Major diagnostic categories

Approximately two-thirds of the patients fell into five major diagnostic groups: myotonic dystrophy type 1 (DM1), DMD/BMD, facioscapulohumeral muscular dystrophy (FSHD), SMA and LGMD. The largest group was the one with DM1. These patients comprised just over a quarter of the total sample (28.1%) with a prevalence of 10.4/100 000 (Table 2). Although all undiagnosed patients with proximal muscle weakness and muscle pain were screened for the CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene, myotonic dystrophy type 2 (DM2) was very uncommon in the northern region, with only five patients confirmed with this diagnosis. All DM1 and DM2 patients had a proven expansion mutation in the respective gene.

FSHD patients accounted for 10.7% (prevalence 3.95/10.0000) of the total patient population. Of the 118 cases, 116 were confirmed to the diagnostic standard (Tables 1 and ​and2)2) with the presence of a contraction of the polymorphic microsatellite repeat D4Z4 on chromosome 4qter.

DMD and BMD comprised ~10% each giving a combined prevalence for the dystrophinopathies of 8.46/100 000 total population (Table 2). For males only, the prevalences for DMD and BMD were 8.29 and 7.29, respectively. The dystrophinopathy category included those with intermediate muscular dystrophy (IMD, 0.47/100 000 males) and manifesting carriers of either DMD or BMD (0.43/100 000 total population). All cases were confirmed to the diagnostic standard of having a deletion, duplication or point mutation within the dystrophin gene.

The geographical distribution of patients with DM1, FSHD, DMD and BMD is shown in Fig. 2, with data points illustrated by postcode. As may be expected, the majority of patients are clustered around the major population centres. These cities have relatively easy access to services whereas much of the northern region consists of open countryside which patients with restricted mobility may find more challenging.

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Figure 2

Geographical distribution of cases within northern region of England.

Myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

The combined prevalence of SMA was 5.1%. Seventy per cent of the patients had a deletion of the SMN1 gene and were either classified as SMA I, II or III. The remainder of cases were assigned a diagnosis of SMA III on the basis of clinical and neurophysiological features and exclusion of other diagnoses (Table 2).

Comparison of major diagnostic groups with other population prevalence studies

The most common condition in our database was myotonic dystrophy type 1 (DM1) with a prevalence figure of 10.4/100 000. The combined child and adult population study from Northern Ireland (Hughes et al., 1996) produced a similar figure of 8.4/100 000. Darin’s study (Darin and Tulinius, 2000) found five per 100 000 cases in children; one would expect fewer in this younger population. Other estimates of the prevalence of DM1 vary widely according to geography, ranging from one per 100 000 in Japan (Davies et al., 1992) to 10/100 000 in Iceland (Leifsdottir et al., 2005). In some regions such as Quebec, the prevalence is much higher due to founder effects (Yotova et al., 2005). Precise data for the overall worldwide prevalence are not available but one estimate is 1:8 000 (Harper 1989). Our relatively high prevalence figure reflects systematic family tracing, extrapolating from the proband in an attempt to ascertain all family members potentially at risk of having inherited the condition. One aim was to find cases at risk of cardiac arrhythmia and to institute medical intervention when required. A second aim was to offer timely genetic counselling, particularly to mothers at risk of having a child with congenital myotonic dystrophy. The prevalence number of DM1 in our region might well be higher than 10.4/100 000 as not all asymptomatic at-risk family members have accepted the offer for genetic testing.

Prevalence of myotonic dystrophy type 2 also varies geographically. The condition is not described in comparable population study papers, but separate studies show a much higher prevalence in Southern Germany, again possibly due to a founder effect (Bachinski et al., 2003). The estimate discussed in the report of the 115th European Neuromuscular Centre workshop of 1/100 000 in Germany was considered to be the minimum prevalence figure (Udd et al., 2003).

FSHD prevalence was 3.95/100 000 in our study. Figures allowing direct comparison are listed in Emery’s review from 1991 and range from 0.22 to 6.69/100 000. The two most widely differing figures are from two individual states in the USA although this apparent divergence is based on only two cases in each study. The figure quoted from the Netherlands of 1.87/100 000 had been re-assessed and was estimated to be ~5/100 000 (Padberg et al., 1995) with an assumed complete ascertainment. A recent study from Italy, although of a smaller population, reported a prevalence of 4.4/100 000 (Mostacciuolo et al., 2009). Thus, our figure of 3.95/100 000, based on 118 cases, may well be a fairly accurate one.

Dystrophinopathies comprised 22.9% of our clinic population with a combined prevalence of 8.46/100 000. Of these, DMD prevalence was 8.29, IMD 0.47 and BMD 7.29/100 000 males. Hughes remarked that his ascertainment of DMD and other severe cases was probably complete and his figure of 8.2/100 000 (Hughes et al., 1996) males aligns very well with ours. For BMD, Hughes’ prevalence was 3.26/100 000 males, which is under half of our figure, presumably reflecting the difference in severity affecting complete ascertainment. Darin’s figures were 16.8 for DMD and 1.6 for BMD per 100 000 males under 16 years (Darin and Tulinius, 2000). The higher figure for DMD in the childhood population is perhaps a more accurate representation for this group in the past, although increasing life expectancy will have increased the point prevalence in our current clinic population. Eagle noted that the mean survival of DMD patients had improved in each successive decade since the 1960s, increasing from 14 years in the 1960s to 19 years for those in 1990 (not ventilated), presumably reflecting better overall care (Eagle et al., 2002), with the most striking change in mean survival to 25.3 years for those using nocturnal non-invasive ventilation.

The next major group was those with SMA. Hughes produced a figure of 1.4 (Hughes et al., 1996), Darin 2.8 (Darin and Tulinius, 2000) and our study 1.87/100 000. All three studies included patients under 16 years and so would be expected to capture all forms of SMA although the proportion of the total clinic population will be relatively higher in the childhood-only study. Approximately a third of our SMA III patients did not show a mutation in the SMN1 gene, which is in accordance with the literature (Wirth, 2000). It is also possible that genetic advances have re-assigned patients from this group to other categories, thus lowering the prevalence in our study compared with Darin’s (Darin and Tulinius, 2000).

Limb girdle muscular dystrophy patients from the northern region and comparison with other studies

Our study population of 1105 patients contains 68 classified as having a form of LGMD, representing a population prevalence of 2.27/100 000. Several recent papers have examined the relative frequencies of the LGMD subtypes in their patient populations whereas others have focused on a particular subtype.

Using a methodical approach of immunohistochemical analysis and then DNA sequencing successive genes, van der Kooi and colleagues updated a previous study of 105 LGMD patients from the Netherlands and were able to classify 51% of them into a definite subtype (van der Kooi et al., 2007). Calpainopathy was the most frequent diagnosis, similar to our study, affecting 21% of the families, with sarcoglycanopathy more common than LGMD2I. This is in marked contrast to the relatively low prevalence of LGMD2A in Denmark (Duno et al., 2008), which the authors estimate to be 5- to 6-fold lower in ethnic Danes compared with other European countries. Conversely LGMD2I appears to be relatively more common in Northern Europe compared with North America. A study from Denmark showed a high proportion of LGMD2I (38% of LGMD2-classified patients) (Sveen et al., 2006). Although there were phenotypic differences between the patients homozygous or heterozygous for the 826C>A mutation, testing for this mutation in this population detected all the cases. Our population had a prevalence of LGMD2I closest to the Danish study, perhaps reflecting previous migration from Denmark to the Northern region of England.

A study from Italy examined 181 LGMD patients (155 families) and was able to confirm a diagnosis in 72.9% (Guglieri et al., 2008). They found the most common groups to be calpainopathy with 28.4%, which has also been shown in other Southern European epidemiological studies (Angelini, 2004; Fanin et al., 2005; Saenz et al., 2005; Balci et al., 2006). The authors emphasize the importance of confirming the suspected diagnosis through molecular genetic testing, especially given the fairly poor predictive value of calpain-3 protein analysis, for example, with CAPN3 gene mutations detected in only 61% of those in whom a reduction in the level of calpain-3 was found on western blot. The next most common LGMD group in this study (Guglieri et al., 2008) was dysferlinopathy at 18.7% and the combined sarcogly-canopathies at 18.1% (all percentages are of families). The percentage of combined sarcoglycanopathy (LGMD2C-E) patients in our study was 11.7% (0.27/100 000), slightly lower than in the Italian studies. A Dutch study detected a sarcoglycanopathy in 23% of their LGMD2 patients, in whom α- and β-sarcoglycan deficiency was equally common (Ginjaar et al., 2000). In our patients, γ-sarcoglycan mutations were twice as frequent as the other subtypes.

The frequency of dysferlinopathy varied among the study populations. In our study, these patients were relatively few (5.9% or 0.13/100 000) compared with other areas, including 18.7% in the Italian population (Guglieri et al., 2008), but in keeping with the low frequency in the Dutch LGMD population where only one patient was identified (van der Kooi et al., 2007). In contrast, there seem to be founder effects in certain regions such as Israel, markedly raising the local prevalence (Leshinsky-Silver et al., 2007). With 18% LGMD2B was also the most common diagnosis in a study that examined paediatric and adult LGMD subtypes from six centres in the USA (Moore et al., 2006). The second most common LGMD forms were sarcoglycanopathy and dystroglycanopathy (LGMD2I), both at 15%, with calpainopathy fourth most frequent at 12%. The authors comment that their study population was ethnically diverse but are unable to provide prevalence data as their patients were from a referral rather than population base.

Thus, these studies concur on certain points. First, the studies emphasize the comprehensive diagnostic effort required to classify LGMD patients, noting that careful attention to the combination of clinical, immunohistochemical and molecular genetic data is required and that reliance on just one aspect may be misleading. Nevertheless, all studies had a significant proportion of patients classified as LGMD but without a definite diagnosis, mostly in a similar range to our figure of 27.9% (van der Kooi et al., 2007, 41.3%; Guglieri et al., 2008, 29%). Second, all re-affirm that autosomal recessive LGMD is much more common than autosomal dominant LGMD. In our study, the proportion of patients affected with dominant subtypes was 8.8% and 13.5% in the Dutch study, all of whom were affected by laminopathy. There was a striking lack of LMNA mutations detected in the Italian study with all of their 10 patients with dominant inheritance affected by mutations in caveolin-3 (in contrast to our study where we found none). Moore et al. (2006) found <1% with LGMD1A and 4% with LGMD1B but none with LGMD1C. Finally, the studies show the relative frequencies of confirmed LGMD subtypes in different populations. Calpainopathy is the most frequent diagnosis in those European populations studied but only fourth most frequent in the referral pool in the USA, which might be explained by a less comprehensive immunoanalysis of muscle biopsies and/or genetic testing. Dysferlinopathy seems less frequent in the North of UK and caveolinopathy is very rare in our catchment area.

Comparison of minor diagnostic groups with other population prevalence studies

Even when taken as a group of conditions, epidemiological data for many of the rarer inherited muscle diseases from other studies are limited. Emery (1991) does not mention the congenital myopathies at all. Hughes et al. (1996) estimated their prevalence to be 3.5/100 000 and Darin and Tulinius (2000) 5.0/100 000. Central core myopathy prevalence is unknown but it is probably more common than other congenital myopathies (Jungbluth, 2007).

Here, for the first time, we are able to present data on the prevalence of three myopathies. The most common group in our study was Bethlem myopathy with a prevalence of 0.77/100 000, the second most common central core disease with a prevalence of 0.40/100 000 and lastly nemaline myopathy at 0.20/100 000. The combined prevalence of 1.37/100 000 is still rather lower than the figures from Hughes et al. (1996) and Darin and Tulinius (2000), but all of our cases have been rigorously assessed according to clear diagnostic criteria. We found no patients with other forms of congenital myopathy such as centronuclear myopathy.

Congenital muscular dystrophies

The CMD are a complex group of conditions whose classification is made through the combination of clinical and laboratory studies (Lisi and Cohn, 2007; Muntoni et al., 2008). A recent study examines the frequency of CMD subtypes in a cohort of 101 patients from Australia (Peat et al., 2008). The authors were able to reach a definitive diagnosis in 24% of their patients and to assign a diagnosis on the basis of immunofluorescence changes in 45%. The most common group were those with defects in glycosylated α-dystroglycan (25%), the second most common were those with collagen VI abnormalities (12%) and 8% with a primary laminin α2 (merosin) abnormality (Peat et al., 2008). The study was not population-based and no prevalence figures were given. The most common category in our study was MDC1A (merosin deficiency) at a prevalence of 0.60/100 000. All patients had a confirmed mutation in the LAMA2 gene. A study from Japan found that primary collagen VI deficiency accounted for the second most common CMD, with Fukuyama CMD being the most frequent (Okada et al., 2007). Although 34 patients were found to have a collagen VI deficiency, only 26 of these had a mutation in one of the collagen VI genes. The percentage of their total CMD cases with collagen VI deficiency was 7.2%. In our study, UCMD and rigid spine muscular dystrophy were equally as common as each other with a prevalence of 0.13/100 000. We had only one patient with a defect in α-dystroglycan. Our combined CMD prevalence figure including UCMD was 0.89/100 000. Figures from previous studies were 2.5 (Darin and Tulinius, 2000) and 0.6/100 000 (Hughes et al., 1996).

X-linked Emery–Derifuss muscular dystrophy (EDMD-X) was very uncommon in our study with a prevalence of 0.13/100 000. Prevalence data for this disease are difficult to find but overall it is far less common than autosomal dominant EDMD.

There have been many advances in myofibrillar and distal myopathies in recent years but prevalence data for this set of diseases are sparse (Udd, 2007, 2009; Goebel et al., 2008; Selcen, 2008). Prevalence of some disorders such as tibial muscular dystrophy vary geographically with a particularly high prevalence of this disorder in Finland (8/100 000) but less certain frequencies elsewhere. Only 0.9% of our patients were found to have a distal myopathy.

The authors thank the National Commissioning Group (NCG) for supporting the diagnostic work in the LGMD population. We are grateful to Prof. Carol Bower, Telethon Institute for Child Health Research, University of Western Australia and Prof. Heather Cordell, Institute of Human Genetics at Newcastle University (UK) for helpful comments and discussion. We are thankful to Jane Barnes, Jessica Hoogendijk and Geoff Bell for their support with the databases. P.F.C is a Wellcome Trust Senior Fellow in Clinical Science.

Funding: This work was supported by the Medical Research Council (UK) as part of the MRC Centre for Neuromuscular Diseases and the Muscular Dystrophy Campaign (UK). V.S. is a member of the German Muscular Dystrophy Network (MD-NET 01GM0601) funded by the German Ministry of Education and Research (BMBF, Bonn, Germany); www.md-net.org. MD-NET is a partner of TREAT-NMD (EC, 6th FP, proposal #036825; www.treat-nmd.eu).