Relationships between long-term observations of motor milestones and genotype analysis results in childhood-onset Japanese spinal muscular atrophy patients

Kaneko, Kaori; Arakawa, Reiko; Urano, Mari; Aoki, Ryoko; Saito, Kayoko

doi:10.1016/j.braindev.2017.04.018

Cited by 16 publications

(29 citation statements)

References 35 publications

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“…In parallel, physical abilities of the SMA subjects were assessed using the Hammersmith Functional Motor Scale (HFMS) and the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Individuals with SMA type I–III were classified into the clinical subtypes for this study, based on individual motor milestone changes, and were assessed as we previously reported [ 25 ] ( Table 1 , n.d.: not determined ).…”

Section: Methodsmentioning

confidence: 99%

A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein

et al. 2018

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Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by insufficiency of functional survival motor neuron (SMN) protein. Several clinical trials have been conducted with the aim of upregulating the expression of the SMN protein in SMA patients. In order to evaluate the efficiency of these SMN-targeted approaches, it has become necessary to verify SMN protein levels in the cells of SMA patients. Accordingly, we have developed a method allowing the evaluation of the functional SMN protein with < 1.5 mL of peripheral blood using imaging flow cytometry. The expression of SMN protein in CD3+, CD19+, and CD33++ cells obtained from SMA patients, was significantly reduced compared with that in cells from control subjects. In spot analysis of CD33++ cells, the intensities of SMN spots were significantly reduced in SMA subjects, when compared with that in controls. Therefore, SMN spots implied the presence of functional SMN protein in the cell nucleus. To our knowledge, our results are the first to demonstrate the presence of functional SMN protein in freshly isolated peripheral blood cells. We anticipate that SMN spot analysis will become the primary endpoint assay for the evaluation and monitoring of therapeutic intervention, with SMN serving as a reliable biomarker of therapeutic efficacy in SMA patients.

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Section: Methodsmentioning

confidence: 99%

A new biomarker candidate for spinal muscular atrophy: Identification of a peripheral blood cell population capable of monitoring the level of survival motor neuron protein

et al. 2018

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“…70,71 These findings are consistent with observations in high-ROB natural history studies, 66,72 although one study found significantly better motor function outcomes in patients with type 3a SMA compared with patients with type 3b with regard to stair climbing (Table S5). 26 An RCT of olesoxime in types 2 and 3 SMA found no effect of disease severity (defined by Motor Function Measure Domain 1 + Domain 2 total score) on outcomes (Table 4). 49 The effect of ambulatory status at baseline on motor function (6-minute walk distance (6MWD), HFMSE, and GMFM (Gross Motor Function Measure) were assessed in two low-ROB natural studies in types 2 and 3 SMA (Table 6).…”

Section: Reviewmentioning

confidence: 99%

“…Our review found only two high-ROB studies reporting on respiratory outcomes, 26,66 which included no evidence from individuals REVIEW treated with DMTs. These studies observed that disease severity and age influence outcomes in SMA.…”

Section: Factors Affecting Respiratory Measuresmentioning

confidence: 99%

“…Individuals can sit unsupported, and some can stand with braces, but they will never achieve independent ambulation 24,25 . Type 2 SMA can be further stratified into two subgroups based on age at independent sitting: types 2a (>8 months of age) and 2b (≤8 months) 26 . Disease progression can vary greatly; however, nearly all individuals will develop scoliosis due to weakness of the axial muscles 27 .…”

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confidence: 99%

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Prognostic Factors and Treatment‐Effect Modifiers in Spinal Muscular Atrophy

Baranello

Gorni

Daigl

et al. 2021

Clin Pharma and Therapeutics

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Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years of age. Individuals with types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of types 1, 2, and 3 SMA. In untreated infants with type 1 SMA, absence of symptoms at birth, a later symptom onset, and a higher survival of motor neuron 2 ( SMN2 ) copy number are all associated with increased survival. Disease duration, age at treatment initiation, and, to a lesser extent, baseline function were identified as potential treatment‐modifying factors for survival, emphasizing that early treatment with disease‐modifying therapies (DMT) is essential in type 1 SMA. In patients with types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age, and ambulatory status. Individuals aged 6–15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment‐effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching, or summarizing results from different studies on the treatments for SMA.

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“…Respiratory insufficiency is fatal in SMA type 1 and a serious problem for SMA types 2 and 3. A retrospective study in Japan 1 showed that noninvasive positive pressure ventilation (NPPV) was needed for 52% and 13% of SMA types 2 and 3 patients, respectively.…”

Section: Figmentioning

confidence: 99%