Drug treatment for spinal muscular atrophy types II and III

 

Abstract

Background

Spinal muscular atrophy (SMA) is caused by degeneration of anterior horn cells, which leads to progressive muscle weakness. Children with SMA type II do not develop the ability to walk without support and have a shortened life expectancy, whereas children with SMA type III develop the ability to walk and have a normal life expectancy. There are no known efficacious drug treatments that influence the disease course of SMA. This is an update of a review first published in 2009.

Objectives

To evaluate whether drug treatment is able to slow or arrest the disease progression of SMA types II and III and to assess if such therapy can be given safely. Drug treatment for SMA type I is the topic of a separate updated Cochrane review.

Search methods

We searched the Cochrane Neuromuscular Disease Group Specialized Register (8 March 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (January 1991 to February 2011), EMBASE (January 1991 to February 2011) and ISI Web of Knowledge (January 1991 to March 8 2011). We also searched clinicaltrials.gov to identify as yet unpublished trials (8 March 2011).

Selection criteria

We sought all randomised or quasi-randomised trials that examined the efficacy of drug treatment for SMA types II and III. Participants had to fulfil the clinical criteria and have a deletion or mutation of the survival motor neuron 1 (SMN1) gene (5q11.2-13.2) that was confirmed by genetic analysis.

The primary outcome measure was to be change in disability score within one year after the onset of treatment. Secondary outcome measures within one year after the onset of treatment were to be change in muscle strength, ability to stand or walk, change in quality of life, time from the start of treatment until death or full time ventilation and adverse events attributable to treatment during the trial period.

Data collection and analysis

Two authors independently reviewed and extracted data from all potentially relevant trials. Pooled relative risks and pooled standardised mean differences were to be calculated to assess treatment efficacy. Risk of bias was systematically analysed.

Main results

Six randomised placebo-controlled trials on treatment for SMA types II and III were found and included in the review: the four in the original review and two trials added in this update. The treatments were creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants), and combination therapy with valproate and acetyl-L-carnitine (61 participants). None of these studies were completely free of bias. All studies had adequate blinding, sequence generation and reports of primary outcomes.

None of the included trials showed any statistically significant effects on the outcome measures in participants with SMA types II and III. One participant died due to suffocation in the hydroxyurea trial and one participant died in the creatine trial. No participants in any of the other four trials died or reached the state of full time ventilation. Serious side effects were infrequent.

Authors' conclusions

There is no proven efficacious drug treatment for SMA types II and III.

 

Plain language summary

Drug treatment for spinal muscular atrophy types II and III

Spinal muscular atrophy (SMA) is a neuromuscular disorder that results in progressive muscle weakness with onset in childhood and adolescence. There are three main types of SMA. Drug treatment for SMA type I is discussed in a separate Cochrane review. This review is of drug treatment for SMA types II and III. Both of these reviews were first published in 2009 and are now updated. The age of onset of SMA type II is between six and 18 months. Children with SMA type II will never be able to walk without support; they survive beyond two years and may live into adolescence or longer. The age of onset of SMA III, also known as Kugelberg-Welander disease, is after 18 months. Children with SMA type III develop the ability to walk at some time and their life expectancy is normal. From six randomised controlled trials, there is no evidence for a significant effect on the disease course when patients with SMA types II and III are treated with creatine (55 participants), phenylbutyrate (107 participants), gabapentin (84 participants), thyrotropin releasing hormone (9 participants), hydroxyurea (57 participants) or combination therapy with valproate and acetyl-L-carnitine (61 participants). The risk of bias of the included trials was systematically analysed and none of the studies were completely free of bias. Thus, there is still no known efficacious drug treatment for SMA types II and III.

 

摘要

背景

脊髓性肌萎縮(spinal muscular atrophy)第二型暨第三型之藥物治療方式

脊髓性肌萎縮是由於前角細胞退化，造成漸進性肌肉無力。 第二型脊髓性肌萎縮的病童必須藉由支撐才能走路，且壽命不長。第三型脊髓性基萎縮的病童則能夠走路且擁有正常的壽命。 對於能影響脊髓性肌萎縮病程的有效藥物，目前仍未可知。

目標

評估藥物是否減緩或停止第二型或第三型脊髓性肌萎縮之惡化，及藥物安全性。 針對第一型脊髓性肌萎縮的藥物治療則是另一項研究課題。

搜尋策略

我們搜尋 Cochrane Neuromuscular Disease Group Trials Register (2008年9月30日), The Cochrane Library (Issue 3, 2008年), MEDLINE (1966年1月至2008年6月), EMBASE (1980年1月至2008年6月), ISI (1988年1月至2008年6月), 及ACP Journal Club (1991年1月至2008年6月).

選擇標準

我們搜尋所有關於第二型和第三型脊髓性肌萎縮藥物治療的隨機或半隨機研究。研究參與者必須符合臨床標準，而且在以基因分析確立診斷的研究中，必須有SMN1基因(5q11.2−13.2)變異或缺損。 評估初級結果的方式是以開始治療的一年內，失能評分之變化。 評估次級結果的方式是以開始治療的一年內，肌肉強度變化、站立或走路的能力、生活品質變化、從發病到死亡或是完全使用呼吸器的時間、以及進行治療時發生的副作用。

資料收集與分析

從所有可能相關的試驗中收集資料。計算相對危險比(relative risks)和 加權平均標準差(weighted standardized mean differences)以評估治療成效。

主要結論

搜尋到四個關於第二型和第三型脊髓性肌萎縮隨機安慰劑對照試驗。這些治療包括肌酸(creatine)，丁酸苯酯(phenylbutyrate)，加巴潘汀(gabapentin) 和促甲狀腺激素釋放激素(thyrotropin releasing hormone)。這些試驗並沒有發現對第二型和第三型脊髓性肌萎縮病患有任何療效。 四個試驗中沒有病患死亡或是完全依賴呼吸器。副作用亦不常見。

作者結論

沒有證據證實治療第二型和第三型脊髓性肌萎縮的藥物有療效。

翻譯人

本摘要由新光醫院彭馨婷翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

脊髓性肌萎縮(spinal muscular atrophy)第二型暨第三型之藥物治療方式：脊髓性肌萎縮是一種在兒童時期或青少年時期發作的神經肌肉疾病，會造成漸進性肌肉萎縮。脊髓性肌萎縮有三種類型。對於第一型脊髓性肌萎縮的藥物治療另有論述。第二型脊髓性肌萎縮發病年齡介於6個月至18個月大。第二型脊髓性肌萎縮病童必須藉由支撐才能走路；他們可以存活超過兩年至青少年期或更久。第三型脊髓性肌萎縮，即KugelbergWelander disease， 發病年齡在18個月大之後。第三型脊髓性肌萎縮病童可以自行走路，壽命正常。四個關於第二型和第三型脊髓性肌萎縮隨機安慰劑對照試驗，分別以肌酸(creatine)，丁酸苯酯(phenylbutyrate)，加巴潘汀(gabapentin) 和促甲狀腺激素釋放激素(thyrotropin releasing hormone)治療。這些試驗並沒有發現對第二型和第三型脊髓性肌萎縮病患有任何療效。