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performed until the sibling is of childbearing age. Thus it is imperative that individuals understand the limitations of the molecular testing: subjects who test negative for the search of heterozygous deletion may have two SMN1 copies in cis on one chromosome 5, may be carriers of rare subtle mutations, and the occurrence of extremely rare de-novo mutations cannot be ruled out. As (in the case of other) is true for carrier screening programs, SMA testing must be voluntary, performed in adults only, and upon informed consent and assurance of confidentiality [6]. In most cases, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning (prenatal diagnosis or pre-implantation diagnosis). In these cases, we suggest to test at risk individuals first and, in case of testing positive, to analyze also the partner. Thus in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%); in these cases, antenatal screening by chorionic villi sampling can be carried out between the 11th and 13th week of pregnancy. In all other instances, i.e. relatives of patients, carrier testing is sufficient to reduce markedly the risk of SMA for the offspring. In our opinion, prenatal diagnosis should be offered only Table 2 other forms of SMA not linked to SMN gene SMA variant Inheritance/gene Clinical features Scapuloperoneal SMA AD 12q24.1-q24.31 Progressive weakness of scapuloperoneal and laryngeal muscles SMA with pontocerebellar hypoplasia AR VRK1 Brainstem and cerebellar hypoplasia, early onset (0-6 mo) X-linked infantile SMA with arthogryposis X-linked Xp11.3-q11.2 UBA1 Contractures, onset at birth or infancy, early death SMA with respiratory distress type I AR-IGHMBP2 Early onset (< 3 mo), eventration of diaphragms, distal weakness, pes equines. Congenital distal SMA AD12q23-q24 Early onset with contractures, nonprogressive Distal SMA-V/CMT2d AD 7p15 GARS Distal SMA with upper limb predominance D’Amico et al. Orphanet Journal of Rare Diseases 2011, 6:71 http://www.ojrd.com/content/6/1/71 Page 5 of 10 when both partners test positive to the carrier screening; however, the clinical severity of a potentially affected foetus cannot be established a priori and the predictive power of SMN2 copy number assessment is not sufficient to establish an accurate prognosis. Indeed testing for SMN2 copy number in an affected fetus is problematic when there are 3 copies, as types I, II and III can all result in this setting and thus no prognosis can be established. Having a single copy is rare but is highly predictive of a severe type I baby with a very poor prognosis. A copy number of 2 is typical for a type I phenotype but could be a type II, again making any prognosis difficult. These considerations and facts have impact on neonatal screening, an argument that is growing with the progress in treatment prospective in SMA [6]. The purpose of newborn screening is to identify affected infants prior to the presentation of clinical symptoms. Newborn screening has been an extremely successful program and has improved the quality of life of many children with a variety of disorders. There has now been an expansion of the number of conditions included in many newborn screening panels. The benefits achieved through newborn screening have traditionally referred to the direct benefits to the affected child. However, there are currently a number of disorders screened which do not have a welldefined medical treatment, and this is the case for SMA. While a number of potential therapies are currently in clinical trials for SMA [46-50], their success may depend on identifying individuals as early as possible in order to begin treatment before potentially irreversible neuronal loss. In infants with type I SMA, rapid loss of motor units occurs in the first 3 months and severe denervation with loss of more than 95% of units within 6 months of age [51]. Therefore a very small window for
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