From the Archives
A form of familial degeneration of the cerebellum. By Gordon Holmes, M.D. (From the Neurological Research Department, National Hospital, Queen Square, London.) Brain 1907: 30; 466–489: A clinical study of an heredo-familial disease resembling disseminated sclerosis. By Fergus R. Ferguson and Macdonald Critchley. (From the National Hospital, Queen Square, W.C.) Brain 1929: 52; 203–225; and The clinical features and classification of the late onset autosomal dominant cerebellar ataxias: a study of 11 families, including descendants of ‘the Drew family of Walworth’ by A.E. Harding. (From the MRC Clinical Genetics Unit, Institute of Child Health, London). Brain 1982: 105; 1–28.
Although accounts of familial ataxia begin with Pierre Marie, the cases he described were a mixed bag, and MD Sanger Brown had already described a four generation pedigree, showing dominant inheritance, characterised by ataxia, optic atrophy, ophthalmoplegia and cognitive impairment (MD Sanger Brown: On hereditary ataxy, with a series of twenty-one cases. Brain 1892: 15; 21–34; and see Brain 2004: 127; 2382). Gordon Holmes points out that, of the cases categorised by Pierre Marie as ‘L'hérédo-ataxie cérebélleuse’, one only of the relatively few coming to autopsy had anything the matter with the cerebellum. Holmes describes a sibship of eight in which three of five brothers, and one of three sisters progressively lost balance from their mid-30s. Inco-ordination of the arms and dysarthria started about five years later, with a long period of severe disability leading to death at an advanced age, usually from unrelated causes. The three brothers were hypogonadal. At first, three of the siblings were considered to have disseminated sclerosis or Friedrich's ataxia. Gordon Holmes had observed case 4 in life and, when that person died in January 1907 aged 70 years, the central nervous system was examined. Macroscopically, especially the cerebellum but also the pons and medulla were atrophied—being reduced to about one third their expected weight (see Figure 1). The cerebellum retained its normal configuration, but in miniature, and with selective atrophy of the vermis and flocculus. The tonsils and uvula were relatively spared (see Figure 2). Microscopically, there was selective loss of neurones in the granular layer, the few surviving cells appearing abnormal and with abundant nuclear fragments (see Figure 3). Even more striking was the loss of ‘Purkinje’ cells (from Jan Evangelista Purkyn
, 1787–1869). In the most affected parts, not one surviving cell was visible. The dentate nuclei and superior cerebellar peduncle were relatively normal, as were connections from the pontine nuclei through the middle cerebellar peduncle. The inferior and accessory olives were severely depleted of neurones, and much atrophied, with loss of the medullary tracts normally connecting the olives to the opposite cerebellar hemisphere (see Figure 4). Throughout, there was intense neuroglial proliferation. Neuronal loss was accompanied by profound demyelination although the glial and neuronal elements showed markedly different distributions.
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Holmes debates the nature of fibre arrangement in the olives and concludes that it is normally cerebellofugal. The olivary changes are secondary to neuronal depletion in the cerebellum, and represent ‘reaction à distance’—other afferent connections to the cerebellum being spared. Thus, the condition is a disorder of selected cerebellar cortical neurones, their afferent pathways, and the association fibres passing between folia and connections with the intrinsic nuclei, but not those neurones themselves or their outflow pathways. For the rest, the pons, cerebrum, optic nerves, spinal cord, and peripheral nerves are normal. Functionally, the ability to sort crude afferent impulses and transmit a more organised arrangement to the deep nuclei is lost, so that these remain silent or active intermittently and, as a result, movement lacks coordination.
By 1906, Holmes is classifying cases as having primary parenchymatous degeneration (his own family being a good example), olivopontocerebellar degeneration (the first description of any such disorder having been provided by P Menzel: Beitrag zur Kenntniss der hereditären Ataxie und Kleinhirnatrophie. Archiv für Psychiatrie und Nervenkrankheiten 1891: 22; 160–190), and degeneration confined to the spinocerebellar tracts (as described by MD Sanger Brown). Later, although the pattern of inheritance was evidently recessive and the phenotype included hypogonadism, the term ‘Holmes’ type cerebello-olivary atrophy came to be used as the descriptor for all late onset dominantly inherited ataxias lacking genital abnormalities, especially if the pathology was suggestive. But opinion continued to differ on whether the ‘lesion’ lay primarily in the cerebellum or the olives.
Despite having no pathological material on which to comment, Fergus Ferguson and Macdonald Critchley cannot accept the working diagnosis of disseminated sclerosis in 13 individuals from 3 generations in the Drew family of Walworth, South London. Various members of the pedigree had attended the National Hospital since the late 19th century. Considering 33 relatives on whom they had some information, onset is usually in the fourth decade: males and females are both affected; and the course is progressive from onset with variable survival. The main clinical features are intention tremor; dysarthria and loss of balance; ‘euphoria’ and impairment of intellect; optic atrophy; failure of upgaze and (in some instances) horizontal eye movements, with lid retraction; weakness and pyramidal signs including Babisnki responses; Parkinsonism, manifesting as bradykinesis and rest tremor; widespread but somewhat variable sensory loss; and impaired sphincter control. Pes cavus and spinal deformities are uncommon. So, from what condition do the Drews of Walworth suffer? Not familial disseminated sclerosis or Schilder's disease; not progressive lenticular degeneration nor pseudo-sclerosis, whatever that label might represent; not neurosyphilis (although more than one affected person was considered also to have that disorder); not obviously Friedrich's or Marie and Londe's disorders; slightly reminiscent of Sanger Brown's description, the closest fit is with ‘Holmes’ disorder. So, Ferguson and Critchley tackle the tricky nosology of the heredo-familial ataxias touring the literature for case reports and listing similarities and dissimilarities between their own and these earlier accounts. They try both an elastic (or ‘catholic’, as they also style it) and a narrow position on Marie's ‘hérédo-ataxie cérebélleuse’, and pay particular attention to erroneous diagnoses of familial disseminated sclerosis, including one perpetrated by the illustrious Jean-Martin Charcot. Clearly, clinical phenotype is not a reliable indicator, and even the pathology may not be stereotyped. Does the Drew family illustrate a new entity; an atypical example of Marie's disorder; or merely represent one of the overlapping group of heredo-familial ataxias that includes everything thus far described? "We are probably justified in regarding them all as abiotrophies differing merely in anatomical incidence or in viability".
Ninety years after Sanger Brown, Anita Harding points out that description and classification have still not resolved the relationship of these various disorders. Families are segregated, on the basis of pathology, into olivopontocerebellar atrophy, cerebro-olivary degeneration, and parenchymatous cortical cerebellar atrophy. But other structures are often involved. Most families show more extensive clinical features than just the progressive cerebellar syndrome; and the phenotype often varies within a given pedigree. Pleitropic effects seem probable.
For Harding, very few reports in the literature actually match the entity of parenchymatous cortical cerebellar atrophy and, when they do, the changes are rarely confined to the cerebellum. The core features are usually degeneration of the cerebellum and olives but also with involvement of the dentate, pontine and hypoglossal nuclei; the substantia nigra and spinocerebellar tracts or posterior columns; and the anterior horn cells. Anita Harding relates how, over the years, a good deal of semantic bickering has characterised the shifting classifications of these disorders. Now, a system that is sensitive to the pathological, and the genealogical and clinical features, is needed. Her contribution is to describe 11 pedigrees, each with the onset of autosomal dominant ataxia in the late 30s, from amongst a trawl of 200 potential families seen at institutions in central London over the previous 15 years, and with a proband still living in southern England. Taken together, only one pedigree has pure cerebellar ataxia. Various combinations of dementia, ophthalmoplegia, optic atrophy, myoclonus, deafness and pigmentary retinopathy are usually also observed. Of these, the distribution of optic atrophy (usually without much impairment of vision), supranuclear upward saccadic vertical gaze paresis, extrapyramidal features including chorea, and dementia are random amongst pedigrees irrespective of disease duration. Pigmentary retinal degeneration, often preceding the awareness of ataxia, sensorineural deafness, myoclonus, and onset beyond the sixth decade all cluster within families.
Clinical analysis leads Anita Harding to conclude that different genes must be responsible for the group of autosomal dominant cerebellar ataxias of late onset, and to consider that (following Gordon Holmes), varying considerably within families, some features cannot be specific markers for any one genetic defect. She considers that optic atrophy (usually with relative preservation of vision), supranuclear ophthalmoplegia, dementia (used to describe alterations of mood and severe cognitive failure), extrapyramidal features (chorea, facial impassivity and rigidity), and amyotrophy occurring with cerebellar ataxia, may be the expression of a single pleotropic gene mutation. A second is marked by ataxia with retinal degeneration; these cases may or may not have ophthalmoplegia, dementia and extrapyramidal involvement. Thirdly, cerebellar ataxia may occur in isolation. And, last, there are families in which ataxia is associated with myoclonus and deafness. The presence, or not, of pyramidal signs and loss of tendon reflexes adds little to the system of classification.
This clinical detective work occurred in an era before linkage analysis and molecular diagnosis were generally available. But the classical genetic analyses of Holmes, Ferguson and Critchley, and Harding laid a brilliant foundation for the mapping and characterisation of 26 genetic loci (SCA9 has yet to be assigned)—to which Claudia Cagnoli and colleagues now add one more.
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