Familial Cerebral Amyloidosis and Spongiform Encephalopathy

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.45.1.37 on 1 January 1982. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1982;45:37-45 Familial cerebral amyloidosis and spongiform encephalopathy JANE ADAM, TJ CROW, LW DUCHEN, F SCARAVILLI, E SPOKES* From the Department of Neuropathology, Institute of Neurology, The National Hospital, Queen Square, London and the Clinical Research Centre, Northwick Park, Harrow SUMMARY Clinical and neuropathological investigations are presented of the "W" family in which there is a dominant inheritance of slowly progressive cerebellar ataxia and dementia. The disease is of insidious onset and its average duration more than 4 years. Pathological findings included amyloid deposition in cerebellar and cerebral tissue; vascular amyloid in one case; and spongiform encephalopathy and astrocytic hyperplasia typical of Creutzfeldt-Jakob disease. Neuritic plaques of the senile (Alzheimer) type were present to a lesser extent. This study confirms the familial association between cerebral amyloidosis and spongiform encephalopathy. Progressive neurological disorders with dementia amyloid and astrocytic hyperplasia--characteristics known to have an hereditary basis include of CJD. One other member (JW) of this family had Alzheimer's disease particularly in its atypical emigrated to the USA and developed CJD.7 Inocu- Protected by copyright. formsl 2 and Creutzfeldt-Jakob disease (CJD).3 In an lation of cerebral tissue from this case into non- analysis of many families with CJD it was estimated4 human primates transmitted an encephalopathy.4 that more than 15 % of cases occurred within families in which two or more members were affected. Since Clinical histories CJD has been transmitted by intracerebral inocula- tion into susceptible animals5 the relationship Case ] JM. Male, born 1912. Fifth generation, 111-25 in between heredity and infectivity poses considerable the pedigree of Rosenthal et al.7 In 1972 he began to have problems. difficulty in remembering. In 1973 examination showed In this paper we present the clinical histories and little abnormality except brisk reflexes with flexor plantar neuropathological findings in four members of the responses and psychometric testing revealed generalised "W" family of which 23 members in seven genera- intellectual impairment. The EEG record was described a neuro- as "poorly organised". Examination of cerebrospinal tions (fig 1) were affected by progressive fluid and haematological investigations gave normal logical disease usually with dementia. The family's results. Air encephalography showed enlarged ventricles origins are in Bedfordshire, England and seven gen- particularly of the frontal horns. Intellectual functions erations were traced back to 1791 by Cameron and deteriorated and he died in 1975. Postmortem examina- Crawford,6 though no details of the five earliest tion showed terminal pneumonia and it was noted that http://jnnp.bmj.com/ affected members are available. The disease has the cardiovascular system was virtually free of atheroma. affected both males and females and has been The brain and spinal cord were received at the National transmitted by both males and females. The pattern Hospital after fixation. of inheritance is thus consistent with transmission of Case 2 JJ. Female,born 1920. Fifth generation, III-38 by an autosomal dominant gene complete pene- in the pedigree of Rosenthal et al.7 Until 1970 this patient trance. The morphological features of the brains of was well except for a right-sided below-knee amputation these four cases include spongiform encephalopathy, for at age 9. At the age of 50 yr she began osteomyelitis on September 27, 2021 by guest. to experience difficulty in walking and within 2 years was *Present address: Department of Neurology, General admitted to hospital unable to get out of bed or walk Infirmary, Leeds. without assistance. She was severely depressed and Address for reprint requests: Professor LW Duchen, Depart- withdrawn, forgetful and confused, neglectful of personal ment of Neuropathology, Institute of Neurology, The hygiene and doubly incontinent. On examination she was National Hospital, Queen Square, London WCIN 3BG, UK. demented with slurring of speech, a flaccid hemiparesis Received 31 July 1981 and hypotonia of both arms. By 1973 she was debilitated, Accepted 3 September 1981 mute, unresponsive and totally bedridden. Pupils were 37 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.45.1.37 on 1 January 1982. Downloaded from 38 Adam, Crow, Duchen, Scaravilli, Spokes Fig 1 Family tree. 0-male; O-female; -sex unknown; solid symbol-affected by progressive neurological disease; open symbol-unaffected aged over 50; \-aged under 50; 7-deceased; x -deceased under 50; ?-cause ofdeath unknown; ?-descendants untraced; 0-infant death; only limited information about age of death and descendants in generations I-111 and Part of IV. Protected by copyright. dilated and reacted sluggishly to light and left disc pallor scopically normal but no sections were available for was noted. There was no nystagmus. She died of broncho- histological examination. The brain was divided mid- pneumonia 3 years after the onset of her illness. The post- sagittally, the left half deep frozen and subsequently mortem examination was done at the National Hospital samples of this were inoculated intracerebrally into (Professor Blackwood). laboratory animals at the National Institutes of Health, Bethesda, USA. To date no inoculated animals have Case 3 EU. Female, born 1914. Fifth generation, III- developed encephalopathy but they are still under 50 in the pedigree of Rosenthal et al.7 She was well until observation (Gajdusek, personal communication). 1971 when she became unsteady on her feet, had numer- ous falls and sustained minor injuries. In 1972 she was Case 4 JC. Female, born 1934. Sixth generation, IV-58 noted to be depressed but without abnormal physical signs. in pedigree of Rosenthal et al.7 Formerly a theatre sister. Within a year her unsteadiness was worse, she had Her first symptoms appeared in spring 1974 and consisted difficulty in climbing stairs, was tearful and slept poorly. of paraesthesiae in both thighs and difficulty in running. Examination showed dysarthria, an immobile face with a Subsequently her gait became more unsteady with positivejawjerk and a left hemiparesis with a left extensor occasional falls when turning round. In 1975 she devel- plantar response. By 1974 she was confined to a wheel oped intermittent diplopia on near vision, slurring of chair because of progressive weakness and ataxia and speech and clumsiness of fine movements involved in http://jnnp.bmj.com/ her handwriting was illegible. Her final admission to sewing and writing. She would also be woken at night hospital was in 1975 by which time she was withdrawn, with painful cramps in the limbs. On examination in confused, disorientated and doubly incontinent. There March 1977 her higher functions were normal and there was no spontaneous speech and mixed dysphasia was was minimal dysarthria. Her gait was broad-based and noted. Marked weakness of both lower limbs was present she showed truncal ataxia. The cranial nerves were intact with absent deep tendon reflexes and bilateral extensor and there was no nystagmus. In the limbs there was plantar responses. Investigations which gave normal generalised hypotonia and mild cerebellar ataxia but results included ESR, urea and electrolytes, liver function muscle bulk and power were normal. The tendon reflexes tests, B12, folate, chest and skull radiographs and WR. were brisk in the arms but absent in the legs. The plantar on September 27, 2021 by guest. Haemoglobin was 17 g/dl, white cell count raised at responses were flexor and the abdominal reflexes absent. 17 000/mm3 with a normal differential, a random blood There was no sensory impairment. At this time she glucose 100 mg/dl and fasting cholesterol 380 mg/dl. declined hospital admission for further investigations. She died in January 1976, 5 years after the appearance of She was seen again in September 1978 and admitted to symptoms. Postmortem examination (Professor Black- hospital. She was now no longer able to walk unaided wood) showed bronchopneumonia, pulmonary infarcts and her ataxia had increased. Her intellect was pre- and calf vein thrombosis. The viscera were macro- served but there was marked slurring dysarthria. Pursuit J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.45.1.37 on 1 January 1982. Downloaded from Familial cerebral amyloidosis and spongiform encephalopathy 39 eye movements were jerky and there was first degree the family are briefly summarised in the Appendix and horizontal and vertical nystagmus. Paresis of convergence are included in tables 1-3. and accommodation was present. Cranial nerve functions were otherwise normal. The upper limbs were hypotonic Table 2 Presenting complaints in 16 cases ataxia but with normal muscle bulk and with cerebellar Unsteady gait 8 power; the lower limbs were mildly spastic with a Disturbance of memory, cognition or affect 4 pyramidal distribution of weakness. Deep tendon Leg weakness 4 reflexes were increased in the arms and absent in the legs. Paraesthesiae 4 Inco-ordination arms 3 Plantar responses were extensor. There was subjective Scotomata or photopsia 3 impairment to cutaneous sensation in a stocking distri- Loss of taste and smell I bution to mid-calf level. Examination of other systems Deafness I I was normal. The following

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