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Familial prion diseases are associated with underlying mutations in the prion protein gene located on the short arm of human chromosome 20.1 The normal and wild type of the prion protein gene encodes the cellular prion protein, PrPC, and it is thought that there is a post-translational modification to a disease related form, protease resistant PrPSc. PrPSc and PrPC have the same amino acid sequence, but PrPSc is richer in β sheets. PrPSc is distinguished from PrPC in that it is protease resistant and associated with infectivity. It is known that PrPSc deposition is associated with the pathological changes of spongiform degeneration, neuronal loss, and astrocytic gliosis. Underlying mutations are point mutations and octapeptide repeat (24 bp repeat) insertional mutations. In healthy people, the repeat is designated R1-R2-R2-R3-R4, where only R1 is a nonapeptide and the others are octapeptides, between codon 51 and 91.2 Prion disease families with mutations of one, two, four, five, six, seven, eight, or nine extra octapeptide repeat insertions have been reported.
We report a case with a 120 bp insertional mutation in the prion protein gene. To our knowledge, this is the first such case studied in Japan. The patient, a 45 year old woman, showed signs of dementia and cerebellar atrophy at the onset. In the next 4 years, her motor function did not become worse, though her higher brain function was deteriorating gradually. Cases with the same mutant protein have been reported in an American family, an American family of Ukrainian origin, and a German family.2–4 The clinical features of this case are very similar to those of the reported cases, but there are subtle differences in the DNA sequence of the octapeptide repeat region.
A 45 year old woman had shown difficulty in calculation as an initial symptom, and exhibited some difficulty in her job because of memory deficits. She showed psychomotor retardation and became housebound; her full activity gradually declined and her need for support for daily living activities became gradually greater.
She had graduated from junior college at 20 years of age, worked as a childminder until the age of 26 years, and had married at 24 years. She had begun to help in her mother’s business at 43 years of age. She has a medical history of hypertension, and no history of neurosurgery or tissue grafting. There is no known family history of neurodegenerative disease.
When admitted to our hospital at 45 years of age, she was cooperative and well nourished. On examination, she was disorientated in time and place, showed memory impairment for recent events, and had difficulty in concentration and calculation. Her Mini Mental State Examination (MMSE) score was 21, and her verbal IQ from the Wechsler Adult Intelligence Scale - Revised was 70. Evaluation of cranial nerve function was normal. Muscle tonus and reflexes were physiological and symmetric. She showed mild cerebellar ataxia in the left upper and lower limbs, but could walk by herself. Routine biochemical and haematological investigations were almost normal except for mild anaemia, and her thyroid function was also normal. Brain magnetic resonance imaging (MRI) showed mild atrophy in cerebral cortex and cerebellar vermis, but there was no evidence of hyperintensity of grey matter in T2 weighted images. Single photon emission computed tomography (SPECT) showed general hypoperfusion in cerebral cortex. Electroencephalogram (EEG) showed a 9∼10 Hz, 20∼40 μV diffuse wave pattern, but no paroxysmal discharge. Cerebrospinal fluid 14-3-3 was not examined.
The DNA analysis revealed that she had a 120 bp insertional mutation in the prion protein gene, and that the codon 129 polymorphism was Met/Met. The patient’s children have not been tested for the insertion, because we could not obtain informed consent.
Two years later, when the patient was aged 47 years, her neurological signs showed no remarkable change, and brain MRI revealed mild cerebral and cerebellar atrophy. SPECT and EEG showed no remarkable change. At 49 years of age, MMSE score was 13, where disorientation and attention deficit were apparent, but she showed little deterioration in cerebellar ataxia and could walk by herself.
Our research involved a patient with slowly progressive dementia and five extra octapeptide repeat insertions in the human prion protein gene. At 45 years of age, she exhibited disorientation, difficulty in concentration, and cerebellar ataxia. Over the next 4 years, she showed no marked deterioration in cerebellar ataxia, but mild deterioration in orientation, attention, and memorisation.
The clinical features of published cases with insertions of five extra octapeptide repeats are shown in table 1. The average age at onset in those cases, 44 years (range 26 to 61), is relatively young, and cases with long duration of illness have been observed. Goldfarb et al reported that the long extra octapeptide repeat was associated with early age at onset and long duration of the illness.2 In the same family, there is little variation in symptoms at the onset and in clinical course. Common clinical features in reported cases are progressive dementia, progressive cognitive impairment, personality change, cerebellar ataxia, and spasticity. With regard to the symptomatic change in time course, patients often showed mental disorder at an early stage, which remained stable for several years, followed by rapid deterioration ending to death. In almost all of the cases, brain MRI showed cerebral and cerebellar atrophy, but no specific findings. EEG showed a diffuse slowing, and in few cases periodic synchronous discharges.
The expanded octapeptide repeat regions of this case and published cases with 120 bp insertion mutations are shown in table 1.2–4 In our case, the repeat is designated R1-R2-R2a-R2-R2-R3g-R2-R2-R3-R4, and this DNA sequence is different from other sequences in the reported cases. The clinical features in this case are progressive dementia, disorientation, and cerebellar signs. The patient’s motor function has shown no marked decline in 4 years, but her higher brain function has become gradually worse. In this case, no other members of this family show similar symptoms. Genetic testing for prion disease should be considered as a differential diagnosis in unusual cases of impaired mental disorder.
The authors gratefully thank Dr T Kitamoto (Tohoku University School of Medicine) for performing DNA analysis.
Competing interests: none declared
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