Brain (1990) 113, 721-747 FAMILIAL CEREBRAL AMYLOID ANGIOPATHY WITH NONNEURITIC AMYLOID PLAQUE FORMATION byG. T. PLANT, 1 ' 2 T. RE'VE'SZ,2 R. O. BARNARD, 2 A. E. HARDING 1 and P. C. GAUTIER-SMITH 1 (From 'The National Hospital for Nervous Diseases, Queen Square, and 2The Department of Neuropathology, Maida Vale Hospital, London, UK) SUMMARY INTRODUCTION Worster-Drought et al. (1933) first reported a family with an autosomal dominant condition characterized clinically by the onset in the fifth decade of dementia, progressive spastic tetraparesis and cerebellar ataxia. Subsequently the autopsy findings were described in two siblings (Worster-Drought et al., 1940, 1944). These papers have been extensively quoted and are of particular interest because the pathological findings constitute the earliest English language descriptions of cerebral amyloid (congophilic) angiopathy (CAA). The appearances were described in the original papers as a form of hyaline degeneration of the blood vessels and it was not until some years later (McMenemey, 1952, 1970) that the pathological material was reviewed and the fact that the material had the staining properties of amyloid was appreciated. The classification of this family has remained uncertain (Baraitser, 1982) and it has been quoted as an example of atypical Alzheimer's disease (Corsellis and Brierley, 1954; Boellaard and Schlote, 1980; Aikawa et al., 1985); an example of the Gerstmann-Straussler syndrome (GSS) (Masters et al., 1981a; Keohane et al., 1985; de Courten-Myers and Mandybur, 1987; Pearlman et al., 1988); and has also been likened to other familial amyloid angiopathies usually associated with intracranial haemorrhage and thus regarded as a specific form of primary CAA (Gudmundsson et al., 1972; Shaw, 1979; Pro et al., 1980; Vinters, 1987). Correspondence to: Dr Gordon T. Plant, National Hospital for Nervous Diseases, Queen Square, London WC1N 3BG, UK. © Oxford University Press 1990 Downloaded from by guest on June 15, 2015 Two families have been described previously with the features of an autosomal dominant familial cerebral amyloid angiopathy with nonneuritic plaque formation. The clinical features of the cases were dementia, spastic paralysis and ataxia. It has now been established that both families were descended from a common ancestor and the case histories of 26 affected individuals in 5 generations of this pedigree are reported. An autopsy study has been performed on a recent case. The findings are described and compared with the four previously published autopsy studies in this family, which is then discussed in the context of recent advances in the nosology of familial disorders in which cerebral amyloid angiopathy and other forms of cerebral amyloid deposition occur. 722 G. T. PLANT AND OTHERS Griffiths et al. (1982) have recently described autopsy findings in two siblings who had died from an illness which the authors suggested was 'clearly the same' as that reported by Worster-Drought et al. (1940, 1944). They were able to identify very few other cases that truly resembled the 2 siblings in a thorough survey of the literature. The purpose of this paper is to report genealogical evidence which has shown that the 2 'families' are descended from a common progenitor: the clinical details of 26 affected members in 5 generations of this pedigree are now available, together with pathological findings in a newly autopsied case. The disorder is then discussed in the light of the considerable recent advances in the understanding of familial CAA and other syndromes involving amyloid deposition in the central nervous system. Some of the findings have been published in abstract form (Plant and R6v6sz, 1989). PATIENTS AND METHODS Family study Postmortem examination A postmortem examination was carried out on a further affected family member (Case V41 in fig. 1 and Appendix) and the findings have been compared with the results obtained in 4 previously published cases (TV13, IV15, Worster-Drought et al., 1940, 1944; V4, V7, Griffiths et al, 1982) and 1 recently deceased unpublished case (V45, material provided by courtesy of P. L. McGeer). Postmortem examination was carried out 24 h after death. The right half of the brain, including brainstem and cerebellum and also parts of the lower cervical and thoracic spinal cord, were immersed and fixed in 10% buffered formalin while the left half was deep frozen and kept for further neurochemical studies. The right half of the brain was cut in coronal slices after 3 wks of fixation. Several representative blocks were taken and these were embedded in paraffin-wax and celloidin. Sections of 20 /tm thickness were cut from the celloidin blocks, and 7 — 10 /tm thick sections from those embedded in paraffin-wax. These were stained with haematoxylin and eosin, Kluver-Barrera luxol fast blue and cresyl violet, modified Bielschowsky silver, periodic acidSchiff (PAS) and haematoxylin, Mallory phosphotungstic acid haematoxylin (PTAH), Heidenhain myelin, Congo red and thioflavin T. Sections (7 /jm) of paraffin-wax embedded blocks were used for the immunohistochemical demonstration of glial fibrillary acidic protein (GFAP). One block of the parietal area was cut serially in order to establish vascular changes in connection with a cystic infarct (lacune). The frequency of perivascular and other amyloid plaque-like deposits in different areas of cerebral cortex and subcortical white matter was estimated in a semiquantitative way using 10 /an PAS-stained sections. Amyloid plaques were counted in 25 consecutive fields of each gyrus from neocortical areas investigated at X100 magnification, and were also counted in different areas of the hippocampal formation over 1 to 3 fields. The results were then averaged to provide single plaque counts for 1 mm2 area of each anatomical region. The frontal and parieto-occipital plaque counts were compared with the help of Mann-Whitney U test. Several pieces of cerebral cortex, hippocampus, cerebellum, fixed originally in formalin, were washed in phosphate buffer, postfixed in 1 % buffered osmium tetroxide, dehydrated in ethanol and embedded in Araldite. Semithin and ultrathin sections were cut and the ultrathin sections examined in a Siemens Elmiskop I electron microscope after double staining with uranyl acetate and lead citrate. Downloaded from by guest on June 15, 2015 Reliable information has been assembled concerning 26 affected family members. The detailed clinical histories are given in the Appendix, together with their sources. FAMILIAL CAA WITH PLAQUES 723 RESULTS Family study Downloaded from by guest on June 15, 2015 The pedigree is shown in fig. 1 to illustrate the transmission of the gene in this family. Apart from bringing the pedigree up to date, genealogical analysis has permitted us to combine 2 previously published pedigrees. In the pedigree published by WorsterDrought et al. (1940), Case 7 (III1 in fig. 1) was recorded as unaffected although it was known that a daughter had died in an asylum. This pedigree had been compiled from information provided by the husband of IV15 at a time when she was demented. However, in the National Hospital case notes of IV12 (admitted twice, in 1924 and 1926), a family history given by IV15 at a time when she was unaffected by the disease clearly states that m i had died of the family disease. Furthermore, details such as the married name of HI 1 and the occupation of her husband have proved that the grandmother of the siblings reported by Griffiths et al. (1982; 'A' in the published family tree) was also our Case n i l . Further research has provided a more detailed account of the descendants of UI1 than was available to Griffiths et al. (1982). The main symptoms of the illness in the affected members are given in Table 1 {see Appendix for detailed case histories). The mean age of onset of symptoms has been 47 (range 40—57) yrs and the mean age at death 56 (range 50—66) yrs. All cases have in the late stages of the illness manifested a chronic vegetative state; they were mute and unresponsive, doubly incontinent with severe spasticity and often contractures. In all cases dementia and spasticity have been prominent clinical features. Memory impairment has been the earliest manifestation of the dementia. In the case of V41 a psychometric assessment was carried out at an early stage in the disease (she had had symptoms for 1 yr): verbal IQ was well preserved at 115 but there was marked impairment of memory with milder impairment on perceptual tests. Similar results were obtained in V2 3 yrs following the onset of symptoms. Cerebellar signs have been a common feature. Some affected individuals have sustained stroke-like episodes but there have been no instances of massive intracranial haemorrhage except in V40, who was found at autopsy to have a ruptured berry aneurysm. The brain was not examined in detail and it is likely that this was a coincidental aneurysm. In view of the facts that he had no symptoms before the subarachnoid haemorrhage and was aged only 48 yrs at death there is no way of knowing whether or not he was affected by the disease unless either of his 2 sons begin to show signs of it. Less constant clinical features have been headaches, personality change and 'blackouts'. Two cases have been found to have depressed tendon reflexes despite spasticity and 1 of these 2 had myoclonus. It is possible that the clinical course has been modified in those cases known to have had coexisting hypertension (V2, V4, V45), all of whom suffered stroke-like episodes. The autosomal dominant mode of inheritance has been confirmed by the continued uninterrupted transmission from one generation to the next and the segregation and sex ratios (Table 2). In this analysis, in the absence of autopsy information, it has been 05) (•») 0 0 (£» IB) (f» < FIG. 1. Pedigree. («) (43) (42) (J7) (3D (T7) > (I» OH (S») ( i » Q Q No descendants 0 D Age at death or In 1989 (where known) 0 0 Deceased O D Uncertain or not at risk © H Unaffected (for segregation analysis) • • Affected Downloaded from by guest on June 15, 2015 in m D O H z r p 44 43 57 54 50 F M M F M M F F V4 V7 V15 V28 V32 V33 V41 V45 51 55 52 50 65 64 61 56 63 52 60 54 53 66 50 53 52 56 51 56 54 54 56 0 0 0 + 0 0 + + + + + + +• +• +• + + + + 0 + + +• + + + + +* + + +• + +• + + + + + + + + + + + + + + • + + + + + + +• +• ± 0+ + + 0 +• 0 +• +• +• + + + 0 0 + +• 0 0 0 + 0 0 +* + 0 0 + + + 0 +* 0 0 0 0 + 0 + 0 0 +• 0 0 0 + 0 0 0 0 + + 0 0 0 +• +• + 0 0 0 0 0 u 0 0 + 0 0 0 0 0 0 + + 0 00 0 0 0 + + 0 0 0 0 00 0 0 "0 + 1--• 'Blackouts', hypertension, diminished tendon reflexes Areflexia, unrcactive pupils, 'blackouts', hypertension 'Blackout', hypertension Kyphoscoliosis from his teens + = definitely present; ± = definitely present, but to a minor degree; 0 = definitely absent; blank = insufficient information; • = earliest manifestation. 48 56 42 45 50 46 57 44 48 48 48 40 + 42 46 45 50 44 Case Sex 111 F 112 F 1111 F 1112 M III3 F 1114 F 1115 F III6 F IV! M 1V2 F IV3 F 1V6 M IV9 F 1V12 F 1V13 M IV15 F IV17 F V2 F Brainstem Age at Personality Progressive symptoms onset of Age at changes Progressive cerebellar (diplopia, symptoms death (irritability memory Progressive ataxia giddiness, Stroke-like loss paralysis Spasticity dysarthria bulbar palsy) Headaches episodes (yrs) d epres birs) 40 53 + + + 0 0 0 + Additional features TABLE I. CLINICAL FEATURES OF THE DISORDER IN AFFECTED FAMILY MEMBERS SHOWN IN FIG I Downloaded from by guest on June 15, 2015 C > x t n 2 p - 726 G. T. PLANT AND OTHERS TABLE 2. GENETIC ANALYSIS OF THE PEDIGREE DATA, SEGREGATION AND SEX RATIOS' Sibs Affected Unaffected Segregation ratio Sex ratio (affected) Sex ratio (unaffected) Female 16 15 Male 8 11 Total 24 26 31 19 50 24/50 = 48% 8/24 = 33.3% male 11/26 = 42.3% male (P > 0.05) (P > 0.05) (P > 0.05) * In this analysis it has been assumed that any individuals who have reached the age of 60 yrs without showing evidence of the disease were unaffected. Siblings who have died before reaching age 60 of an unrelated cause have been excluded. There is a preponderance of females in this group and the low proportion of affected males is not statistically significant (x2 test with Yates correction). assumed that individuals who have reached the age of 60 yrs without symptoms did not have the disease. FIG. 2. Case V4I. CT brain scan performed 1 yr following the onset of symptoms at age of 58 showing white matter changes. Downloaded from by guest on June 15, 2015 CT and MRI scan appearances Fig. 2 shows a CT brain scan of Case V41, 1 yr following the onset of her symptoms at the age of 58 yrs, showing mild ventricular dilatation and excess low attenuation in frontal and parietal white matter. These appearances are more clearly demonstrated in the MRI scan shown in fig. 3 which was carried out on V2 at age 60, 3 yrs following the onset of symptoms. These images show abnormal periventricular white matter with U fibre sparing, a relatively normal appearance of the basal ganglia and no cortical atrophy. Abnormal areas of high signal are also seen in the brainstem and white matter of the cerebellar hemispheres. F A M I L I A L CAA WITH PLAQUES 721 FIG. 3. Case V2. MRI brain scan at age of 60 yrs, 3 yrs following onset of symptoms, showing extensive periventricular white matter changes. Histological findings The pathological changes are summarized in Table 3 and a detailed description is given below. The main histological findings were of severe and widespread deposition of amyloid in small cerebral arteries and arterioles; the presence of amyloid plaques of different types; the presence of neurofibrillary tangles (NFTs); and ischaemic white matter damage. Downloaded from by guest on June 15, 2015 Pathological findings (Case V41) The immediate cause of death was bilateral bronchopneumonia. The coronary arteries, and the thoracic and abdominal aorta showed minimal atherosclerosis. The unfixed brain weighed 1400 g. There were no relevant findings, and especially no amyloid, on microscopic examination of extraneural tissues. The right half of the brain weighed 650 g after fixation. The leptomeninges were slightly thickened over the frontal and central gyri. The hemisphere sulci were slightly widened and the cerebellum seemed to be moderately, but diffusely, atrophied. The cerebral cortex appeared to be well preserved throughout. In the deep periventricular white matter and corona radiata there were several small cystic infarcts. The most affected parietal and occipital white matter was greyish in colour and the surface was finely granular (fig. 4). In addition, the deep white matter was considerably atrophied and all parts of the lateral ventricle were enlarged. With the exception of the anterior third of the corpus callosum, which was relatively well preserved, this structure appeared significantly shrunken. The brainstem and the lower cervical and thoracic spinal cord, the only segment of the spinal cord received for investigation, were normal. 728 G. T. P L A N T A N D O T H E R S TABLE 3. TOPOGRAPHICAL DISTRIBUTION OF MAIN PATHOLOGICAL FINDINGS Area investigated Frontal cortex Parietal cortex Temporal cortex Occipital cortex Hippocampus Amygdala Cerebral white matter N. basalis Meynert Striatum Pallidum Thalamus Subthalamic nucleus Red nucleus Substantia nigra Mesencephalon Pontine raphe Inferior olive Medullary pyramids Restiform body Spinal cord Ccrebellar cortex Cerebellar white matter Dentate nucleus LGP — + + + + + + — _ _ _ _ _ _ + + _ _ + + _ Amyloid plagues SMP PVP NP NFTs . . + — + + + + + + + + + + + — + — — + + _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ + _ _ _ _ _ _ _ _ + + + _ _ _ _ _ _ _ _ — + — — + — + — _ + _ _ Vascular amyloid + + + + + + + + + + + + + + + + + + + + + + + Neuron loss + + — — _ + _ _ — + — _ + + -I- Gliosis Subpial Subpial Subpial Subpial + + + — _ + _ _ — + + + + — + + + Myelin pallor — + — — — + + + + + + LGP = large plaques; SMP = small plaques; PVP = perivascular plaques; NP = neuritic plaques; NFTs = neurofibrillary tangles; + = pathological change found; - = pathological change not found. Downloaded from by guest on June 15, 2015 FIG. 4. Case V4I. Parieto-occipito-temporal brain slice showing grey discolouration of periventricular white matter. F A M I L I A L CAA WITH P L A Q U E S 729 Blood vessels The main trunks of cerebral arteries in the meninges showed only rare intimal thickening and atherosclerotic changes. However, the small arteries and arterioles of the generally thickened leptomeninges, cerebral and cerebellar cortices and white matter, basal ganglia, diencephalon, brainstem and spinal cord all exhibited severe generalized deposition of PAS and Congo red positive material. This was birefringent, with the characteristic apple-green colour in polarized light after Congo red staining, and was fluorescent in thioflavin T preparations, thus confirming the presence of amyloid (fig. 5A). The diameter Downloaded from by guest on June 15, 2015 •-V : * . V FIG. 5. A, arteriolar thickening with deposition of amyloid showing birefringence. Congo red, polarized light. Bar = 100 fim. B, electron micrograph of an arteriole showing a thickened wall composed of fibrillary structure with radiating fibrils. Bar = 0.5 ftm. Insert: cortical capillary with amyloid. PAS stain. Bar = 50 ton. of the vessels affected by amyloid deposition was never larger than 150 /xm. Capillaries in the parietal and occipital cortex, cerebral white matter, cerebellar cortex, brainstem and spinal cord were frequently involved. Amyloid did not appear to be present in veins. Different stages of amyloid deposition resulted in different types of degenerative changes. (1) Severe homogeneous thickening of the arteriolar wall resulting in narrowing or complete obstruction of the lumen. This change was most often found in the cerebral white matter. Thickening of capillary walls also resulted in narrowing of lumina and 730 G. T. PLANT AND OTHERS occasionally complete obliteration (fig. 5B). (2) Frequent fibrous intimaJ thickening with an 'onion skin' appearance, and fragmentation of the internal elastic lamina and significant narrowing of the lumen, associated with amyloid. (3) Splitting of the arteriolar wall producing the picture of 'double barrelling', observed most frequently in the wall of the leptomeningeal, cortical and white matter arterioles. (4) Occasional peri vascular and rare transmural inflammatory infiltrates composed mainly of lymphocytes were seen. In a few instances plasma cells and multinucleated histiocytic cells were also present. (5) Thinning of the degenerate arteriolar wall with occasional aneurysmal formation was also a feature. (6) Spicules of amyloid frequently spread radially from capillaries into perivascular neural tissue, to produce perivascular plaques (drusige Entartung; Scholz, 1938). These were seen in many areas of the cerebral hemispheres, brainstem, cerebellum and spinal cord {see below). Downloaded from by guest on June 15, 2015 Plaque formation 'Large'plaques. These plaques (approximate maximum diameter: 150 /tin) appeared as large globular masses, often with a central, strongly congophilic star-shaped core and peripheral radiating fine spicules or coarser processes. The outermost part of these plaques was always composed of a finely fibrillated pale, congophilic area (fig. 6A). Some of the cortical plaques were similar to Kuru plaques {see, e.g., Boellaard and Schlote, 1980; Schlote et ai, 1980). There were occasional microglial cells inside or near these plaques. With PTAH and GFAP stains a fine network of glial fibres was revealed around the outside of the large plaques, and delicate glial fibres appeared to spread into the centre from the periphery (fig. 6B). These plaques were most numerous in the fascia dentata, CA3 and CA4 segments of the hippocampal pyramidal cell layer, presubiculum, and basolateral nucleus of the amygdala. They were occasionally seen in the cerebellar cortex, cerebral cortex, subcortical white matter, brainstem and spinal cord (fig. 6c and D). 'Small'plaques. These plaques (maximum diameter around 30 /tm) closely resembled the central core of the large plaques, but were naked and did not show any peripheral pale zone. They were made up of a more or less homogeneous central area from which either fine peripheral spicules or coarser, irregular processes radiated. Many of these small plaques had irregular outlines. The small plaques also gave positive reactions for amyloid (fig. 7A). They were numerous in the CA1 and, in part, CA2 segments of the hippocampal pyramidal cell layer (fig. 7B). Similar small plaques were only occasionally seen in the granular cell layer of the cerebellum and also the basolateral subnucleus of the amygdala. An interesting pattern of distribution of plaques was noted in the hippocampus. The small plaques were found in CA1 and CA2, while the large ones were restricted to CA3, CA4, the granular cell layer of the fascia dentata and prosubiculum. In CA1 only occasional neurons were seen, while the number of remaining neurons in CA2, CA3, CA4 and prosubiculum was slightly higher. 'Perivascular'plaques. These plaques appeared as pale, homogeneous or fibrillated structures around capillaries or arterioles. They were faindy PAS positive, but not FAMILIAL CAA WITH PLAQUES 731 •;>,•• Downloaded from by guest on June 15, 2015 jjkg . ;*>'' thsM i) FIG. 6. A, 'large' plaques in the end-plate and fascia dentata of the hippocampus. PAS stain. Bar = 100 jun. B, 'large' plaques surrounded by numerous reactive astrocytes in the end-plate of the hippocampus. GFAP stain. Bar = 50 jim. c, 'large' plaque in the cerebellar granular cell layer. Bielschowsky silver stain. Bar = 50 /im. D, electron micrograph of a 'large' cortical amyloid plaque showing a core with fibrillary material and peripheral radiating processes. Bar = 0.5 jim. Insert: for comparison, the light microscopic picture of the core of a 'large' plaque from the inferior parietal lobule. PAS stain. Bar = 20 jun. urn I * • Downloaded from by guest on June 15, 2015 v- G. T. PLANT AND OTHERS ; •<<5. •J FIG. 7. A, CAl segment of the hippocampal pyramidal cell layer crowded with 'small' amyloid plaques (arrows). There is marked astrocytic gliosis (arrowheads). PAS stain. Bar = 25 [im. B, neurofibrillary tangles and 'small' nonneuritic plaques (arrows) in the same area. Bielschowsky silver stain. Bar = 15 jun. c, neurofibrillary tangles in the nucleus basalis of Meynert. Bielschowsky silver stain. Bar = 20 pm. F A M I L I A L CAA WITH P L A Q U E S 733 uncommonly had a strongly congophilic core. When they had a dense core these plaques were very similar to the large plaques, except that they contained a centrally or more peripherally arranged capillary whose lumen was often completely or nearly completely obliterated. These plaques were seen in the molecular and granular cell layers of the cerebellar cortex and also in the cerebral cortex and white matter. Most of the plaques in the cerebral and cerebellar cortex and white matter seemed to be perivascular in origin. With Bielschowsky preparations the cores of all three types of plaques were argyrophil, but only a minority of the large plaques in the hippocampus, amygdala and subiculum seemed to contain dystrophic neurites, resembling neuritic plaques of Alzheimer type. The distribution and frequency of amyloid plaques in different neocortical areas and the hippocampal formation are shown in Table 4. The number of amyloid plaques/mm2 is given. Statistical analysis revealed that cortical areas of the parieto-occipital region contained a significantly larger number of amyloid plaques than frontal cortex (P < 0.007; Mann-Whitney U test). TABLE 4. DISTRIBUTION OF AMYLOID PLAQUES IN DIFFERENT AREAS OF CEREBRAL CORTEX Number of plagues (per mm2) Area investigated Superior frontal gyrus Middle frontal gyrus Inferior frontal gyrus Orbital gyri Gyrus rectus Cingulatc gyrus Motor cortex Sensory cortex Inferior parietal lobule Paracentral lobule Precuneus Superior temporal gyrus Middle temporal gyrus Inferior temporal gyrus Fusiform gyrus Lingual gyrus Hippocampal gyrus (entorhinal cortex) CA1 CA2-3 CA4 Dentate fascia Prosubiculum Subiculum Pre and parasubiculum Striate cortex Occipital gyri Cortical Subconical white matter 0.2 0.2 0.1 0.1 0.1 0.0 0.4 0.3 1.0 0.4 0.1 0.6 0.1 0.4 0.3 0.8 0.6 0.2 0.7 0.5 0.2 0.2 0.1 0.7 0.2 0.4 0.4 0.5 0.9 0.5 0.6 0.3 63.0 27.3 34.1 12.5 45.1 2.3 1.3 3.0 2.8 0.7 0 0 0 0 0 0 0 0.6 0.4 1.3 Downloaded from by guest on June 15, 2015 Neurofibrillary tangles (NFTs) NFTs were numerous from CA1 to CA4 segments of the pyramidal cell layer of the hippocampus, in prosubiculum, subiculum, para- and presubiculum, entorhinal cortex, 734 G. T. PLANT AND OTHERS lingual gyrus, and amygdala (fig. 7B). They were also found in the nucleus basalis of Meynert and pontine raphe nucleus (fig. 7c). Few neurons remained in the pyramidal cell layer of the hippocampus that did not show this change. From the prosubiculum to the lingual gyrus NFTs were mainly seen in the superficial areas of the cortex, where they were found in great number. Downloaded from by guest on June 15, 2015 Other findings Subpial gliosis was often seen over some of the gyri, particularly in the medial temporal cortex. The cerebral cortex was generally well populated with neurons and no gliosis was seen in the deeper cortical layers. There were, however, several small ischaemic lesions and also a few small mainly perivascular, haemorrhagic foci composed of haemosiderin-laden macrophages. Myelin preparations showed significant rarefaction and pallor of the hemisphere white matter affecting all major regions. These changes were generally more pronounced in the corona radiata and periventricular areas, while the parietal and occipital white matter, specifically around the trigone and occipital horn of the lateral ventricle, appeared to be the most severely affected. The myelin loss was patchy and tended to spare the subcortical U fibres. It was always accompanied by axon damage and loss. In the affected areas astrocytic gliosis was constant but variable. There was several small lacune-like lesions in the frontal and more often in the parietal white matter. The penetrating small arteries and arterioles of the cerebral white matter were among those most severely involved by amyloid deposition. Several vessels with markedly thickened walls and very narrow lumina were present, especially in the frontal and parietal lobes (fig. 5A). Close to one of the lacunes in parietal white matter a small artery with severe amyloid deposition, 'double barrelling' and fibrous occlusion of its lumen was found. The lentiform and caudate nuclei were normal. The blood vessels in these structures were only slightly involved. However, the small vessels of the thalamus were more significantly affected by amyloid deposition. In the ventrolateral nucleus there was a small cavity partly occupied by lipid-laden macrophages. The subthalamic nucleus was normal. The changes in the cerebellum were widespread and severe, resulting in disruption of the structure in many areas. Congophilic angiopathy of the small arteries, arterioles and frequently capillaries, as well as the presence of amyloid plaques, most frequently perivascular, were all prominent features. Structures near to the midline, including the vermis, were among those most severely affected. There was some diffuse cell loss in the granular cell layer and more severe Purkinje cell loss. Axonal torpedoes were numerous. There was moderate to severe isomorphic gliosis in the molecular layer. In addition there were focal ischaemic lesions with tissue necrosis and cavitation in the cerebellar cortex and white matter. There was gliosis in and around the hilum of the dentate nucleus, which also showed neuron loss. In the mesencephalon slight periaqueductal gliosis was present. In the rostral pons there was very slight astrocytic gliosis in the paramedian reticular formation. FAMILIAL CAA WITH PLAQUES 735 Myelin pallor due to long tract degeneration was seen in the pyramids of the medulla. In addition, other white matter structures, notably the middle segment of the restiform body and the ventral spinocerebellar tract, were also involved. There was severe diffuse neuron loss accompanied by gliosis in both inferior olives. There was significant pallor of myelin staining and also loss of axons of the efferent fibres in the hilum and also that of the circumamicular fibres. In the dorsal part of the medial accessory olive there was neuronal loss and gliosis. Only the lower cervical and thoracic portions of the spinal cord were available for neuropathological examination. Mild pallor of myelin staining of the gracile and cuneate fasciculi and also of the lateral funiculus involving the corticospinal and dorsal and ventral spinocerebellar tracts was found. The uncrossed corticospinal tract was also involved. In addition, the involvement of the subpial region in the whole circumference of the cord was a general feature. A few large plaques and perivascular plaques were seen in both grey and white matter. DISCUSSION Clinicopathological correlation The clinical features of the condition may be summarized as a dominantly inherited disorder, with onset around the fifth decade, characterized by progressive dementia, spasticity and cerebellar ataxia. These three elements differ in degree between cases. Stroke-like episodes occur occasionally. The pathological features are consistent in the 6 cases autopsied to date and the following features have been common to all; severe and widespread amyloid angiopathy of the brain and spinal cord with perivascular amyloid plaque formation; periventricular white matter change resembling Binswanger's leukoencephalopathy; small haemorrhagic lesions and infarcts; nonneuritic amyloid plaques affecting cerebellum, hippocampus, amygdala and occasionally cerebral cortex; and neurofibrillary tangle formation in hippocampal neurons. Inconstant features have been: senile (neuritic) plaques in the hippocampus in IV13 (Worster-Drought et al., 1940, Case 1) and V4 (Griffiths et al., 1982, Case 1). Amyloid plaques were more widespread in some cases, being found in white matter, cerebral cortex and brainstem (V4, V7 and V41). In 1 case (V7) the vessels of the spinal cord were relatively spared. It is interesting to note that haemorrhagic changes were most prominent in case V4 who Downloaded from by guest on June 15, 2015 Electron microscope findings The walls of arterioles and affected capillaries were completely replaced by interwoven bundles of ~ 10 nm filaments which were rather short and were arranged in a disorderly way. These filaments tended to radiate into the surrounding neural tissue (fig. 5B). NO basement membrane was found around the affected vessels. The amyloid deposits in plaques showed crisscrossing and, at the periphery, radially arranged fibrils with an approximate diameter of 10 nm (fig. 6D). 736 G. T. PLANT AND OTHERS Relationship to other familial conditions We cannot attempt to provide a definitive classification of this disorder but wish to compare it with a number of other familial conditions. Whether this disorder is unique or a variant of another disease discussed below will not be known until the identity of the amyloid protein has been determined and/or the defective genes have been analysed in detail. Familial Alzheimer's disease Since 1932 at least (Schottky, 1932), there have been a number of reports of familial Alzheimer's disease. A recent report describing 24 kindreds with pathologically verified familial Alzheimer's disease (Bird et al., 1989) has emphasized the phenotypic heterogeneity of the disorder which can be associated clinically with spasticity and ataxia. Pathologically, neurofibrillary tangle formation in hippocampal neurons is, of course, characteristic: congophilic angiopathy can occur, occasionally with ischaemic changes similar to those seen in this family (Corsellis and Brierley, 1954; Mandybur, 1975; CDH family of Bird et al., 1989): amyloid plaques may be seen in the cerebellum (Pro et al., 1980). However, we agree with both Worster-Drought et al. (1940) and Griffiths et al. (1982) that as far as the neuropathological evidence is concerned, the important distinction between these cases and Alzheimer's disease is the plaque morphology and, to some extent, the white matter destruction. Some recent workers have suggested that plaque morphology may not be as reliable a means of classifying plaques as immunohistochemistry (Kitamoto et al., 1988; Roberts et al., 1988). Indeed, positive immunostaining with antiprion protein (PrP) has resulted in a family previously reported as Downloaded from by guest on June 15, 2015 was known in life to have had hypertension and whose clinical course was punctuated by at least one stroke which may have been due to a cerebellar haemorrhage. We agree with Worster-Drought et al. (1940, 1944) that the subcortical ischaemic change is likely to have been a direct result of the amyloid angiopathy, and to have contributed substantially to the clinical course of the disease. As in Binswanger's leukoencephalopathy, chronic hypoperfusion of subcortical white matter secondary to involvement of penetrating arterioles is the likely mechanism (De Reuck, 1980). In recent years the occurrence of cerebral amyloid angiopathy in a variety of conditions has become better appreciated (see Vinters, 1987, for a recent review) and Binswanger's subcortical leukoencephalopathy has been reported in association with sporadic cerebral amyloid angiopathy in a group of elderly patients (aged from 52 to 83 yrs) with and without hypertension (Gray et al., 1985). We suggest, however, that the early appearance of spasticity and its ultimate severity is difficult to account for entirely on the basis of the white matter ischaemic change. Perhaps the involvement of the spinal cord vessels followed by ischaemic damage to the cord parenchyma may, at least in part, be responsible for this. The plaque formation and neuronal degeneration in hippocampus and cerebellum and also ischaemic changes in this latter structure would account for the prominent and early amnestic syndrome and ataxia, respectively (Zola-Morgan et al., 1986; Ball, 1988). FAMILIAL CAA WITH PLAQUES 737 familial Alzheimer's disease being reclassified as a variant of GSS (Heston et al., 1966; Nochlin et al., 1989; see below). However, the present authors are unaware of any example of nonneuritic amyloid hippocampal and cerebral cortical plaques of the type seen in this family that have been shown to stain with anti-/S-peptide which is (in Alzheimer's disease) known to be the constituent protein of cerebrovascular amyloid (Glenner and Wong, 1984), of cortical neuritic plaques (Masters et al., 1985), and also of the rare diffuse and compact cerebellar amyloid plaques in Alzheimer's disease (Yamaguchi et al., 1989). Gerstmann-Strdussler-Scheinker disease (GSS) It has been established that examples of this familial disease (first described by Gerstmann et al., 1936) and conditions that have been classified as familial examples of Creutzfeldt-Jakob disease (CJD) or spongiform encephalopathy (e.g., Adam et al., 1982) are related to the transmissible encephalopathies, namely sporadic CJD and kuru in man and scrapie in sheep and other mammals. This relationship was first suggested by pathological similarities (Seitelberger, 1962) and subsequently by transmissibility (Tateishi et al., 1979; Masters et al, 19816). PrP antibody immunoreactivity of GSS plaques has been demonstrated (Roberts et al., 1986; Baron et al., 1988; Kitamoto et al., Downloaded from by guest on June 15, 2015 Familial cerebral haemorrhage with amyloidosis Autosomal dominant hereditary cerebral haemorrhage occurring in Icelandic families was first described by Arnason (1935). Gudmundsson et al. (1972) demonstrated that cerebral amyloid angiopathy was responsible and it has subsequently been shown that the amyloid protein is a variant of cystatin C or 7-trace (Cohen et al., 1983; Jensson et al., 1987). Clinically, the course of the illness depends on the severity of the cerebral haemorrhages: an affected individual may be struck down by a catastrophic stroke or may live for many years sustaining multiple strokes of varying severity. The onset of symptoms is early (mean age around 30 yrs). A chronic progressive history, such as is most typical in the present family, is unusual. In the Icelandic cases the distribution of the amyloid angiopathy is very extensive and it is found in cerebral, cerebellar and brainstem arteries, but there is no plaque formation and neurofibrillary tangles have not been reported. Hereditary cerebral haemorrhage with amyloidosis in Dutch patients is another autosomal dominant disease in which, characteristically, healthy normotensive individuals spontaneously develop intracerebral haemorrhage although at a later age than in the Icelandic type (mean around 55 yrs) (Wattendorff et al., 1982; Luyendijk et al., 1986). Pathologically, the distribution of the amyloid angiopathy is in the main limited to the cerebral cortex and leptomeninges, plaques resembling senile plaques are found in the cortex, there are no neurofibrillary tangles and the amyloid protein has been identified as being /3-peptide (Van Duinen et al., 1987). Important differences exist between these disorders and that reported here, both clinically and pathologically. 738 G. T. PLANT AND OTHERS Familial oculoleptomeningeal amyloidosis Oculoleptomeningeal forms of familial amyloidosis occur (see, e.g., Goren et al., 1980); recently an unusual variety has been described in which meningeal involvement resulted in cerebral haemorrhage and myelopathy (Uitti et al., 1988). An anomalous prealbumin (transthyretin) was identified in serum. There is, however, no example known to the authors of prealbumin being implicated in cerebral amyloid angiopathy or parenchyma! cerebral amyloid deposits. Downloaded from by guest on June 15, 2015 1988). Very recently mutations of the PrP gene on chromosome 20 have been linked to the disease in some families (Collinge et al., 1989; Hsiao et al., 1989; Owen et al., 1989). Most nonneuritic cerebral cortical plaques that have been examined with immunostains have been shown to be PrP positive, but this may not be universally true (Rosenberg et al., 1989) and plaque morphology alone may not be a reliable guide to the constituent amyloid protein. The clinical features and pathological findings are variable, even within different members of the same family. In typical GSS there is a chronic progressive history of predominantly cerebellar symptoms with dementia. Spasticity and lower limb areflexia are common but not invariable features. Where the clinical history is long and is 'characteristic' of GSS rather than CJD, atypical amyloid plaques of the type observed in the present family are always found in cerebellum and cortex. The only significant difference between the plaque morphology in the present family and GSS is that the plaques are frequently multicentric in GSS (Boellaard and Schlote, 1980; Schlote et al., 1980). Although neurofibrillary degeneration has only rarely been described in GSS (see de Courten-Myers and Mandybur, 1987), it appears that in a subgroup of patients the presence of NFT-s is a constant finding (Hsiao et al., 1989). Rare NFTs were noted in a recently described familial dementia with anti-PrP positive plaques (Nochlin et al., 1989). However, amyloid angiopathy is not common in GSS. There is, to the authors' knowledge, only 1 example of a case of proven familial GSS in which cerebral amyloid angiopathy was a prominent feature (Case 3 of Adam et al., 1982), although there are other cases which may be examples of GSS (not established on the basis of either immunostaining or transmissibility) with amyloid angiopathy (Kornfeld, 1984; de Courten-Myers and Mandybur, 1987; Koo et al., 1987). Amyloid angiopathy also occurs in animal scrapie (Bendheim et al., 1984; Gilmour et al., 1986). Furthermore, in those cases of GSS or possible GSS in which amyloid angiopathy has been found, immunostaining to confirm that the vascular amyloid protein is also PrP has not been carried out. The importance of this has recently been highlighted in a case of sporadic CJD with amyloid angiopathy (Keohane et al., 1985) in which it has been found that the amyloid angiopathy stained with anti-/3-protein, while the cerebellar plaques show anti-PrP immunoreactivity (Roberts et al., 1988). FAMILIAL CAA WITH PLAQUES 739 Familial multi-infarct dementia There have been a few reports of familial disorders characterized by dementia and other evidence of CNS vascular damage, some with an autosomal dominant mode of transmission (Sourander and Wilinder, 1977; Stevens etal., 1977; Yokoi and Nakayama, 1985; Sonninen and Savontaus, 1987). Pathological data are available in 2 families in which minor stroke-like episodes occurred and dementia developed at an early age. Small vessel arteriopathy, fibrinoid necrosis, inflammatory infiltrate, lamellar elastosis, hyaline degeneration of the vessel wall and occlusion of the lumen were observed, but there was no deposition of amyloid (Sourander and Walinder, 1977; Stevens et al., 1977). In the Japanese cases (Yokoi and Nakayama, 1985) the symptoms also started at a young age (25—29 yrs), but the presentation was slowly progressive rather than stepwise, with the development of memory disturbance, dementia and spastic paraplegia. In all these cases a tendency to baldness and 'lumbago' were described. Pathologically, extensive white matter damage, seen as pallor and rarefaction on myelin preparations, as well as cystic infarcts in the white matter and basal ganglia, were detected. The small arteries of the brain parenchyma and leptomeninges presented severe arteriosclerosis and only the pial arteries of medium size showed occasional staining for amyloid. ACKNOWLEDGEMENTS We are very grateful to family members who have cooperated in this study. Professor P. L. McGeer and Dr M. Esiri permitted us to review histological material from their respective laboratories. Many physicians who have encountered living and deceased members of the family kindly provided valuable information. Professor L. Duchen, Dr D. R. Oppenheimer, Dr G. Roberts and Dr B. Frangione provided considerable assistance through discussion. Without the cooperation of the late Dr R. Griffiths it would have been impossible to complete the family study. Downloaded from by guest on June 15, 2015 Conclusions There are a number of familial disorders in the literature where cerebral amyloid angiopathy and plaque formation have been the major pathological findings. Many of these were discussed by Griffiths et al. (1982) and presented by them in tabular form (the cases of van Bogaert et al., 1940; Liiers, 1947; Corsellis and Brierley, 1954; Neumann, 1960; Hollander and Strich, 1970; Gerhard et al., 1972). To the list should be added the family described more recently by Love and Duchen (1982). This case showed autopsy features similar to those reported here except that the hippocampal involvement was less severe. In life the proband and 3 affected relatives had had cerebellar ataxia without dementia. The published details of the family make it unlikely that the case was descended from any as yet untraced descendants of HL2, III5 or III6 in fig. 1. It is unlikely that an attempt to classify these disorders based on either clinical features or neuropathological features such as plaque morphology will be successful. It is the identification of the amyloid protein and the defective genes that is critical, and in the family reported here is the subject of further investigation. 740 G. T. PLANT AND OTHERS REFERENCES ADAM J, CROW TJ, DUCHEN LW, SCARAVILU F, SPOKES E (1982) Familial cerebral amyloidosis and spongiform encephalopathy. Journal of Neurology, Neurosurgery and Psychiatry, 45, 3 7 - 4 5 . AIKAWA H, SUZUKI K, IWASAKI Y, IIZUKA R (1985) Atypical Alzheimer's disease with spastic paresis and ataxia. Annals of Neurology, 17, 297-300. ARNASON A (1935) Apoplexie und ihre Vererbung. Ada Psychiatrica et Neurologica, Supplement VII, 1-180. BALL MJ (1988) Hippocampal histopathology—a critical substrate for dementia of the Alzheimer type. In: Interdisciplinary Topics in Gerontology, Volume 26. Edited by J. Ulrich. Basel: Karger, pp. 16-37. BARAITSER M (1982) The Genetics of Neurological Disorders. Oxford: Oxford University Press, pp. 61 —66. BARON H, BARON-VAN EVERCOOREN A, BRUCHER J-M (1988) Antiserum to scrapie-associated fibril protein reacts with amyloid plaques in familial transmissible dementia. Journal of Neuropathology and Experimental Neurology, 47, 158—165. BENDHEIM PE, BARRY RA, DEARMOND SJ, STITES DP, PRUSINER SB (1984) Antibodies to a scrapie prion protein. Nature, London, 310, 418-421. BIRD TD, SUMI SM, NEMENS EJ, NOCHLJN D, SCHELLENBERG G, LAMPE TH, SADOVNICK A, CHUI H, COLUNGE J, HARDING AE, OWEN F, POULTER M, LOFTHOUSE R, BOUGHEY AM, SHAH T, CROW TJ (1989) Diagnosis of Gerstmann-Straussler syndrome in familial dementia with prion protein gene analysis. Lancet, ii, 15 — 17. CORSELUS JAN, BRIERLEY JB (1954) An unusual type of pre-senile dementia: (atypical Alzheimer's disease with amyloid vascular change). Brain, 77, 571—587. COURTEN-MYERS G DE, MANDYBUR TI (1987) Atypical Gerstmann-Straussler syndrome or familial spinocerebellar ataxia and Alzheimer's disease? Neurology, Cleveland, 37, 269—275. GERHARD L, BERGENER M, HOMAYUN S (1972) Angiopathie bei Alzheimerscher Krankheit. Zeitschrift far Neurologic, 201, 43-61. GERSTMANN J, STRAUSSLER E, SCHEINKER I (1936) liber eine eigenartige hereditar-familiare Erkrankung des ZentraJnervensystems: Zugleich ein Beitrag zur Frage des vorzeitigen lokalen Alterns. Zeitschrift fUr die Gesamte Neurologic und Psychiatrie, 154, 736-762. GILMOUR JS, BRUCE ME, MACKELLAR A (1986) Cerebrovascular amyloidosis in scrapie affected sheep. Neuropathology and Applied Neurobiology, 12, 173—183. GLENNER GG, WONG CW (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochemical and Biophysical Research Communications, 120, 885-890. GOREN H, STEINBERG MC, FARBOODY GH (1980) Familial oculoleptomeningeal amyloidosis. Brain, 103, 473-495. GRAY F, DUBAS F, ROULLET E, ESCOUROLLE R (1985) Leukoencephalopathy in diffuse hemorrhagic cerebral amyloid angiopathy. Annals of Neurology, 18, 54—59. GRIFFITHS RA, MORTIMER TF, OPPENHEIMER DR, SPALDING JMK (1982) Congophilic angiopathy of the brain: a clinical and pathological report on two siblings. Journal of Neurology, Neurosurgery and Psychiatry, 45, 396-408. Downloaded from by guest on June 15, 2015 MINER GW, TINKLENBERG J (1989) Phenotypic heterogeneity in familial Alzheimer's disease: a study of 24 kindreds. Annals of Neurology, 25, 12—25. BOELLAARD JW, SCHLOTE W (1980) Subakute spongiforme Encephalopathie mit multiformer Plaquebildung. Acta Neuropathologica, Berlin, 49, 205-212. BOGAERT L VAN, MAERE M, SMEDT E DE (1940) Sur les formes familiales precoces de la maladie d'Alzheimer. Monatsschrift far Psychiatrie und Neurologic, 102, 249—301. COHEN DH, FEINER H, JENSSON O, FRANGIONE B (1983) Amyloid fibril in hereditary cerebral hemorrhage with amyloidosis (HCHWA) is related to the gastroentero-pancreatic neuroendocrine protein, gamma trace. Journal of Experimental Medicine, 158, 623-628. FAMILIAL CAA WITH PLAQUES 741 GUDMUNDSSON G, HALLGR/MSSON J, JONASSON TA, BJARNASON 6 (1972) Hereditary cerebral haemorrhage with amyloidosis. Brain, 95, 387-404. HESTON LL, LOWTHER DLW, LEVENTHAL CM (1966) Alzheimer's disease: a family study. Archives of Neurology, Chicago, 15, 225-233. HOLLANDER D, STRICH SJ (1970) Atypical Alzheimer's disease with congophilic angiopathy presenting with dementia of acute onset. In: Alzheimer's Disease and Related Conditions: A Ciba Foundation Symposium. Edited by G. E. W. Wolstenholme and M. O'Connor. London: J. and A. Churchill, pp. 105-124. HSIAO K, BAKER HF, CROW TJ, POULTER M, OWEN F, TERWILUGER JD, WESTAWAY D, OTT J, PRUSINER SB (1989) Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature, London, 338, 342-345. JENSSON O, GUDMUNDSSON G, ARNASON A, BU5NDAL H, PETURSDOTTIR I, THORSTEINSSON L, GRUBB A, LOFBERG H, COHEN D, FRANGIONE B (1987) Hereditary cystatin C (7-trace) amyloid angiopathy of the CNS causing cerebral hemorrhage. Ada Neurologica Scandinavica, 76, 102 — 114. KEOHANE C, PEATFIELD R, DUCHEN LW (1985) Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease) with amyloid angiopathy. Journal of Neurology, Neurosurgery and Psychiatry, 48, 1175 — 1178. KITAMOTO T, TATEISHI J, SATO Y (1988) Immunohistochemical verification of senile and kuru plaques in Creutzfeldt-Jakob disease and the allied disease. Annals of Neurology, 24, 537-542. Koo EH, DEARMOND SJ, HART J, GORDON B, SELKOE DJ, PRICE DL (1987) Cerebellar plaques in presenile LUVENDIJK W, BOTS GTAM, VEGTER-VAN DER V U S M, WENT LN (1986) Familiare hersenbloedingen als gevolg van cerebrale amyloide angiopathie. Nederlands Tijdschrift voor Geneeskunde, 130, 1935-1940. MCMENEMEY WH (1952) Discussion. In: Proceedings of the First International Congress of Neuropathology, Rome, Volume 2. Turin: Rosenberg and Sellier, pp. 4 3 2 - 4 3 6 . MCMENEMEY WH (1970) Discussion. In: Alzheimer's Disease and Related Conditions: A Ciba Foundation Symposium. Edited by G. E. W. Wolstenholme and M. O'Connor. London: J. and A. Churchill, pp. 132-133. MANDYBUR TI (1975) The incidence of cerebral amyloid angiopathy in Alzheimer's disease. Neurology, Minneapolis, 25, 120-126. MASTERS CL, GAJDUSEK DC, GIBBS CJ (1981a) The familial occurrence of Creutzfeldt-Jakob disease and Alzheimer's disease. Brain, 104, 535-558. MASTERS CL, GAJDUSEK DC, GIBBS CJ (1981*) Creutzfeldt-Jakob disease virus isolations from the Gerstmann-Straussler syndrome: with an analysis of the various forms of amyloid plaque deposition in the virus-induced spongiform encephalopathies. Brain, 104, 559—588. MASTERS CL, S I M M S G , WEINMAN NA, M U L T H A U P G , MCDONALD BL, BEYREUTHERK (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proceedings of the National Academy of Sciences of the USA, 82, 4245-4249. NEUMANN MA (1960) Combined amyloid vascular changes and argyrophilic plaques in the central nervous system. Journal of Neuropathology and Experimental Neurology, 19, 370—382. NocHLiN D, SUMI SM, BIRD TD, SNOW AD, LEVENTHAL CM, BEYREUTHER K, MASTERS CL (1989) Familial dementia with PrP-positive amyloid plaques: a variant of Gerstmann-Straussler syndrome. Neurology, Cleveland, 39, 910-918. Downloaded from by guest on June 15, 2015 dementia: Gerstmann-Straussler syndrome or Alzheimer's disease? Journal of Neuropathology and Experimental Neurology, 46, 338. KORNFELD M (1984) Gerstmann-Straussler syndrome with features of Alzheimer's disease: two entities or one? Journal of Neuropathology and Experimental Neurology, 43, 321. LOVE S, DUCHEN, LW (1982) Familial cerebellar ataxia with cerebrovascular amyloid. Journal of Neurology, Neurosurgery and Psychiatry, 45, 271—273. LOERS T (1947) tiber die familiSre juvenile Form der Alzheimerschen Krankheit mit neurologischen Herderscheinungen. Archiv filr Psychiatrie und Nervenkrankheiten, 179, 132—145. 742 G. T. PLANT AND OTHERS OWEN F, POULTER M, LOFTHOUSE R, COLUNGE J, CROW TJ, RISBY D, BAKER HF, RIDLEY RM, HSIAO K, PRUSINER SB (1989) Insertion in prion protein gene in familial Creutzfeldt-Jakob disease. Lancet, i, 5 1 - 5 2 . PEARLMAN RL, TOWFIGHI J, PEZESHKPOUR GH, TENSER RB, TUREL AP (1988) Clinical significance of types of cerebellar amyloid plaques in human spongiform encephalopathies. Neurology, Cleveland, 38, 1249-1254. PLANT GT, Rivgsz T (1989) Familial presenile dementia with congophilic plaques and angiopathy. Neuropathology and Applied Neurobiology, 15, 596. PRO JD, SMITH CH, SUMI SM (1980) Presenile Alzheimer disease: amyloid plaques in the cerebellum. Neurology, New York, 30, 820-825. REUCK J DE, CREVITS L, COSTER W DE, SIEBEN G, EECKEN H VANDER (1980) Pathogenesis of Binswanger chronic progressive subcortical encephalopathy. Neurology, New York, 30, 920—928. ROBERTS GW, LOFTHOUSE R, BROWN R, CROW TJ, BARRY RA, PRUSINER SB (1986) Prion-protein immunoreactivity in human transmissible dementias. New England Journal of Medicine, 315, 1231-1233. ROBERTS GW, LOFTHOUSE R, ALLSOP D, LANDON M, KIDD M, PRUSINER SB, CROW TJ (1988) CNS amyloid proteins in neurodegenerative diseases. Neurology, Cleveland, 38, 1534—1540. ROSENBERG RN, GREEN JB, WHITE CL, SPARKMAN DR, DEARMOND SJ, KEPES JJ (1989) Dominantly inherited dementia and parkinsonism, with non-Alzheimer amyloid plaques: a new neurogenetic disorder. Annals of Neurology, 25, 152-158. SCHLOTE W, BOELLAARD JW, SCHUMM F, ST6HR M (1980) Gerstmann-Straussler-Scheinker's disease: TATEISHI J, OHTA M, KOGA M, SATO Y, KUROIWA Y (1979) Transmission of chronic spongiform encephalopathy with kuru plaques from humans to small rodents. Annals of Neurology, 5, 581 —584. UITTI RJ, DONAT JR, ROZDILSKY B, SCHNEIDER RJ, KOEPPEN AH (1988) Familial oculoleptomeningeal amyloidosis: report of a new family with unusual features. Archives of Neurology, Chicago, 45, 1118-1122. VAN DUINEN SG, CASTANO EM, PRELLJ F, BOTS GTAB, LUYENDUK W, FRANGIONE B (1987) Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease. Proceedings of the National Academy of Sciences of the USA, 84, 5991 -5994. VINTERS HV (1987) Cerebral amyloid angiopathy: a critical review. Stroke, 18, 311-324. WATTENDORFF AR, BOTS GTAM, WENT LN, ENDTZ LJ (1982) Familial cerebral amyloid angiopathy presenting as recurrent cerebral haemorrhage. Journal of the Neurological Sciences, 55, 121 —135. WORSTER-DROUGHT C, HILL TR, MCMENEMEY WH (1933) Familial presenile dementia with spastic paralysis. Journal of Neurology and Psychopathology, 14, 27—34. WORSTER-DROUGHT C, GREENFIELD JG, MCMENEMEY WH (1940) A form of familial presenile dementia with spastic paralysis: (including the pathological examination of a case). Brain, 63, 237—254. Downloaded from by guest on June 15, 2015 electron-microscopic observations on a brain biopsy. Acta Neuropathologica, Berlin, 52, 203-211. SCHOLZ W (1938) Studien zur Pathologie der Himgefasse; die drusige Entartung der Hirnarterien undcapillaren. (Eine Form seniler Gefisserkrankung). Zeitschrift fir die Gesamte Neurologie und Psychiatrie, 162, 694-715. SCHOTTKY J (1932) Uber prasenile Verblodungen. Zeitschrift ftir die Gesamte Neurologie und Psychiatrie, 140, 333-397. SEITELBERGER F (1962) Eigenartige familiar-hereditare Krankheit des Zentralnervensystems in einer niederosterreichischen Sippe. Wiener Klinische Wochenschrifi, 74, 687—691. SHAW C (1979) Primary idiopathic cerebrovascular amyloidosis in a child. Brain, 102, 177-192. SONNINEN V, SAVONTAUS M-L (1987) Hereditary multi-infarct dementia. European Neurology, 27, 209-215. SOURANDER P, WAUNDER J (1977) Hereditary multi-infarct dementia: morphological and clinical studies of a new disease. Acta Neuropathologica, Berlin, 39, 247-254. STEVENS DL, HEWLETT RH, BROWNELL B (1977) Chronic familial vascular encephalopathy. Lancet, i, 1364-1365. FAMILIAL CAA WITH PLAQUES 743 WORSTER-DROUGHT C, GREENFIELD JG, MCMENEMEY WH (1944) A form of familial presenile dementia with spastic paralysis. Brain, 67, 38—43. YAMAGUCHI H, HIRAI S, MORIMATSU M, SHOJI M, NAKAZATO Y (1989) Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated by |3-protein immunostain. Acta Neuropathologica, Berlin, 77, 314-319. YOKOI S, NAKAYAMA H (1985) Chronic progressive leukoencephalopathy with systemic arteriosclerosis in young adults. Clinical Neuropathology, 4, 165 — 173. ZOLA-MORGAN S, SQUIRE LR, AMARAL DG (1986) Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. Journal of Neuroscience, 6, 2950-2967. (Received June 16, 1989. Accepted July 7, 1989) APPENDIX Case histories / / , 12. No information. ///, female. Born 1830, died 1883. Taken ill at age 40 yrs, died age 53. Said to have had a stroke and died of paralysis. 112, female. Reputed to have had a similar history to III but nothing else known of her. 113. There is said to have been a brother and a sister but nothing is known of them. ////, female. Born 1851, died 1903. Although it is not stated in Worster-Drought et al. (1940, 1944), it is recorded in the NHND case notes for IV13 that she died of paralysis; the informant was IV15. In Griffiths et al. (1982) she is case 'A' in the published pedigree, said to have died from 'creeping paralysis' and to have been confined to a wheelchair towards the end of her life. At some stage in the illness she was treated with electroconvulsive therapy for depression. 1112, male. Bom 1853, died 1913. Developed paralysis at age 57 yrs and died at 60. Two children were unaffected in 1933. No further information. 1113, female. Born 1855, died in 1909 aged 54 yrs in Tooting Bee Asylum. Illness began at 44 with paralysis followed by dementia. Was examined when 50 in 1905 by Dr Farquar-Buzzard. Six months previously lost power in left hand which recovered in one month. Her memory had been impaired for 6 months and there had been frequent giddiness and some difficulty in swallowing. Three weeks previously she had lost her speech. On examination she was noted to have defective memory and weakness and ataxia of limbs. She was also dysarthnc and lethargic. According to an account given by IV8 she became very slack with the household, wanting to sit still for hours, taking no interest in anything and if asked to do anything would fly into a temper. In the course of the illness she went to the door to see the milkman and when she got there she was unable to speak properly. She burst out crying and said that she had her mother's illness. After this she spoke in a spluttering kind of way and shuffled her feet when walking. 1114, female. Born 1857. Entered Banstead Asylum aged 48 yrs and died there at age 53. Developed dementia first, then paralysis. 1115, female. Bom 1861. .Died aged 66 yrs. Taken ill with paralysis at 48. Dementia less severe. Bedridden for 16 yrs; towards the end limbs and tongue useless but could understand everything said to her. Did not require certification. Had 5 sons and 1 daughter whose ages would have ranged from 85 to 104 if alive in 1989 but nothing is known of them except that none was affected in 1933. 1116, female. Bom 1865. Died 1915 at 50 yrs having developed paralysis only 2 yrs previously. She had 9 children; none was affected in 1933; ages would have ranged from 81 to 101 if alive in 1989. 1117, male. Bom 1870, died later than 1933. Neither he nor his 2 children were affected in 1933 but no more is known of them. 1118, female. Born 1872. Mentally subnormal. Unable to walk until 5 yrs and died aged 14 from scarlet fever. Downloaded from by guest on June 15, 2015 The sources of the information given below are the papers of Worster-Drought et al. (1933, 1940, 1944) and Griffiths et al. (1982); genealogy compiled in 1933 by the husband of IV15 for Worster-Drought; the accounts given by IV15 and her husband to the house officer when IV12 was admitted to the National Hospital for Nervous Diseases (NHND) in 1924 and 1926; the NHND case notes of IV12, IV13, V38, V36; Dr S. A. Hashimoto of Vancouver, BC, who examined V45 in 1973-1974 and DrR. Grosch of New Westminster, BC, who examined her in 1988; Dr P. O. Williamson of St Leonards, NSW, who examined V2 in 1987; the notes of the late Dr R. A. Griffiths; and information from several surviving family members. 744 G. T. P L A N T AND O T H E R S 1119, female. Bom 1874. Well at age 60 yrs in 1933. III10, female. Born 1875. Described as fit when 58 yrs of age. Had 12 children. The eldest known to be alive in 1933 would be 84 and the youngest 71 in 1989. 1V1, male. Born approximately in 1896. Died aged 53 yrs. Married with no descendants. His wife had been a neighbour of IV1 and knew of the family illness. He had a stepdaughter who remembers that he developed an unsteady gait in his 5th decade. He was a sailor and was badly burned while at work. A doctor advised that he should stop work. Loss of memory occurred relatively late and he died in Chartham Asylum near Dover. No stroke-like episodes. IV2, female. Born 1897, died aged 52 yrs. Cause of death on the death certificate given as 'familial muscular dystrophy'. At age 43 she developed headaches and other symptoms including diplopia which led to a posterior fossa craniotomy carried out at the NHND for a suspected tumour. Thereafter she developed progressive dementia and paralysis and died in St Luke's Hospital, Chelsea, having become totally dependent. (B4 in Griffiths el al., 1982.) IV3, female. Bom 1882. Died aged 56 yrs in St Bartholomew's Hospital, Rochester, Kent. Became ill at age 46 when she began to walk 'crooked' and also complained of headaches. In 1931 her daughter married and she attended the wedding being unable to walk or feed herself and incontinent of urine although still able to comprehend the significance of the event. (B5 in Griffiths et al., 1982.) 1V13, male. Bom 1882, died 1936. At 46 yrs developed a personality change become ill-tempered. At 47 noticed difficulty walking after drinking 1 glass of beer and the following day reported for duty at the wrong time (he was an engine driver). When first examined at 47 his gait was normal but there was increased tone in lower limbs and increased reflexes. Forgetfulness, irritability and difficulty walking progressed. At 50 he was discharged from his work following a medical examination. By 51 he had become apathetic and incontinent, had a spastic gait and was dysarthnc with a poor memory. He became severely amnesic, tone was increased in all 4 limbs and his gait was spastic. He was admitted to the NHND in 1934 at the age of 52 under Dr MacDonaW Critchley. There was a global dementia and mild nystagmus. He was very spastic with exaggerated reflexes but flexor plantar responses. The CSF protein was 1.1 g/1. In the last year of his life he was unable to walk or feed himself and was doubly incontinent. He died aged 54. Autopsy findings were reported by Worster-Drought et at. (1940). 1V14, male. According to the account given by IV8 in 1934 this brother died at 38, unaffected by the illness although the cause of death is not known. No more is known of him and he does not appear in the previously published pedigree (Worster-Drought et at., 1940, 1944). 1V15, female. Bom 1889, died 1944 aged 56 yrs. At the age of 44 developed memory impairment and personality change, becoming irritable. Within a year she was unsure of her feet when walking. She was examined at age 51. Speech was slow and slurred, gait ataxic and there was slight horizontal nystagmus. All 4 limbs were spastic with ankle clonus but uncertain plantar responses. CSF examination was normal and (AEG) air encephalography showed dilatation of the lateral ventricles. Dementia progressed and she developed a severe spastic paraplegia and pronounced nystagmus. She died 'practically inanimate' at the age of 56. Autopsy findings were reported by Worster-Drought el al. (1944). Downloaded from by guest on June 15, 2015 1V4, female. Bom 1889, died aged 74 yrs. Cause of death was a cerebral haemorrhage but there was no progressive disease. One son died in 1942 (drowning). Survived by a son of 76 and a daughter of 62 both of whom are well in 1989. IV5, male. Date of birth uncertain. Died aged 80 yrs. Cause of death unknown but there was no progressive illness. Married but had no children. IV6, male. Bom 1890. Lost a leg in an accident on the railway at age 18 yrs. Died aged 51. Became ill in his mid-40s with headache, deteriorating speech and memory. The family recall a personality change—became 'bad-tempered'. Three daughters who are alive and well in 1989. Had 1 son who died of the disease. 1V7, female. Bom 1880, died aged 63 yrs. Cause of death given as cerebral thrombosis; no progressive illness leading up to this. Her 7 children arc all deceased but none is known to have had the disease. 1V8, male. Date of birth uncertain, died aged >70 yrs. Cause of death unknown but in the family he is considered not to have had the disease. 1V9, female. Bom 1879, died aged 56 yrs. Illness began with 'collapse' at age of 50, progressive thereafter and died in Buckland Hospital, Dover; no records survive. IV10—11. Nothing is known of the 2 children of III2 except that both were unaffected in 1933 when their ages would have been greater than 50. IV12, female. Bom 1879, died 1933 aged 54 yrs. Developed paralysis at 44 and progressive dementia ensued. Admitted to NHND at age 45; 4 months before this tried to get out of bed one day and found that she could not stand or talk properly. On examination she had dysarthria, was emotional and complained of giddiness. Her memory was poor and she spoke in a slow halting fashion. Cranial nerves were normal and there was limb weakness and ataxia but normal reflexes. CSF examination was normal. Two yrs later she was readmitted. She complained of occasional dizziness when out in the street and had fallen several times. Dysarthria was about the same but memory worse. Thereafter her speech and memory deteriorated and she developed spasticity. Her gait was noted to be spastic 3 yrs before her death. Bedridden and incontinent during remainder of her life. FAMILIAL CAA WITH P L A Q U E S 745 1V16, male. Born 1892. Died 1965 aged 73 yrs following influenza. IV17, female. Born 1895, date of death uncertain. From the age of 43 yrs developed progressive memory impairment and difficulty in walking; became depressed and tearful. When examined at age 45 noted to have dysarthria, exaggerated tendon reflexes, spasticity and poor coordination of lower limbs. Details of the progression of the illness not known. IV18, male. Born 1896. Died 1959 aged 63 of a myocardial infarction. 1V19-33. No information. 1V34-35. Well in 1933. No further information. IV36—44. No information. IV45-50. Six children of III 10 died in infancy. VI, 3, 6, 8, 9, 11, 13, 14, 23-26, 30, 37, 38, 42, 43, 44, 46. Alive and well in 1989. V2, female. Born 1925, died aged 63 yrs. Was well until age of 57 when she had 4 episodes of tingling affecting right side of the body lasting 10 min on each occasion. For 1 yr had been unsteady on her feet. Long history of headache ascribed to migraine. Noted to have unreactive pupils, absent tendon reflexes and mild gait ataxia. CT brain scan within normal limits. Two yrs later, balance had deteriorated further, she had occasional myoclonic jerks and some memory impairment. Psychometric assessment revealed 'reasonable' verbal and performance IQ but impaired memory. By age of 60 had developed dysarthria and diplopia with further deterioration in gait and memory. Plantar responses then extensor. Became depressed and died at home 3 yrs later. She was in the bath attended by her husband, began to complain of severe chest pains and died 30 min later from a presumed myocardial infarction. When she was 60, 3 yrs following the onset of the illness, an MRI scan showed extensive white matter high signal with 'U' fibre sparing (see fig. 3). Shortly before death a further CT scan performed because of persistent headaches showed low attenuation in frontal and occipital periventricular regions. (C4 in Griffiths et al., 1982.) V5, female. Born 1906, died aged 80 yrs of an unrelated condition. V7, male. Bom 1915, died aged 56 years. At age of 50 he developed weakness of all 4 limbs, ataxia, dysarthria and memory impairment. He complained of pins and needles in the fingers of both hands. On examination he had a kyphoscoliosis which had been present from his teens, gait ataxia, dysarthria, and limb weakness and ataxia. Muscle tone and tendon reflexes were normal. AEG revealed moderate ventricular dilatation. CSF examination was normal. The disorder was progressive thereafter. He had a transient right abducens paresis. By age 54 dementia was obvious and the disorder progressed to a vegetative state with marked spasticity. An autopsy study was reported by Griffiths et al. (1982; Case C9). V10, male. Bom 71922. Died in the Second World War (drowning). No descendants. V12, female. Born 1911. Alive and well in 1988 when she suffered a skull fracture and cerebral injury in a road traffic accident. Although she survived this she remains in hospital in 1989. V15, male. Bom 1915, died aged 51 yrs. At around age of 45 began walking as if drunk and complained of giddiness. Investigated at the Brook Hospital in 1964/1965. No records have survived. Progressive dementia and paralysis until his death. He married twice. One daughter died at age of 36 of cancer; his son from his second marriage survives him. V16, female. Bom 1901, died aged 80 yrs, 'cerebrovascular accident'. No progressive illness. V17, male. Bom 1903. Died aged 54 yrs, cancer. VI8, female. Bom 1905. Died aged 78 yrs, 'cerebrovascular accident'. No progressive illness. V19, female. Born 1909. Died aged 50 yrs, 'cerebral thrombosis'. No progressive illness. V20, male. Bom 1911, died aged 72 yrs. Two minor strokes in his late 60s. Died suddenly either from 'heart attack' or aortic dissection. Autopsy at Orpington Hospital. V21, male. Bom 1915. Died aged 73 yrs, haematemesis. Had had hypertension and renal failure. V22, female. Bom 1918. Died aged 68 yrs, myocardial infarction. V27, female. Bom 1899, died aged 4 yrs. V28, female. Bom 1901, died aged 55 yrs. In her fifth decade she became 'bad-tempered'. At age 50 she collapsed on a bus and the next morning was found to have weakness of left arm and leg. From that day she gradually deteriorated over 4 yrs by which time she could walk but swayed as if drunk. In the last 2 yrs of her life memory loss was profound. Downloaded from by guest on June 15, 2015 V4, female. Born 1905, died aged 61 yrs. Married with no children. At age of 54 developed ataxia and dysarthria; 1 yr later was found to have a spastic-ataxic gait and nystagmus. She was hypertensive. CSF examination was normal. At age 56 her legs 'gave way' in the street and she became unconscious for 24 h. Three days later she was disorientated and dysarthric; had nystagmus and an extensor left plantar response. She never left hospital, lapsing into a vegetative state. A year before her death she was bedridden, unresponsive and doubly incontinent, lying in a flexed posture, with widespread muscle wasting, with spasticity, exaggerated tendon reflexes and extensor plantar responses. Her autopsy findings were reported by Griffiths et al. (1982; Case C6). 746 G. T. PLANT A N D O T H E R S Spent last 18 months in Leamington Park Hospital, became paralysed and developed contractures. Cause of death given on death certificate as 'multiple cerebral thromboses'. No autopsy. Case notes destroyed. V29, male. Born 1902. Died 1979 aged 77 yrs, unaffected by the disease, carcinoma of prostate. V30, female. Born 1903, alive and well in 1989. V3I, male. Born 1904. Died aged 72 yrs, unaffected. 'Cancer of liver' on death certificate. V32, male. Born 1906. First symptoms around age 40 yrs. Died 1958 aged 52 in St Augustine's Hospital, Canterbury, of the disease. No further details. No autopsy. V33, male. Born 1910, died 1965 aged 54 yrs. At age 48 developed paralysis but precise details are not known. Four children, including twins. In last 2 yrs of his life was paralysed and in the last year mute. He died in Hellingley Hospital, Hailsham, Sussex. It is understood that an autopsy was carried out. V34, male. Bom 1913. Died aged 74 yrs in Ontario, Canada. Four children. Unaffected by the disease. V35, male. Born 1922, died 1955 aged 33 yrs. At age 25 (when his wife first met him) he was unwell, being very forgetful and would from time to time wake with severe headache and vomiting. He was training to be a telephone engineer when, at the age of 31, he was found to have hypertension and was investigated at King's College Hospital, London. A diagnosis of essential hypertension was made. He continued to have difficulties with memory but otherwise did not develop any specific symptoms until his sudden death of a ruptured aorta. It is likely that a coroner's postmortem was carried out. It remains uncertain whether or not he was affected by the disease. V41, female. Bom 1923, died aged 65 yrs. Well until 56 when she noticed difficulty in walking, clumsiness of her hands and slurring of her speech. At about the same time noticed impairment of her memory and took to writing things down, otherwise would go shopping repeatedly for the same items. Mild urgency of micturition but no other specific symptoms. Was investigated at NHND in 1981, a year after onset of symptoms. Psychometric assessment showed a verbal IQ of 115 and a performance IQ of 104 on the WAIS with a predicted IQ of 116 on a reading test. Memory functions were weak, scoring below average on a forced choice recognition test and there was patchiness in her performance on perceptual tests. Her speech was mildly dysarthnc. Spastic ataxic gait. First degree nystagmus observed on right and left gaze and positional nystagmus of central type with head back to left and right; optokinetic nystagmus grossly deranged horizontally and absent vertically. Caloric testing revealed exaggerated symmetric responses with no enhancement in the dark. Cranial nerves were otherwise normal. Spasticity in all 4 limbs without weakness. Jaw jerk and all tendon reflexes exaggerated, abdominal reflexes absent and plantar responses bilaterally extensor. Mild finger-nose and heel-shin ataxia but no sensory deficit. CT scan (fig. 2) showed mild cerebral atrophy and extensive bifrontal and biparietal white matter low attentuation. Nerve conduction studies, EEG, SEPs, BAEPs and VEPs within normal limits. CSF examination normal with no oligoclonal IgG bands on electrophoresis. At age of 64 was totally dependent, being cared for in a nursing home, unable to swallow liquids and choking on solids. When visited by her husband she would say his name but nothing else. In the last year of her life she was observed to turn to a sound but nothing more; was very spastic. An autopsy was performed and is reported in this article. She had no descendants. V45, female. Bom 1924, died aged 64 yrs. Became ill in 1966 with impaired memory and deterioration in reading and writing. Had 2 episodes of loss of consciousness in 1970 and 1973. In 1973 she was being treated for hypertension and was seen by a neurologist who found her to be severely demented with good power in the limbs but spasticity and a left extensor plantar response. An AEG showed severe atrophy but a left carotid angiogram was normal. An EEG showed a focal abnormality in the mid portion of the right hemisphere and a lesser abnormality on the left. By the following year she had deteriorated. Her speech was unintelligible and her legs had become extremely spastic. She had a left hemianopia and both plantar responses were extensor. At about this time a diagnosis of Alzheimer's disease was made. At age of 63 she was examined and found to be requiring total nursing care, was doubly incontinent and unable to feed herself. For 2 yrs had shown no sign of recognizing her family but was still able to follow with her eyes. On examination she was lying mute with no indication that she understood what was said to her. She followed a moving object and nystagmus was noted. Primitive reflexes were present. There were flexion contractures of upper Downloaded from by guest on June 15, 2015 V36, female. Born 1909. At age of 24 yrs described as myopic and very nervous. No further details. V38, male. Born 1919. Retired for social reasons at 63 yrs. When examined at age of 68 was entirely well; remains so in 1989. V39, female. Bom 1920. Was seen at NHND at the age of 61 yrs when there was no evidence of intellectual deterioration on formal psychometric testing; a CT scan was normal. V40, male. Bom 1923. Died 1972 aged 48 yrs of a cerebral haemorrhage. Died suddenly at home and a coroner's autopsy was carried out at Pontypool, Wales. He had asthma as a child but was otherwise well until this episode; had become a skilled glassblower. The cause of death was a ruptured berry aneurysm of the circle of Willis; the brain was not examined histologically. F A M I L I A L CAA WITH P L A Q U E S 747 and extension contractures of lower limbs. Tendon reflexes were diminished with bilaterally extensor plantar responses. She died a few weeks following this assessment. The following members of generation VI were alive and well in 1989 {see fig. 1 for ages, where known): 1 - 2 0 , 23-28, 30-54, 56-58. VI2I, female, Date of birth uncertain. Died aged 36 yrs of cancer. Has 2 sons and 2 daughters who live in the USA. VI22, male. Date of birth uncertain. Died aged 29 yrs, supposedly of a 'heart attack' but details not known. VI32, female. Born 1940. Died aged 46, carcinoma of bronchus. VI55, female. Born 1963. At age 13 yrs saw a neurologist. For several months she had been liable to trip. Noted to have weakness bilaterally of ankle dorsiflexion and eversion. She was obese and of poor intellectual development. No other abnormal physical signs. Three years later she was noted again to have a kyphosis and mild pes cavus. At age of 25 she was evaluated by Professor P. McGeer. It is considered possible, but not certain, that she is affected. Figure legends Downloaded from by guest on June 15, 2015