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The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(12): 2555–2558© 2012 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2012.703720

Spinal muscular atrophy (SMA) is an autosomal recessive neuro-muscular disorder that is caused by degeneration of α motor neurons in the spinal cord anterior horns. This degeneration can lead to progressive atrophy of proximal muscles, weakness, respiratory failure and death in severe cases. SMA is the most common neuromuscular disease of childhood and one of the main causes of infant death, with no cure in sight. This review highlights the impact of the disease in families, summarizes genetics and ultrasound advances, discusses how obstetricians can work towards its early detection and explores the options for reproductive planning.

Keywords: Carrier screening, genetics, prenatal diagnosis, spinal muscular atrophy, ultrasound

Clinical manifestations and classificationSpinal muscular atrophy (SMA) is the second most common severe hereditary disease in infancy and early childhood after cystic fibrosis and has an incidence of 1/5000 to 1/10000 births and a carrier frequency of 1/35 to 1/50 [1,2]. According to the criteria set by the International SMA Consortium, SMA patients are classified into three types on the basis of age at onset and clinical severity of the disease (see Table I [3,4]). Type I SMA (or Werdnig-Hoffmann disease) is the most severe form and it is characterized by generalized muscle weakness and hypotonia at birth or within the first six months of life. Children are never able to sit unaided. Death from respiratory failure usually occurs within the first 2 years of life. Type II SMA (or intermediate form) is distinguished by onset after 6 months. Children are able to sit but they never walk. Type III SMA (or Kugelberg–Welander disease) is the mildest form and appears after 18 months. Patients who are initially able to walk but they later develop weakness and are eventually wheelchair-bound. Outliers of this classification are type 0 SMA [5] and type IV SMA. In type 0 SMA, severe manifestations are already present at birth and life expectancy is usually a matter of weeks. Type IV SMA, however, appears in adults, about the third decade of life (from 20 to 30 years), and symptoms are mildest in this group. Exceptionally, females affected with the chronic SMA forms may become pregnant and have a child [6]. Special issues concerning the follow-up, anaesthesia and delivery should be taken into account in these females but are out of the scope of the present review. All SMA forms are the result of an SMN protein deficiency which in turn endangers motor neurons [7]. SMN is encoded by two genes (SMN1 and SMN2) located in tandem in a complex region of chromosome 5 (5q13) (Figure 1A [8]).

GeneticsSMA is caused by the homozygous loss (95–96%) or subtle muta-tions (3–4%) of the SMN1 gene [9]. SMN2 is highly homologous to SMN1, differing only in five nucleotide exchanges. These changes do not alter the amino acid sequence of the protein but render exon 7 from SMN2 more prone to be skipped in mRNA. Therefore, most of the mRNA transcribed from SMN1 is full length (FL-SMN) whereas most of the SMN2 transcripts lack exon 7 (Δ7-SMN). Thus, SMN2 encodes mainly a protein (SMNΔ7) which is unstable and only partially functional. Even though all SMA patients, who lack SMN1, carry SMN2 genes, the production of functional SMN protein is not sufficient to prevent progressive motor neuron degeneration. Several studies have shown that the copy number of SMN2 modifies the pheno-type, indicating an inverse correlation between the number of SMN2 copies and the severity of SMA disease. Thus, most type I SMA patients carry two, or in a few cases only one SMN2 copy (Figure 1, 1D and 1E), while most type II SMA patients carry three copies and type III SMA patients carry three or four copies of SMN2 [10,11].

Prenatal detectionPrenatal detection of SMA is based on molecular genetic studies usually performed after chorionic villus sampling. Two main prenatal aspects of the disease must be considered: the first refers to genetic detection and the second to ultrasound findings.

Genetics

The discovery that SMN1 is responsible for SMA allowed accurate diagnosis and, given the severity of the disease, prenatal testing has been implemented in couples at risk. Most couples with a previous affected child request early prenatal detection because the risk of recurrence is 25% in this setting. After chorionic villus sampling at around 11–12 weeks of pregnancy, a simple diag-nostic DNA test to determine the homozygous absence of exons 7 and 8 of the SMN1 gene detects approximately 95% of SMA cases. A small percentage of patients may have absence of SMN1 in one allele and a point mutation in the other. In our experience, these cases have been also effectively detected prenatally in couples at risk. Prenatal molecular diagnosis has been successfully used in obstetric practice over the last 15 years [12]. Another option for couples at risk is to undergo preimplantation genetic diagnosis after in vitro fertilization to select unaffected embryos [13].

Review

Raising obstetricians’ awareness of spinal muscular atrophy: towards early detection and reproductive planning

Juan Parra1 & eduardo F. Tizzano2

1Department of Obstetrics and Gynecology and 2Department of Genetics, Hospital Sant Pau, and Ciberer U-705(3), Barcelona, Spain

Correspondence: Eduardo F. Tizzano, M.D., Ph.D. Genetics, Hospital de la Santa Creu i Sant Pau, Sant Quintí 89, 08041 Barcelona, Spain. Fax: +34 93 553 7373. Tel: +34 93 553 7369. E-mail: etizzano@santpau.cat

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Prenatal screening is not currently undertaken for SMA in pregnancies without a family history of the disease. A more cost-effective and more reasonable preventive strategy would be to identify carriers by preconception tests (see below) (Table II).

Ultrasound

SMA studies during fetal life may help to understand the mecha-nisms of the disease and could identify possible early manifesta-tions detectable by ultrasound. Although maternal perception of diminished fetal movements has been reported in SMA during the third trimester [14], particularly in severe cases, there were no specific studies on movement patterns in SMA fetuses. In a system-atic analysis of control fetuses, SMA carrier fetuses and SMA affected fetuses between 11–14 weeks gestation [15] we recently verified that at this fetal stage, there is no observable alteration in the qualitative assessment of movements by SMA affected fetuses as compared to control and carriers. We found that general move-ments, isolated arm and legs movements, head movements and quick generalized movements lasting about 1 s (startle and hiccup) were indistinguishable even in fetuses predicted to develop a very severe neonatal form [15]. This observation reinforces the idea that alteration of fetal movements would be a late phenomenon during pregnancy in SMA and suggests that neuromuscular connections are functionally sufficient during these early stages of development, opening the way for a possible early therapeutic intervention in a presymptomatic fetal stage.

It has been suggested that an increase in nuchal translucency (NT) thickness may be an early sign of the disease. However, only a few isolated cases have been reported, and most of these had associated structural malformations or hydrops. Two recent series of 12 [16] and 19 SMA fetuses [17] indicated that an increase in NT is very uncommon in SMA. In our study, we have stressed that the genetic context, such as the number of SMN2 copies, may play a particular role in the development of these fetuses [17]. Thus, when two SMN2 copies are present, fetuses show no structural malformations, and normal NT. On the other hand, the presence of only one SMN2 copy appears to be related to very severe congenital SMA forms, to cardiac defects and to increased NT [17]. Further research is warranted in fetuses with congenital heart disease and its possible association with severe SMA to establish the relevance for genetic counseling.

Postnatal aspectsMost SMA cases are undetectable at birth and in the first weeks of life as weakness generally appears later. Only babies with congen-ital or type 0 SMA (around 5% of cases) can be detected at birth; they present marked hypotonia, areflexia, feeding problems and, occasionally, arthrogryposis whereas weakness in typical type I patients commonly appears after the neonatal period. Patients present rapid loss of motor units in the first 3 months and severe denervation with loss of more than 95% of units within 6 months [18]. Advances in molecular characterization of the disease, including the discovery of the SMN1 gene and elucidation of its mutational spectrum, have significantly improved SMA clinical diagnostic testing. Moreover, it is no longer necessary to perform an invasive muscle biopsy to confirm the diagnosis.

Newborn screening

Even though there is as yet no cure for SMA, issues concerning standard of care may alleviate clinical symptoms and improve quality of life. In a number of genetic disorders the success of such care may depend on diagnosis being made as early as possible. In SMA, the most obvious rationale would be to begin treatment before irreversible neuronal loss occurs. Considering the onset of the severe forms, the therapeutic window for a putative benefi-cial intervention is therefore very small. Thus, current proactive measures with regard to nutrition, physical therapy, respiratory care [19] and new possible therapies will need to be implemented and administered within the newborn period for maximum benefit. Neonatal identification of patients may be achieved through DNA testing, which yields the diagnosis in around 95% of cases [9]. It has been reported that DNA analysis of blood spots can be used successfully for SMA newborn screening [20]. The most crucial aspect, however, is the ethical issue of prognosis: when an asymptomatic newborn with a homozygous deletion is detected, the SMN2 copy number can be established, but if a patient has three SMN2 copies, it would be unfeasible to explain

Table I. Classification of SMA according to onset, milestones, clinical symptoms and number of SMN2 copies.SMA type Onset Motor milestones Outcome SMN2 copies0 Neonatal Severe weakness and

arthrogryposisDeath in the first weeks Usually 1 copy

I Before 6 months Never sit Death within the first two years Usually 2 copiesII After 6 months and before 18

monthsNever walk Respiratory problems and scoliosis may

complicate outcome and survivalUsually 3 copies

III After 18 months Able to walk but later may be wheelchair bounded

Reach adult life. Respiratory problems and scoliosis may appear in sitters

Usually 3–4 copies

IV Appears in adult life Usually walkers No major complications Usually 4 copies

Figure 1. Simplified scheme of the SMN1 and SMN2 genes showing the most frequent characteristic genotypes in: (A) Normal population; (B) Classical 1/0 SMA carriers; (C) 2/0 SMA carriers; (D) type I SMA affected babies and (E) Severely affected newborns or type 0 SMA. For simplicity, in (C) the SMN2 gene in the chromosome with two copies of SMN1 in cis is not represented. Individuals with loss of both, SMN1 and SMN2 genes, have not been reported, indicating that the SMN protein produced by these genes is essential for life.

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a categorical prognosis as outcome may vary tremendously. Newborn screening in SMA is currently under intense debate and is a promising measure to allow presymptomatic diagnosis leading to an early genetic counseling and intervention.

Carrier testing

Given that SMA is one of the most common lethal genetic disor-ders, with a carrier frequency of 1/35–1/60, carrier testing is requested by many families. The method is a quantitative DNA test to determine the number of SMN1 copies (one copy represents a carrier and two copies represent a non-carrier). Furthermore, genetic testing can be applied to parents of a child who has died and no sample is available for study. A single SMN1 dose in these parents will confirm carrier status of a deletion in the SMN1 gene. Consequently, prenatal diagnosis can be offered and other possible carriers in the family can be investigated. It is worth mentioning here that about 3-4% of SMA carriers have two SMN1 copies in one chromosome and 0 copies in the other (most carriers have one SMN1 copy in one chromosome and none in the other) (see Figure 1, 1B and 1C). Dosage studies in the SMN1 gene do not discriminate non-carriers (typically 1/1) from 2/0 carriers and give a false negative in carrier analysis. Thus, the finding of two SMN1 copies significantly reduces the risk of being a carrier, although there is still a residual risk. Besides quantification of the SMN1 gene, marker analysis of the SMA genetic region can identify the at risk-haplotype inherited by an individual under study comple-menting carrier diagnosis in a given family. However, this method is unsuitable for families where key members are inaccessible or dead. Furthermore, the parents of a child with SMA are not always carriers given that de novo or germ line mutations may occur in approximately 2% of cases [21]. Obstetricians may also be consulted by couples consisting of a confirmed carrier and a partner from the general population. Assuming that the partner has an “a priori” risk of approximately 1/50 of being a carrier (carrier frequency of the general population), the final risk for the couple would be around 1/200 (1/4 × 1/50). These figure risks may differ somewhat according to the ethnicity of the couple [22,23,24]. In cases with 1/200 risk, carrier studies based on quantitative analysis can be offered to the partner. Alternatively, prenatal diag-nosis can be performed to detect the homozygous loss of SMN1. SMN1 dosage is a useful tool to apply in these couples because if the partner has two SMN1 copies it may help to decrease the

risk from approximately 1 in 200 to 1 in 4000. On the other hand, if the partner has only one SMN1 copy the risk increases to 1 in 4 [12,25]. Another situation where SMN1 dosage may be applied is the screening of gamete donors when the recipient is a known carrier [26]. Besides these familial situations, it is estimated that the spinal muscular atrophy carrier detection rate is about 90% and has the benefit to reduce the burden of giving birth to an affected baby [27]. Thus, The American College of Medical Genetics recommends population carrier screening for SMA to facilitate informed reproductive decisions [28] However, the American College of Obstetricians and Gynecologists (ACOG) Committee on Genetics does not yet recommend universal preconception and prenatal screening for SMA [29] defending the need for addi-tional large-scale studies before implementing general population screening. A recent study of pan-ethnic carrier screening of more than 68400 individuals without a family history of SMA resulted in a carrier frequency of 1/54 and a carrier detection rate of 91%, supporting the feasibility of wide-scale screening of carriers to prevent the disease [24].

Perspectives in therapyA significant body of research is focusing on new therapeutic possi-bilities in SMA and two main strategies emerge: SMN dependent and SMN independent approaches. The former attempts to address the genetic defect via SMN2 stimulation by drugs [30] or via SMN1 replacement by gene therapy [31]. The latter aims to provide motor neuron protection and improve skeletal muscle function. It is likely that one therapeutic solution alone will not be sufficient and combined therapeutic strategies may be considered. To test the effi-cacy of these new strategies earlier SMA detection will be essential.

ConclusionsAt present most fetal SMA cases pass unnoticed until after birth. Despite isolated reports on diminished fetal movements during the third trimester of pregnancy, fetuses predicted to develop severe forms of SMA move in an apparently normal way during the first and early second trimester of pregnancy. Furthermore, the association between SMA and thickened NT is very unusual. However, the present data suggest a relationship between some genetic forms of SMA and cardiac defects that may lead to

Table II. Genetic screening of frequent chromosomal and monogenic disorders. Further explanation in the text.

Disease InheritancePan-ethnic carrier frequency

Population risk in pregnancies Ultrasound markers Genetic studies References

Down´s Syndrome

NAa NAa 1/650b Increased nuchal trans-lucency and others

Cytogenetic/aneu-ploidy tests

[32]

Fragile-X X-linked 1/350 females and 1/1000 males carry premutationc

1/1000–1/2000 No Unstable CGG trinucleotide repeat FMR1 gene

http://www.acmg.net/resources/poli-cies/FragileX_GIM_2005.pdf

Cystic Fibrosis Autosomal recessive

1/25 (both sexes) 1/2500 Hyperechogenic bowel in some cases

CFTR mutation analysis

http://www.acog.org/~/media/Committee%20Opinions/Committee%20on%20Genetics/co486.pdf?dmc=1&ts=20120523T0656083299

Spinal Muscular Atrophy

Autosomal recessive

1/35–1/50 (both sexes)

1/6000–1/10000 Possible increase of nuchal translucency and presence of cardiac malformations in type 0 SMA.

SMN1 deletion tests

See references and details in the present review

aMost cases of Down’s Syndrome result from free trisomy of chromosome 21. bRisk is modified according to maternal age. cFMR1 alleles in the range of 61–200 repeats.NA, Not applicable.

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thickened NT. Further ultrasound research and raised awareness of the illness by obstetricians will promote earlier SMA detec-tion, thereby increasing our knowledge of the pathogenesis of the disease and allowing improved genetic counseling.

Declaration of Interest: This work was partially supported by GENAME Project, FIS 08-0729 and FIS 11–2606, Spain. We are indebted to Carolyn Newey for her contribution in the final edition and revision of this manuscript, María Amenedo for technical help and to Sara Bernal, Laura Alías, Rebeca Martínez-Hernández and Eva Also for their helpful comments and invalu-able collaboration in SMA research.

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