Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review

Prevalence

When examining all types of SMA together, in most cases a prevalence of around 1–2 per 100,000 persons is observed. In some studies a somewhat higher prevalence was observed. A study from Bologna, Italy, in 1992 calculated a prevalence of 6.56 per 100,000 persons aged less than 20 years [22]. Three studies in Scandinavia showed a prevalence of 4.18 per 100,000 persons aged 18 years or less, and 3.23 and 2.78 per 100,000 persons aged below 16 years [23–25]. This could indicate regional differences in the incidence of SMA, i.e. gene pools. However, there are several other factors that may account for this observation. First of all, all studies were performed in small regions and thereby small populations were studied. For rare diseases like SMA, a small error in the detection of the number of cases can have a large impact on the estimated prevalence (sample bias). Secondly, these studies only took children into account, which is likely to influence the numbers in an upward direction. Furthermore, in the case of Sweden higher prevalence rates have also been observed in studies into other neuromuscular disorders, which could be due to a greater awareness and a good health system in Sweden, making it easier to identify patients for such a study [26–28]. A study in Northeast Saudi Arabia also found a very high prevalence rate. Although the prevalence of SMA might be different in the Middle East when compared to Europe, in more than half of the cases parental consanguinity was observed, which could at least partially explain the high prevalence [29].

Prevalence by SMA subtype

Although SMA type I is expected to account for more than half of all new SMA cases [30], the studies that examined a SMA type I only showed a prevalence of 0.04 to 0.28 per 100,000 [24, 25, 31–34], which is much lower than the 1–2 per 100,000 persons noted for all SMA. Due to its severity, patients with SMA type I have a short life expectancy. Therefore often no or only few patients are alive on the date of the study, which could account for this lower prevalence. Nowadays, a median life expectancy of around one year of age is estimated for type I patients [35–37], whereas in type II 75–93% of patients survive beyond 20 years of age [37–40] and life expectancy for type III is thought to be close to the normal population [20, 39].

The prevalence of both SMA type II and III together has been estimated around 1.5 per 100,000 [31, 32, 41–43]. Of three studies that investigated type II and type III separately, two found a higher prevalence of type III compared to type II [24, 32]. This may be explained by the longer life expectancy of type III patients compared to type II SMA patients.

Incidence

When evaluating the incidence of all types of SMA combined, on average an incidence of around 8 per 100,000 live births is found (~1 in 12,000). Some studies show a somewhat lower or higher incidence. In a study in Iceland an incidence of 13.7 per 100,000 live births was found. This is a study on an island with a relatively small population, where it might be easier to identify all patients. A study in Slovakia found a high incidence of 17.8 per 100,000, but details of the number of patients or population size were unavailable, making it difficult to interpret these findings [44]. In a recent study in Cuba a lower incidence of 5.0 per 100,000 was seen [45]. Patients were detected via an obligatory governmental registry and approximately 70% of the patients were genetically confirmed. This study also examined the ethnicity of the SMA type I patients. The majority of these patients were White (30/36), 5/36 were of mixed race and 1/36 patient was Black. Although this could be partially explained by the racial composition of the Cuban population, still relatively more White people were affected. There are several reasons that could account for this. First, there is a difference in incidence between various ethnicities. There are also reports of lower SMA carrier frequencies among Hispanics [46, 47]. However, it could also be the case that there are differences in the access to health care between different ethnicities. In a small study among 75,000 persons in Libya, a high incidence (24 per 100,000 live births) was found, and this may partially be explained by a high degree of consanguinity [48].

Incidence by subtype

In 1991, Alan Emery published a review estimating the incidence for SMA type I to be around 4–6 in 100,000 (1 in 12,500–1 in 16,667) live births [49], which was based on only three studies [50–52]. We identified 17 studies, which taken together indicated an SMA I incidence of approximately 6 per 100,000. In the USA (North Dakota) in a study that pre-dated genetic testing, high incidence was observed (14.9 per 100,000); however this study was performed in a very small population, and any error in the accuracy of case identification may be associated with the high incidence. All patients studied were Caucasian and no consanguinity was observed [53]. In a regional study in Germany, a higher incidence of 9.8 per 100,000 was found [33]. In Libya, a high incidence, as found for total SMA, was not observed among type I patients (8.0 per 100,000) [48]. This is again based on a small population and could be due to a lack of awareness of SMA at the time the study was conducted. Furthermore, SMA type I patients might have been missed due to their short life span. In two small communities a very high incidence was observed. On Reunion Island in a European community a founder effect (loss of genetic variation that occurs when a new population is established by a very small number of individuals, which could lead to a high incidence if in one of these founders a mutation was present) was clearly seen, leading to an incidence of 79 per 100,000. In an Egyptian Karaite community in Israel, where in more than half of the affected families consanguinity was observed, an incidence of as high as 250 per 100,000 live births was found.

For type II and III, a high incidence of both types combined was observed (10.6 per 100,000) in a German study in the same region as the previously mentioned type I study that partially covered the same time period [33, 43]. The healthcare system in Germany may partly explain these observations. Furthermore, there might be regional differences in SMA incidence. The authors suggest that SMA might be more prevalent in central and Eastern Europe than in Western Europe. For type II and type III SMA the highest occurrence was observed in Libya (16 per 100,000) [48].

A study not added in Table 3 is a study from Kurland et al. in Rochester, USA, studying the period 1945–1954. This study found only one SMA type I patient and the calculations used the total population size instead of the number of live births to calculate the incidence. Furthermore, this total population consisted of only 30,000 persons [54].

The epidemiologic burden of SMA is not equally divided over the subtypes. In 2004 Ogino et al. reviewed several studies and calculated incidence rates of 5.83 per 100,000 live births for SMA type I, 2.66 per 100,000 live births for type II and 1.20 per 100,000 live births for type III. This implied that SMA type I, II and III constituted 60%, 27% and 12% of all SMA cases, respectively [30]. This overview included the study of Radhakrishan et al. in Libya, in which for half of the families parental consanguinity was observed [48]. In our analysis, we calculated the percentages in two ways yielding nearly identical results. First by only taking studies into account in which all types of SMA were studied separately, as this makes a direct comparison possible; and, secondly by taking all studies presented into account. In both cases this resulted in incidence rates of around 5.5, 1.9 and 1.7 per 100,000 for type I, II and III, respectively. This yields a percentage of around 60% for the incidence of SMA type I; with the remaining 40% of the cases equally divided between type II and type III. This indicates that SMA I indeed makes up the largest proportion of the total SMA.

Considerations for comparing studies

To date, there are few studies of the prevalence and/or incidence of SMA, with a small number of these being recent. Most of the studies have been carried out in Europe. Furthermore, four of the ten studies done outside of Europe were performed in the countries with high consanguinity or small communities, thereby they are not considered to be representative of the overall SMA prevalence and incidence. No worldwide studies have been published to date.

A number of limitations should be taken into account when estimating prevalence/ incidence of SMA and comparing the presented studies. Most studies have been performed before 1995 when the genetic cause for SMA, deletion of the SMN1 gene, was identified [3], where after genetic diagnosis was implemented. Therefore, most studies rely on the less accurate clinical diagnosis of SMA. This increases the chance of misdiagnosis of diseases with clinical features similar to SMA. Another difficulty comparing studies is that the classification of SMA has slightly changed over the years and it is not always clear which classification system has been used. For example, in the studies of John Pearn in Northeast England patients were defined as SMA type I if they had an onset of symptoms before the age of 12 months, so this might also include some early diagnosed SMA type II patients [41, 52]. Chronic SMA was classified as patients living beyond 18 months old. However, in the study in West-Thüringen, Germany patients had to survive till at least four years of age to be classified as chronic SMA [43]. This is further exemplified by the study of Spiegler et al. in Warsaw, Poland. In this study type Ib patients are mentioned, and are defined as patients diagnosed at birth or in the first months of life and living up to 30 years, whereas type II SMA was described as having an onset at the age of one year onwards [42]. In the study of Zellweger et al. in Switzerland it is not clearly specified which definitions were used, but it is conceivable that some type II patients are included in the numbers of type I patients [55]. Currently, the classification of the main subtypes: I, II and III (and sometimes IV) as described in Table 1 is used.

Another factor that should be taken into account is that the studies have been performed in different time periods. The natural history of SMA has changed over the years as the standards of care and associated outcomes have largely improved in the recent years. For example for type I comparison of studies showed the mean age of death increased from 8.8–10 months in studies performed before 1995 to 10.4 months up to 4 years in studies performed after 2000 [35, 36]. This is partly due to the availability of assisted ventilation (non-invasive or through tracheostomy) and of tube feeding through a gastrostomy [36].

Lastly, most of the studies have been performed in small geographical areas, thereby including a relatively small study population. One or two patients more or less in a small patient population will have a strong effect on the calculated prevalence or incidence. All these factors make a comparison between the studies and the interpretation of the findings difficult.

In conclusion, few prevalence and incidence studies have been performed for SMA, of which most are based on clinical diagnosis and are performed in European countries or regions, using small study populations. In addition to prevalence and incidence studies, carrier frequencies can provided useful additional information about, for example, ethnic subpopulations.

Subpopulation differences

Some of the studies have examined differences between ethnic groups within their study population [46, 62–65, 77, 80]. The main finding was that copy numbers were significantly higher in Black (Sub-Saharan African ancestry) people. This was seen in African Americans [46, 62, 77], as well as in Black Africans [66] and would indicate a higher proportion of 2-copy (duplication) alleles, thereby suggesting a higher number of ‘2 + 0’ carriers. This could account for a lower detection rate (around 70% for Black people versus 90–95% for other ethnicities), leading to a high number of false negatives. The study in Africa found a significantly lower carrier frequency compared to Eurasians [66]. Lower carrier frequencies were also seen in a study comparing Black and White people in South Africa and a study among samples of the 1000 genome project [65, 80]. However, these studies could not detect the ‘2 + 0’ carriers, which could reduce the observed differences. Some studies also found lower carrier frequencies in Hispanics [46, 77], but this was not seen in other studies [62, 69, 80]. Lastly, Luo et al. identified a specific haplotype, present in Ashkenazi Jews and Asians detectable by microsatellite analysis, that could distinguish duplication alleles (present in ‘2 + 0’ carriers) from normal ‘1 + 1’ genotypes [77].

We carried out an analysis of differences between ethnic groups and studies. Fig. 2 shows a comparison of all studies described in Additional file 2 (ethnicities are indicated). The grey area indicates the 95% confidence interval based on the average carrier frequency of all studies combined (0.019).¹ Most studies fall within this area, indicating no large differences in carrier frequency. Two populations (a Muslim Arab village in Israel and a specific group of Hutterites in South Dakota, USA) showed a particularly high carrier frequency. However, these are isolated populations with a high degree of inbreeding [81, 89]. Also in an Iranian population a higher carrier frequency was seen (1 in 20). However this is based on one study with a small sample size, furthermore, in Iran, consanguineous marriages are common [91]. Combined estimates of carrier frequencies for ethnic groups were calculated (large symbols in Fig. 2 and Table 4).

Population	Number of identified carriers	Number of study participants	Carrier frequency	95% CI
Araba	152	9058	0.017	0.014–0.019
Asian	2492	119,718	0.021	0.020–0.022
Asian Indian	20	1465	0.014	0.008–0.020
Black (Sub-Saharan ancestry)	80	8012	0.010	0.008–0.012
Caucasian	680	31,549	0.022	0.020–0.023
Hispanic	127	9649	0.013	0.011–0.015
Jewish	1059	59,196	0.018	0.017–0.019

Median and 95% posterior intervals of SMA carrier frequencies, based on studies presented in Additional file 2. Only ethnicities studied in more than one study are included

CI confidence interval

^a) The isolated Muslim Israeli Arab village [59] has been omitted

The results show that the highest frequencies are found in Caucasian and Asian populations (around 1 in 50) and the lowest in Black (1 in 100) and Hispanics (1 in 76) populations. However, it is important to note that genetically Hispanics are a very mixed group, making generalizations difficult. This is also demonstrated by the fact that some studies among Hispanics found much higher frequencies [69, 80], while others found that the frequencies were lower [46].

SMN1 copy number differences between populations

In 2014, MacDonald et al. have performed a meta-analysis comparing the SMA carrier frequency among different ethnicities. In their analysis they included 14 studies where ethnicities were described and results were broken down by SMA copy number [47]. They took the different carrier genotypes described above into account and determined the carrier rates in the ethnic groups. Furthermore, they calculated the reduced risk of being a carrier if a 2- or 3-copy result was found. This again showed a substantially higher carrier risk with a 2-copy test result for Black people. In addition a very high carrier risk and 2-copy risk in Iranians was found. However, this is based on one study only [91].

The incorporation of estimated carrier risks for people with a 2 copy number result, generates only a slightly lower incidence (~1 in 54) for the Black populations compared to most other populations (~1 in 45), due to presence of a much higher number of multiple SMN1 copy number alleles in this population. The estimation of the combined carrier frequency in Hispanics is lower than in other populations (1 in 65), as was also seen in the previous estimations. It must be noted however that here only a subset of studies is used compared to the comparison of all studies (Fig. 2 and Table 4), which can also contribute to differences in estimations.

The combined results lead to the highest incidence estimations of around 1 in 8000 in Asians and Caucasians, whilst lower incidence of around 1 in 20,000 are estimated in the Black and Hispanic populations.

In Caucasians, the incidence rate estimated from carrier frequencies is higher than the observed incidence rates in studies (Table 3, ~1 in 11,000). Carrier frequency estimates are solely based on genetic studies, whilst most incidence studies were based on clinical diagnosis and are mostly much older. However, carrier frequency incidence estimates could be an overestimation of the true incidence due to reduced penetrance. Here a penetrance of 100% is assumed. If the penetrance is decreased by 10% (i.e. penetrance of 90%) the incidence would also decrease by 10%. It might be that some cases of SMA are so severe that they lead to premature death in utero. SMN2 is absent in 10–15% of the general population [101], and deletions of both SMN1 and SMN2 are embryonically lethal. Furthermore increased awareness could lead to more genetic counselling of couples at risk, certainly in couples who have previous children or family members with SMA. In addition, sporadic cases of unaffected individuals without functional SMN1 cases have been described [96, 102–109]. This might be due to high copy numbers of SMN2, since, as mentioned before, SMN2 copy number influences the severity of the disease [7–9]. Therefore, it is important to take SMN2 copy number into account when performing newborn screening.