The Problem SMA
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder. It is caused by the loss of a gene called the survival motor neuron gene, also known as SMN1. This gene affects specialized nerve cells, called motor neurons, that relay messages to the muscles to contract and thereby produce movement. If these cells degenerate, muscles become weak and atrophy.
The clinical characteristics of SMA vary widely. The disorder can appear soon after birth, or not until adulthood. Patients are clinically classified into three subtypes. Type I, the severe form, affects infants before the age of six months and these children never sit unaided. Type II is the intermediate form and it has an onset after six months; these children never walk unaided. Type III is the mild form and it affects patients after 18 months. Patients in this group are able to walk but they may later lose this ability. This classification is useful to help doctors communicate with each other internationally to developing strategies for clinical trials. Treatment for SMA is a major challenge because the clinical variations between patients are extensive. To design suitable clinical trials we therefore need to take many factors into account. These include the type of SMA type, the patient’s age, the severity status of the disease, the type of therapeutic approach, the timing of the proposed intervention in relation to disease progression, the availability of a reliable marker for prognostic and evolution of the disease and the relative homogeneity of the group under study.
To understand the aims of possible therapies in SMA we need to understand some basic genetic aspects of this disorder. Most people have two copies of a specific gene called the survival motor neuron gene 1, also referred to as SMN1. We inherit one copy from each parent. SMA patients, however, have alterations or absence of both copies of these genes.
Although all SMA patients have absence or mutations in the SMN1 gene, they all possess a complete copy of a similar gene, called SMN2. Both these genes produce a protein called SMN, but SMN2 produces a smaller amount of protein due to subtle differences in its sequencing (see Figure 1). The SMN2 gene is therefore the only source of SMN protein in SMA patients.
The SMN protein is essential for life and a small amount may be sufficient to live but insufficient to avoid the appearance of the disease.
The disease manifests itself according to the amount of protein that an individual may produce. This is directly related to the number of SMN2 copies that a patient may have. Most SMA patients have 2 to 3 copies from a possible range of 1 to 5 copies. The lack of both SMN1 and SMN2 genes has never been described.