Clinical Description of Affected Family Members

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Clinical description of affected family members.

First generation.

Case I,1. woman, born 1876. The youngest of 8 siblings. She had a personality change at the age of 56 years. She had been a hard working, caring individual but became odd, apathetic and forgetful. She spoke less and gradually became mute. She died aged 68 years, her death certificate recorded an "infection of the brain".

Second generation.

Case II, 1. woman, born 1893. She developed a dementia at the age of 61 years. This progressed and 6 years later she had become reclusive and aggressive. She developed urinary incontinence. She suffered syncopal episodes associated with pallor and sweating. She died at the age of 70 years old. Her death certificate recorded a cerebral insult and an emboli to her right leg.

Case II, 2. man, born 1895. A farmer who developed a cognitive decline from the age of 60 years. He slowly deteriorated until he could only recite his own name and age. At first he was restless, he then became aggressive and was often incontinent of urine. Later in his illness he became withdrawn. On admission to a psychiatric hospital at the age of 63 years old, he was noted to be oligomimic with a positive Rossolimo sign on the left side and increased limb tone. An EEG examination was normal. He died at the age of 65 years old, his death certificate recorded a "cerebral insult". No autopsy examination was performed.

Case II, 3. man, born 1897. As a younger man, he was described as calm and hard working. At the age of 59 years he became restless, his memory deteriorated and he became apathetic. Later in his illness he was aggressive. Three years later he was admitted with cardiac failure and episodes of syncope. Later the same year he was admitted to a psychiatric hospital where at first he was euphoric, but later became withdrawn, he developed stereotyped behaviour and was incontinent of urine. A cardiac arrhythmia was noted. Wassermann reaction was negative. Spinal fluid contained lymphocytes (numbers not recorded). An air encephalogram showed generalised cerebral atrophy with secondary hydrocephalus. He died at the age of 64 years old.

An autopsy examination revealed predominantly frontal cortical atrophy, with atrophy of the insula and dilated temporal horns, the cerebral vessels showed moderate arteriosclerosis. Histological examination (reported in 1987) revealed mild atrophy of the frontal lobes and insula. Histological examination revealed some cortical neuronal loss, in the white matter there was some perivascular fibrosis and patchy white matter gliosis and demyelination. Similar changes were found in the cerebellum and pons. There were no Alzheimer plaques or tangles and no swollen achromatic neurons or intracytoplasmic inclusion bodies.

Case II, 4. woman born 1899. The wife of a gravedigger who from the age of 59 years became increasingly apathetic. She started to wander, became disorientated and developed incontinence of urine. She spoke less and eventually would say only her name and birthday. She retained insight. Later in her illness she was aggressive and nihilistic. She became "stiff". She was admitted to psychiatric hospital at the age of 61 years and died 5 years later. No autopsy examination was performed.

Case II, 5. woman, born 1900. Retired farmer’s wife. Seen at the age of 92 years. She complained of mild memory problems over the previous 2 years. She scored 18 out of 30 on the MMSE, failing on orientation and delayed recall. Calculation, naming and speech were normal. Clinical assessment suggested she had Alzheimer's disease rather than the familial dementia.

Case II, 6. man, born 1902. Died in a road traffic accident at the age of 51 years with no cognitive symptoms.

Case II, 7. woman, born 1906. A farmer’s wife. At the age of 64 years her personality changed. She became loquacious and euphoric. She was restless and became aggressive, her memory remained relatively well preserved. Later she developed stomach cancer. She died at the age of 67 years. No autopsy examination was performed.

Case II, 8. woman, born 1908. A farmer's wife. Seen in 1991 at the age of 83 years and in 2001 at the age of 92 years cognitively normal.

Case II, 9. man, born 1911. A farmer. As a younger man, he was intelligent, quiet and caring. At the age of 59 years he started perseverating and repeating stories about his childhood. His personality changed, he became angry, uneasy, restless and disorientated. He developed incontinence of urine. At the age of 64 years, when admitted to a psychiatric hospital, he knew only his name and birthday. He lacked insight. He died the following year. An autopsy examination (reported in 1987) revealed slight frontal and temporal lobe atrophy. No cortical changes were noted and only minor white matter abnormalities.

Case II, 10. man, born 1912. A grave digger. He developed an insidious onset of memory problems and personality change at the age of 54 years. He became aggressive. He was admitted to psychiatric hospital at the age of 58 years. He became calmer, and still knew his date of birth. An air encephalogram showed marked internal atrophy of third and lateral ventricles and to a lesser degree also external atrophy. He died at the age of 61 years.

An autopsy examination on a heavily autolyzed brain (reported in 1987) showed slight blurring of the leptomeninges and marked dilatation of the frontal horns of the lateral ventricles sparing the temporal horns. No abnormalities were reported in the autolyzed cortex. Some white matter changes were found.

Case II, 11. man, born 1914. A farmer. Died at the age of 70 years with no reported cognitive problems.

Case II, 12. woman born 1919. A farmer’s wife, an intelligent, hard working woman. She had an insidious onset of cognitive problems from the age of 55 years. She had difficulty in initiating tasks. Whilst able to drive a tractor she became unable to turn it round at the end of a field. She was no longer able to keep the farm accounts; her writing became illegible. She remained well informed. She became aggressive and restless. She began to shout at people and pull odd faces. By the age of 60 years she was seriously cognitively impaired. She was initially talkative and prying but later lost all speech. At the age of 64 years old she was able to stand but not walk. She was admitted for long term care and gradually became bed-bound.

She was assessed at the age of 71 years, 16 years into her illness. She was on a small dose of haloperidol. She was totally dependent on nursing staff. Her only actions were occasional grunts and non-purposeful limb movements. She retained full ocular pursuit movements, had a pout reflex and an exaggerated jaw jerk. Her left arm was held extended at the elbow and metacarpophalangeal joints but flexed at the wrist. Her right had a fixed flexion deformity of the elbow. Both legs were extended with fixed plantiflexion deformities at the ankle. She had markedly increased axial and limb tone. All tendon reflexes were pathologically brisk with extensor plantar responses. When reassessed 16 months later she had developed orofacial dyskinesiae, but otherwise her signs were unchanged. She died at the age of 76 years old.

Pathology results described in main paper.

Third generation.

For ethical reasons, the clinical details in this generation are limited to individuals known by the family to be affected.

Case III, 1. woman, born 1918. She developed mild thyrotoxicosis in her early sixties. At the age of 63 her personality changed. She became irritable and restless. She started repeatedly turning objects upside down to inspect their bases. She developed a groin abscess and whilst being treated in hospital was noted to be behaving oddly, unaware of recent events and laughing at her own fatuous remarks. A CT scan of the brain was performed and showed generalised atrophy. She died at the age of 66 years from a ventricle cancer. No autopsy examination was performed.

Case III, 3. woman born 1921. She developed an insidious personality change at the age of 60 years. She became aggressive towards her grandchildren but otherwise more placid. She developed increasing amnesia and dyscalculia. She was assessed at the age of 72 years. She was loquacious and disinhibited. She scored 19/30 on the MMSE. She was unable to perform serial 7s or 4s and could register but not recall 3 words. She perseverated when copying the interlocking pentagons. Her handwriting had deteriorated. She refused physical examination. Two years later she was re-examined. She had reduced speech output and walked around her house performing stereotyped routines. She ate any available food immediately. Her relatives noted she was more apathetic and had become less kept. She had no difficulty dressing. She recognised acquaintances. She tended to turn the radiator to an excessive temperature and could walk along the streets in winter in a summer dress. She turned on the radio, so she could not hear the doorbell. She had lost her sense of time and if for example she was told that she could see the hairdresser the next day, she would telephone the salon repeatedly day and night. She had little insight into her problems.

On examination she remained disinhibited. Her speech was perseverative and she had echolalia. There was no abnormalities in her cranial nerves, limbs or gait. She had no release reflexes. She scored 11/30 on the MMSE. She was orientated in place but not in time. She could still perform simple addition. She could no longer repeat a sentence or start the three part command. She could name everyday real objects but only scored 3/10 on the naming test in the Queen Square Screening Test for Cognitive Deficits booklet (QSSTCD) 23. She could not copy the interlocking pentagons and perseverated in drawing shapes when later asked to write a sentence. She obeyed the written command. She was unable to sort playing card. She could count dots. She was unable to recite the months of the year. She could spell 3 letter words. She named no words on the verbal fluency test. Her picture description was fluent but empty. She could not give cognitive estimates or interpret proverbs. Her reading was slow with normal phonation and prosody. She had great difficulty copying hand postures; she refused to mime actions or perform alternating hand movements. She had no forced utilisation behaviour.

She was reassessed in November 1998 at the age of 77 years. She had been started on Valproate, but not apparently for epilepsy. She was virtually mute but at times had pallilalia. She had a tendency to stuff food into her mouth. She appeared depressed. She had a flexed posture with a wide-based, stiff gait. She had orofacial dyskinesiae.

Case III, 4. man born 1923. A postman. He developed dyscalculia and a personality change at the age of 65 years becoming more irritable and losing his sense of time. He developed a severe progressive dementia and lacked insight into his illness. He died at home at the age of 69 years. No autopsy examination was performed.

Case III, 10. man, born 1923. He developed progressive memory problems at the age of 51 years. He could only recall his own name and date of birth. He became stubborn and restless. Later he became apathetic and mute. He was admitted for long term care at the age of 57 years old. He died of bronchopneumonia 2 years later. No autopsy examination was performed.

Case III, 12. woman, born 1927. Home helper. At the age of 53 years she began to have difficulty helping her clients. She forgot items when shopping and her concentration deteriorated. She became awkward. She had early word finding difficulty and had apraxic and agnostic difficulties. She became mentally slow. An EEG examination was unremarkable. CT scan showed central and cortical atrophy. She was admitted to a nursing home following her husband's death. She died at the age of 62 years. No further information is available.

Case III, 13. woman, born 1928. She began to have problems concentrating and remembering details at the age of 50 years. She became fatuous. Early in her illness she bought about 100 Christmas decorations in a shopping trip. Later she was unable to explain her action. She was investigated 2 years later. An EEG-examination was normal, a CT-scan showed severe cortical and moderate central atrophy. She died in a nursing home at the age of 61 years.

Pathological results are included in the main paper.

Case III, 17. man born 1924. A farmer. Described as always anxious. At the age of 50 years he complained of fatigue and dizziness. He was often disorientated and his behaviour was unpredictable. Two years later, he was seen by a neurologist who noted a dementia with receptive problems. An air encephalogram showed extreme central and cortical atrophy. His illness progressed and by the age of 54 years old he was severely demented, restless and uncooperative. His speech became monotonous, unintelligible and perseverative. He appeared tense and restless. He suffered hallucinations. He developed urinary incontinence. On examination he had brisk reflexes and a unilateral extensor plantar response. He was admitted locally for long term care at the age of 57 years with a diagnosis of Alzheimer's disease. He died 2 years later. The result of an autopsy examination is not available.

Case III, 20. Clinical details are described in the main paper.

Case III, 22 Clinical details are described in the main paper.

Case III, 26. woman, born 1923. A farmers wife. At the age of 62 years she gradually became more apathetic, stubborn and socially withdrawn. She became less skilled as a cook. She developed progressive memory problems and dyscalculia. She had no route finding or dressing problems.

She was assessed at the age of 70 years. She scored 21/30 on the MMSE, scoring 7/10 on orientation and 3/5 on serial 7s. When asked to write a sentence she paused, then wrote her name. She was unable to sort playing cards. She could not count the numbers of letter “E”s on a page. She described the picture superficially but fluently. She read a passage fluently but had no recall of the contents. Her verbal fluency was reduced to 6 letters in a minute. Her cognitive estimates were poor. She had no perceptual problems. Neurological examination of her cranial nerves and limbs was unremarkable.

The following year she developed nocturnal confusion and was unconcerned about her incontinence of urine. On examination she was distractible and had perseveration of speech. She rarely spoke spontaneously. Her MMSE score was 14/30. She scored 3/10 on orientation. Registered 3 objects but could not recall them. She scored 1/5 on serial 7s but could perform serial 4s. She could copy the interlocking pentagons accurately and scored well on naming. She obeyed the written and verbal commands. She gave concrete interpretations of proverbs. Verbal fluency was reduced to 3 words. She perseverated on the card sorting test. Her picture description was hesitant and superficial. Her reading remained excellent. Her recitation of the months of the year was hesitant and incomplete. She could mime actions but copying gestures was poor. Her gait was hesitant and stiff. Her cognitive functions slowly declined and she died aged 75 years. No autopsy examination was performed.

Case III, 28. man, born 1926. He was a farmer and later a clerk. He was known for his good memory. At the age of 61 years old he began to develop cognitive problems and emotional lability. He became less able at chess. On one occasion he became lost. His problems slowly worsened over the next five years. His memory deteriorated he became verbally aggressive. He became apathetic. He began eating 500 g of raw sugar a week and became less fussy in his choice of food. He began to perseverate in his speech. He had no insight into his illness. He had no route finding problems and no difficulty recognising relatives.

He was assessed at the age of 67 years. He scored 23/30 on the MMSE, scoring 9/10 on orientation, 3/5 on serial 7s and recalled 2/3 objects. He could not repeat a complex sentence, copy the interlocking pentagons or write a sentence. He performed alternating hand movements. He could count the number of dots on a page but not "E"s. He scored 7/10 on the QSSTCD naming test scoring better for objects than animals. His picture description was superficial and needed prompting. He read a passage fluently and correctly with some recall. He named 8 words beginning with S in a minute. He had perceptual problems scoring 2/4 on incomplete images and not recognising incomplete letters. He could sort playing cards with prompting. Cognitive estimates were adequate. On general examination he had a quiet ejection systolic murmur.

He was seen again at the age of 68 years. He was irritable. His thoughts were concrete. He now smoked more heavily. His family reported he was more apathetic. He had no dressing difficulties and could perform simple household duties. On examination he showed perseveration of writing and speech. He had little spontaneous speech and was distractible. MMSE had fallen to 12/30. He was partially orientated in place but not in time. He could only register 1 object and had no recall. He could not perform serial 7s and had difficulty with serial 4s. He could follow a written command. He could not write a sentence and sorted cards in 1 way with help. He could count dots. His picture description limited to "some figures". He scored 5/10 on the QSSTCD naming test. He named 4 words on the verbal fluency test. He could not start to recite the month of year. He could not give cognitive estimates or interpret proverbs. His copying of meaningless hand postures was poor, but he could mime actions. His reading was fluent but now contained errors. He had a mild increase in limb tone. Fine finger movements were slow. His gait was stiff and slightly stooped.