ABSTRACT
BACKGROUND AND OBJECTIVE: Spinal muscular atrophy (SMA) is one of the most common monogenic neuromuscular diseases, and the pathogenesis mechanisms, especially the brain network topological properties, remain unknown. This study aimed to use individual-level morphological brain network analysis to explore the brain neural network mechanisms in SMA. METHODS: Individual-level gray matter (GM) networks were constructed by estimating the interregional similarity of GM volume distribution using both Kullback-Leibler divergence-based similarity (KLDs) and Jesen-Shannon divergence-based similarity (JSDs) measurements based on Automated Anatomical Labeling 116 and Hammersmith 83 atlases for 38 individuals with SMA types 2 and 3 and 38 age- and sex-matched healthy controls (HCs). The topological properties were analyzed by the graph theory approach and compared between groups by a nonparametric permutation test. Additionally, correlation analysis was used to assess the associations between altered topological metrics and clinical characteristics. RESULTS: Compared with HCs, although global network topology remained preserved in individuals with SMA, brain regions with altered nodal properties mainly involved the right olfactory gyrus, right insula, bilateral parahippocampal gyrus, right amygdala, right thalamus, left superior temporal gyrus, left cerebellar lobule IV-V, bilateral cerebellar lobule VI, right cerebellar lobule VII, and vermis VII and IX. Further correlation analysis showed that the nodal degree of the right cerebellar lobule VII was positively correlated with the disease duration, and the right amygdala was negatively correlated with the Hammersmith Functional Motor Scale Expanded (HFMSE) scores. CONCLUSIONS: Our findings demonstrated that topological reorganization may prioritize global properties over nodal properties, and disrupted topological properties in the cortical-limbic-cerebellum circuit in SMA may help to further understand the network pathogenesis underlying SMA.
Subject(s)
Brain , Magnetic Resonance Imaging , Humans , Female , Male , Brain/pathology , Brain/diagnostic imaging , Adult , Spinal Muscular Atrophies of Childhood/pathology , Young Adult , Adolescent , Gray Matter/pathology , Gray Matter/diagnostic imaging , Child , Nerve Net/pathology , Nerve Net/diagnostic imagingABSTRACT
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by recessive pathogenic variants affecting the survival of motor neuron (SMN1) gene (localized on 5q). In consequence, cells lack expression of the corresponding protein. This pathophysiological condition is clinically associated with motor neuron (MN) degeneration leading to severe muscular atrophy. Additionally, vulnerability of other cellular populations and tissues including skeletal muscle has been demonstrated. Although the therapeutic options for SMA have considerably changed, treatment responses may differ thus underlining the persistent need for validated biomarkers. To address this need and to identify novel marker proteins for SMA, we performed unbiased proteomic profiling on cerebrospinal fluid derived (CSF) from genetically proven SMA type 1-3 cases and afterwards performed ELISA studies on CSF and serum samples to validate the potential of a novel biomarker candidates in both body fluids. To further decipher the pathophysiological impact of this biomarker, immunofluorescence studies were carried out on spinal cord and skeletal muscle derived from a 5q-SMA mouse model. Proteomics revealed increase of LARGE1 in CSF derived from adult patients showing a clinical response upon treatment with nusinersen. Moreover, LARGE1 levels were validated in CSF samples of further SMA patients (type 1-3) by ELISA. These studies also unveiled a distinguishment between groups in improvement of motor skills: adult patients do present with lowered level per se at baseline visit while no elevation upon treatment in the pediatric cohort can be observed. ELISA-based studies of serum samples showed no changes in the pediatric cohort but unraveled elevated level in adult patients responding to future intervention with nusinersen, while non-responders did not show a significant increase. Additional immunofluorescence studies of LARGE1 in MN and skeletal muscle of a SMA type 3 mouse model revealed an increase of LARGE1 during disease progression. Our combined data unraveled LARGE1 as a protein dysregulated in serum and CSF of SMA-patients (and in MN and skeletal muscle of SMA mice) holding the potential to serve as a disease marker for SMA and enabling to differentiate between patients responding and non-responding to therapy with nusinersen.
Subject(s)
Muscular Atrophy, Spinal , Spinal Muscular Atrophies of Childhood , Adult , Humans , Child , Mice , Animals , Proteomics , Muscular Atrophy, Spinal/genetics , Spinal Muscular Atrophies of Childhood/drug therapy , Spinal Muscular Atrophies of Childhood/pathology , Motor Neurons/pathology , Biomarkers/cerebrospinal fluid , Disease Models, AnimalABSTRACT
Hirayama disease, or brachial monomelic amyotrophy, is not a common neurological disease characterized by unilateral or asymmetric bilateral lower motor weakness of distal upper limbs. The basic pathophysiology is compression of the dural sac and spinal cord during flexion of the neck. A case of a 21-year-old male presented with chief complaints of tremors in both hands (right more than left) with gradually progressive weakness of the right hand and forearm. Electromyography (EMG), nerve conduction velocity (NCV), and magnetic resonance imaging (MRI) neck in flexion showed focal atrophy of lower cervical myotomes and confirmed the diagnosis of monomelic amyotrophy.
Subject(s)
Spinal Muscular Atrophies of Childhood , Male , Humans , Young Adult , Adult , Spinal Muscular Atrophies of Childhood/diagnosis , Spinal Muscular Atrophies of Childhood/pathology , Upper Extremity , Electromyography , Magnetic Resonance ImagingABSTRACT
A 28-year-old man with Hirayama disease presented with a peculiar hand posture called "horn hand" ("main en corne"). The patient noticed that he could not extend his 3rd and 4th fingers when extending the fingers of his right hand 1 year prior to presentation. On neurological examination, the strength of the finger extension is severely weak in the 1st, 3rd and 4th fingers, causing a drop finger posture, but it is only moderately weak in the 2nd and 5th fingers, enabling him to sustain the extension finger posture. The finger posture is like a bull's horns and is named "horn hand". Amyotrophy of the ulnar side of the right forearm, so-called "oblique amyotrophy", and amyotrophy of the right hand are observed. MRI examination reveals atrophy of the lower cervical spinal cord and compression of it in the neck flexion posture. Diagnosis of Hirayama disease (juvenile muscular atrophy of the distal upper extremity) is confirmed. Horn hand has been reported so far in some cases of lead neuropathy, chronic inflammatory demyelinating polyneuropathy, and distal myopathy; a "peripheral" horn hand is characterized by partial and selective lesion of the radial nerve or of the finger extensor muscles. Meanwhile, a "spinal" horn hand in this patient with Hirayama disease represents the partial and selective lesion of the spinal anterior horn neurons.
Subject(s)
Spinal Muscular Atrophies of Childhood , Adult , Hand/pathology , Humans , Male , Muscular Atrophy/pathology , Spinal Cord Compression , Spinal Muscular Atrophies of Childhood/complications , Spinal Muscular Atrophies of Childhood/diagnosis , Spinal Muscular Atrophies of Childhood/pathology , Upper Extremity/pathologyABSTRACT
OBJECTIVE: To describe clinical and genetic studies on a patient with early-onset spinal muscular atrophyX3 (SMAX3) with novel variant of ATP7A. METHODS: Clinical, neurophysiological, neuroimaging and pathological examinations were performed. Whole exome sequencing was applied to search genetic bases of this patient. RESULTS: The patient had gait abnormality from early infantile period. Muscle imaging at 42 years old showed predominant involvement of proximal muscles as compared to the distal muscles. The patient had a novel variant of ATP7A, which was the fourth genotype of ATP7A exhibited as SMAX3. Contrary to previous reports of distal motor neuropathy, the clinical and neuroimaging findings in this case revealed dominant involvement in the proximal portion of the extremities and trunk, which is similar to patients with type III SMA. CONCLUSION: The dominant involvement of proximal motor system in this patient may expand the phenotypic variability of SMAX3. We need to be aware of this disorder in differential diagnosis of patients with type III SMA-like phenotype.
Subject(s)
Copper-Transporting ATPases/genetics , Spinal Muscular Atrophies of Childhood/diagnosis , Spinal Muscular Atrophies of Childhood/genetics , Adult , Humans , Male , Spinal Muscular Atrophies of Childhood/pathology , Spinal Muscular Atrophies of Childhood/physiopathologyABSTRACT
Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans.
Subject(s)
Biological Products/adverse effects , Genetic Therapy/adverse effects , Recombinant Fusion Proteins/adverse effects , Spinal Muscular Atrophies of Childhood/therapy , Survival of Motor Neuron 1 Protein/genetics , Autopsy , Biological Products/administration & dosage , DNA/genetics , Female , Genetic Vectors/administration & dosage , Genetic Vectors/adverse effects , Genetic Vectors/genetics , Humans , Infant , Infant, Newborn , Male , Motor Neurons/drug effects , Motor Neurons/pathology , RNA, Messenger/genetics , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/genetics , Spinal Muscular Atrophies of Childhood/genetics , Spinal Muscular Atrophies of Childhood/mortality , Spinal Muscular Atrophies of Childhood/pathology , Tissue Distribution/drug effectsABSTRACT
AIM: To summarize the current knowledge on brain involvement in spinal muscular atrophy (SMA) type 1, focusing on brain pathology, cognition, and speech/language development. METHOD: A scoping review was performed using the methodology of the Joanna Briggs Institute. Five databases and references from relevant articles were searched up to December 2019. Articles were screened on the basis of titles and abstracts. Full-text papers published in peer-reviewed journals in English were selected. RESULTS: Nineteen articles met eligibility criteria. Eight case series/reports on brain pathology showed abnormalities in few SMA type 0/1 cases, supported by findings in three post-mortem examinations in mice. Four studies (three case-control, one cross-sectional) on cognition reported contradictory results, with impaired cognitive performances in recent, small groups with SMA type 1. Four studies (three cross-sectional, one observational) on speech/language showed that untreated SMA type 1 patients rarely achieve functional and intelligible speech, with data limited to parent reports/non-formal evaluations. INTERPRETATION: Brain involvement is an under-investigated aspect of SMA type 1, requiring further exploration in longitudinal studies. A deeper knowledge of brain involvement would improve the interpretation of clinical phenotypes and the personalization of rehabilitation programmes supporting patients' autonomies and quality of life. Additionally, it may help to define further outcome measures testing the efficacy of current and new developing drugs on this domain. WHAT THIS PAPER ADDS: Brain involvement is under-investigated in spinal muscular atrophy (SMA) type 1. Neuropathological data suggest progressive brain involvement in severe forms of SMA. Impaired cognitive performances are reported in small groups with SMA type 1. Data on language in those with SMA type 1 are limited to parent reports and non-formal assessments.
Subject(s)
Brain/pathology , Cognition/physiology , Language Development , Spinal Muscular Atrophies of Childhood/psychology , Humans , Speech , Spinal Muscular Atrophies of Childhood/pathologyABSTRACT
BACKGROUND: The diagnosis of uncommon pediatric neuromuscular disease (NMD) is challenging due to genetic and phenotypic heterogeneity, yet is important to guide treatment, prognosis, and recurrence risk. Patients with diagnostically challenging presentations typically undergo extensive testing with variable molecular diagnostic yield. Given the advancement in next generation sequencing (NGS), we investigated the value of clinical whole exome sequencing (ES) in uncommon pediatric NMD. METHODS: A retrospective cohort study of 106 pediatric NMD patients with a combination of ES, chromosomal microarray (CMA), and candidate gene testing was completed at a large tertiary referral center. RESULTS: A molecular diagnosis was achieved in 37/79 (46%) patients with ES, 4/44 (9%) patients with CMA, and 15/74 (20%) patients with candidate gene testing. In 2/79 (3%) patients, a dual molecular diagnosis explaining the neuromuscular disease process was identified. A total of 42 patients (53%) who received ES remained without a molecular diagnosis at the conclusion of the study. CONCLUSIONS: Due to NGS, molecular diagnostic yield of rare neurological diseases is at an all-time high. We show that ES has a higher diagnostic rate compared to other genetic tests in a complex pediatric neuromuscular disease cohort and should be considered early in the diagnostic journey for select NMD patients with challenging presentations in which a clinical diagnosis is not evident.
Subject(s)
Exome Sequencing , Neuromuscular Diseases/diagnosis , Adolescent , Biopsy , Child , Child, Preschool , Cohort Studies , Electromyography , Female , High-Throughput Nucleotide Sequencing , Humans , Infant , Infant, Newborn , Male , Microarray Analysis , Mitochondrial Myopathies/diagnosis , Mitochondrial Myopathies/genetics , Mitochondrial Myopathies/pathology , Molecular Diagnostic Techniques , Muscular Dystrophies/diagnosis , Muscular Dystrophies/genetics , Muscular Dystrophies/pathology , Muscular Dystrophies, Limb-Girdle/diagnosis , Muscular Dystrophies, Limb-Girdle/genetics , Muscular Dystrophies, Limb-Girdle/pathology , Myopathy, Central Core/diagnosis , Myopathy, Central Core/genetics , Myopathy, Central Core/pathology , Myositis/diagnosis , Myositis/genetics , Myositis/pathology , Neural Conduction , Neuromuscular Diseases/genetics , Neuromuscular Diseases/pathology , Retrospective Studies , Sequence Analysis, DNA , Spinal Muscular Atrophies of Childhood/diagnosis , Spinal Muscular Atrophies of Childhood/genetics , Spinal Muscular Atrophies of Childhood/pathology , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Spinocerebellar Ataxias/pathologyABSTRACT
Spinal muscular atrophy (SMA) is largely linked to deletion or mutation of the Survival motor neuron 1 (SMN1) gene located on chromosome 5q13. Type III (Kugelberg-Welander disease) is the mildest childhood form and patients may become ambulatory and have a normal life expectancy. We report the clinical history and morphological findings of a 55-year-old woman who began to experience motor problems at the age of two. She was never fully ambulatory, and her severe scoliosis required the insertion of surgical rod at age 19. Unexpectedly, around 35 years of age, she began to experience sensory symptoms best characterized as a myelo-radiculo-neuropathy with pain as the dominant symptom. Investigations never clarified the etiology of these symptoms. Molecular confirmation of SMA type III was done post-mortem. Neuropathological examination showed classic changes of lower motor neuron neurodegeneration, in line with those reported in the single molecularly confirmed case published so far, and with findings in rare cases reported prior to the discovery of the gene defect. A key autopsy finding was the presence of a severe superficial siderosis of the lower half of the spinal cord. In recent years, the concept of duropathy was put forward, associating superficial siderosis of the spinal cord with various spinal abnormalities, some of which were present in our patient. The presence of significant hemosiderin deposits in the spinal cord and sensory nerve roots with associated tissue and axonal damage provide a plausible explanation for the unexpected sensory symptomatology in this mild lower motor neurodegeneration.
Subject(s)
Hemosiderin/metabolism , Hemosiderosis/pathology , Neuralgia/physiopathology , Radiculopathy/physiopathology , Spinal Cord Diseases/pathology , Spinal Muscular Atrophies of Childhood/pathology , Female , Hemosiderosis/metabolism , Hemosiderosis/physiopathology , Humans , Hyperalgesia/physiopathology , Middle Aged , Paresthesia/physiopathology , Spinal Cord Diseases/complications , Spinal Cord Diseases/metabolism , Spinal Cord Diseases/physiopathology , Spinal Muscular Atrophies of Childhood/complications , Spinal Muscular Atrophies of Childhood/genetics , Survival of Motor Neuron 1 Protein/genetics , Survival of Motor Neuron 2 Protein/geneticsABSTRACT
Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deletion or mutation of SMN1. Four subtypes exist, characterized by different clinical severities. New therapeutic approaches have become available in the past few years, dramatically changing the natural history of all SMA subtypes, including substantial clinical improvement with the severe and advanced SMA type 1 variant. Trials have now demonstrated that phenotypic rescue is even more dramatic when pre-symptomatic patients are treated, and emerging real-world data are demonstrating the benefits of intervention even in the chronic phase of the condition. Here, we critically review how the field is rapidly evolving in response to the new therapies and questions that the new treatments have posed, including the effects of treatment at different ages and stages of disease, new phenotypes and long-term outcomes in patients who would not have survived without treatment, and decisions of who to treat and when. We also discuss how the outcomes associated with different timing of therapeutic intervention are contributing to our understanding of the biology and pathogenesis of SMA.
Subject(s)
Muscular Atrophy, Spinal/therapy , Humans , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/pathology , Spinal Muscular Atrophies of Childhood/genetics , Spinal Muscular Atrophies of Childhood/pathology , Survival of Motor Neuron 1 Protein/genetics , Treatment OutcomeABSTRACT
Spinal muscular atrophy (SMA) encompasses a group of disorders with loss of spinal motor neurons.The report describes the neuropathological findings including brain and spinal cord at autopsy in a five-and-half-month-old boy with suspected type 1 SMA. The anterior motor neurons, Clarke's column at all the levels of spinal cord showed neuronal loss and degeneration while neurons at all the deep grey nuclei were preserved apart from variable degree anoxic changes. Skeletal muscle biopsy revealed features of neurogenic atrophy consistent with SMA. A differential diagnosis like storage disorders was excluded using electron microscopy. No extra-neural manifestations were seen. Neuropathological features at autopsy have seldom been reported in the literature.
Subject(s)
Muscular Atrophy, Spinal , Spinal Muscular Atrophies of Childhood , Autopsy , Humans , Infant , Male , Motor Neurons/pathology , Muscular Atrophy/pathology , Muscular Atrophy, Spinal/pathology , Spinal Cord/pathology , Spinal Muscular Atrophies of Childhood/pathologyABSTRACT
Spinal muscular atrophy (SMA) is a common autosomal recessive genetic disorder characterized by degeneration of motor neurons and weakness and muscle atrophy. Approximately 95% of SMA patients are caused by homozygous deletions of the SMN1 gene, whereas the remaining 5% of patients harbor compound heterozygous mutations such as an SMN1 deletion allele and an intragenic mutation (insertions, deletions, or point mutations) in the other SMN1 allele. Although analysis for the SMN1/SMN2 copy number is relatively easy, molecular genetic testing for patients with subtle mutations is still compromised due to the presence of a highly homologous SMN2 gene. Herein, we analyzed the SMN1/SMN2 copy number by multiplex ligation-dependent probe amplification (MLPA) and subtle mutations by long-range PCR (LR-PCR) for two "nondeletion" SMA patients. We identified a missense mutation (c.280G > T, p. (Val94Phe)) and a splicing mutation c.*3+3A > T in SMN1 gene not previously described in the scientific literature. Giving the severe phenotype of the two patients, we speculated that these two point mutations could significantly affect the function of SMN proteins. Our results provide important information for genetic counseling and prenatal diagnosis in these families and enrich the SMN1 mutation database.
Subject(s)
Phenotype , Point Mutation , Spinal Muscular Atrophies of Childhood/genetics , Survival of Motor Neuron 1 Protein/genetics , Humans , Infant , Male , Mutation, Missense , RNA Splicing , Spinal Muscular Atrophies of Childhood/pathologyABSTRACT
Spinal muscular atrophy type 0 is the most severe phenotype of the disease, with patients presenting with contractures, weakness, and respiratory failure at birth, and is typically fatal within weeks. We describe the case of a patient with spinal muscular atrophy type 0 who was treated with both nusinersen and onasemnogene abeparvovec. She has made modest motor improvements since treatment initiation with a 30-point improvement in CHOP-INTEND score, and continues to make motor gains at age 13 months without regression of function, although she remains profoundly weak. Although she has had motor improvements, she has also had continued systemic complications from her spinal muscular atrophy, including chronic respiratory failure, dysphagia, congenital heart malformation, digit necrosis, and diffuse macular rash. This case highlights the challenges in treating those with more severe disease phenotypes and raises questions of how some systemic complications may respond to current SMN replacement therapies.
Subject(s)
Biological Products/therapeutic use , Oligonucleotides/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Spinal Muscular Atrophies of Childhood/drug therapy , Female , Heart Diseases/etiology , Heart Diseases/pathology , Humans , Infant, Newborn , Nervous System Diseases/etiology , Nervous System Diseases/pathology , Nutritional Support , Osteomyelitis/etiology , Osteomyelitis/pathology , Respiration Disorders/etiology , Respiration Disorders/pathology , Skin Diseases/etiology , Skin Diseases/pathology , Spinal Muscular Atrophies of Childhood/complications , Spinal Muscular Atrophies of Childhood/pathology , Treatment OutcomeABSTRACT
Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder which encompasses a large group of genetic disorders characterized by slowly progressive degeneration of lower motor neurons. The mutation is seen in the SMN1 gene mapped on chromosome 5. Depending on the age of the onset and the degree of severity, SMA has three subtypes. We discuss the autopsy findings in a case of Type 1 SMA also known by the name Werdnig-Hoffmann disease, to highlight the primary changes in the spinal cord, and skeletal muscle with association changes in the liver and terminal respiratory complications.
Subject(s)
Humans , Male , Infant , Spinal Muscular Atrophies of Childhood/pathology , Autopsy , Fatal Outcome , Gliosis , Genetic Diseases, Inborn , LiverABSTRACT
Autosomal dominant missense mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. BICD2 is a key component of the cytoplasmic dynein/dynactin motor complex, which in axons drives the microtubule-dependent retrograde transport of intracellular cargo towards the cell soma. Patients with pathological mutations in BICD2 develop malformations of cortical and cerebellar development similar to Bicd2 knockout (-/-) mice. In this study we sought to re-examine the motor neuron phenotype of conditional Bicd2-/- mice. Bicd2-/- mice show a significant reduction in the number of large calibre motor neurons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2 results in a similar reduction in L4 ventral axons comparable to global Bicd2-/- mice. Rab6, a small GTPase required for the sorting of exocytic vesicles from the Trans Golgi Network to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated that BICD2 is required for physiological flow of constitutive secretory cargoes from the Trans Golgi Network to the plasma membrane using a VSV-G reporter assay. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology in the motor nervous system, which has important implications for future therapeutic approaches in SMALED2.
Subject(s)
Ganglia, Spinal/pathology , Microtubule-Associated Proteins/genetics , Motor Neurons/pathology , Muscle Spindles/pathology , Muscle, Skeletal/pathology , Neuromuscular Junction/pathology , Spinal Muscular Atrophies of Childhood/genetics , Spinal Nerve Roots/pathology , Animals , Cell Membrane/metabolism , Disease Models, Animal , Fibroblasts/metabolism , Humans , Mice , Mice, Knockout , Muscle Spindles/innervation , Muscle, Skeletal/innervation , Secretory Pathway/genetics , Secretory Vesicles/metabolism , Spinal Muscular Atrophies of Childhood/pathologyABSTRACT
BACKGROUND: A very limited spectrum of ASCC1 pathogenic variants had been reported in six (mostly consanguineous) families with spinal muscular atrophy with congenital bone fractures 2 [OMIM #616867] since 2016. METHODS: A proband from a non-consanguineous Chinese family presented with neonatal severe hypotonia, respiratory distress, muscle weakness, and atrophy, as well as congenital bone fractures was performed by exome sequencing. RESULTS: A compound heterozygosity of a nonsense (c.932C>G,p.Ser311Ter) and an exon 5 deletion in ASCC1 segregating with phenotypes was detected, both variants are novel and pathogenic. Since ASCC1 is a relatively new disease gene, we performed the gene curation by ClinGen SOP. The existing evidence is sufficient to support a "Definitive" level of disease-gene relationship. CONCLUSION: This case report expended the mutation spectrum of ASCC1 and support the notion that this novel disease also occurs in outbreed populations and this is a rare disease but may still be underdiagnosed due to its perinatal lethal outcomes.
Subject(s)
Carrier Proteins/genetics , Fractures, Bone/congenital , Mutation , Phenotype , Spinal Muscular Atrophies of Childhood/genetics , Fractures, Bone/genetics , Fractures, Bone/pathology , Heterozygote , Humans , Infant, Newborn , Male , Spinal Muscular Atrophies of Childhood/pathologyABSTRACT
The antisense oligonucleotide Nusinersen has been recently licensed to treat spinal muscular atrophy (SMA). Since SMA type 3 is characterized by variable phenotype and milder progression, biomarkers of early treatment response are urgently needed. We investigated the cerebrospinal fluid (CSF) concentration of neurofilaments in SMA type 3 patients treated with Nusinersen as a potential biomarker of treatment efficacy. The concentration of phosphorylated neurofilaments heavy chain (pNfH) and light chain (NfL) in the CSF of SMA type 3 patients was evaluated before and after six months since the first Nusinersen administration, performed with commercially available enzyme-linked immunosorbent assay (ELISA) kits. Clinical evaluation of SMA patients was performed with standardized motor function scales. Baseline neurofilament levels in patients were comparable to controls, but significantly decreased after six months of treatment, while motor functions were only marginally ameliorated. No significant correlation was observed between the change in motor functions and that of neurofilaments over time. The reduction of neurofilament levels suggests a possible early biochemical effect of treatment on axonal degeneration, which may precede changes in motor performance. Our study mandates further investigations to assess neurofilaments as a marker of treatment response.
Subject(s)
Neurofilament Proteins/cerebrospinal fluid , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides/administration & dosage , Spinal Muscular Atrophies of Childhood/drug therapy , Adolescent , Adult , Age of Onset , Aged , Biomarkers/cerebrospinal fluid , Child, Preschool , Female , Humans , Intermediate Filaments/metabolism , Male , Middle Aged , Oligonucleotides/adverse effects , Oligonucleotides, Antisense/adverse effects , Spinal Muscular Atrophies of Childhood/cerebrospinal fluid , Spinal Muscular Atrophies of Childhood/pathology , Treatment OutcomeABSTRACT
To define the relationship between the survival motor neuron 1 gene (SMN1) and SMN2, and explore the variability of these two genes within the generations, SMN1 and SMN2 copy numbers were determined for 227 SMA families. The association analysis indicated that there was a negative correlation between the copy number of SMN1 and SMN2 (Spearman = -0.472, P < 0.001) in 227 SMA children and 454 of their parents. The average SMN copies from father and mother in each SMA family were used to represent the copy number in the parent's generation. Subsequently, SMN transmission analysis showed that the similar distribution trend of SMN1 and SMN2 copy number was not only in the SMA children and their parents' generation but also in the non-SMA families. Moreover, when the SMN2 copy number was one in the parent's generation, 75% of their SMA children had type I and 25% of them had type II/III. However, when the SMN2 copies were three in the parent's generation, all of their SMA children were type II/III. Therefore, the diversity of SMN copies was mostly inherited and the SMN2 copy number in the parent's generation could predict the disease severity of SMA children to some extent.
Subject(s)
Gene Dosage , Spinal Muscular Atrophies of Childhood/genetics , Survival of Motor Neuron 1 Protein/genetics , Child , China , Family , Humans , Male , Spinal Muscular Atrophies of Childhood/pathology , Survival of Motor Neuron 2 Protein/geneticsABSTRACT
Only few studies have reported muscle involvement in spinal muscular atrophy using muscle MRI but this has not been systematically investigated in a large cohort of both pediatric and adult patients with type 2 and type 3 spinal muscular atrophy. The aim of the present study was to define possible patterns of muscle involvement on MRI, assessing both fatty replacement and muscle atrophy, in a cohort of type 2 and type 3 spinal muscular atrophy children and adults (age range 2-45 years), including both ambulant and non-ambulant patients. Muscle MRI protocol consisted in T1-weighted sequences acquired on axial plane covering the pelvis, the thigh, and the leg with contiguous slices. Each muscle was examined through its whole extension using a grading system that allows a semiquantitative evaluation of fatty infiltration. Thigh muscles were also grouped in anterior, posterior, and medial compartment for classification of global atrophy. The results showed a large variability in both type 2 and type 3 spinal muscular atrophy, with a various degree of proximal to distal gradient. Some muscles, such us the adductor longus and gracilis were always selectively spared. In all patients, the involvement was a combination of muscle atrophy and muscle infiltration. The variability observed may help to better understand both natural history and response to new treatments.