phenotype analysis. MethodsWe presented two families with SMN1-deleted individuals in two continuous generations, the father and daughter of family 1 and the mother and daughter of family 2 were determined to be homozygous for the deletion of the SMN1 gene. Quantitative analysis of SMN1 and SMN2 was carried out by real-time fluorescence quantitative PCR and multiplex ligation-dependent probe amplification. ResultsQuantitative analysis showed that the father of family 1 possessed three copies of SMN2, and his daughter had only two SMN2 copies; the slightly affected mother of family 2 had three copies of SMN2, but her sick daughter had only two copies of SMN2; we also performed prenatal prediction for family 1 and a healthy boy was born under our suggestion. ConclusionFor the phenotypes of patients from different generations within the same family are obviously different, the results of a genotype–phenotype analysis may be more convincing, which strongly support the hypothesis that SMN2 is an important modifier for SMA, and SMN2 copy number should be considered in the prenatal diagnosis situation.

Spinal Muscular Atrophy Associated with Progressive Myoclonic Epilepsy Is Caused by Mutations in ASAH1

Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by the degeneration of lower motor neurons. The most frequent form is linked to mutations in SMN1. Childhood SMA associated with progressive myoclonic epilepsy (SMA-PME) has been reported as a rare autosomal-recessive condition unlinked to mutations in SMN1. Through linkage analysis, homozygosity mapping, and exome sequencing in three unrelated SMA-PME-affected families, we identified a homozygous missense mutation (c.125C>T [p.Thr42Met]) in exon 2 of ASAH1 in the affected children of two families and the same mutation associated with a deletion of the whole gene in the third family. Expression studies of the c.125C>T mutant cDNA in Farber fibroblasts showed that acid-ceramidase activity was only 32% of that generated by normal cDNA. This reduced activity was able to normalize the ceramide level in Farber cells, raising the question of the pathogenic mechanism underlying the CNS involvement in deficient cells. Morpholino knockdown of the ASAH1 ortholog in zebrafish led to a marked loss of motor-neuron axonal branching, a loss that is associated with increased apoptosis in the spinal cord. Our results reveal a wide phenotypic spectrum associated with ASAH1 mutations. An acid-ceramidase activity below 10% results in Farber disease, an early-onset disease starting with subcutaneous lipogranulomata, joint pain, and hoarseness of the voice, whereas a higher residual activity might be responsible for SMA-PME, a later-onset phenotype restricted to the CNS and starting with lower-motor-neuron disease.

Spinal Müsküler Atrofi ve Moleküler Genetiği

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting aproximately 1 in 6,000 - 10,000 live births, and with a carrier frequency of aproximately 1 in 40- 60. The childhood SMAs can be classified clinically into three groups. Type I (Werdnig-Hoffmann) is the most severe form, with onset at ‹ 6 months of age and with death typically at ‹2 years of age. Type II SMA patients display an intermediate severity, with onset at ‹18 months of age and with an inability to walk. Type III (Kugelberg –Walender) individuals are able to walk independently and have a relatively mild phenotype, with onset at ›18 months of age. The gene involved in type I–III SMA has been mapped to 5q12-q13 by linkage analysis, and refined to a region of about 500 kb. The region contains a large inverted duplication consisting of at least four genes, which are present in a telomeric (t) and a centromeric (c) copy: survival motor neuron gene (SMN1 or SMNt and SMN2 or SMNc); neuronal apoptosis inhibitory protein gene (NAIP); basal transcription factor subunit p44 (BTFp44t and BTFp44c); and a novel protein with unknown function H4F5. Although homozygous deletions encompassing all these genes are found in SMA patients, it is now well established that mutations or deletions of SMN1 (MIM#600354) cause the disease. SMN2 (MIM# 601627) gene, however, does not prevent the disease but attenuates disease severity. Therefore, upregulating functional SMN protein level via inducing gene expression and/or restoring splicing is an important therapeutic approach such as use of histone deacetylase (HDAC) inhibitors.

Advances in the genetics of spinal muscular atrophy in childhood

Spinal muscular atrophy in childhood is one of the most common neuromuscular disorders with an autosomal recessive mode of inheritance. The main pathogenesis is homozygous loss and small intragenic mutations of the SMN1. SMN2 ,as a very identical copy of SMN1, modulates the disease severity. The functional difference between both genes is a variance of single nucleotide within the coding region, causing silent mutation obviously to decrease SMN2 transcripts. Histone deacetylase inhibitors have been shown better perspective in clinical trials. Key words: Spinal muscular atrophy in childhood; SMN gene

SMN, Gemin2 and Gemin3 Associate with β-Actin mRNA in the Cytoplasm of Neuronal Cells In Vitro

Childhood spinal muscular atrophy is caused by a reduced expression of the survival motor neuron (SMN) protein. SMN has been implicated in the axonal transport of β-actin mRNA in both primary and transformed neuronal cell lines, and loss of this function could account, at least in part, for spinal muscular atrophy onset and pathological specificity. Here we have utilised a targeted screen to identify mRNA associated with SMN, Gemin2 and Gemin3 in the cytoplasm of a human neuroblastoma cell line, SHSY5Y. Importantly, we have provided the first direct evidence that β-actin mRNA is present in SMN cytoplasmic complexes in SHSY5Y cells.

Analysis of SMN-neurite granules: Core Cajal body components are absent from SMN-cytoplasmic complexes

Childhood spinal muscular atrophy (SMA) is caused by a reduction in survival motor neuron (SMN) protein. SMN is a ubiquitously expressed house keeping protein that is involved in RNA production and processing. However, although SMN is expressed in every cell type, only the lower motor neurons of the spinal cord are degraded in SMA. It remains unclear why this is the case. Recently, SMN has been linked to the axonal transport of β-actin mRNA from the cell body down to the growth cones. β-Actin is transported actively in neurite granules (NGs). However, it remains unclear which known SMN-binding partners are present in these SMN-NGs. To address this we have analysed SMN-NGs in a human neuronal cell line, SH-SY5Y, using antibodies against the majority of reported SMN-binding partners, including: Gemin2, Gemin3, Gemin4, Gemin5, Gemin6, Gemin7, Sm core proteins, fibrillarin, EWS, PFNII, Unrip and ZPR1. The obtained results highlight the metamorphic nature of the SMN complex, suggesting that not all the “core” SMN-binding proteins are transported in SMN-NGs.

SMN and the Gemin proteins form sub-complexes that localise to both stationary and dynamic neurite granules

Childhood spinal muscular atrophy (SMA) is caused by a reduction in survival motor neuron (SMN) protein. SMN is expressed in every cell type, but it is predominantly the lower motor neurones of the spinal cord that degenerate in SMA. SMN has been linked to the axonal transport of β-actin mRNA, a breakdown in which could trigger disease onset. It is known that SMN is present in transport ribonucleoproteins (RNPs) granules that also contain Gemin2 and Gemin3. To further characterise these granules we have performed live cell imaging of GFP-tagged SMN, GFP-Gemin2, GFP-Gemin3, GFP-Gemin6 and GFP-Gemin7. In all, we have made two important observations: (1) SMN granules appear metamorphic; and (2) the SMN–Gemin complex(es) appears to localise to two distinct subsets of bodies in neurites; stationary bodies and smaller dynamic bodies. This study provides an insight into the neuronal function of the SMN complex.

P108 Abnormal fatty acid metabolism in childhood spinal muscular atrophy (SMA) may predispose to perioperative Reye's-like syndrome and fulminant liver failure

P108 Abnormal fatty acid metabolism in childhood spinal muscular atrophy (SMA) may predispose to perioperative Reye's-like syndrome and fulminant liver failure

A population‐based study of genotypic and phenotypic variability in children with spinal muscular atrophy

To describe the occurrence of spinal muscular atrophy (SMA) in childhood; to evaluate if any of the genes in the SMA region on chromosome 5q13 correlates with disease severity; to make genotype-phenotype correlations; to evaluate the variability of different disease alleles in carriers and the sensitivity of multiplex ligation-dependent probe amplification (MLPA) for detecting carriers. In a population-based study from Western Sweden MLPA was used to determine the copy-numbers of several genes in the SMA region (SMN1, SMN2, BIRC1, GTF2H2 and SERF1A) in SMA-patients and their parents. We estimated the incidence of SMN1-related SMA in childhood at 1 in 11 800 live births and confirmed the relationship between the number of SMN2 copies and the severity of disease. No other direct relationships were found. All but one of the analysed parents were confirmed as carriers by MLPA analysis. A total of at least 30 different disease alleles were identified and no specific disease allele represented more than 15% of the total. The childhood incidence of SMA in the Swedish population is around 1 in 12,000 live births and it is unlikely that there is any founder effect involved in SMA in western Sweden.

Childhood spinal muscular atrophy induces alterations in contractile and regulatory protein isoform expressions

Although modifications of the survival motor neurone gene are responsible for most spinal muscular atrophy (SMA) cases, the molecular pathophysiology and the muscular target proteins involved are still unknown. The aim of this study was to compare the expression of contractile and regulatory protein isoforms in quadriceps muscles from SMA children with age-matched control quadriceps. The isoform patterns of myosin heavy chains (MHC), troponin subunits (T, C and I) and tropomyosin were determined by immunoblotting, reverse transcription-polymerase chain reaction and mass spectrometry analyses. Depending on the disease severity, their expression levels were followed in specific variants of SMA populations (types I, II and III), with comparison with age-matched control muscles. The isoform transitions in SMA muscles were different from the fast-to-faster transitions occurring in normal muscles from children aged 1 month to 5 years old. Moreover, the expression of the neonatal MHC isoform was not repressed in SMA muscles. The presence of the neonatal MHC isoform in SMA muscles indicates an alteration of the phenotype in these diseased muscles. It is strongly suggested that MHC and troponin T proteins may be good markers for the SMA pathology.