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disease severity can be tempered to intermediate and mild phenotypes by adding additional transgenes that express various wild-type isoforms or weak mutant forms of SMN [29]. Two main hypothesis have been postulated to explain the pathogenesis of SMA: (a) SMN is involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs) and in mRNA splicing: thus SMN reduction may determine a general perturbation in snRNP assembly (to which motor neurons may be more sensitive), and/or SMN complex is involved in the splicing of one or few transcripts with a key function in motor neurons; or (b) SMN has a motor neuron specific function, independent from snRNPs assembly, such as mRNA transport along the axon. Hypothesis (a) is supported by different experimental evidences: SMN protein is a part of a high molecular weight complex including at least eight other proteins, and it is necessary for proper assembly of Smith class core proteins in the Uridine-rich snRNPs (U snRNP). U snRNPs are the principal components of spliceosomes, the cellular particles that executes pre-mRNA splicing. Although SMN protein is expressed in all somatic cells, why motor neurons of the spinal cord are specifically vulnerable in spinal muscular atrophy is puzzling. Some studies suggest that SMN protein might play a key role in cellular functions unique to motor neurons [30-32]. Also hypothesis (b) is supported by different lines of evidence: several studies suggest that SMN protein might sustain the survival of motor neurons by allowing normal axonal transport and maintaining the integrity of neuromuscular junctions. Low concentrations of SMN protein might be specifically detrimental to motor neurons due to the length of axons and to their unique interactions with skeletal muscles [33-40]. Furthermore, SMN protein is localized in ribonucleoprotein granules in neurites and growth cones of motor neurons; for this reason some Authors suggested that SMN protein might be involved in transportation of ribonucleoprotein complexes containing b-actin, and/or specific mRNAs [41]. Very recently, in a mouse model of SMA it has been observed that morphological changes occurring at early stages of the disease, include reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These changes occur first in motor neurons innervating proximal hindlimb muscles and in medial motor neurons innervating axial muscles. At an endstage disease deafferentation of motor neurons occur for motor neurons innervating distal hind limb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern [42]. Diagnosis Clinical features are highly suggestive for the diagnosis of SMA particularly in the severe variant of a floppy baby or weak child. The attentiveness and intellect is always good. The weakness is usually symmetrical and more proximal than distal; generally it is greater in the legs than in the arms. The severity of weakness correlates with the age of onset with delayed motor milestones according to clinical classification (see table 1). Sensitivity is preserved and deep tendon reflexes are more or less involved depending on age at onset and duration of the disease. In the most severe form moreover other clinical features include: impaired head control, weak cry and cough, swallowing and feeding D’Amico et al. Orphanet Journal of Rare Diseases 2011, 6:71 http://www.ojrd.com/content/6/1/71 Page 3 of 10 difficulty, atrophy and fasciculation of the tongue and the infant relies on the diaphragm for breathing (abdominal breathing).. The algorithm of the diagnostic procedures that should be guide to diagnosis of SMA is summarized in Figure 1. The first level diagnostic test for a patient suspected to have SMA should be the search of SMN1 gene homozygous deletion. The absence of SMN1 exon 7 (with or without deletion of exon 8) confirms the diagnosis of SMA. The test achieves up to 95% sensitivity and nearly 100% specificity [43]. If the first level assay tests negative, further laboratory exams including creatine kinases dosage and electrophysiological tests such as electromyography (EMG), and nerve
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