Disease impact on general well-being and therapeutic expectations of European Type II and Type III spinal muscular atrophy patients

ObjectiveTo report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).MethodsAnalyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2–15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196–413 days). Assessments included the Hammersmith Functional Motor Scale–Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.ResultsTwenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.ConclusionsNusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.Clinicaltrials.gov identifierNCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).Classification of evidenceThis study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.

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Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander): evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x1996000300007 ◽

1996 ◽

Vol 54 (3) ◽

pp. 402-406 ◽

Cited By ~ 16

Author(s):

Márcia C. B. Cunha ◽

Acary S. B. Oliveira ◽

Rita Helena D. D. Labronici ◽

Alberto Alain Gabbai

Keyword(s):

Muscle Strength ◽

Spinal Muscular Atrophy ◽

Daily Living ◽

Muscular Atrophy ◽

Swimming Pool ◽

Type Ii ◽

Spinal Muscular Atrophy Type ◽

Type Iii ◽

Conventional Physiotherapy

We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy was performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and for forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.

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Clinical and Genetic Study of Algerian Patients with Spinal Muscular Atrophy

Journal of Neurodegenerative Diseases ◽

10.1155/2013/903875 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Y. Sifi ◽

K. Sifi ◽

A. Boulefkhad ◽

N. Abadi ◽

Z. Bouderda ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Muscular Atrophy ◽

Disease Type ◽

Intermediate Form ◽

Type I ◽

Type Ii ◽

Type Iii ◽

Type Iv ◽

Form Type ◽

Homozygous Deletions

Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder. It is divided into the acute Werdnig-Hoffmann disease (type I), the intermediate form (type II), the Kugelberg-Welander disease (type III), and the adult form (type IV). The gene involved in all four forms of SMA, the so-called survival motor neuron (SMN) gene, is duplicated, with a telomeric (tel SMN or SMN1) and a centromeric copy (cent SMN or SMN2). SMN1 is homozygously deleted in over 95% of SMA patients. Another candidate gene in SMA is the neuronal apoptosis inhibitory protein (NAIP) gene; it shows homozygous deletions in 45–67% of type I and 20–42% of type II/type III patients. Here we studied the SMN and NAIP genes in 92 Algerian SMA patients (20 type I, 16 type II, 53 type III, and 3 type IV) from 57 unrelated families, using a semiquantitative PCR approach. Homozygous deletions of SMN1 exons 7 and/or 8 were found in 75% of the families. Deletions of exon 4 and/or 5 of the NAIP gene were found in around 25%. Conversely, the quantitative analysis of SMN2 copies showed a significant correlation between SMN2 copy number and the type of SMA.

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Clinical and molecular analysis of spinal muscular atrophy in Brazilian patients

Genetics and Molecular Biology ◽

10.1590/s1415-47571999000400005 ◽

1999 ◽

Vol 22 (4) ◽

pp. 487-492 ◽

Cited By ~ 5

Author(s):

C.A. Kim ◽

M.R. Passos-Bueno ◽

S.K. Marie ◽

A. Cerqueira ◽

U. Conti ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Muscular Atrophy ◽

Disease Type ◽

Survival Motor Neuron ◽

Type I ◽

Type Ii ◽

Inhibitory Protein ◽

Type Iii ◽

Smn Gene ◽

Naip Gene

Spinal muscular atrophy (SMA), the second most common lethal autosomal recessive disorder, has an incidence of 1:10,000 newborns. SMA is divided into acute (Werdnig-Hoffmann disease, type I), intermediate (type II) and juvenile forms (Kugelberg-Welander disease, type III). The gene of all three forms of SMA maps to chromosome 5q 11.2-13.3. Two candidate genes, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene, have been identified; SMN is deleted in most SMA patients. We studied both genes in 87 Brazilian SMA patients (20 type I, 14 type II and 53 type III) from 74 unrelated families, by using PCR and single strand conformation polymorphism (SSCP). Deletions of exons 7 and/or 8 of the SMN gene were found in 69% of the families: 16/20 in type I, 9/12 in type II and 26/42 in type III. Among 51 families with deletions, 44 had both exons deleted while seven had deletions only of exon 7. Deletions of exon 5 of the NAIP gene were found in 7/20 of type I, 2/12 of type II and 1/42 of type III patients. No deletion of SMN and NAIP genes was found in 112 parents, 26 unaffected sibs and 104 normal controls. No correlation between deletions of one or both genes and phenotype severity was found.

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