A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients

Zerres, Klaus; Rudnik‐Schöneborn, Sabine; Forrest, Eric; Łusakowska, Anna; Borkowska, Julita; Hausmanowa-Pétrusewicz, I

doi:10.1016/s0022-510x(96)00284-5

Cited by 240 publications

(221 citation statements)

References 9 publications

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“…SMAs are generally classified into types I to III according to age at onset and highest motor milestone achieved. 1,2 SMA type III is the most clinically variable form, with symptoms onset before (type IIIa) or after (type IIIb) age 3 years, 3 normal achievement of motor milestones, variable severity of scoliosis, tendon retractions and joint contractures, and eventual loss of walking ability.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

Tiziano¹,

Lomastro²,

Pietro³

et al. 2012

Eur J Hum Genet

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Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2), which produces insufficient levels of functional survival motor neuron (SMN) protein due to the alternative splicing of exon 7. The availability of potential candidates to the treatment of SMA has raised a number of issues, including the availability of biomarkers. This study was aimed at evaluating whether the quantification of SMN2 products in peripheral blood is a suitable biomarker for SMA. Forty-five adult type III patients were evaluated by Manual Muscle Testing, North Star Ambulatory Assessment scale, 6-min walk test, myometry, forced vital capacity, and dual X-ray absorptiometry. Molecular assessments included SMN2 copy number, levels of full-length SMN2 (SMN2-fl) transcripts and those lacking exon 7 and SMN protein. Clinical outcome measures strongly correlated to each other. Lean body mass correlated inversely with years from diagnosis and with several aspects of motor performance. SMN2 copy number and SMN protein levels were not associated with motor performance or transcript levels. SMN2-fl levels correlated with motor performance in ambulant patients. Our results indicate that SMN2-fl levels correlate with motor performance only in patients preserving higher levels of motor function, whereas motor performance was strongly influenced by disease duration and lean body mass. If not taken into account, the confounding effect of disease duration may impair the identification of potential SMA biomarkers.

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Section: Introductionmentioning

confidence: 99%

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

Tiziano¹,

Lomastro²,

Pietro³

et al. 2012

Eur J Hum Genet

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“…10 These patients suffer from proximal muscle weakness, frequent falls, and significant fatigue, yet 40 years after onset, 59% remain ambulatory. 11 Often, these individuals go on to start families of their own.…”

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confidence: 99%

Spinal Muscular Atrophy Genetic Counseling Access and Genetic Knowledge: Parents' Perspectives

2007

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Spinal muscular atrophy is characterized by degeneration of α motor neurons in the anterior horns of the spinal cord, which leads to progressive symmetrical muscle weakness and atrophy. Spinal muscular atrophy is the leading fatal autosomal recessive disorder in infancy, and genetic counseling is an essential component of the care of families of these patients. However, little guidance is available in the published literature regarding the process and benefit of genetic counseling for families. Accordingly, the authors designed a questionnaire to assess parents' knowledge of the disease, gauge their access to genetic counseling, and determine how parents use information gained from counseling to guide choices for future pregnancies. The questionnaire specifically targeted when genetic counseling was received, from whom, parental knowledge regarding spinal muscular atrophy genetics, parental choices regarding spinal muscular atrophy and their child, frequency of prenatal testing, perceived relevance of newborn screening, and opinions regarding the disease. Most families clearly received some type of genetic counseling. Yet how and from whom they received the information varied greatly, as did their genetic knowledge of spinal muscular atrophy. The highest percentage of families received counseling from neurologists, who may not be appropriately prepared to provide formal genetic counseling. Many respondents reported having a negative experience with genetic counseling, possibly because it occurred at the time of diagnosis or shortly afterward, a period of great emotional turmoil. These data suggest that a consistent approach for facilitating how and when genetic counseling is received is greatly needed. Keywordsspinal muscular atrophy; genetic counseling; genetic testing; carrier testing; parents' perspectives Spinal muscular atrophy is caused by a deletion or mutation in the survival motor neuron 1 (SMN1)gene. SMN1 was discovered in 1995 and is located on chromosome 5q11-q13. 1 SMN1 contains 9 exons that encode a 294 amino acid protein. Spinal muscular atrophy is characterized by degeneration of α motor neurons in the anterior horns of the spinal cord, which leads to progressive symmetrical muscle weakness and atrophy. It affects approximately 1 in 6000 to 10 000 white newborns and previously was the second most common fatal autosomal recessive disorder after cystic fibrosis. 7 Advances in the treatment of cystic fibrosis have resulted in a marked decrease in childhood mortality in that disorder, such that spinal muscular atrophy is now the leading fatal autosomal recessive disorder of infancy. Spinal muscular atrophy is clinically subdivided into 3 types. 8 Type 1 (Werdnig-Hoffmann) is characterized by muscle weakness prior to 6 months of age. Affected infants are unable to sit without support. Spinal muscular atrophy type 1 infants account for 60% to 70% of cases. Prognosis is grave, with most not surviving beyond their second birthday without substantial respiratory support. 9 Type 2 is characterized ...

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“…Dla pacjentów chodzących najtrudniejszy wydaje się wiek dojrzewania (skoku wzrostowego), w którym wielu chorych traci zdolność samodzielnego chodzenia. Prawdopodobieństwo zachowania zdolności samodzielnego chodzenia po 10, 20 i 40 latach trwania choroby wynosi odpowiednio 73%, 44% i 34% dla grupy 3a oraz 97%, 89% i 67% dla grupy 3b [17].…”

Section: Historia Naturalnaunclassified

Spinal muscular atrophy – novel therapies, new challenges

Jędrzejowska¹,

Kostera‐Pruszczyk²

2017

Child Neurology

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STRESZCZENIERdzeniowy zanik mięśni jest postępującą chorobą neurodegeneracyjną, w przebiegu której dochodzi do utraty motoneuronów rdzenia kręgowego, a w konsekwencji osłabienia i zaniku mięśni. Choroba charakteryzuje się bardzo dużą zmiennością przebiegu klinicznego -od letalnej formy wrodzonej po postać dorosłą, o średniej przeżycia jak w populacji ogólnej. Choroba związana jest z mutacjami genu SMN1. Liczba kopii bliźniaczo podobnego genu SMN2 warunkuje nasilenie objawów klinicznych. Analizy ostatnich lat zaowocowały weryfikacją aktualnej klasyfikacji, poprawą standardów opieki, poznaniem przebiegu historii naturalnej choroby. W zderzeniu z nowymi badaniami nad podłożem molekularnym i patogenezą choroby możliwe stało się podjęcie prób terapeutycznych. Badania kliniczne wykazały skuteczność nusinersenu (anysensowny oligonukleotyd), i doprowadziły do rejestracji leku do leczenia SMA. Najlepsze efekty uzyskano u pacjentów, u których włączono leczenie w okresie przedobjawowym. Trwają badania nad kolejnymi substancjami, których działanie oparte jest o różnorodne strategie-począwszy od terapii genowej (AVXS101), przez mikromolekuły modyfikujące składanie pre-mRNA SMN2 (LMI070, RG7916), po neuroprotektory (Olesoxime) i wiele innych. W pracy dokonujemy przeglądu najnowszych danych dotyczą-cych klasyfikacji, historii naturalnej, standardów opieki i prób terapeutycznych. Wczesne rozpoznanie i leczenie może zmienić historię naturalną choroby. Dlatego tak ważne wydaje się wczesne rozpoznanie, a w przyszłości być może wprowadzenie skriningu noworodkowego. Słowa kluczowe: SMA 5q, białko SMN, terapia. ABSTRACTSpinal muscle atrophy (SMA) is a progressive neurodegenerative disease that results in the loss of motoneurons in the spinal cord and, consequently, in muscle weakness and atrophy. The disease is characterized by high variability of the clinical course -from the early neonatal form to the adult form, with the average survival as in the general population. The disease is caused by mutations in the SMN1 gene. The number of copies of a similar SMN2 gene determines the severity of clinical symptoms. Recent analyzes allowed to verify current classification, improve care standards, learn the natural history of SMA. Clinical studies showed the efficacy of nusinersen (an antysense oligonucleotide) and led to the registration of the drug for SMA treatment. The best results were seen in presymptomatic patients. Research is underway on substances that are based on a variety of strategies, from gene therapy (AVXS101) to SMN2 pre-mRNA modulation micronucleus (LMI070, RG7916) to neuroprotectants (Olesoxime) and many others. We review the latest data on classification, natural history, care standards and therapeutic trials. Early diagnosis and treatment can change the natural history of the disease. That is why it is so important to have an early diagnosis and, perhaps, a neonatal screening in the future.

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A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients

Cited by 240 publications

References 9 publications

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study

Spinal Muscular Atrophy Genetic Counseling Access and Genetic Knowledge: Parents' Perspectives

Spinal muscular atrophy – novel therapies, new challenges

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