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conduction study should be performed. If EMG suggests a motor neuron disease, then further testing for SMN mutations should be pursued. Genetic tests now offer quick and reliable SMN1 gene copy number testing by using Multiplex ligation-dependent probe amplification (MLPA) or real time PCR. Semiquantitative assays improve diagnostic sensitivity up to 98% [24,44]. If the patient has a single SMN1 copy, it is mandatory to sequence the coding region of the undeleted allele to identify the second causative mutation, generally subtle sequence variations, including point mutations, insertions, and deletions. However, in about one third of patients with a typical clinical picture and a single SMN1 copy, the second mutation is not found in SMN1/SMN2 coding region. This finding is more common in type III SMA and might be due to the presence of deep intronic mutations, unidentified so far (personal unpublished observation). Finally, sequence analysis of SMN1 gene is suggested also in those patients who have a typical clinical picture, 2 SMN1 copies, and are born to consanguineous parents or originate from genetic isolates. Indeed, rare patients homozygous for SMN1 subtle mutations have been occasionally reported [45]. Conversely, in a patient with 2 SMN1copies, SMA diagnosis, related to SMN1 mutations is virtually Figure 1 Diagnostic algorithm for spinal muscular atrophy. D’Amico et al. Orphanet Journal of Rare Diseases 2011, 6:71 http://www.ojrd.com/content/6/1/71 Page 4 of 10 excluded and other motor neuron disorders such as spinal muscular atrophy with respiratory distress (SMARD1), X-linked spinal muscular atrophy, distal SMA, and juvenile amyotrophic lateral sclerosis should be considered. If the electrophysiological examination excludes a motor neuron disease the child should be reexamined and must receive additional diagnostic testing considering other disorders. Differential diagnosis In general, the most important differential diagnostic conditions for an infant presenting with hypotonia and/ or weakness are congenital myopathies, i.e. myopathies with typical structural or ultrastructural features (rods, cores, central nuclei) on the muscle biopsy, congenital myotonic dystrophy, congenital myasthenic syndromes, metabolic myopathies, congenital disorders of the motor neuron and the peripheral nerve (congenital hypomyelinating neuropathy), as well as non-neuromuscular conditions including genetic syndromes such as, PraderWilli syndrome, acute hypoxic ischemic encephalopathy, neonatal sepsis and dyskinetic or metabolic conditions. The most important tools to address these differential diagnostic possibilities beyond the clinical examination and a careful family history are CK determination (note however that the CK can be only moderately elevated in chronic forms of SMA), EMG/nerve conduction studies to discriminate neurogenic conditions and abnormalities of neuromuscular transmission, MRI of the brain, muscle biopsy, and specific genetic or metabolic testing,. Other inherited motor neuron disorders, not caused by mutation of the SMN gene, that present with early weakness should be considered and are listed in table 2. Some clinical symptoms may suggest the diagnosis including joint contractures, distal rather than proximal weakness, diaphragmatic paralysis with early respiratory failure, and pontocerebellar degeneration. Genetic counseling and prenatal diagnosis Spinal muscular atrophy is one of the most common genetic disorders, with a carrier frequency of about 1/ 50, and direct carrier testing could be beneficial to community as screening test. Since the most common mutation found in patients is the homozygous absence of SMN1 gene, the majority of carriers bear the heterozygous deletion of one SMN1 allele. As in the case of second level diagnostic test, carrier testing is based on semiquantitative real time PCR or MLPA. Since the sensitivity of the molecular test is 93-95% [43], it is important to provide all couples performing molecular test with formal genetic counselling for the assessment of residual risk of having a child affected from SMA. The carrier test does not always identify if SMA is present and is not typically
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