Brain Advance Access originally published online on May 13, 2008
Brain 2008 131(6):1671-1673; doi:10.1093/brain/awn088
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Book Review |
‘Come sleep, O sleep, the certain knot of peace’ (Sir Philip Sidney, 1554–86)
This book addresses many of the major questions concerning the nature of human prion diseases by combining a chronological approach to the identification, study and diagnosis of these diseases with an historical account of one of the rarest human prion diseases, fatal familial insomnia (FFI). The author describes the effects of FFI on a Venetian family of supposed noble ancestry and interweaves the effects of this strange illness across several generations with descriptions of different forms of prion diseases in animals and humans, beginning with scrapie, passing on to Creutzfeldt-Jakob disease (CJD) and kuru, and progressing to bovine spongiform encephalopathy (BSE) and variant CJD. It is an ambitious attempt to encapsulate ‘prionology’ with personal descriptions of a devastating familial disorder, many of which are historical fiction, albeit informed by a detailed knowledge of the clinical features of FFI and an ability to evoke the changing atmosphere of Venice over the past three centuries.The tale of the family begins with a doctor who is thought to have lived near the Jewish ghetto in Venice in the mid 18th century, a time when Venice was in decline with the lagoon silting up and political influence of the city greatly reduced. The lifestyle and daily activities of a well-connected doctor of that time are described in compelling detail and as the strange disease takes its grip on the doctor, now a patient, the futility of likely attempts at both diagnosis and treatment are given compelling authenticity. One of the most powerful drugs available at that time in Venice, Triaca or ‘Venetian Treacle’, was a foul-tasting concoction that of course had little effect on the patient, who was subsequently consigned to the care of the priests. The decline of the Venetian aristocracy and its effect on the local economy in the early 19th century sets the scene for the next two cases of FFI in a presumed nephew of the Venetian doctor and his son, who pre-deceases his father with a suggested diagnosis of pellagra. The father, developing symptoms of FFI in his mid-50s, is suggested to have died of malaria, which could be treated with quinine at that time. The autosomal dominant inheritance of FFI is then depicted in subsequent generations of this family, some of who blamed their red-headed grandmother for the disease although it was her husband who carried the mutant gene.
The more recent effects of this undiagnosed inherited illness on the family (who by the 20th century have compiled a family tree) can be assessed in greater detail. The shame of belonging to a family with an inherited disorder and the attitudes of other families (who perhaps unsurprisingly were reluctant to allow their offspring to marry into the afflicted family) are tellingly depicted. The manifestations of FFI and their variable symptoms at onset (dizziness, unusual sensations throughout the body before the progressive sleep disorder and autonomic disturbances) contribute to the continued difficulty in establishing a diagnosis (familial encephalitis is by now the most favoured suggestion). These problems are not helped by the depicted attitudes of the general pathologists, who, searching for a lesion in the brain at the time of autopsy, cut the brain into ribbons while unfixed, effectively precluding any meaningful anatomical and histological assessment. However, in more recent cases the brain was preserved intact after the autopsy, although again no specific histological diagnosis was made. The story of the family moves onto 1983, when another middle-aged male member of the family became ill, but this time was referred to Elio Lugaresi, Director of the Sleep Clinic at the University of Bologna. The patient is able to recount a full family history to the physicians in Bologna and informs them exactly what will happen to him based on his observations of the deaths of his father and two sisters. His predictions prove entirely correct, but a clinical diagnosis was still not established at the time of his death.
This time, following autopsy the brain was sent to a neuropathologist, Pierlugi Gambetti in Cleveland. He found that the pathology of this disease was centred in the thalamus, with severe neuronal loss and atrocytosis particularly in the anteroventral and dorsomedial thalamic nuclei. The clinicopathological description of this disease, now termed FFI, was published in 1986. It was not evident at that time that this was an inherited form of prion disease; the appearances of periodic complexes in the electroencephalogram in two subsequent patients from the family suggested a similarity to CJD. This possibility was reinforced by the identification of spongiform change in the brains of these two patients, who had a longer duration of illness than most of the family members who had died recently. The eventual identification of the pathogenic mutation D178N in the human prion protein gene (PRNP) responsible for this illness allowed genetic screening of this family who, like many other families affected by hereditary incurable diseases, found it difficult to judge the value of this particular investigation. The possibility of a cure for prion diseases is discussed at length in relation to this family, but unfortunately, as with so many other fatal neurodegenerative disorders, there is still no effective therapy. The human tragedy resulting from FFI on both a personal and family basis is strongly conveyed throughout; FFI is referred to as ‘the worst disease that you can ever have’. Without wishing to start a competition, I would not necessarily agree with this, but it seems a particularly unpleasant disorder, robbing its victims of sleep and rest, with little chance of even a fleeting episode of peace of mind.
The author laments the lack of progress in finding a treatment (far less a cure) for this disorder, but the impact of FFI has been more extensive than he has described. Several affected families have been identified in Europe, particularly in Germany and Spain, with other kindreds across the world. Studies of these families have shown that the phenotype of FFI is more variable than the portrayal in this book, with some individuals having an illness similar to sporadic CJD, while others have been described with an autosomal dominant cerebellar ataxia-like illness. What is the basis for this remarkable phenotypic variability, given that all affected individuals carry the D178N mutation in the PRNP gene? One possible explanation is the effect of the naturally occurring polymorphism at codon 129 in the PRNP gene, which can result in either methionine or valine being encoded. In FFI, the D178N mutation is associated with methionine at codon 129 in the mutant allele, but either methionine or valine can be encoded in the non-mutant allele. It has been suggested that methionine homozygosity at codon 129 with the D178N mutation is associated with a shorter duration of the clinical illness in FFI, but this appears not always to be the case. The presence of valine on the mutant allele is associated with the phenotype of familial CJD, not FFI, and it has, therefore, been suggested that FFI and familial CJD with the D178N mutation represent extreme ends of a spectrum rather than two distinct and separate entities. Recent haplotype analysis of FFI cases in Europe has suggested that at least two independent D178N-129M mutational events seem to have occurred in the PRNP gene; interestingly, the family in the region of Venice seems to have a different haplotype from another FFI family in the Tuscany region, but which is similar to an affected German family.
The striking thalamic pathology in FFI has allowed a reappraisal of the role of the thalamus in sleep. The anteroventral and dorsomedial nuclei constitute the major part of the thalamus connecting the limbic and paralimbic regions of the cerebral cortex with other subcortical structures including the hypothalamus. Release of the hypothalamus from corticolimbic control appears to result in uncontrolled activation of autonomic activity and loss of sleep, suggesting that the thalamus may have a role in the origin of slow wave sleep. The term agrypnia excitata has been proposed by Lugaresi as a diagnostic category for organic insomnia characterized by severe or complete lack of sleep and motor and autonomic hyperactivation. These features are not specific for FFI and are encountered in several other conditions, including delirium tremens, which result in dysfunction of the medial thalamus and related limbic areas. Serial neurophysiological and 18FDG-PT studies in both symptomatic and asymptomatic carriers of the D178N mutation (published recently in this journal) have suggested that the process of neurodegeneration in the thalamus begins around 1–2 years prior to the onset of symptoms in FFI. There are still no good answers as to why the neurodegeneration in FFI targets selected thalamic nuclei with such precision, or why the relative lack of other conventional neuropathological features of prion diseases (spongiform change and accumulation of the disease-associated isoform of prion protein in the brain) is associated with such severe clinical abnormalities in this disorder.
The history of scrapie is fascinating and well conveyed by the author, who subscribes to the theory that selective inbreeding in many English flocks in the 18th century contributed to the spread of this disease, which may originate from imported merino sheep from Spain—were these imported sheep known by the exporters to be suffering from scrapie? The enormous impact of scrapie on British agriculture at that time is understandably not widely appreciated in medical or scientific circles, yet on reading this account of the illness one is struck by the parallels with the effects of BSE on British agriculture in the late 20th century. Scrapie remains a complex disease, not only least in terms of the genetic polymorphisms in the ovine prion protein gene that have a marked effect on disease susceptibility, but also more recently in the identification of ‘atypical’ forms of scrapie, which appear to result from infection with a prion agent possessing distinct biological properties from the ‘typical’ form of scrapie described here. The identification of atypical scrapie has revealed that this disease may be more widespread geographically in Europe that the typical form, suggesting that ‘atypical’ may not be the most appropriate term for this form of scrapie. Although it is generally accepted that typical scrapie is not pathogenic to man, atypical scrapie is still under investigation, including experimental transmission to transgenic mice engineered to possess a copy of the human prion gene.
In contrast to scrapie, kuru is a disease that has fascinated a wide range of commentators including historians, anthropologists, epidemiologists, geneticists and pathologists. The account of this disease offered here goes someway towards explaining this fascination, beyond the immediate (if repulsive) fascination of cannibalism, since this seems to be the main route of transmission. The identification of kuru and its subsequent experimental transmission to primates is indelibly linked with Carlton Gajdusek, who was awarded the Nobel Prize for Medicine in 1976. The portrait of Gajdusek in this book is not attractive—a brilliant man, flawed in his approach to science and medicine and with an interest in young males that resulted in his imprisonment for sexual abuse in 1997. It appears that Gajdusek was indeed a more complex individual than most, but the emphasis here on his sexuality is unhelpful in understanding his other contributions to this field. Another individual portrait that dominates the later sections of this book is that of Stanley Prusiner. This portrait seems to me to be incomplete—it does not include the enormous difficulties that Prusiner faced following the publication of his prion hypothesis in 1983 and although it is emphasized on more that one occasion that this hypothesis is not yet proven, recent work including the synthesis and transmission of ‘artificial prions’ and the generation of infectious prions de novo using the protein misfolding cyclical amplification technique go some considerable way to providing more supportive evidence. The author could have been more generous in acknowledging the work of Prusiner and his group over many years of sustained and productive research.
The emergence and spread of BSE in the UK in the 1980s is given due prominence in bringing the world of ‘prionology’ to a wider public, although inevitably the description lacks the comprehensive authority of the BSE Inquiry and instead focuses on selected details, including a criticism of the Ministry of Agriculture, Food and Fisheries in restricting access to BSE-infected tissue by leading international prion research institutes. Some of the criticisms are valid, but there seems to be a lack of understanding of the timescales involved in investigative studies of prion diseases, particularly those involving experimental transmission where incubation periods are generally measured in months or years rather than the days or weeks associated with conventional pathogens. The epizootic of BSE is now in its final stages in the UK, but many concerns remain, such as the proposed relaxation of controls on the use of animal foodstuffs containing ruminant proteins that were responsible for the initial spread of BSE in the UK, and the emergence of the novel prion disease bovine amyloidotic spongiform encephalopathy, neither of which are discussed in the text.
The other forms of human prion disease are also given an historically based description, written with a considerable feel for the period in which they are set and a clear sense of the scientific progress evolving from the classical descriptions of sporadic and familial CJD. The commendation of Creuzfeldt in this context is interesting, since review of Creuzfeldt's original case by Prof. Colin Masters and others has suggested it is not what we would currently accept as a human prion disease or spongiform encephalopathy—a reminder that today's novel entity may well be tomorrow's misclassification, a lesson well taken by those of us involved in this area of research. This small example is one of several instances in the account of human prion diseases where an uncritical approach to published evidence is apparent, often accompanied by the opinions of family members who have relatives suffering from a prion disease, or with quotes from scientists or medical practitioners who, although opinionated, often have limited personal experience or history of peer-reviewed research in this field. This is unfortunate, making this section of the book weaker than the others, with a lack of the clarity and detail of the historical narrative surrounding variant CJD and BSE that other writers have achieved (Deadly Feasts, Richard Rhodes, 1997; Cannibals, Cows and the CJD Catastrophe, Jennifer Cook, 1998).
Despite this shortcoming, The Family that Couldn't Sleep is an interesting and enjoyable book to read. I found myself transported with considerable atmosphere to 18th century Venice and England, and the ravages caused by FFI on the Italian family in whom the disease was eventually characterized and named are movingly described. The author's literary talents are matched by a care for historical accuracy and an immediacy of involvement in the sections concerning the Italian family. The account of the evolution of the prion hypothesis, despite the negative personal comments concerning several leading characters, is a firm base on which the remainder is built. There are numerous notes to accompany the enthusiastic reader (or reviewer) who wishes to explore the basis of the histological reconstructions provided throughout the book and I was not disappointed in the standard or clarity of discussion in these footnotes.
But what of the author himself? He is also a patient suffering from a progressive neurological disorder in which a clear diagnosis has not yet been made. The alternatives appear to lie between a form of spinal muscular atrophy or Charcot-Marie-Tooth disease. Why not read this interesting book and reach your own conclusion?—I am sure that the author would appreciate your further opinions.
National CJD Surveillance Unit
University of Edinburgh
United Kingdom
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