Inherited Prion Disease P102L
Appendix 1. Clinical case histories
I.1
This individual died aged 69 of unknown cause before the introduction of statutory death
certification. Genealogical links to three of her children suggest that either she or her husband
carried the mutation.
I.2
The husband of I.1 died aged 65 of unknown cause.
II.1
This woman appears to have transmitted the mutation to her descendents.
II.2
This man died aged 69 years. The death certificate lists the cause as ‘heart disease and
bronchitis’. No additional causes or information is available. He appears to have transmitted the
mutation from which his sister II.3 was symptomatic to his descendents.
II.3
This woman was a laundress. She mothered at least 10 children in the early years of the 19th
century. Admitted to the county asylum when aged 40, she was said to be suffering from insanity
related to the death of her mother. Interestingly, the doctor issuing the certification of insanity
declared that the condition was not hereditary. It is noted that the patient had never been
‘deranged’ before this event and the duration of her illness on admission is listed as only six
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Inherited Prion Disease P102L
weeks. She was stated to be of ‘insane mind’, to have no lucid intervals in her condition and to
be a danger to herself. She was treated with ‘leeches, cold applications to the head [and] with
purgative medicines…’. She was in the asylum for five months until her death in September
1834. Her death occurred before statutory death certification so no further information is
available.
III.1
This woman died aged 66. The death certificate lists the cause of death as ‘heart disease 4 years;
dropsy’ – the term usually used to refer to oedema caused by heart failure. It is likely that she
transmitted the mutation to her descendents.
III.2
This man died aged 74 years. The death certificate gives the cause of death as cirrhosis of the
liver. It is likely that he carried and transmitted the mutation, however.
III.3
This farm labourer had at least seven children. Aged between 44 and 54, he became an inmate of
the workhouse with two of his daughters [IV.3 & IV.4]. His wife went to live with her parents
and took up a trade. This family split probably occurred because he had become symptomatic
from prion disease. Shortly before his death in the 1870s, he was admitted to the local lunatic
asylum. His condition was noted to be hereditary and reference is made to his brother and mother
who were also inmates in the same asylum. He was noted to be disorientated with memory
problems on admission, also ‘decrepit’ and ‘scarcely able to move one leg before the other’. His
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Inherited Prion Disease P102L
condition deteriorated and he rapidly became bedbound and needed to be fed. He died aged 53.
His cause of death was listed on the certificate as ‘paralysis’.
III.4
This man, also a labourer and brother of III.4, was admitted to the same asylum with
‘melancholia’ and paranoia aged 50 years. After two discharges from hospital followed by
readmission in emaciated condition, he was noted to be progressively less aware of his
surroundings and to require feeding. He became mute and bed bound ultimately before dying
from a chest infection aged 52. Pulmonary consumption (tuberculosis) was listed as the cause of
death on the death certificate.
III.5
This woman worked as a laundress, as had her mother, and had five illegitimate children. All of
these children were baptized many years after their births when they were in their early teens.
This was highly unusual for the time and probably relates to their illegitimate status. She died
aged 68. The death certificate lists the cause of death as ‘Chronic rheumatism’ but also
‘Paralysis’ listed as a separate cause, which is the same cause listed for her brother making it
likely that she was also affected. It is probable that she transmitted the mutation to her
descendents (see VII.22).
IV.1
This woman appears to have transmitted the mutation. Her exact date of death and therefore her
death certificate have not been found.
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Inherited Prion Disease P102L
IV.2
This man died aged 64 years. The death certificate listed the cause of death as ‘cerebral
degeneration’. He transmitted the mutation to his descendents, although his son and
granddaughter who appear to have transmitted the mutation died from non-neurological causes,
perhaps before the development of frank P102L-related disease.
IV.3
The daughter of III.3, and twin sister of IV.4, this woman died aged 55 years in the workhouse
infirmary. The cause of death was listed as 1. cerebral haemorrhage and 2. paralysis. No post
mortem was performed.
IV.4
This woman died aged 56, fifteen months after her sister. Descendents reported them to have
been identical twins. She was admitted to the workhouse infirmary eight months before her death
suggesting that she was symptomatic for at least this length of time. The death certificate listed
‘senile dementia’ as the cause of death. Of interest, the first description of this case in Rosenthal
et al 1973 reported her death certificate as stating ‘disseminated sclerosis’ which is not the case.
It was, however, possible to confirm by obtaining the death certificates that both sisters died with
only a short difference in ages but with apparently different primary symptoms.
IV.5
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Inherited Prion Disease P102L
This woman apparently emigrated to Canada and the genealogical link was made by researchers
there. It has not been possible during the present study to trace her genealogically and therefore
no new information on her or her descendents is offered.
IV.6
This man drowned in the village river aged 60. An inquest gave the cause of death as accidental,
although a suicide cannot be ruled out. He is likely to have transmitted the mutation to his
descendents.
V.1
This man was apparently diagnosed with Motor Neurone Disease in life according to his family.
He died aged 54 in the local general hospital. No clinical records have survived. The cause of
death was given as 1a. bronchopneumonia and b. Huntington’s Chorea.
V.2
This woman was said to be affected by neurological disease by family members. No further
information has been found regarding her condition.
V.3
This woman was well until a few months before her death. At this point, aged 58, she fell and
broke her leg. From then on she was noted to be ‘not her normal self’ by the family. This change
was put down to her head injury. Her behavioural change progressed to the point where she was
admitted to a psychiatric hospital, and then transferred to the general hospital where the
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Inherited Prion Disease P102L
possibility of a brain tumour was raised. Exploratory surgery was planned but she died while
awaiting transfer to another hospital for this to be carried out. The death certificate listed left
intracranial haemorrhage as the cause of death, apparently after a Coroner’s post mortem without
inquest. She transmitted the mutation to her son, VII.1.
V.4
This man was said by family members to have developed slurring of his speech, with weakness
in his legs and unsteadiness prior to his death aged 69. He progressed from being wheelchair to
bedbound and unable to move, hear or see. A diagnosis of possible multiple sclerosis was
discussed with the family who subsequently believed that he had been affected by the same
disease as his siblings. The death certificate gives the cause of death as cardio-respiratory failure
and cerebellar degeneration.
V.5
This man died aged 69. The death certificate listed the cause of death as: 1a) myocardial
degeneration and b) arteric sclerosis. He apparently transmitted the mutation to some of his
descendents.
V.6
Case II-5 in Rosenthal et al 1976. Died aged 58 years.
V.7
Case II-8 in Rosenthal et al 1976. Onset aged 47, died aged 52.
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Inherited Prion Disease P102L
V.8
Case II-11 in Rosenthal et al 1976. Onset aged 46, died aged 49.
V.9
Case II-15 in Rosenthal et al 1976. Onset age 66, died aged 69.
V.10
Case II-18 in Rosenthal et al 1976. Died aged 56.
V.11
This woman died seven months after her first symptoms developed when she was aged 61. The
family reported that she did not have any significant cognitive symptoms prior to her death at
home. The cause of death is listed on the certificate as ‘hereditary cerebellar degeneration’.
V.12
This man died in a general hospital from a similar disease to that which had affected his sisters
aged 60. The death certificate listed the cause of death as ‘1a. bronchopneumonia’ and ‘II.
Progressive cerebellar degeneration’.
V.13
This woman was affected by a similar progressive disease and died aged 61. The death certificate
gives the cause of death as ‘disseminated sclerosis’.
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Inherited Prion Disease P102L
V.14
This woman died at home from a progressive disease similar to her elder sister aged 60. The
death certificate listed the cause of death as ‘disseminated sclerosis’.
V.15
The family reported that she was affected by a progressive loss of balance, weakness in her legs,
slurring of her speech and ultimately loss of memory. She died aged 62, apparently within 2
years of the start of her illness. Her death certificate lists the cause of death as 1a Syncope and 1b
coronary thrombosis.
V.16-19
From Canadian branch described in Young et al 1995.
V.20
This man, the son of IV.6, was one year older than, and lived next door to V.21 who had an
illegitimate son (VI.22) who appears to have transmitted the mutation. It is probable that V.20,
descended from known affected individuals, was the father of VI.22 and therefore transmitted
the mutation. He died aged 70 and the death certificate lists the cause of death as carcinoma of
the bowel.
V.21
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Inherited Prion Disease P102L
See explanation for V.20. This woman had two illegitimate children when in her late teens, one
of whom was affected with neurological disease and transmitted the mutation to his descendents.
She subsequently married and had further children who do not seem to have been affected,
making it unlikely that she herself carried the mutation.
VI.1
This man left school without any qualifications and unable to read or write. He worked for the
same company for many years in various manual roles. Aged 49 he had a generalized seizure
while in the bath. Following this was noted to have personality change and he became liable to
aggressive outbursts. He developed some stereotyped behaviour and lost his job as a result. Over
the next few months he became withdrawn and dependent, requiring to be dressed and fed,
although on occasion when prompted he was able to do these things independently. He lost
interest in his previous occupations. He was thought to be depressed and was treated with
antidepressants. He appeared to have visual hallucinations. On examination a year after his
symptoms developed he was dyspraxic and had ataxia on walking. He was hyper-reflexic
however his plantar responses were down-going. His power was thought to be normal although
family members described him being unable to rise from a chair without using his arms. CT
scanning of the brain did not demonstrate any abnormalities. MRI brain showed bi-parietal
atrophy. EEG showed some excess of temporal slow-wave activity. He deteriorated quite rapidly
after this point and his hallucinations and aggressive outbursts lead to him being admitted into
psychiatric intensive care for treatment. He continued to have repeated episodes of reduced
consciousness heralded by stereotyped behaviour such as rubbing his nose. He became doubly
incontinent. He was noted to have parkinsonism, although he was taking antipsychotics and it
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Inherited Prion Disease P102L
was unclear whether the extrapyramidal signs were disease or medication related. In view of the
fluctuations, prominent hallucinations and the MRI findings, the diagnosis was thought to be one
of dementia with Lewy bodies. A later MRI showed more diffuse cerebral atrophy. Over the next
year his behaviour improved. He was still mobile and still occasionally appeared to be
responding to internal stimuli but his aggression was much less marked. He continued to
deteriorate and died finally aged 54.
VI.2
This woman had a fall while at work aged 63. Shortly after this fall she noticed that she was
unsteady while walking. She continued to have a series of falls. She described some vertical
diplopia while watching television and reported some deterioration in her hand-writing.
On examination at this first review she was not thought to have any cognitive symptoms or signs
on bed-side testing. There were no cranial nerve signs. She had a slow, ataxic gait. The reflexes
in the lower limbs were absent, although normal in the upper limbs.
Following the post-mortem diagnosis in her daughter (VII.1), blood was taken and sent for
PRNP analysis confirming the presence of the P102L mutation. The codon 129 genotype was
homozygous for methionine. When reviewed 2 years after first presentation she had become
unable to walk due to lower limb ataxia. She had developed dysarthria and dysphagia with
choking after swallowing. On examination she had horizontal nystagmus and broken saccadic
movements. Romberg’s test was positive. There were some minor cognitive symptoms affecting
memory but her MMSE score was relatively preserved at 26/30. Shortly after this review a
urinary catheter was sited in view of increasing urinary frequency and difficulty voiding
adequately. She developed marked weakness in her legs which further affected her mobility and
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Inherited Prion Disease P102L
the ease with which she could be cared for. She had no psychiatric symptoms or parkinsonism.
She was cared for at home, finally requiring sedative medications via a syringe driver for
agitation before dying aged 66.
VI.3
This woman died aged 55 from heart disease and therefore probably before developing overt
signs of prion disease. She apparently transmitted the mutation to her descendents.
VI.4
Case III-19 in Rosenthal et al 1976. Onset at age 65, died age 67.
VI.5
Case III-21 in Rosenthal et al. Onset age 54, died aged 65.
VI.6
Case III-24 in Rosenthal et al. Onset age 57, died aged 60.
VI.7
Case III-25 in Rosenthal et al. Case 1 in Adam et al 1982. Onset aged 60, died aged 63.
VI.8
Case III-29 in Rosenthal et al. Onset aged 48, died aged 53.
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Inherited Prion Disease P102L
VI.9
Propositus in Rosenthal et al 1976, Case III-32. Onset aged 42, died aged 43, duration 13
months.
VI.10
Case III-38 in Rosenthal et al 1976. Case 2 in Adam et al 1982. Onset aged 50, died aged 53.
VI.11
Case III-42 in Rosenthal et al 1976. Onset aged 39, death aged 45.
VI.12
This woman became symptomatic aged 48. Initially she was affected by difficulty concentrating
on her work and subsequently by shaking of her left arm which led her to retire from her job. She
developed a quite rapid onset of cognitive decline in the following months. On examination four
months after the onset of her symptoms, she was noted to be orientated to time and place. Her
cranial nerve examination was normal. Her deep tendon reflexes were brisk but her plantars were
down-going. There were no other significant neurological signs reported. Neuropsychometry
demonstrated severe impairment with striking visuo-spatial perseverative tendencies. Follow-up
Neuropsychometry only four months after the initial test showed evidence of significant decline
even over this short time interval. A year into her illness and she was severely demented with
little awareness of events around her. Her legs were noted to be stiff but she was apparently still
independently mobile. She continued to deteriorate and died aged 51 from pneumonia.
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Inherited Prion Disease P102L
VI.13
Case III-50 in Rosenthal et al 1976. Case 3 in Adam et al 1982. Onset aged 57, died aged 63.
VI.14
This woman presented aged 66 with a six month history of difficulty in walking, tremor in her
hands and noticing her handwriting becoming smaller. She had also noted urinary urgency. She
denied any cognitive symptoms. She was noted to have some myoclonus in her fingers. Although
initially she did not appear to have significant neurological signs she developed sialorrhoea, and
bradykinesia in addition to worsening myoclonus of her arms and legs on review and was given a
trial of L-dopa to see if this would improve her symptoms. No significant benefit was gained
from the L-dopa. Subsequently she developed cerebellar signs with dysdiadocokinesis.
Examination now revealed some unilateral pyramidal signs in combination with absent ankle
jerks and extensor plantar responses. The other deep tendon reflexes were normal. There was
diminished vibration sense in her lower limbs. The possibility of corticobasal degeneration was
raised.
Formal neuropsychometry was performed one year after symptom onset demonstrating
significant generalized cognitive decline with frontal preponderance. An EEG showed nonspecific abnormalities suggesting an encephalopathic process. SPECT imaging showed
multifocal areas of diminished cerebral perfusion combined with MRI evidence of multiple white
matter lesions thought to be consistent with infarcts. The possibility of Binswanger’s disease was
raised on the basis of these results, although a systemic vasculitic process was also considered in
view of a history of rheumatoid arthritis and aortic regurgitation.
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Inherited Prion Disease P102L
CSF examination showed normal protein and cell counts. A cerebral angiogram was normal.
Faint oligoclonal banding was seen on electrophoresis of serum immunoglobulins as well as CSF
suggesting a source outside of the CNS. She was discharged from neurological follow-up with a
diagnosis of either Binswanger’s or a non-vascular neurodegenerative process perhaps of a
multisystem atrophy type.
Over the next few years her mobility progressively deteriorated and she was cared for in a
nursing home. From here she was admitted with a series of septic episodes to the local hospital.
Reports from her carers continued to indicate that when she was not acutely septic she was
orientated and able to communicate her needs and wishes to staff. She developed a sacral
pressure sore which became infected and deteriorated in spite of antibiotic therapy. She died
finally aged 69 years. The death certificate listed the cause of death as Ia septicaemia and Ib
urinary tract infection. The presence of the P102L mutation and the genealogical connection was
established subsequently. Of note, the patient did not inform investigating clinicians about her
family history of which she seems to have been unaware.
VI.15
This man was working normally until he was 58 years of age. At this point he was noticed to be
uncharacteristically irritable and to be cutting up his food in unusual ways. Some time after this
he collapsed and was admitted to hospital. The exact cause of this collapse was unclear.
However, following it he was noted to be mute with marked dyspraxia. He did not appear to
recognize his family. He was difficult to examine however initially he was noted to have brisk
reflexes. On examination two months later his deep tendon reflexes were difficult to elicit. His
plantars were flexor. A CT brain scan was reported as normal. CSF examination was
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Inherited Prion Disease P102L
unremarkable. An EEG was grossly abnormal with little evidence of normal alpha rhythm and
generalized slow-wave activity.
His illness progressed rapidly and he died of a chest infection after only 8 months of symptoms.
A limited post mortem examination was performed. Moderate global cortical atrophy was noted
on macroscopic examination. Microscopic findings were widespread spongiosis with kuru-like
and multicentric plaques. A diagnosis of GSS was made on the basis of these findings and the
presence of the P102L mutation was confirmed after his death. The codon 129 genotype was
methionine valine heterozygous.
VI.16
This woman became unwell aged 58 years and died subsequently after a four year course, aged
62 years. She had a post mortem which showed only minor decrease in the size of the pons with
no other remarkable features on macroscopic examination. Microscopic examination revealed
extensive spongiform change in all cortical areas examined. Asteroid plaques were seen which
stained positively for the prion protein. Increased gliosis was seen. Small granular eosinophilic
plaques were present in throughout the basal ganglia with mild spongiform change. In the
cerebellum, granular asteroid eosinophilic plaques were present along with mild spongiform
change. Occasional plaques were also seen in the granular layer. All the plaques stained
positively for the prion protein. No evidence of spinal cord spongiform change or plaque
deposition was seen.
VI.17-21
Canadian cases. No further information available (Young, Jones et al 1995).
15
Inherited Prion Disease P102L
VI.22
As discussed under V.20, this individual was illegitimate and his father is unknown. He appears
to have transmitted the mutation to his descendents. He died in the local general hospital aged 74
years of age. Unfortunately, the hospital records were destroyed before they could be examined
for this study. The death certificate gives the cause of death as: 1a. Cerebrovascular accident and
2. Neurofibromatosis and multiple lipomata. There is no history of neurofibromatosis in the
family and family members had no recollection of this being discussed as a diagnosis. This
would be the oldest death from IPD P102L reported, although the possibility of non-penetrance
has to be considered even if, as it appears, he did transmit the mutation.
VI.23
Wife of VI.22, she died aged 69. The death certificate lists the cause of death as 1a Heart Failure
b. pneumonia, c. obstruction of the large bowel and 11. cerebrovascular accident. No
genealogical link has been found between her and the remainder of the kindred. It remains a
possibility that it was her and not her husband who carried and transmitted the mutation to some
of their children.
VI.24
This woman died aged 76 at home. The death certificate listed the cause of death as; 1a) cardiac
failure 1b) myocardial degeneration and 1c) arteriosclerosis. No genealogical link to the W
kindred could be established. This combined with her death in old age of apparently non-
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Inherited Prion Disease P102L
neurological disease, as well as the healthy illegitimate daughter born many years after her
husband’s death makes it probable that she did not carry the mutation.
VI.25
This man died in his thirties apparently from the effects of poison gas used during the First
World War. It is likely that he carried the mutation and transmitted it to his two children, VII.17
and VII.18. His parents were both born within five miles of the known W kindred cases.
Genealogical work has succeeded in tracing his branch of the family back to the mid 18th century
in the same locality without finding a link to the W kindred. In view of the shared microsatellite
haplotype background in his descendents and geographical proximity, the possibility of nonpaternity in one of the traced ancestors or of a genealogical link predating the mid 18th century
are both explanations for the inability to link this arm of the family genealogically.
VII.1
This woman became unwell aged 27. She presented with unsteadiness in her gait, accompanied
with back pain shortly after the birth of her son. Additionally she had noticed that her writing had
deteriorated, becoming spidery and indistinct. She also reported on questioning a longer history
of being woken in the night by dysasthesiae in her legs which had been present for a year before
her other symptoms. On examination she was found to have limited up-gaze, slurred dysarthric
speech and bilateral optic disc pallor. She had a generalized dystonia with orofacial dyskinesias,
accompanied by dystonic movements of her neck and limbs. She had a cerebellar ataxia, initially
normal power throughout with absent lower limb reflexes and up-going plantar responses. She
later developed weakness of hip flexion with widespread muscle wasting, deafness and urinary
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Inherited Prion Disease P102L
frequency and urgency before becoming incontinent. Neuropsychometry demonstrated a
deterioration in her estimated premorbid level of functioning and frontal executive deficits. She
was seen by a number of eminent neurologists over the next five years in three different
neurological centres, although no definite diagnosis was reached. A wide range of investigations
revealed only non-specific EEG abnormalities. CT brain, a myelogram, nerve conduction
studies, cerebrospinal fluid analysis and multiple blood tests as well as DNA analysis for SCA
and DRPLA were all normal or negative. On examination she was noted to have ataxia,
dysarthria, impaired vertical gaze, absent lower limb reflexes and up-going plantars. She had
unsuccessful trials of levodopa in case her dystonia was dopa-responsive as well as benzhexol
without success. Her condition continued to progress until she was wheelchair and subsequently
bed-bound. Later investigations demonstrated evidence of delayed visual evoked responses and
abnormal electro-retinogram showing no rod, and impaired cone responses.
She died aged 33 after six years of illness and had a post mortem. Multi-centric amyloid plaques
associated with Gerstmann-Sträussler-Scheinker syndrome were found on histology and post
mortem PRNP gene testing confirmed the diagnosis. The codon 129 genotype was homozygous
for methionine. The prominent dystonic features have not been reported before in IPD P102L
and this individual has the youngest age at onset and death reported here.
VII.2
This man was said by the family to have suffered from dementia. He died aged 47 in hospital.
The hospital notes were destroyed before they could be reviewed for this study. A post mortem
without inquest was carried out by the local coroner and the cause of death listed as
bronchopneumonia. No supplementary or contributing cause was noted.
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Inherited Prion Disease P102L
VII.3
Case IV-57 in Rosenthal et al 1976. Onset aged 43, death aged 47.
VII.4
Case IV-58 in Rosenthal et al 1976. Onset aged 40, died aged 46.
VII.5
This man presented when he developed severe hip pain initially thought to relate to joint disease.
An operation was planned but not carried out due to concerns relating to his known risk of
inherited prion disease. PRNP analysis was carried out after presymptomatic counselling and
demonstrated the presence of the P102L mutation with homozygosity for methionine at codon
129. On review in the neurology clinic he reported only some slight difficulty writing, with
slowing and reduction in size of his words, and some gait difficulties put down to his hip pain.
On direct questioning he also reported occasional involuntary jerking movements. On
examination, however, he had a marked parkinsonian appearance with shuffling gait and reduced
arm swing. He also had loss of fine touch sensation in his legs in a stocking distribution and his
lower limb reflexes were reduced. He died suddenly at home before he was seen again.
VII.7
This man was referred to a neurologist when he was only 38 years of age. The clinician
commented in his letter ‘this unfortunate man…has the sword of Damocles hanging over him…’
The family history and risk was obviously well known to him and he had seen the disease take
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Inherited Prion Disease P102L
hold in his mother and in an aunt by whom he was subsequently looked after following his
mother’s death. He first noticed some unsteadiness and difficulty walking when he was 37 years
of age. This progressed to the point where he was unable to ride a bicycle. He denied any
clumsiness in his upper limbs. He had also noticed some forgetfulness, although he had put this
down to the stress he had been under. His wife reported that he had exhibited some strange
behaviour about a year before his legs became weak. He had poured water instead of milk on his
breakfast cereal. She had also noticed a change in personality with uncharacteristic irritability.
On examination at the time of presentation approximately one year following the first symptoms,
there were brisk upper limb reflexes with increased tone and markedly increased tone in the
lower limbs. The plantar responses were extensor. There was no weakness. His gait was broadbased and unsteady. Sensory examination was normal.
An MRI brain scan did not demonstrate any abnormality. An EEG was non-specifically
abnormal. CSF examination was acellular with a protein at the upper limit of normal. There were
no oligoclonal bands seen. A blood sample was taken for PRNP analysis which confirmed the
presence of the P102L mutation. The codon 129 genotype was methionine homozygous.
This man’s symptoms progressed rapidly following an inpatient admission for investigations
aimed at ruling out an alternative treatable cause for his symptoms. On examination 15 months
after symptom onset, he demonstrated a severely impaired slow and unsteady gait, requiring
assistance to stand and a wheel chair to mobilize any distance. He was slurring his words and had
emotional lability. No formal neuropsychometry was performed although the clinician reviewing
him did not find evidence of obvious deficits. A mini mental state examination was scored at
29/30 with inability to copy intersecting pentagons. Discussions took place regarding the
possible use of rifampicin as an anti-amyloid agent, although the patient declined it.
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Inherited Prion Disease P102L
He was reviewed by a psychiatrist two years after the onset of his symptoms having developed
visual hallucinations and secondary delusions. These were controlled with thioridazine in low
dose. At this stage he was only partially orientated to time and place. He demonstrated severe
emotional lability and had difficulty responding to questions in view of perseverative speech.
Shortly before his death he became unresponsive and developed a pressure sore which became
infected. He died from a chest infection aged 39. Pathological findings have been reported
previously (in Wadsworth et al 2006).
VII.9-11
Canadian cases, no further information available (Young, Jones et al 1995).
VII.12
This man died aged 65 in the local general hospital. His death certificate listed the cause of death
as 1a acute pulmonary oedema 1b. bronchopneumonia 1c. Multiple cerebrovascular accidents
and 2 diabetes mellitus. The hospital notes were destroyed before they could be examined for
this study. Family members felt that he had a similar illness to his siblings prior to his death.
VII.13
This patient had a history of severe depression, treated with electro-convulsive therapy some
years before her neurological symptoms began and apparently without recurrence. She
subsequently had short lived visual loss affecting the upper quadrants in both eyes, without
recurrence. She developed unsteadiness on walking and falls aged 59 years. She described this as
being as though she was drunk. Shortly afterwards she developed burning pain behind both her
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Inherited Prion Disease P102L
knees which radiated into her thighs. This was intermittent at first but became almost continuous
later. She did not have any numbness or dysaesthesiae. She also reported urge incontinence. On
examination she had no cognitive signs or symptoms. She was noted to have a parkinsonian
appearance. There was mild ataxia. Tone was increased in the legs with weakness of hip flexion.
Her lower limb reflexes were brisk with some non-sustained ankle clonus and up-going plantars.
There were no significant sensory signs. A CT scan was performed which did not show any
abnormalities. CSF analysis showed normal protein and cells but with positive oligoclonal bands.
There is no record of whether or not comparative serum analysis was carried out.
Neuropsychology carried out 18 months after the onset of unsteadiness and falls showed no
evidence of intellectual deterioration. The initial diagnosis was felt to be late-onset multiple
sclerosis complicating posterior circulation ischaemia. The patient continued to decline and
finally died in 1985 aged 66. The death certificate stated the cause of death as 1a
bronchopneumonia and b multiple sclerosis. She transmitted the mutation to her son (VIII.1).
VII.14
This patient died in the local general hospital aged 61 years of age. The cause of death is listed
on the death certificate as ‘hereditary progressive ataxia’. Unfortunately the hospital records had
been destroyed before they could be examined for this study.
VII.15
This woman died in the local general hospital aged 55 years. The hospital records were destroyed
before they could be examined for this study. The cause of death was listed as 1a.
Bronchopneumonia and 1b cerebellar degeneration.
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Inherited Prion Disease P102L
VII.16
This patient was looked after for many years in an asylum. She was given a diagnosis of
schizophrenia. However, family members report her having eccentric and unpredictable
behaviour without clear delusions or hallucinations. They feel that she was affected by the family
illness and did not feel that her treatment in a psychiatric institution was appropriate. She died
aged 37 years in the local general hospital. Unfortunately, the hospital notes were destroyed
before they could be examined for this study. The death certificate states the cause of death as 1a
bronchopneumonia and 2 Schizophrenia.
VII.17
This woman first developed word-finding difficulties aged around 47 years. She would be unable
to name objects that she was looking for or wanted passed to her. 2 years later she developed
difficulty walking with unsteadiness. Her mobility deteriorated quite rapidly until her husband
needed to carry her to bed. The family moved house in order to facilitate her care. She lost
weight dramatically, having been overweight before the onset of her symptoms. Investigations
were carried out at Guy’s hospital in London. At this point the family was told that the diagnosis
was motor neurone disease. Later in her illness she developed an intention tremor but there were
no seizures of fits. She had difficulty remembering even recent events or important bits of
biographical information and finally became mute. Her father had died from the effects of
poisonous gas following the First World War in his thirties. Perhaps because of his early death
there was no apparent family history and the hereditary nature of her condition was not
recognized. She was admitted to the local hospital a few weeks before her death aged 53
23
Inherited Prion Disease P102L
following a 6 year history of illness. Her death certificate lists the cause of death as: 1a)
bronchopneumonia and b) cerebral and cerebellar cortical atrophy. Unfortunately her hospital
notes were destroyed before they could be reviewed for this study.
VII.18
This man died aged 62 years in a local hospital. The cause was described by family members
from their recollections of discussions with medical staff as being either motor neurone disease
or cerebellar atrophy. His death certificate lists the cause of death as: 1a bronchopneumonia and
1b spinal cerebellar degeneration. He transmitted the mutation to all three of his children. The
hospital records were destroyed before they could be examined for this study.
VIII.1
This woman died in a nursing home aged 49, 5 years after the onset of her symptoms. According
to a family member she was affected by dementia and immobility with apparently no malcoordination or involuntary movements. The diagnosis of inherited prion disease was made on
PRNP analysis a year after her symptoms developed. The codon 129 genotype was methionine
valine heterozygous. According to her death certificate she died from pneumonia related to
immobility.
VIII.3
This 58 year old man presented with a two year history of unsteadiness causing difficulty
walking. In addition he felt that his legs were heavy and he had hyperaesthesia in his feet. He
subsequently developed slurring of his speech and urinary urgency. There was also nocturnal
24
Inherited Prion Disease P102L
myoclonus. The family history of confirmed inherited prion disease P102L cases meant that
PRNP analysis was carried out early on confirming the presence of the mutation. The codon 129
genotype was methionine valine heterozygous.
On examination two years after the onset of symptoms the patient had no evidence of cognitive
impairment on bedside testing. He was noted to have emotional lability and some mild
disinhibition possibly indicating some frontal involvement. Cranial nerve examination revealed
some dysarthria. His gait was waddling in character reminiscent of a myopathic pattern with
bilateral foot-drop. Tone and power were normal in the upper limbs however the deep tendon
reflexes were brisk. Hoffman’s sign was negative. There was evidence of weakness particularly
at hip flexion bilaterally. The deep tendon reflexes were absent at both knees and ankles with
extensor plantar responses bilaterally. Sensory examination revealed reduced joint position sense
with some subjective loss of soft touch in the distal lower limbs.
Formal neuropsychological testing initially showed no evidence for cognitive decline compared
to estimated premorbid functioning 2 years after symptom onset. MRI brain revealed no
significant abnormalities. EEG showed no abnormalities. CSF examination showed normal
protein and cell counts. The 14-3-3 was positive and the s100b elevated. Oligoclonal bands were
negative. Nerve conduction studies showed evidence of a mild sensorimotor axonal neuropathy.
His symptoms continued to progress with worsening mobility requiring the constant use of a
wheelchair. Later neurological examinations over the next year showed nystagmus on lateral
gaze with some broken pursuit movements. The leg weakness progressed and his speech became
progressively harder to understand due to low volume and dysarthria.
Serial neuropsychological testing over the following two years showed anterior dysfunction
evidenced by frontal executive impairment with worsening nominal skills.
25
Inherited Prion Disease P102L
VIII.4
This woman was well until she was 63 years of age.
At this age she developed cognitive decline with poor memory accompanied by unsteadiness,
slurred speech and deteriorating writing. Her unsteadiness developed over two years to the point
where she was unable to walk unaided. She had very poor insight into her difficulties which
made caring for her safely very difficult. In addition she developed prominent psychiatric
symptoms with suspiciousness and agitation accompanied by paranoid ideation directed at
carers. On examination she scored only 16/30 on MMSE. She lost marks for attention and
calculation, repetition and orientation. In addition she was unable to recognize fragmented
letters, perform simple arithmetic and had concrete interpretation of proverbs. She was unable to
mime everyday tasks and had very poor recall for recent tasks. Initially she had declined to have
PRNP analysis carried out, but finally this was performed and demonstrated the presence of the
P102L mutation. She was methionine valine heterozygous at codon 129.
EEG examination at the time of diagnosis showed an excess of generalized slow waves with
multifocal epileptiform activity without clinical correlates. MRI brain demonstrated mild global
atrophy with some T2 and FLAIR hyperintensities in the deep white matter thought to be
consistent with small vessel ischaemic disease. She died aged 67 years.
VIII.5
This woman, the monozygotic twin of VIII.6, became unwell aged 53 with stiffness in both her
legs and slurring of her speech. Subsequently she developed urinary urgency and incontinence
along with dysphagia. On examination three years after onset, she was found to be ataxic, with
26
Inherited Prion Disease P102L
dysarthria and dysdiadocokinesis. Although power in the limbs was normal, the deep tendon
reflexes in the limbs were absent. She had a positive pout reflex and was orientated to place and
person with a normal digit span. Formal cognitive assessment was not performed. There was
glove and stocking loss of sensation in both legs.
Screening blood tests were normal, and an MRI performed 3 years after symptom onset showed
no atrophy or abnormal signal change. Nerve conduction studies demonstrated evidence of an
axonal polyneuropathy with mostly sensory but some motor involvement. In view of the strong
family history, a spino-cerebellar ataxia was suspected until the presence of the P102L mutation
was established on PRNP sequencing. After diagnosis she deteriorated relentlessly becoming
wheel-chair bound by the age of 58. She died aged 60 from pneumonia. No post mortem was
performed.
VIII.6
This woman is the monozygotic twin of VIII.5. Around the time of her twin’s death, and seven
years after her sister became symptomatic, she began to have problems with unsteadiness while
walking. She saw a neurologist with back pain and a left foot-drop initially put down to a lumbar
radiculopathy, although no evidence of root impingement was found on magnetic resonance
imaging. She subsequently developed slurring of her speech.
On examination a year into her illness, she had a positive pout reflex with nystagmus and broken
pursuit movements. She had dysdiadocokinesis with an ataxic and a myopathic gait, with
positive Trendelenberg’s test and unilateral foot drop. There were no sensory abnormalities on
examination. Cognitive examination revealed some mild impairment of mental arithmetic and
recall.
27
Inherited Prion Disease P102L
Confirmation of monozygosity between VIII.5 and VIII.6, was performed by analysis of multiple
unlinked microsatellite markers. Both individuals shared 12/12 alleles at D18S51, D2S1338,
D19S433, D8S1179, D16S539, and D3S1358.
2.VI.2
This woman died aged 49 years. The death certificate listed the cause of death as 1a.
bronchopneumonia and 1b. progressive cerebellar ataxia. She passed the mutation on to her
children. The dates and causes of her parents’ deaths could not be found and therefore the family
link could not be traced any further. Family lore suggests that the mother of 2.VI.2 may have had
extra-marital affairs, supporting the possibility of non-paternity.
2.VII.1
This woman became unwell aged 41 years with unsteadiness of gait and difficulty swallowing.
She also developed memory problems during her illness. She died aged 47 years. A diagnosis of
GSS was made on post mortem, although no DNA analysis was possible.
2.VII.2
This man became unwell aged 52 when he developed severe hip and thigh pain. At the same time
he developed problems with his balance and had slurring of his speech. Two years into his illness
he was found to have a markedly ataxic gait, with reduced lower limb reflexes and flexor
plantars, a stocking-pattern reduction in sensation was found in the lower limbs. He showed
some subtle deficits on bed-side cognitive testing affecting attention. PRNP analysis was
performed when the mutation was identified in family members. MRI brain showed cerebellar
28
Inherited Prion Disease P102L
atrophy, and EEG was within normal limits initially but showed some mild non-specific
abnormalities in the late stages of the disease. He deteriorated progressively and died from
pneumonia aged 58.
2.VIII.1
This woman presented aged 41 and died 4 years later from her illness. PRNP analysis confirmed
the P102L mutation and homozygosity for methionine at codon 129.
2.VIII.2
This woman had predictive genetic testing confirming the presence of the mutation after it was
identified in the family. The codon 129 genotype was methionine homozygous. She became
unwell with unsteady gait aged 41, progressed steadily and died aged 44.
2.VIII.3
This woman became unwell with unsteady gait and slurred speech aged 34 years. Her condition
deteriorated and she died aged 39 years. She was homozygous at codon 129.
3.IV.1
This woman died aged 57 years. The cause of death was listed as ‘cerebrospinal sclerosis’.
3.V.1
This woman died aged 57 after 2 years of illness. The cause of death was given as ‘disseminated
sclerosis’.
29
Inherited Prion Disease P102L
3.VI.1
This man died aged 42. The cause of death was listed as ‘heredofamilial muscular dystrophy’.
3.VII.1
This woman died aged 39 after an illness lasting for 3 years. She had one son (3.VIII.1). The
cause of death was listed as ‘disseminated sclerosis’.
3.VIII.1
This man developed unsteadiness aged 48. This was initially played down by the family until
severe leg pains developed when he was 51 years of age. PRNP analysis confirmed the P102L
mutation and methionine valine heterozygosity at codon 129. On examination following the
diagnosis he was found to be parkinsonian with dysarthria. Deep tendon reflexes were absent in
the lower legs with up-going plantars bilaterally. He had no sensory examination findings. His
condition deteriorated and he developed severe hypomimia, and bradykinesia. Poor attention and
drowsiness limited cognitive testing, although when given time to answer he was orientated to
place and person. He died aged 53.
4.VII. 1
This woman became unwell subacutely aged 57 with unsteadiness and memory difficulties.
Shortly afterwards she developed painful sensory symptoms in her legs. She had visual
hallucinations and paranoid ideation. In view of the relatively rapid onset the diagnosis of sCJD
was considered. PRNP analysis performed as part of the investigations confirmed the diagnosis.
30
Inherited Prion Disease P102L
The codon 129 genotype was methionine valine heterozygous. MRI showed multiple peripheral
white matter lesions in the cortex, especially in the temporal lobes, but no atrophy. EEG showed
excessive slow-wave activity. CSF was acellular with normal protein. 14-3-3 protein was
positive and s100b elevated. Her condition deteriorated relentlessly and she died aged 59. A post
mortem showed findings associated with GSS. Although maternal aunts had developed dementia
before their deaths, no further clinical details could be obtained.
5.VII.1
This woman died aged 42 years. The death certificate lists the causes of death as: a) pulmonary
embolism, b) bronchopneumonia and c) olivo-ponto-cerebellar degeneration. No further clinical
information is available.
5.VII.2
This man died aged 47 with ataxia and dementia. His death certificate lists the cause of death as
‘disseminated sclerosis’.
5.VIII.1
This woman presented age 38 with neck pain, unsteadiness and memory problems. She was
initially treated for depressive pseudo-dementia. Her condition deteriorated relentlessly. An MRI
demonstrated generalised cerebellar atrophy. CSF was acellular with raised s-100b and neurone
specific enolase. 14-3-3 was negative. PRNP analysis confirming the mutation was performed as
part of a screen of possible causes of inherited ataxia. She died aged 45.
31
Inherited Prion Disease P102L
6.VII.1
This 45 year old woman presented with numbness in her feet with paraesthesiae. She also
developed depression and agitation with mild cognitive impairment. In view of her young age
and presentation, vCJD was considered the likely diagnosis, although sCJD was also considered.
MRI brain showed only cerebellar vermal atrophy. EEG was non-specifically abnormal with
positive CSF 14-3-3. There was no family history. Diagnosis was made on PRNP screening
carried out when prion disease was considered likely. She died only seven months after onset of
symptoms.
7.VII.1
This woman suffered from dementia. No further clinical information is available.
7.VII.2
This man suffered from dementia, no further information is available.
7.VII.3
This man suffered from dementia, no further information is available.
7.VIII.1
This woman became unsteady on her feet aged 42 years. She subsequently developed dysarthria
and loss of coordination of her limbs. Her condition progressed and she died aged 48. PRNP
analysis confirmed the presence of the P102L mutation and homozygosity for methionine at
codon 129.
32
Inherited Prion Disease P102L
8.VII.1
This woman died in Italy around age 60 from neurological disease. No further information is
available.
8.VIII.1
This man developed unsteadiness age 57 years, combined with memory loss. He had an unsteady
gait with broken pursuit eye movements and reduced reflexes in the lower limbs with extensor
plantars. EEG was non-specifically abnormal, and MRI showed only evidence of a previous
injury. Nerve conduction studies were unremarkable. Neuropsychology showed evidence of
significant cognitive decline.
8.VIII.2
This woman died at age 54 from neurological disease. No further information is available.
8.VIII.3
This man died at age 57 from neurological disease. No further information is available.
9.VII.1
This woman died aged 58 after developing progressive cognitive problems. She also had
difficultly walking and a complaint of burning pains in her legs.
9.VIII.1
33
Inherited Prion Disease P102L
This woman died aged 54 after several years of a progressive ataxic syndrome.
10.1
Previously fit and well, this man presented after developing gait ataxia and lower limb weakness
aged 37. Three years later this led to him being unable to walk. Four years after onset he was
largely bed-bound. He was first seen by neurologist five years after onset. At this stage he was
noted to have an ataxic syndrome with generalised flaccidity, weakness and absent reflexes
despite intact vibration, joint position sense and light touch. Pinprick and temperature appeared
"less well appreciated". Disseminated Sclerosis was diagnosed, but the neurologist commented
on the flaccidity and areflexia as ‘the interesting feature’. He died about five years after symptom
onset, at age 43.
10.2
This man was the son of 10.1. He developed gait ataxia aged 47. Around five months after onset
he was walking with a stick and just over a year after his first symptoms, he required a wheeled
frame. In view of this rapid deterioration a SCA mutation was thought unlikely. He developed
mild dysarthria five months after onset, and deterioration in handwriting began seven months
after onset. From about nine months after onset, he noticed a decline in his memory and
concentration. He worked in a managerial role in a large company and did not feel that he was
able to cope with his job. Subsequently he developed paraesthesiae below his knees. On
examination 20 months after onset, he had gross gait ataxia and an otherwise moderate pancerebellar syndrome with decreased lower limb tone, what appeared to be a combination of mild
pyramidal and distal lower limb weakness, absent lower limb reflexes, extensor plantars, but
34
Inherited Prion Disease P102L
intact proprioception and vibration and only mildly impaired two-point discrimination at the
toes. Pinprick and temperature perceptions were both impaired to about mid-thigh. Although he
scored 29/30 on MMSE he had a reduced digit span and scored poorly on Stroop test. Three
years after onset, he was confined to a wheelchair, had developed mild neurogenic dysphagia and
further cognitive decline, and was living alone with daily attendant care. Shortly afterwards he
was admitted to a palliative care facility. At this stage his father's notes were retrieved, and it was
immediately apparent that they had the same illness. A repeat MRI now showed patchy cortical
ribbon hyperintensity on FLAIR and DWI, and GSS was diagnosed. He died 42 months after
onset.
35