Late-onset X-linked recessive spinal and bulbar muscular atrophy.

Patient and parent oriented tools to assess health-related quality of life, activity of daily living and caregiver burden in SMA. Rome, 13 July 2019

Diseases are sometimes known by many names 1–9, which complicates the retrieval of publications. Rare and emerging diseases may be especially vulnerable to this. Health sciences librarians do not often encounter rare diseases and may be unaware of the search challenges that these diseases present. To effectively retrieve publications for research, a strategy to identify all the different names of a disease is needed so that these can be incorporated into a comprehensive search. The author was engaged in a research project to create a comprehensive bibliography of the rare disease spinal and bulbar muscular atrophy (SBMA). The project utilized a strategy to identify all of the various names for the disease. This strategy should be helpful not only for SBMA researchers, but for anyone interested in a methodology for obtaining a comprehensive list of names for a disease. Spinal and bulbar muscular atrophy (SBMA) SBMA (ORPHA481, OMIM #313200, SNOMED CT Concept ID 230253001†) is a rare progressive neuromuscular disorder of males marked by proximal muscle weakness, cramping, fasciculations (twitching of individual muscle fibers), and muscle atrophy. Symptoms have been reported to first begin to develop between the third to sixth decades of life. Prevalence of SBMA has been reported alternately as 1 in 40,000 10, 1–2 in 100,000 11, and less than 1 in 50,000 live male births 12, but it is thought to be underdiagnosed 13–15. Degeneration of anterior horn cells (lower motor neurons) in the spinal cord of affected individuals is observed. Additional symptoms may include gynecomastia (abnormal growth of breasts in males), testicular atrophy, dysarthria (difficulty speaking), and dysphagia (difficulty swallowing). At this time, there is no known cure for most such neuromuscular diseases 16. Inheritance of SBMA is by traditional X-linked genetics. The disorder is related to a genetic defect in which a trinucleotide repeat occurs in the first exon of the androgen receptor gene on the X chromosome, first identified by La Spada in 1991 17. The string of three nucleotides of a trinucleotide repeat is present in a normal gene but is an unusually long string in a defective gene. The trinucleotide repeat of SBMA is cytosine-adenine-guanine (CAG), which codes for the amino acid glutamine. The presence of the repeat in DNA translation results in a string of glutamine molecules in the resulting peptide. Normal CAG repeat length in the androgen receptor gene is 11–34. SBMA is diagnosed if the number of CAG repeats exceeds 38 18, 19. Women do not develop SBMA, but heterozygous and homozygous women may exhibit mild symptoms, particularly muscle twitching and cramping 13, 20, 21. SBMA was identified as a unique disorder in 1968 by William R. Kennedy, but the disorder existed before its discovery 22. As far back as 1897, Japanese neurologist Hiroshi Kawahara first described what appeared to be SBMA in two brothers suffering from muscle atrophy and fasciculation of the tongue and limbs, with adult onset and sex-linked recessive inheritance 23, 24. Several disorders of varying severity and outcomes resemble SBMA, and the disorder is thought to be frequently misdiagnosed 25–29. The most well known is amyotrophic lateral sclerosis. The most challenging are the spinal muscular atrophies (SMA). However, SMA is an autosomal recessive genetic disease. Symptoms of most forms of SMA arise in childhood, but SMA3 is suggested to possibly first appear in adolescence or young adulthood. SMA4 symptoms may appear after age 30 30.

Spinal Muscular Atrophy: A Deficiency in a Ubiquitous Protein; a Motor Neuron-Specific Disease

Spinal muscular atrophy (SMA) is characterized by degeneration of spinal cord anterior horn cells and muscular atrophy and has three phenotypes based on clinical severity and age of onset. One of the responsible genes for SMA is the survival motor neuron (SMN) gene, which is homozygously absent or interrupted in more than 90% of SMA patients. The cBCD541 (BCD) gene is a highly homologous copy of the SMN gene, which has a single synonymous transition in the coding region and may compensate for the loss of the SMN gene. To evaluate the effects of the BCD gene expression on the phenotypes of SMA, we examined lymphocyte mRNA from 9 SMA patients lacking the SMN gene, 10 asymptomatic parents, and 15 control subjects. We amplified mRNA fragments containing exon 7 of the SMN or BCD genes using reverse transcription-polymerase chain reaction since the transcript lacking exon 7 encodes a putative protein with a different C-terminal end. We used glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcript as an internal control, and the relative expression level of the SMN or BCD gene was shown as the ratio of SMN or BCD transcript to GAPDH transcript (S/G ratio). The mean S/G ratios of the patients were significantly lower than that of the parents and controls. However, among the patients examined in this study, there was no relationship between the S/G ratios and phenotypes of SMA. The results showed that the BCD gene expression was not related to the phenotypes of SMA. Furthermore, there was an overlap between the S/G ratios in patients and controls. As our discrimination study showed that the S/G ratio reflected the expression of the BCD transcripts in patients and the SMN transcripts in controls, this finding suggested that the BCD gene expression per se does not compensate for the loss of the SMN gene.

Neurology 1968;18:671-680 Progressive spinal muscular atrophy, juvenile proximal spinal muscular atrophy (Kugelberg-Welander), and infantile muscular atrophy (Werdnig-Hoffman) comprise a group of diseases by virtue of their pathological similarity. Chronic degeneration of the lower motor neurons and neurogenic atrophy of the skeletal muscle are common to all. The diseases differ in mode of inheritance, age of onset, distribution of muscular atrophy, and prognosis. Some investigators have considered them as a continuum of the same disease, underscoring the pathological similarity, while others have emphasized the clinical differences and prefer to regard them as distinct entities. This report describes 2 families in which 11 members, all male, were affected by an unusual, slowly progressive spinal and bulbar muscular atrophy. This disease, apparently inherited as a sex-linked recessive trait, becomes manifest clinically in the fourth and fifth decades and initially involves proximal muscles. The proximal weakness gave a clinical picture similar to muscular dystrophy in some patients. A full description is made of the prepositus of each family, but only the more striking features or unusual aspects are mentioned in the other cases. Case 1 (V-9). A 57-year-old white meat packer first noted the onset of low back pain at age 30 (Fig. 2). Five years later, he began to experience muscle cramps and fasciculations. He was able to wield a heavy meat cleaver until age 37 when increasing weakness of the shoulder and pelvic girdle muscles forced him to retire. A neurological examination at that time revealed weakness and fasciculations of the proximal limb and girdle muscles. Fig. 2. ( Left ) Case 1 (V-9). Member of B family. Weakness and atrophy of muscles in extremities, with maximal involvement in girdle musculature. Fig. 3. ( Right ) Case 7 (V-29). Member of B family. Progressive bulbar and limb weakness. He was first examined at the University of …

Only some patients with bulbar and spinal muscular atrophy may develop cardiac disease

Only some patients with bulbar and spinal muscular atrophy may develop cardiac disease

93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) – clinical picture (6–8 April 2001, Naarden, The Netherlands)

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.

AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice

BackgroundThe Pediatric Spinal Muscular Atrophy Registry Program of Iran (PSMAIR) was established as part of the global TREAT-NMD network, which collects data from spinal muscular atrophy (SMA) patients under 18 years of age in Iran. The registry employs a web-based data entry system to collect detailed longitudinal demographic, geographic, clinical, genetic, and treatment outcome data of Iranian children who suffer from SMA.ResultsFrom October 2021 to September 2022, 59 SMA patients were enrolled; 52.5% were female, 47.5% were male, and the average age was 4.98 ± 4.08 years. The majority of registered patients were diagnosed with SMA Type I (47%), followed by Type II (29%) and Type III (24%). Overall, about 19% of the registered patients died; all of them were Type I patients. In the registry, 44% of patients had been hospitalized previously. Usage rates for wheelchairs or other mobility assistive devices, occurrence of scoliosis, tube feeding, and mechanical ventilation among these patients were 15%, 15%, 19%, and 20%, respectively. The data reveal a gradient of severity across SMA types, with earlier symptom onset, lower CMAP amplitude, and lower ACTIVLIM scores associated with more severe SMA (type I), and increments observed moving towards milder forms (type III). The data reveal that symptom onset age, CMAP amplitude, and ACTIVLIM scores progressively increase from SMA type I to SMA type III. The CHOP-INTEND questionnaire's average score was notably higher in children with SMA type II compared to those with type I, while the HFMSE questionnaire scores were notably increased in type III compared to type II patients. A significant correlation between the SMN2 copy number and the SMA phenotype was observed in the population. The geographic distribution of the enrolled patients covers 15 and 18 (out of the 31) provinces of Iran for place of birth and current place of residence, respectively. For patients residing outside Tehran city (where the registry’s referral center is located), the average distance to the registry’s referral center was roughly 463 km.ConclusionsThe PSMAIR offers an important step toward understanding the characteristics of Iranian pediatric SMA patients. The outcome of PSMAIR facilitates data-driven planning and decision-making for Iranian pediatric SMA patients and can help in the advancement of SMA care standards, management, and therapies.

Troponin T in spinal and bulbar muscular atrophy (SBMA)

Spinal Muscular Atrophy (SMA) type I has classically presented extremely severe clinical features. New pharmacological treatments have led to a new phenotype of SMA. The aim of this study was to describe the current health and functional status of children with SMA. A cross-sectional study was conducted based on the STROBE guidelines. Patient questionnaires and standardized tools were used. A descriptive analysis was conducted establishing the proportions of subjects for each of the characteristics of interest. In total, 51 genetically confirmed SMA type I subjects were included. Fifty-seven percent received oral feeding, 33% received tube feeding and 10% combined both. Moreover, 21.6% had tracheostomies, and 9.8% needed more than 16 h/d ventilatory support. Regarding orthopedic status, 66.7% had scoliosis, and 68.6% had hip subluxation or dislocation. Up to 67% were able to sit independently, 23.5% walked with support and one child walked independently. Current SMA type I is a different entity from the classic phenotype but also from types II and III. In addition, no differences were found between SMA type I subgroups. These findings may enable the professionals involved in the care of these patients to improve their interventions in terms of prevention and rehabilitation measures for these children.

P.41 Adult SMA REACH: development and implementation data collection study in the UK Adult SMA population

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is caused by the loss of survival motor neuron 1 (SMN1) gene. SMA is characterized by the degeneration and loss of spinal cord motoneurons (MNs), muscular atrophy, and weakness. SMN2 is the centromeric duplication of the SMN gene, whose numbers of copies determine the intracellular levels of SMN protein and define the disease onset and severity. It has been demonstrated that elevating SMN levels can be an important strategy in treating SMA and can be achieved by several mechanisms, including promotion of protein stability. SMN protein is a direct target of the calcium-dependent protease calpain and induces its proteolytic cleavage in muscle cells. In this study, we examined the involvement of calpain in SMN regulation on MNs. In vitro experiments showed that calpain activation induces SMN cleavage in CD1 and SMA mouse spinal cord MNs. Additionally, calpain 1 knockdown or inhibition increased SMN level and prevent neurite degeneration in these cells. We examined the effects of calpain inhibition on the phenotype of two severe SMA mouse models. Treatment with the calpain inhibitor, calpeptin, significantly improved the lifespan and motor function of these mice. Our observations show that calpain regulates SMN level in MNs and calpeptin administration improves SMA phenotype demonstrating the potential utility of calpain inhibitors in SMA therapy.