Brain (1991), 114, 855-866
HEREDITARY ATAXIAS AND PARAPLEGIAS IN CANTABRIA, SPAIN AN EPIDEMIOLOGICAL AND CLINICAL STUDY by J. M. POLO, J. CALLEJA, O. COMBARROS and J. BERCIANO (From the Services of Neurology and Clinical Neurophysiology, 'Marquis de Valdecilla' National Hospital, University of Cantabria, Santander, Spain)
SUMMARY
INTRODUCTION
Hereditary ataxias and paraplegias encompass a heterogeneous group of disorders of unknown cause, the outstanding characteristics of which are ataxia or spastic paraplegia and spinocerebellar atrophy. Due to their complex nosology there have been many attempts at classification. As stated by Refsum and Skre (1978) 'it is not any great exaggeration to say that there are as many proposed classifications as there are authors on the subject'. Classifications have usually been based on pathological and clinical features (Holmes, 1907; Greenfield, 1954; Konigsmark and Weiner, 1970). These are unsatisfactory because they ignore the genetic heterogeneity both of the clinical picture and pathological framework (Harding, 1982; Berciano, 1988). Recently, Harding (1983, 1984) proposed an accurate classification based on clinical and genetic features that Correspondence to: Dr ]osi Berciano, Servicio de Neurologfa, Hospital Nacional Marques de Valdecilla, 39008 Santander, Spain. © Oxford University Press 1991
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A clinical, genetic and epidemiological study of hereditary ataxias and paraplegias was conducted within a defined area (Cantabria) in Northern Spain from 1974 to 1986. The series comprised 48 index cases and 65 affected relatives. On prevalence day, 103 patients were alive, giving a prevalence of 20.2 cases per 100 000. There were 24 patients (18 families) with Friedreich's ataxia (FA), 12 (6 families) with early onset cerebellar ataxia (EOCA) differing from FA, 6 (3 families) with dominantly transmitted late onset cerebellar ataxia (LOCA), 11 with 'idiopathic' LOCA, 49 (9 families) with 'pure' hereditary spastic paraplegia (HSP), and 1 patient with congenital cerebellar ataxia. The prevalence found here is comparable with the highest figures described in previous surveys. This may in part be due to the great number of secondary cases in our series. A high frequency of parental consanguinity occurred in FA patients, 'pseudodominant' inheritance being observed in 1 family. The clinical features were those of classical FA except for later onset and slower course in 1 family, and retained tendon reflexes in the lower limbs in 2 cases. Such data indicate the need for modification of the essential criteria for the disease. EOCA included 4 patients with normoreflexic ataxia and 1 patient with ataxia and luteinizing hormone-releasing hormone deficiency. In addition, there were 7 patients from 2 unrelated families with a homogeneous syndrome characterized by autosomal recessive inheritance, cerebellar ataxia, retinitis pigmentosa and sensory neuropathy. This syndrome is therefore a well defined nosological entity to be added to the list of autosomal recessive mendelian phenotypes. The clinical picture of patients with LOCA was either a 'pure' cerebellar or a 'cerebellar-plus' syndrome. Genetic subgroups of 'pure' HSP were autosomal dominant type I in 5 families and type II in 2, and autosomal recessive in 2 families.
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has gained worldwide acceptance, and which allows clinicians to diagnose the majority of patients. This is an essential step for epidemiological purposes (Schoenberg, 1978a). Prevalence data for hereditary ataxias and paraplegias are scanty (Bobowick and Brody, 1975) and most studies either departed from clinicopathological classifications or were focused on specific syndromes. The aims of the present study were to screen a limited geographical area in Northern Spain to establish figures for the prevalence and relative frequency of genetic and clinical subtypes of hereditary ataxias and paraplegias. P A T I E N T S AND M E T H O D S
RESULTS
During the period of study, 76 index cases were considered to have hereditary ataxia or spastic paraplegia; 28 cases were excluded (Table 1). Consequently 48 propositi entered finally for epidemiological analysis. Moreover, 178 relatives were examined of whom 51 were found to be affected. A further 14 relatives were known to be affected by history. Ten patients died before the prevalence day. Thus there were 103 patients living on 31 December 1986. The total point prevalence was 20.2 cases per 100 000 population. Prevalence rates for the different subtypes are summarized in Table 2. Congenital cerebellar ataxia Congenital cerebellar ataxia was diagnosed only in 1 patient born of a normal pregnancy. Parental consanguinity was not recognized. He had started walking at 2 yrs.
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The study was performed in the Autonomous Community of Cantabria, which lies in Northern Spain and covers an area of 5289 km2 with a population of 510 000 inhabitants (1981 census). The patients were referred to the National Hospital 'Marques de Valdecilla' between 1974 and 1986. This is the main hospital to which all neurological problems are referred. The 4 private hospitals in the region treat only acute medical and surgical problems and there are no consultant neurologists other than those at the hospital. A recent survey has estimated that more than 90% of people always use the public health service (according to the 1988 official statistics of the Spanish Sociological Investigations Centre). Thus the neurological patient population in this hospital is truly representative of the region of Cantabria. Proband patients were initially evaluated at the hospital. Family trees were routinely performed and cooperative individuals at risk were visited in hospital or at home. Serial clinical examinations, yearly or less, were regularly carried out. Using Harding's (1983, 1984) classification the patients were divided into six groups: congenital cerebellar ataxia; Friedreich's ataxia (FA); early onset cerebellar ataxia (EOCA) differing from FA; late onset cerebellar ataxia (LOCA), autosomal dominant and 'idiopathic'; and hereditary spastic paraplegia (HSP). HSP was accepted here when together with the index case there was objective evidence of disease in at least 1 additional member of the family. Routine haematological and biochemical studies, radiographs of the skull, syphilitic serology, electrocardiography, motor and sensory nerve conduction studies of median and/or peroneal nerves, somatosensory and auditory evoked potentials, electromyography of tibia]is anterior and/or abductor pollicis brevis muscles were performed in each index patient and in most secondary cases. Most patients with hereditary ataxia also had an EEG and cranial CT scan. The majority of FA patients also had an echocardiogram. Specific tests for detecting hexosaminidase deficiency, juvenile Niemann-Pick disease and metachromatic leucodystrophy were performed in selected patients. Patients were considered to be resident if they were residing in Cantabria in 1986. All prevalence rates will be here referred to as point prevalence (Schoenberg, 19786) on the last day of 1986. Since we routinely examined most subjects at risk in each pedigree, virtually all secondary cases were deterted and therefore there was only 1 proband per family.
HEREDITARY ATAXIAS AND PARAPLEGIAS
857
TABLE I. EXCLUDED CASES Not resident in Cantabria
10
Other diagnoses Alcoholic cerebellar atrophy (4) Parkinsonism (2) Phenytoin intoxication (1) Hallervorden-Spatz disease (1) Niemann-Pick disease type C (1) Multiple sclerosis (1) Amyotrophic lateral sclerosis (1) Metachromatic leucodystrophy (1)
12
Incomplete study
6 28
Total
TABLE 2. CASE DISTRIBUTION INTO SUBTYPES Probands 1 18 6 3
11 9 48
Secondary cases -
7 7 5 46 65
Living 31.12.1986 1
24 12 6 11
49 103
Prevalence per 100 000 0.2 4.7 2.3 1.2 2.2 9.6 20.2*
EOCA = early onset cerebellar ataxia; LOCA = late onset cerebellar ataxia. • 95% confidence interval, 16.4-24.3.
Afterwards he manifested gait difficulty, but this was not apparently progressive. On examination at age 17, there was pes cavus, static and kinetic cerebellar ataxia, dysarthria, bilateral impairment of lateral gaze, nystagmus, distal hypopallaesthesia, and extensor plantar responses. Mental status was normal. There was neither optic atrophy nor hypoacusis. Motor and nerve conduction velocities of median and peroneal nerves were normal. CT scan revealed brainstem and vermal atrophy. Friedreich 's ataxia Leaving aside a case affected by history, the clinical characteristics of 24 FA patients were as follows. There were 10 males and 14 females. There was parental consanguinity in 9 families (50%), 'pseudodominant' inheritance being present in 1 (fig. 1). The mean age of onset was 13.08 ±8.37 (range 3-35) yrs. The mean age at the time of study was 25.58± 13.51 (range 7 — 56) yrs, and the average duration of the disease was 12.50±9.63 yrs. Two patients, brother and sister, with onset at 30 and 35 yrs and relatively slow clinical course, belonged to the family with 'pseudodominant' transmission which was included in the genetic study that provided evidence of genetic homogeneity at the FA locus on chromosome 9 (Chamberlain et al., 1989). Initial symptoms included gait disturbances in 24 (100%), foot deformities in 5 (21 %), manual clumsiness in 4 (17%), dysarthria in 4 (17%) and dysphagia in 1 (4%). The
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Subtype Congenital ataxia Friedreich's ataxia (FA) EOCA differing from FA Autosomal dominant LOCA 'Idiopathic' LOCA 'Pure' hereditary spastic paraplegia Total
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J. M. POLO AND O T H E R S
III
IV
FIG. 1. Pedigree of family with FA and 'pseudodominant' inheritance. Broken lines indicate consanguinity. Symbols with horizontal marks correspond to examined patients. Case 11-10 was examined in 1988 and consequently not included in this study.
TABLE 3. FRIEDREICH'S ATAXIA*: ESTABLISHED CLINICAL PICTURE
Cerebellar ataxia Distal hypopallaesthesia Dysarthria Absent knee and ankle jerks Scoliosis Pes cavus Pyramidal weakness in lower limbs Extensor plantar responses Nystagmus Optic atrophy Congenital glaucoma '(n = 24)
No. of cases (%) 24 (100) 24 (100) 22(92) 22 (92) 18(75) 18(75) 17(71) 15 (62) 8(33) 2(8) 2(8)
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clinical picture is summarized in Table 3. All patients had had progressive ataxia. Knee jerks and ankle jerks were preserved in 2 patients, 10 and 15 yrs after onset. One of these was an index case who fulfilled all other essential and additional criteria of FA (Harding, 1984); the other corresponds to Case HI-3 in fig. 1. Two patients had associated congenital glaucoma (Combarros et al., 1988) and were also included in the genetic study reported by Chamberlain et al. (1989). All probands had evidence of the characteristic ECG abnormalities as did 4 out of 6 secondary cases. Serial ECGs in 1 patient revealed the appearance of T wave inversion. Echocardiography showed abnormalities in 13 out of 19 (68%) cases. Only 3 patients had cardiac symptoms consisting of atrial fibrillation with heart failure and systemic embolism (2 cases), and angina (1 case). Cardiac disease caused death in 1 patient (Table 2), postmortem examination revealing the characteristic findings of the disease (Hughes et al., 1968;
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Lamarche et al., 1984; Oppenheimer, 1984). Two (8%) cases had diabetes controlled with insulin and oral hypoglycaemic drugs. Nerve conduction studies were carried out in all 24 patients. Motor conduction velocities in the median nerve ranged from 46 to 69 m-s" 1 (54.4±7.6). Distal sensory potentials of median nerve were absent or reduced (between 0.5 and 3 /iV). A CT scan was performed in 22 cases. As previously described by us (Ramos et al., 1987), the scan either revealed no abnormalities in the posterior fossa (10 patients) or moderate cerebellar atrophy with an increase in the surface area of the fourth ventricle (12 patients). EOCA differing from FA This group includes 12 patients belonging to 6 families. The diagnostic categories were as follows: ataxia, retinitis pigmentosa and sensory neuropathy (7 patients in 2 families), ataxia with retained tendon reflexes (4 patients in 3 families) and ataxia with luteinizing hormone-releasing hormone (LHRH) deficiency (2 patients in 1 family). Inheritance in the 2 families with ataxia, retinitis pigmentosa and sensory neuropathy was either autosomal recessive or 'pseudodominant' (fig. 2). Six patients were examined
FIG. 2. Pedigree of family with cerebellar ataxia, retinitis pigmentosa and sensory neuropathy, and 'pseudodominant' inheritance. For symbols, see fig. 1.
and 1 was affected by history. The age of onset ranged from 2 to 14 yrs. Initial symptoms in the 6 examined patients were gait disturbances in 4 and loss of vision in 2. Age at examination ranged from 4 to 40 (median 22.5) yrs. The clinical picture was homogeneous and included cerebellar ataxia, dysarthria, generalized areflexia, marked distal hypopallaesthesia, and diffuse pigmentary retinopathy with severe loss of visual acuity and tubular vision. In no case was there evidence of ophthalmoplegia, amyotrophy, foot deformities, pyramidal signs, deafness, nystagmus, mental deterioration or ichthyosis. All patients were able to walk without assistance. ECG as well as routine laboratory investigations including betalipoproteins were consistently normal. Nerve conduction studies on the median and/or peroneal nerves, performed in 4 cases, revealed absence of distal sensory potentials with normal motor conduction. In 3 cases CT scans did not reveal abnormalities. Serum phytanic acid levels were not available. In the ataxia with retained tendon reflexes group there were 3 males and 1 female. Parental consanguinity was present in 1 case, but genealogical data were insufficient to determine the pattern of transmission. The onset of symptoms ranged from 6 to 22 yrs.
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The clinical picture was essentially that of moderate spastic ataxia. There was no evidence of cardiomyopathy. Motor and sensory conduction velocities in the median or peroneal nerves were normal. CT scan revealed cerebellar atrophy with normal brainstem parameters. The characteristics of the family with ataxia and LHRH deficiency have been reported previously (Berciano et al., 1982). The proband died during the period of study (Table 2). Unfortunately, postmortem examination was not performed.
'Idiopathic' LOCA This group includes 11 patients (8 males, 3 females). The mean age of onset was 47.4 ±15.3 (range 28 — 70) yrs. Six patients had a 'cerebellar-plus' syndrome consisting of cerebellar ataxia together with pyramidal signs, dementia, supranuclear ophthalmoplegia, dysphagia, sphincter disturbances, hypopallaesthesia or chorea. None of these cases showed parkinsonian signs. Five patients had a 'pure' cerebellar syndrome. The duration of the disease at the time of study in these cases ranged from 11 to 19 yrs. CT scan findings were comparable with those in the previous group. 'Pure' hereditary spastic paraplegia There were 9 index cases; moreover, 109 relatives were examined, of whom 36 were found to be affected. A further 10 relatives were affected by history. Inheritance was autosomal dominant in 7 families and recessive in 2. According to the age of onset of dominant cases, 5 families corresponded to type I (onset below 35 yrs) and 2 to type II (onset over 35 yrs) (Harding, 1981a). Genetic, clinical and electrophysiological details of these families will be published later. DISCUSSION
Since 1923, 13 epidemiological studies on hereditary ataxias and paraplegias have been reported, which are summarized in Table 4. Furthermore, on the basis of the estimates of disease duration, the prevalence rate of hereditary ataxias and paraplegias between 10 and 50 yrs of age was 5.7 cases per 100 000 in the island of Zealand
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Autosomal dominant LOCA There were 8 patients belonging to 3 families with autosomal dominant ataxia. Five patients (2 families) had 'cerebellar-plus' syndrome, consisting of gait and limb ataxia, dysarthria, pyramidal and spinal signs, supranuclear ophthalmoplegia, dysphagia, sphincter disturbances or dementia. Two patients showed parkinsonian signs. Ages at onset ranged from 12 to 40 (median 28) yrs. Pneumoencephalography (1 case) and CT scan (3 cases) revealed severe cerebellar and brainstem atrophy and an increase in the size of the fourth ventricle (Berciano et al., 1983; Ramos et al., 1987). Two sisters died during the period of study, postmortem examination in 1 case revealing olivopontocerebellar atrophy (OPCA) with spinal involvement (Berciano et al., 1983). Three patients, from a family in which the proband and 2 affected cousins were living, had a 'pure' cerebellar syndrome of later onset, this developing at 55 yrs in the only examined patient. A CT scan in this case revealed cerebellar verrnis and hemisphere atrophy with normal brainstem parameters.
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TABLE 4. SUMMARY OF PREVALENCE RATES OF HEREDITARY ATAXIAS AND PARAPLEGIAS Author Hanhart (1923) Sjogren (1943) Kurland (1958) Krcindler et al. (1964) Brewis et al. (1966) Chen et al. (1968) Gudmundsson (1969) Koeppen et al. (1977) Trizio et al. (1980) Skre (1980)4 Lucci et al. (1982) Sridharan et al. (1985) Brignolio et al. (1986) Present series
Area of survey Switzerland Sweden Rochester, Minnesota Rumania Carlisle Guam Iceland Scotland Puglia (Italy) Western Norway Reggio-Emilia (Italy) Benghazi (Libya) Torino (Italy) Cantabria
Time period 1921 1905-1941 1945-1954 1950-1962 1955-1961 1960-1966 1954-1963 ?
? 1960-1968 1965-1980 1982-1984 1945-1982 1974-1986
Population 3500 000 6000 000 29 885 ? 71 101 37 975 187 200 5 228 963 7 725 000 412 324 519 000 2 327 996 510 000
No. of cases 46 120 0 395 5 9 2 163 139 68 21 25 142 103
Prevalence per 100 000 3.7' 2.0 0.0 2.0 2 7.0 23.7 1.1 0.3 3.5 22.1 5 4.2 4.8 6.1 20.2
1 Extrapolated estimate. 2 Average from 20 cities and territories (prevalences ranging from 0.21 to 4.27). 3 Only adult onset hereditary ataxia. 4 Adjusted in relationship to earlier figures. 5 Prevalence corrected by estimation of ascertainment probability.
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(Werdelin, 1986). Since diagnostic criteria, methodology of study and classification of hereditary ataxias have been a changing matter, comparison of our data with previous studies should only be made with caution. In any case, the prevalence found in Cantabria, 20.2/100 000, is comparable with the highest prevalence figures described in other parts of the world (Chen et al., 1968; Skre, 1980). Although in our study we had a greater number of secondary cases, prevalence rate remains high even when only index cases are considered, 9.4/100 000. As described in Patients and Methods, the neurological patient population in our hospital is truly representative of that of Cantabria. Parallel epidemiological data have been obtained for multiple sclerosis, Charcot-Marie-Tooth disorders and motor neuron disease (Mir6 et al., 1984; Combarros et al., 1987; L
HEREDITARY ATAXIAS AND PARAPLEGIAS IN CANTABRIA, SPAIN AN EPIDEMIOLOGICAL AND CLINICAL STUDY by J. M. POLO, J. CALLEJA, O. COMBARROS and J. BERCIANO (From the Services of Neurology and Clinical Neurophysiology, 'Marquis de Valdecilla' National Hospital, University of Cantabria, Santander, Spain)
SUMMARY
INTRODUCTION
Hereditary ataxias and paraplegias encompass a heterogeneous group of disorders of unknown cause, the outstanding characteristics of which are ataxia or spastic paraplegia and spinocerebellar atrophy. Due to their complex nosology there have been many attempts at classification. As stated by Refsum and Skre (1978) 'it is not any great exaggeration to say that there are as many proposed classifications as there are authors on the subject'. Classifications have usually been based on pathological and clinical features (Holmes, 1907; Greenfield, 1954; Konigsmark and Weiner, 1970). These are unsatisfactory because they ignore the genetic heterogeneity both of the clinical picture and pathological framework (Harding, 1982; Berciano, 1988). Recently, Harding (1983, 1984) proposed an accurate classification based on clinical and genetic features that Correspondence to: Dr ]osi Berciano, Servicio de Neurologfa, Hospital Nacional Marques de Valdecilla, 39008 Santander, Spain. © Oxford University Press 1991
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A clinical, genetic and epidemiological study of hereditary ataxias and paraplegias was conducted within a defined area (Cantabria) in Northern Spain from 1974 to 1986. The series comprised 48 index cases and 65 affected relatives. On prevalence day, 103 patients were alive, giving a prevalence of 20.2 cases per 100 000. There were 24 patients (18 families) with Friedreich's ataxia (FA), 12 (6 families) with early onset cerebellar ataxia (EOCA) differing from FA, 6 (3 families) with dominantly transmitted late onset cerebellar ataxia (LOCA), 11 with 'idiopathic' LOCA, 49 (9 families) with 'pure' hereditary spastic paraplegia (HSP), and 1 patient with congenital cerebellar ataxia. The prevalence found here is comparable with the highest figures described in previous surveys. This may in part be due to the great number of secondary cases in our series. A high frequency of parental consanguinity occurred in FA patients, 'pseudodominant' inheritance being observed in 1 family. The clinical features were those of classical FA except for later onset and slower course in 1 family, and retained tendon reflexes in the lower limbs in 2 cases. Such data indicate the need for modification of the essential criteria for the disease. EOCA included 4 patients with normoreflexic ataxia and 1 patient with ataxia and luteinizing hormone-releasing hormone deficiency. In addition, there were 7 patients from 2 unrelated families with a homogeneous syndrome characterized by autosomal recessive inheritance, cerebellar ataxia, retinitis pigmentosa and sensory neuropathy. This syndrome is therefore a well defined nosological entity to be added to the list of autosomal recessive mendelian phenotypes. The clinical picture of patients with LOCA was either a 'pure' cerebellar or a 'cerebellar-plus' syndrome. Genetic subgroups of 'pure' HSP were autosomal dominant type I in 5 families and type II in 2, and autosomal recessive in 2 families.
856
J. M. POLO AND OTHERS
has gained worldwide acceptance, and which allows clinicians to diagnose the majority of patients. This is an essential step for epidemiological purposes (Schoenberg, 1978a). Prevalence data for hereditary ataxias and paraplegias are scanty (Bobowick and Brody, 1975) and most studies either departed from clinicopathological classifications or were focused on specific syndromes. The aims of the present study were to screen a limited geographical area in Northern Spain to establish figures for the prevalence and relative frequency of genetic and clinical subtypes of hereditary ataxias and paraplegias. P A T I E N T S AND M E T H O D S
RESULTS
During the period of study, 76 index cases were considered to have hereditary ataxia or spastic paraplegia; 28 cases were excluded (Table 1). Consequently 48 propositi entered finally for epidemiological analysis. Moreover, 178 relatives were examined of whom 51 were found to be affected. A further 14 relatives were known to be affected by history. Ten patients died before the prevalence day. Thus there were 103 patients living on 31 December 1986. The total point prevalence was 20.2 cases per 100 000 population. Prevalence rates for the different subtypes are summarized in Table 2. Congenital cerebellar ataxia Congenital cerebellar ataxia was diagnosed only in 1 patient born of a normal pregnancy. Parental consanguinity was not recognized. He had started walking at 2 yrs.
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The study was performed in the Autonomous Community of Cantabria, which lies in Northern Spain and covers an area of 5289 km2 with a population of 510 000 inhabitants (1981 census). The patients were referred to the National Hospital 'Marques de Valdecilla' between 1974 and 1986. This is the main hospital to which all neurological problems are referred. The 4 private hospitals in the region treat only acute medical and surgical problems and there are no consultant neurologists other than those at the hospital. A recent survey has estimated that more than 90% of people always use the public health service (according to the 1988 official statistics of the Spanish Sociological Investigations Centre). Thus the neurological patient population in this hospital is truly representative of the region of Cantabria. Proband patients were initially evaluated at the hospital. Family trees were routinely performed and cooperative individuals at risk were visited in hospital or at home. Serial clinical examinations, yearly or less, were regularly carried out. Using Harding's (1983, 1984) classification the patients were divided into six groups: congenital cerebellar ataxia; Friedreich's ataxia (FA); early onset cerebellar ataxia (EOCA) differing from FA; late onset cerebellar ataxia (LOCA), autosomal dominant and 'idiopathic'; and hereditary spastic paraplegia (HSP). HSP was accepted here when together with the index case there was objective evidence of disease in at least 1 additional member of the family. Routine haematological and biochemical studies, radiographs of the skull, syphilitic serology, electrocardiography, motor and sensory nerve conduction studies of median and/or peroneal nerves, somatosensory and auditory evoked potentials, electromyography of tibia]is anterior and/or abductor pollicis brevis muscles were performed in each index patient and in most secondary cases. Most patients with hereditary ataxia also had an EEG and cranial CT scan. The majority of FA patients also had an echocardiogram. Specific tests for detecting hexosaminidase deficiency, juvenile Niemann-Pick disease and metachromatic leucodystrophy were performed in selected patients. Patients were considered to be resident if they were residing in Cantabria in 1986. All prevalence rates will be here referred to as point prevalence (Schoenberg, 19786) on the last day of 1986. Since we routinely examined most subjects at risk in each pedigree, virtually all secondary cases were deterted and therefore there was only 1 proband per family.
HEREDITARY ATAXIAS AND PARAPLEGIAS
857
TABLE I. EXCLUDED CASES Not resident in Cantabria
10
Other diagnoses Alcoholic cerebellar atrophy (4) Parkinsonism (2) Phenytoin intoxication (1) Hallervorden-Spatz disease (1) Niemann-Pick disease type C (1) Multiple sclerosis (1) Amyotrophic lateral sclerosis (1) Metachromatic leucodystrophy (1)
12
Incomplete study
6 28
Total
TABLE 2. CASE DISTRIBUTION INTO SUBTYPES Probands 1 18 6 3
11 9 48
Secondary cases -
7 7 5 46 65
Living 31.12.1986 1
24 12 6 11
49 103
Prevalence per 100 000 0.2 4.7 2.3 1.2 2.2 9.6 20.2*
EOCA = early onset cerebellar ataxia; LOCA = late onset cerebellar ataxia. • 95% confidence interval, 16.4-24.3.
Afterwards he manifested gait difficulty, but this was not apparently progressive. On examination at age 17, there was pes cavus, static and kinetic cerebellar ataxia, dysarthria, bilateral impairment of lateral gaze, nystagmus, distal hypopallaesthesia, and extensor plantar responses. Mental status was normal. There was neither optic atrophy nor hypoacusis. Motor and nerve conduction velocities of median and peroneal nerves were normal. CT scan revealed brainstem and vermal atrophy. Friedreich 's ataxia Leaving aside a case affected by history, the clinical characteristics of 24 FA patients were as follows. There were 10 males and 14 females. There was parental consanguinity in 9 families (50%), 'pseudodominant' inheritance being present in 1 (fig. 1). The mean age of onset was 13.08 ±8.37 (range 3-35) yrs. The mean age at the time of study was 25.58± 13.51 (range 7 — 56) yrs, and the average duration of the disease was 12.50±9.63 yrs. Two patients, brother and sister, with onset at 30 and 35 yrs and relatively slow clinical course, belonged to the family with 'pseudodominant' transmission which was included in the genetic study that provided evidence of genetic homogeneity at the FA locus on chromosome 9 (Chamberlain et al., 1989). Initial symptoms included gait disturbances in 24 (100%), foot deformities in 5 (21 %), manual clumsiness in 4 (17%), dysarthria in 4 (17%) and dysphagia in 1 (4%). The
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Subtype Congenital ataxia Friedreich's ataxia (FA) EOCA differing from FA Autosomal dominant LOCA 'Idiopathic' LOCA 'Pure' hereditary spastic paraplegia Total
858
J. M. POLO AND O T H E R S
III
IV
FIG. 1. Pedigree of family with FA and 'pseudodominant' inheritance. Broken lines indicate consanguinity. Symbols with horizontal marks correspond to examined patients. Case 11-10 was examined in 1988 and consequently not included in this study.
TABLE 3. FRIEDREICH'S ATAXIA*: ESTABLISHED CLINICAL PICTURE
Cerebellar ataxia Distal hypopallaesthesia Dysarthria Absent knee and ankle jerks Scoliosis Pes cavus Pyramidal weakness in lower limbs Extensor plantar responses Nystagmus Optic atrophy Congenital glaucoma '(n = 24)
No. of cases (%) 24 (100) 24 (100) 22(92) 22 (92) 18(75) 18(75) 17(71) 15 (62) 8(33) 2(8) 2(8)
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clinical picture is summarized in Table 3. All patients had had progressive ataxia. Knee jerks and ankle jerks were preserved in 2 patients, 10 and 15 yrs after onset. One of these was an index case who fulfilled all other essential and additional criteria of FA (Harding, 1984); the other corresponds to Case HI-3 in fig. 1. Two patients had associated congenital glaucoma (Combarros et al., 1988) and were also included in the genetic study reported by Chamberlain et al. (1989). All probands had evidence of the characteristic ECG abnormalities as did 4 out of 6 secondary cases. Serial ECGs in 1 patient revealed the appearance of T wave inversion. Echocardiography showed abnormalities in 13 out of 19 (68%) cases. Only 3 patients had cardiac symptoms consisting of atrial fibrillation with heart failure and systemic embolism (2 cases), and angina (1 case). Cardiac disease caused death in 1 patient (Table 2), postmortem examination revealing the characteristic findings of the disease (Hughes et al., 1968;
HEREDITARY ATAXIAS AND PARAPLEGIAS
859
Lamarche et al., 1984; Oppenheimer, 1984). Two (8%) cases had diabetes controlled with insulin and oral hypoglycaemic drugs. Nerve conduction studies were carried out in all 24 patients. Motor conduction velocities in the median nerve ranged from 46 to 69 m-s" 1 (54.4±7.6). Distal sensory potentials of median nerve were absent or reduced (between 0.5 and 3 /iV). A CT scan was performed in 22 cases. As previously described by us (Ramos et al., 1987), the scan either revealed no abnormalities in the posterior fossa (10 patients) or moderate cerebellar atrophy with an increase in the surface area of the fourth ventricle (12 patients). EOCA differing from FA This group includes 12 patients belonging to 6 families. The diagnostic categories were as follows: ataxia, retinitis pigmentosa and sensory neuropathy (7 patients in 2 families), ataxia with retained tendon reflexes (4 patients in 3 families) and ataxia with luteinizing hormone-releasing hormone (LHRH) deficiency (2 patients in 1 family). Inheritance in the 2 families with ataxia, retinitis pigmentosa and sensory neuropathy was either autosomal recessive or 'pseudodominant' (fig. 2). Six patients were examined
FIG. 2. Pedigree of family with cerebellar ataxia, retinitis pigmentosa and sensory neuropathy, and 'pseudodominant' inheritance. For symbols, see fig. 1.
and 1 was affected by history. The age of onset ranged from 2 to 14 yrs. Initial symptoms in the 6 examined patients were gait disturbances in 4 and loss of vision in 2. Age at examination ranged from 4 to 40 (median 22.5) yrs. The clinical picture was homogeneous and included cerebellar ataxia, dysarthria, generalized areflexia, marked distal hypopallaesthesia, and diffuse pigmentary retinopathy with severe loss of visual acuity and tubular vision. In no case was there evidence of ophthalmoplegia, amyotrophy, foot deformities, pyramidal signs, deafness, nystagmus, mental deterioration or ichthyosis. All patients were able to walk without assistance. ECG as well as routine laboratory investigations including betalipoproteins were consistently normal. Nerve conduction studies on the median and/or peroneal nerves, performed in 4 cases, revealed absence of distal sensory potentials with normal motor conduction. In 3 cases CT scans did not reveal abnormalities. Serum phytanic acid levels were not available. In the ataxia with retained tendon reflexes group there were 3 males and 1 female. Parental consanguinity was present in 1 case, but genealogical data were insufficient to determine the pattern of transmission. The onset of symptoms ranged from 6 to 22 yrs.
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Ill
860
J. M. POLO AND OTHERS
The clinical picture was essentially that of moderate spastic ataxia. There was no evidence of cardiomyopathy. Motor and sensory conduction velocities in the median or peroneal nerves were normal. CT scan revealed cerebellar atrophy with normal brainstem parameters. The characteristics of the family with ataxia and LHRH deficiency have been reported previously (Berciano et al., 1982). The proband died during the period of study (Table 2). Unfortunately, postmortem examination was not performed.
'Idiopathic' LOCA This group includes 11 patients (8 males, 3 females). The mean age of onset was 47.4 ±15.3 (range 28 — 70) yrs. Six patients had a 'cerebellar-plus' syndrome consisting of cerebellar ataxia together with pyramidal signs, dementia, supranuclear ophthalmoplegia, dysphagia, sphincter disturbances, hypopallaesthesia or chorea. None of these cases showed parkinsonian signs. Five patients had a 'pure' cerebellar syndrome. The duration of the disease at the time of study in these cases ranged from 11 to 19 yrs. CT scan findings were comparable with those in the previous group. 'Pure' hereditary spastic paraplegia There were 9 index cases; moreover, 109 relatives were examined, of whom 36 were found to be affected. A further 10 relatives were affected by history. Inheritance was autosomal dominant in 7 families and recessive in 2. According to the age of onset of dominant cases, 5 families corresponded to type I (onset below 35 yrs) and 2 to type II (onset over 35 yrs) (Harding, 1981a). Genetic, clinical and electrophysiological details of these families will be published later. DISCUSSION
Since 1923, 13 epidemiological studies on hereditary ataxias and paraplegias have been reported, which are summarized in Table 4. Furthermore, on the basis of the estimates of disease duration, the prevalence rate of hereditary ataxias and paraplegias between 10 and 50 yrs of age was 5.7 cases per 100 000 in the island of Zealand
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Autosomal dominant LOCA There were 8 patients belonging to 3 families with autosomal dominant ataxia. Five patients (2 families) had 'cerebellar-plus' syndrome, consisting of gait and limb ataxia, dysarthria, pyramidal and spinal signs, supranuclear ophthalmoplegia, dysphagia, sphincter disturbances or dementia. Two patients showed parkinsonian signs. Ages at onset ranged from 12 to 40 (median 28) yrs. Pneumoencephalography (1 case) and CT scan (3 cases) revealed severe cerebellar and brainstem atrophy and an increase in the size of the fourth ventricle (Berciano et al., 1983; Ramos et al., 1987). Two sisters died during the period of study, postmortem examination in 1 case revealing olivopontocerebellar atrophy (OPCA) with spinal involvement (Berciano et al., 1983). Three patients, from a family in which the proband and 2 affected cousins were living, had a 'pure' cerebellar syndrome of later onset, this developing at 55 yrs in the only examined patient. A CT scan in this case revealed cerebellar verrnis and hemisphere atrophy with normal brainstem parameters.
HEREDITARY ATAXIAS AND PARAPLEGIAS
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TABLE 4. SUMMARY OF PREVALENCE RATES OF HEREDITARY ATAXIAS AND PARAPLEGIAS Author Hanhart (1923) Sjogren (1943) Kurland (1958) Krcindler et al. (1964) Brewis et al. (1966) Chen et al. (1968) Gudmundsson (1969) Koeppen et al. (1977) Trizio et al. (1980) Skre (1980)4 Lucci et al. (1982) Sridharan et al. (1985) Brignolio et al. (1986) Present series
Area of survey Switzerland Sweden Rochester, Minnesota Rumania Carlisle Guam Iceland Scotland Puglia (Italy) Western Norway Reggio-Emilia (Italy) Benghazi (Libya) Torino (Italy) Cantabria
Time period 1921 1905-1941 1945-1954 1950-1962 1955-1961 1960-1966 1954-1963 ?
? 1960-1968 1965-1980 1982-1984 1945-1982 1974-1986
Population 3500 000 6000 000 29 885 ? 71 101 37 975 187 200 5 228 963 7 725 000 412 324 519 000 2 327 996 510 000
No. of cases 46 120 0 395 5 9 2 163 139 68 21 25 142 103
Prevalence per 100 000 3.7' 2.0 0.0 2.0 2 7.0 23.7 1.1 0.3 3.5 22.1 5 4.2 4.8 6.1 20.2
1 Extrapolated estimate. 2 Average from 20 cities and territories (prevalences ranging from 0.21 to 4.27). 3 Only adult onset hereditary ataxia. 4 Adjusted in relationship to earlier figures. 5 Prevalence corrected by estimation of ascertainment probability.
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(Werdelin, 1986). Since diagnostic criteria, methodology of study and classification of hereditary ataxias have been a changing matter, comparison of our data with previous studies should only be made with caution. In any case, the prevalence found in Cantabria, 20.2/100 000, is comparable with the highest prevalence figures described in other parts of the world (Chen et al., 1968; Skre, 1980). Although in our study we had a greater number of secondary cases, prevalence rate remains high even when only index cases are considered, 9.4/100 000. As described in Patients and Methods, the neurological patient population in our hospital is truly representative of that of Cantabria. Parallel epidemiological data have been obtained for multiple sclerosis, Charcot-Marie-Tooth disorders and motor neuron disease (Mir6 et al., 1984; Combarros et al., 1987; L
