The clinical features of 115 patients from 90 families with Friedreich's ataxia are described. Onset of symptoms was before the age of 25 (mean 10.52) years in all the index cases. An analysis of early cases suggested that limb and truncal ataxia and absent tendon reflexes in the legs were the only consistent diagnostic criteria within five years of presentation. Dysarthria, signs of pyramidal tract dysfunction in the legs and loss of joint position and vibration sense are not necessarily present during the first five years of symptoms, but appear to develop eventually in all cases. Scoliosis and ECG evidence of cardiomyopathy were found in over two-thirds of the patients studied; pes cavus, distal amyotrophy, optic atrophy, nystagmus and deafness were all less frequent. The disorder was gradually progressive in all cases. The mean age of losing the ability to walk was 25 years; 95 per cent were chair-bound by the age of 44 years. About 10 per cent of the patients had diabetes mellitus which was controlled by oral hypoglycaemic drugs in one quarter. Diabetes appeared to be associated with a higher incidence of optic atrophy and deafness. Diabetes also clustered within sibships; the risk of an individual with Friedreich's ataxia developing diabetes if an affected sib has it is over 40 per cent. Similarly, cardiomyopathy ran true within affected members of the same sibship, but there were instances of discordance which suggest that the development of the non-neurological features of Friedreich's ataxia may be controlled by modifying genes rather than heterogeneity of the main gene. Segregation analysis and an increased consanguinity rate amongst parents of patients (5.55 per cent) confirmed that this disorder is of autosomal recessive inheritance. A study of 101 first degree relatives of the patients with Friedreich's ataxia failed to demonstrate any neurological or electrocardiographic abnormalities which could be ascribed to the heterozygous state.

Twenty index patients with hereditary essential tremor and their kindreds were studied to define the phenotype of this condition. Ninety-three first degree and 38 more distant relatives were examined; 53 definite and 18 possible secondary cases were identified. The age of tremor onset was bimodally distributed with a median at approximately 15 years. Segregation analysis indicated autosomal dominant inheritance and penetrance was virtually complete by the age of 65 years. There were no examples of the disease skipping a generation. Men and women were affected in equal proportions. About 50% of cases were alcohol responsive. In the majority of families alcohol responsiveness was either consistently present or did not occur, but in 20% of kindreds definite heterogeneity of responsiveness was encountered within each family. The typical phenotype was a mild symmetrical postural tremor of the upper limbs. Tremor of the legs, head, facial muscles, voice, jaw and tongue occurred but never in isolation and rest, task specific (e.g. primary writing tremor) and primary orthostatic tremors were not found. Head tremor was invariably mild and 75% was of a 'no-no' type. Dystonia (e.g. torticollis and writer's cramp) were not encountered, a finding which strongly suggests that many previous studies of 'essential tremor' were contaminated by cases of idiopathic or hereditary torsion dystonia. No association with Parkinson's disease was found but classical migraine occurred in approximately 26% of cases and co-segregated with tremor. The severity of arm tremor (assessed using a clinical rating scale and by scoring tremor in Archimedes spirals) and disability increased with advancing age and increasing tremor duration, but there was no correlation between age at tremor onset and either tremor severity or disability. Men and women were affected with equal severity. The sex of the affected parent had no influence on the severity of tremor or the degree of disability experienced by an affected child. Disability commenced in the second decade and progressively increased. All the index patients and 59% of the definite secondary cases had tremor induced disabilities. Eighty-five percent of index patients and 38% of secondary cases also reported some degree of social handicap. Twenty-five percent of index patients and 12% of secondary cases had been compelled to change jobs or retire. Biological fitness was normal.

The form and distribution of MRI abnormalities in 114 patients with clinically definite multiple sclerosis (MS) have been compared with observations on 53 apparently healthy individuals, 129 patients with isolated focal neurological lesions with which MS often presents (51 patients with optic neuritis, 44 with isolated brainstem lesions and 34 with isolated spinal cord syndromes) and 105 patients with disorders which may be confused clinically or radiologically with MS. The latter comprised 55 patients with cerebral vascular disease (including 7 cases of dementia with diffuse white matter disease), 24 with degenerative ataxic disorders, 8 with cerebellar tonsillar ectopia, 7 with sarcoidosis and 11 with a variety of other disorders. Periventricular abnormalities were found in all but 2 patients with MS and discrete white matter lesions in all but 12. Characteristically the periventricular changes in MS were irregular in outline. Periventricular abnormalities which were often milder and of smooth outline were seen in 37/55 patients with cerebral vascular disease, 9/24 with cerebellar degeneration, 5/7 with sarcoidosis and in 2/3 apparently healthy individuals over the age of 60. The appearances in the 7 cases of dementia resembled those with advanced MS. Cerebellar and/or brainstem atrophy characteristic of the cerebellar degenerations, in the absence of white matter abnormalities, was helpful in making the distinction from MS. Congenital anomalies and tumours in the region of the brainstem and foramen magnum were readily shown. More than half the patients with symptoms attributable to isolated focal neurological lesions had additional lesions at presentation. MS cannot be diagnosed in these cases at presentation, but repeat scans after 5 to 20 months in 25 patients with optic neuritis and 10 with clinically isolated brainstem lesions have shown new lesions in 7 (20%). The patients with new lesions fulfil the criteria for clinically probable MS (Poser et al., 1983). Measurements of T1 and T2 in vivo permitted the distinction of acute from chronic brainstem lesions. There were quantitative differences in T1 and T2 between the normal appearing white matter in MS and normal brain. Studies of postmortem brains provided convincing evidence that the MRI abnormalities in MS correspond with plaques. Evidence is adduced to support the view that an important source of the abnormal NMR signals in acute lesions is oedema, and in chronic lesions is gliosis; demyelination per se is unlikely to make an important contribution.

SUMMARY In 22 families with the "pure" form of hereditary spastic paraplegia inheritance was autosomal dominant in 19 and autosomal recessive in three. Examination of intrafamilial correlation of age of onset in the dominant cases suggested that the disorder is genetically heterogeneous. Two forms of dominant hereditary spastic paraplegia were identified: one with an age of onset mostly below 35 years (type I), and the other with onset usually over 35 years (type II). In the type I cases, delay in walking was not infrequent and spasticity of the lower limbs was more marked than weakness. The disorder was very slowly progressive and was extremely variable in terms of severity. Sixteen per cent of the patients aged over 20 years were asymptomatic but clinically affected. In the type II group muscle weakness, urinary symptoms and sensory loss were more marked. This form of the disease evolved more rapidly. In the three families demonstrating autosomal recessive inheritance the clinical features were very similar to those of the dominant cases. Biological fitness of patients from both the dominant groups was not impaired and no definite evidence of new mutation was observed. A cumulative frequency curve of age of onset in the type I group was constructed which suggested that an asymptomatic child of an affected parent has a 20% chance of developing the disease at the age of 25 years; the risk is probably even less if the child is clinically normal.The first clear description of hereditary spastic paraplegia (HSP) was that of Strumpell' in 1880 although Seeligmiiller2 had described a similar disorder four years previously. Strumpell reported two brothers in whom spastic paraplegia developed at the ages of 37 and 56 years. The reflexes were increased in the upper limbs but, apart from this, the abnormal findings were confined to the legs. Inheritance was probably autosomal dominant. Strumpell3 later described another similar family; the age of onset was in the third or fourth decade but the clinical features were almost identical to the first. Pratt4 commented "The concept of the disorder was originally clear and distinct . . . these observations formed the ideal picture to which later published examples have on the whole regrettably refused to conform." Pratt refers to the profusion of descriptions of "hereditary spastic paraplegia plus" syndromes in the subsequent literature. These include spastic paraplegia in association with mental retardation and ichthyosis,5 pigmentary retinal degeneration,6 optic atrophy,7 amyotrophy,8 9 exAddress for reprint requests:

The clinical features of 11 families containing 73 individuals with dominantly inherited cerebellar ataxia of late onset are described. Many of the patients had physical signs in addition to cerebellar ataxia, which included dementia, supranuclear ophthalmoplegia, extrapyramidal dysfunction, optic atrophy, pigmentary retinal degeneration, myoclonus and deafness. These associated features were generally very variable within members of the same family. Intrafamilial correlation of age of onset and an analysis of clustering of clinical features within families using X2 tests suggested that there was little evidence of genetic heterogeneity in the eight kindreds where ophthalmoplegia, optic atrophy, dementia, or extrapyramidal signs were found in affected individuals. One of these families contained descendants of the 'Drew family of Walworth' described by Ferguson and Critchley in 1929. The three other families contained patients with clinically distinct syndromes which were: cerebellar ataxia with pigmentary retinal degeneration; a later onset (over 60 years) 'pure' cerebellar syndrome; and an ataxia disorder associated with myoclonus and deafness. A simple classification of the autosomal dominant cerebellar ataxias is proposed and discussed in relation to previous attempts to classify these disorders on clinical and pathological grounds.