Single-Gene Neurological Disorders in South Wales: An Epidemiologcal Study J. C. MacMillan, MRCP(UK), and P. S. Harper, M D

Single-gene neurological disorders account for a significant proportion of the work load of any regional genetics unit. In an attempt to assess the likely impact of recombinant DNA technology on these debilitating diseases, a population

prevalence study of the major neurogenetic diseases was carried out in the South Wales region of Great Britain. The minimum overall prevalence of these disorders was estimated to be 58.6/100,000 population. MacMillan JC, Harper PS. Single-geneneurological disorders in South Wales: an epidemiological study. Ann Neurol 1991;30:411-414

Inherited neurological disorders have been the focus of extensive investigation in recent years through the use of recombinant DNA technology. The technique of positional cloning (“reverse genetics”) has provided a means of elucidating the fundamental molecular pathobiology of several debilitating familial neurological diseases [I, 2) and engendered the hope that some of these disorders may eventually be “treatable.” In those disorders where the gene product and its function are not yet known, accurate chromosomal localization of the relevant gene (or genes) increases the reproductive options for couples at risk by permitting prenatal diagnosis through linkage analysis and termination of affected fetuses. In any attempt to assess the likely impact of D N A diagnostic services in this field, it is essential to know the frequency of these diseases in the population. This article reports the results of a population study of the major single-gene neurological disorders in the South Wales area of Great Britain. Materials and Methods A retrospective search of hospital inpatient records, genetic outpatient records, and all electromyography(EMG) records for the health districts of Mid and South Glamorgan for the years 1968 to 1990 was carried out for the conditions listed in Table 1. The records were assessed for criteria for diagnosis, family history, and area of residence. Those persons who had confirmed diagnoses (meeting accepted criteria for affected status) of one of the disorders listed in Table 1 and were alive and lived in the study area on prevalence day (June 1, 1988) were included in the study. A family study was instigated by contacting the index patient after obtaining permission from his or her general practitioner. Additional family members living in the study area were then assessed for evidence of

From the Institute of Medical Genetics for Wales, University of Wales College of Medicine, Heath Park, Cardiff, Unired Kingdom. Received Dec 18, 1990, and in revised form Feb 28, 1991. Accepted for publication Mar 19, 1991.

the disorder, if they agreed to participate. If the index patient had left the study area prior to interview or had died, family members living in the study area were contacted and assessed

when possible. If the index patient refused to participate, only that person was included in the prevalence data: The exrended family was not contacted directly. The data were collected on an IBM-compatible microcomputer using the MEGABASE data management system [4}.The midyear estimates of population for the areas of Mid and South Glarnorgan are shown in Table 2.

Results Table 3 shows the prevalence of these disorders expressed per 100,000 population of Mid and South Glamorgan on June 1, 1988. The 95% confidence intervals for the estimates were obtained using standard tables of the Poisson distribution [GI. The group of disorders known as the spinal muscular atrophies (SMA) is phenotypically heterogeneous, ranging from early-onset, rapidly fatal type I SMA (Werdnig-Hoffmann disease) to late-onset, chronic forms such as Kennedy disease. The prevalence figure for SMA given in Table 3 contains a solitary case of type I1 childhood SMA, with the rest comprising autosomal dominant distal SMA and Kennedy disease. No patient with acute, type I infantile SMA was known to be alive on prevalence day. The average annual incidence between 1973 and 1989 of type I SMA was 4.41 100,000 live births (95% confidence interval, 2.0 to 8.3) and the average incidence of Duchenne muscular dystrophy (DMD) over the same period was 34.71 100,000 live male births (95% confidence interval, 24.5 to 47.9). These average annual incidence rates are equivalent to figures of 1/23,009 total live births for acute SMA

Address correspondence to Dr MacMillan, Institute of Medical Genetics for Wales, University of Wales College of Medicine, Heath Park, cF4 4xw United Kingdom.

Copyright 0 1991 by the American Neurological Association 41 1

Table 3. Prevalence of Major Single-Gene Neurological Disorders in South Wales

Table 1. Major Single-Gene Neurological Disorders in South WaleJ

Hereditary motor and sensory neuropathv Myotonic dystrophy Duchenne muscular dystrophy Becker muscular dystrophy Facioscapulohumeral muscular dystrophy Spinal muscular atrophy Huntington's disease Tuberous sclerosis von Hippel-Lindau disease Hereditary spastic paraplegia Neurofibromatosis type 1 ~~

~

"Includes types I, 11, and V as defined by Dyck [ 3 ] .

Table 2. Midyear Estimates of Population (in Thousands) for Mid and South Glrmorgan, Wales,June 1988"

Prevalence 95% Confidence (per 100,000) Interval 12.9 Hereditary motor and sensory neuropathy Myotonic dystrophy 7.1 Duchenne muscular 9.6" dystrophy Becker muscular dys5.0" trophy Facioscapulohumeral 2.9 muscular dystrophy Spinal muscular atrophy 1.3b Huntington's disease 8.4' Tuberous sclerosis 1.6 von Hippel-Lindau 0.6

3.2-7.6

1.9-4.1 0.7-2.2 6.6- 10.5 0.9-2.6 0.2-1.4

3.4

2.3-4.8

13.3

11.1- 15.8

plegia

101.1 107.1 248.7 456.9

Females

Age < 16 yr 2 16 yr Total Total population

5.5-9.1 7 .O- 12.9

disease

Hereditary spastic para-

Males

Age < 16 yr 16-30 y r > 30 yr Total

10.7-15.4

961 386.3 482.4 937.3

*Data from [51.

and 1/2,880 live male births for DMD. This latter figure is likely to be an underestimate, as ascertainment of patients born since 1985 (those under 5 years old) will be incomplete r7). While it is useful to be able to compare the crude population frequencies for a variety of conditions, it is equally important that age-specific and sex-specific rates be considered in appropriate situations. Table 4 compares the prevalence of DMD, with the denominator delimited by age and sex.

Discussion The minimum overall disease prevalence of the major single-gene neurological disorders in South Wales is approximately 58.6/ 100,000 population. This is a signlficant burden of disability in the population and affects predominantly a younger age group than do most chronic debilitating neurological diseases. A comparison can be drawn with the prevalence of multiple sclerosis, which affects 117.0/100,000in the same population IS}. The figures shown in Table 3 are;however, likely to be underestimates of the true prevalence of these disorders in the population. The very nature of the disorders under study will have contributed to the underascertainment, as early symptoms may not have

Neurofibromatosis

"Per 100,000 males. bSee rexr. 'Data provided by A. Tyler (personal comrnunicarion, 1991).

Table 4. Duchenne iMuscular Dystrophy: Prevalence per 100,000 land 95 % Confidence Interval)

Total population Male population Males < 30 yr

4.7

9.6 21.1

(3.4-6.3) (7.0-12.9) (15.3-28.4)

been recognized by individuals who did not therefore seek medical attention, and misdiagnosis of subtle disease manifestations by primary care physicians may not have resulted in hospital referral. The scrutiny of only genetic and EMG outpatient records may also have resulted in underascertainment of minimally affected individuals, especially for conditions such as the hereditary motor and sensory neuropathies and type 1 neurofibromatosis, as these individuals would have been unlikely to have had inpatient care. Loss of index patients to private health practitioners is unlikely to be a major problem, as the area is served by the same three neurologists in both the private and public health service; in addition, there are no private EMG services in the region. It is difficult to calculate the number of patients lost in this study through failure of primary ascertainment, but this can be estimated using the ascertainment probability (n),which is the conditional probability that an affected member of the population be detected as a ptoband 191. It is calculated from the total number of affected individuals ascertained and the number who are detected as probands; for the hereditary motor and sensory neuropathies, the ascertainment probability

412 Annals of Neurology Vol 30 No 3 September 1991

( 7 ~ )is 0.77. No data are available as to whether those ascertained as probands differed in disease severity from those ascertained through the family studies (23% in the case of hereditary motor and sensory neuropathy). It might be expected that for severe, earlyonset diseases such as tuberous sclerosis, ascertainment of probands through the methods used in this study is likely to be more complete than, for example, in the hereditary neuropathies. A further source of “lost cases” is when the index patient refused to participate in the study. This was not a problem when probands other than the propositus agreed to be assessed, but a small number of families were only ascertained through one individual. This was most evident in the hereditary motor and sensory neuropathies, for which 10.2% of probands declined to participate. There is, however, no accurate way of estimating the numbers of additional affected family members not ascertained because of this. Again, one could speculate that this is more likely to occur in those disorders for which the perceived disability is minor or manifests at a later age. The annual incidence rates for most of these disorders (with the exception of type I SMA and DMD) have not been calculated: The date of inclusion in the incidence data for inherited disorders should be the date of appearance of the affected genotype in the population (i.e., birth). Traditional epidemiological inclusion points such as date of onset of first symptoms or date of diagnosis are of less value when considering many genetic conditions. The early onset of symptoms and signs in type I SMA and DMD facilitates the calculation of incidence figures: This situation does not exist for such conditions as the hereditary motor and sensory neuropathies or Huntington’s disease. In these

disorders, recollection of possible early symptoms by the patient or their family is notoriously unreliable, as often is the date of an accurate diagnosis by a clinician. In a short-term study such as this, retrospective reconstruction of the series data would be required to calculate incidence figures: This would introduce inaccuracies arising from migration, in addition to the factors alluded to above. Comparison of the data in this study with those of previous surveys should take into account whether the reported data refer to a single disorder studied in a particular area [lo} or to a general epidemiological survey of all neurological conditions in a population 111). A single-disorder study would be expected to generate a higher prevalence figure than a general study, as ascertainment of minimally affected or asymptomatic individuals will be more likely. In addition, some studies in smaller regions used more extensive ascertainment methods. In the study of neurological diseases in Carlisle, United Kingdom, Brewis and colleagues [ll) collected data from hospital records, general practitioner sources, private practice records, death certificates, and household interviews. They found that general practice records were of limited value, as only 10% of the total cases were found exclusively in this source, and that the household survey provided poor diagnostic information. In a study of multiple sclerosis in South Wales, only 0.9% of patients were identified solely from general practice records [S}. It has also been pointed out { 12) that finding cases through individual examinations of the population is impractical for diseases of low frequency, a consideration of importance for single-gene neurological disorders. Table 5 summarizes some previously published neuroepidemiological statistics. Various explanations can be offered to account for

Tabk 5 . Previous Epidnniologiral Data on Single-Gene Neurological Diseases

Disease Hereditary motor and sensory neuropathy

Prevalence (per 100,000)

Incidence (per 100,000)

4.7

-

5.0

0.2

5.5

13.5 16.8”

Reference 10 13

Muscular dystrophies

M yotonic Duchenne Becker Facioscapulohumeral Spinal muscular atrophy Type 1 Type I1 Huntington’s disease Tuberous sclerosis Hereditary spastic paraplegia Neurofibromatosis

2.8” 2.0 6.7

-

0.7

3.3

0.3

1.2 4.2 5.0 3.3 3.0

0.4

20.0

-

-

0.1

-

14 15 16 12 12 17 11 18 19 18 20

aPer 100,000 male population.

MacMillan and Harper: Neurogenetic Epidemiology 41 3

the differences between the present study and previous reports; some of these have been discussed with respect to ascertainment methods but this is unlikely to account for all the differences. Higher values in this study may be due to better ascertainment or to truly higher drsease frequencies. In genetic disorders, this may be due to a founder effect, although none of the discrepancies are large enough to make this a likely explanation. Variation in gene frequency between populations may account for lower figures in this study for severe, early-onset disorders such as tuberous sclerosis, but for facioscapulohumeral muscular dystrophy and type I SMA it is likely that the figures of Kurland [12) are falsely elevated as the Rochester population was only 30,000 and calculated rates would therefore be subject to appreciable chance fluctuation. The advantage of the present study is that it provides epidemiological data for the major single-gene neurological disorders in a single relatively large population. This makes it easier to compare the data for the different conditions and should enable a more rational strategy to be established for resource allocation and the management of these conditions. The ascertainment methods attempted to maximize diagnostic accuracy by using inpatient and only genetic and EMG outpatient records, but this is likely to have resulted in underascertainment of minimally affected individuals in those disorders with a wide spectrum of disease severity. No attempt has been made to calculate the heterozygotel gene frequencies for these disorders. The aim of the study was not to identify presymptomatic gene carriers, although this is feasible for several of these conditions. The emphasis was placed on identifying those individuals in the population with clinical manifestations and who are most likely to request the services of a regional molecular genetics unit.

This work was supported by a grant from the Welsh Office and Department of Health. We should like to thank the many clinicians at the Institute of Medical Genetics for Wales, both past and present, whose family studies of specific neurogenetic diseases provided much of the data for this study; Dr Peter Elwood of the Medical Research Council epidemiology unit, Cardiff, for useful advice on the methodology of this study; and the families in South Wales who cooperated in the study.

References 1. Hoffman EP, Brown RH, Kunkel LM.Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 1987;5 1:911-928 2. Wallace MR, Marchuk DA, Anderson LB, et al. Type 1 ncurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 1990;249:181-186 3. Dyck PJ. Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In: Dyck PJ, Thomas PK, Lambert EH, Bunge RP, eds. Peripheral neuropathy. 2nd ed. Philadelphia: WB Saundrrs, 1984:1557-1594 4. Penton I, Sandkuijl LA, Aldred MJ. A clinical and DNA database capable of drawing pedigrees and communicating with the LINKAGE analysis package. Am J Hum Genet 1990;47 (suppl):A56 5. LXgest of Welsh Statistics. Welsh Office, Government Statistical Service, 1989;35:1-4 6. Lentner C. Geigy scientific tables, vol 2. Basel, Switzerland: Ciba-Geigy, 1982:152 7. Emery AE. Duchenne muscular dystrophy. 2nd ed. Oxford monographs on medical genetics 15. Oxford: Oxford Medical, 1987:25-42 8. Swingler RJ, Compston DAS. The prevalence of multiple sclerosis in South East Wales. J Neurol Neurosurg Psychiatry 1988;51:1520-1524 9. Morton NE. Outline of genetic epidemiology. Basel, Switzerland: Karger, 198247-68 10. Davis CJF, Bradley WG, Madrid R. The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. I. Clinical, genetic and electrophysiological findings and classification. J Genet Hum 1978;26:311-349 11. Brewis M, Poskanzer DC, Rolland C , Miller H. Neurological disease in an English city. Acta Neurol Scand Suppl 1966;24:42 12. Kurland LT. Descriptive epidemiology of selected neurologic and myopathic disorders with particular reference to a survey in Rochester, Minnesota J Chronic Dis 1958;8:378-418 13. Kurtzke JF. Neuroepidemiology. Ann Neurol 1984;16:265277 14. Harper PS. Myotonic dystrophy. 2nd ed. London: WB Saunders, 1989:316-320 15. Gardner-Medwin D. Muration rate in Duchenne type of muscular dystrophy. J Med Genet 1970;7:334-337 16. Emery AEH. The muscular dystrophies. In: Emery AEH, Rimion DL, eds. Principles and practice of medical genetics. 2nd ed. Edinburgh: Churchill-Livingstone, l970:539-563 I;. Tandan R, Bradley WG. Motor neuron diseases. In: Asbury K, McKhann GM, McDonald WI, eds. Diseases of the nervous system. London: Heinemann, 1986:1239-1257 18. Kurtzke JF. The current neurologic burden of illness and injury in the United States. Neurology 1982;32:1207-12 14 19. Baraitser M. Neurocutaneous disorders. In: Asbury K, McKhann GM, McDonald WI, eds. Diseases of the nervous system. London: Heinemann, 1986:1571-1577 20. Husvn S, Harper PS, Compston DAS. Von Recbnghausen neurofibromatosis: a clinical and population study in South-East Wales. Brain 1988;111: 1355-1 381

414 Annals of Neurology Vol 30 No 3 September 1991

Single-gene neurological disorders in South Wales: an epidemiological study.

Single-gene neurological disorders account for a significant proportion of the work load of any regional genetics unit. In an attempt to assess the li...
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