MM1 is the reference point for the rest of the classification. The subtype hub is at sporadic CJD subtypes.
What defines the subtype and how common is it?
Parchi and colleagues examined 300 sporadic CJD patients, with clinical features, PRNP genotype and PrPSc properties determined in all and neuropathology and PrP immunohistochemistry in 187. Seventy percent showed the classic CJD phenotype with PrPSc type 1 and at least one methionine allele at codon 129, which is the group that gives MM1 and MV1 their definition. The ataxic and kuru-plaque variants, associated with type 2 and with valine homozygosity or heterozygosity, made up 25 percent.
The clinical picture in that group is the one reproduced in textbooks and in the diagnostic criteria: rapidly progressive dementia with myoclonus, periodic sharp wave complexes on EEG in a substantial proportion, and short survival. In the MV2K comparison series described below, mean duration in typical MM1 was 3.4 months.
Is MM1 one subtype or two?
Two other classifications split MM1 by molecular mass and by disease duration, which would make the commonest subtype two entities. Cali and colleagues tested this directly. They divided 22 subjects with confirmed MM1 by duration, under 5 months against over 7 months, then examined PrPSc molecular mass under conditions allowing wide pH variability and under stringent pH conditions, using high-resolution gel electrophoresis, two-dimensional immunoblot, a conformational stability immunoassay and sucrose gradient fractionation, alongside clinical and pathological comparison.
The design matters more than any single result here, because it shows that the apparent molecular difference between short and long duration cases was sensitive to the pH of the PrPSc preparation. A classification criterion that moves with preparation conditions is a weak basis for splitting a subtype. Readers who need the exact outcome measures should take them from the paper, which was read here as an abstract.
How often does MM1 occur with another PrPSc type?
Often enough to are important for both diagnosis and strain work. Parchi and colleagues carried out systematic regional typing in 225 cases and detected concurrence of PrPSc types 1 and 2 in 35 percent, with the proportion higher in methionine homozygotes than in MV or VV subjects. When both types were present, their deposition was not random: each brought with it the phenotypic features described for the pure subtypes. Type 1 accumulation and its related pathology predominated in MM and MV cases, while type 2 prevailed in VV cases. Neuropathological examination identified mixed type 1 and 2 features best in MM cases, while molecular typing was the better method in VV cases and in MV cases with kuru plaques.
The practical consequence is that a case reported as MM1 from a single region or by a single method may carry type 2 pathology elsewhere in the brain. For the classification problem this creates, see the subtypes hub.
Does MM1 differ molecularly from the other common subtype?
Tarozzi and colleagues compared MM1 and VV2 using targeted DNA sequencing of 118 genes in 48 CJD patients and full exome RNA sequencing of post-mortem frontal cortex in a subset. They report different functional impairment between the subtypes: VV2 was associated with greater impairment of pathways related to dopamine secretion, regulation of calcium release and GABA signalling, with similarities to Parkinson disease at both genomic and transcriptomic levels, while MM1 showed an expression profile sharing traits with several neurodegenerative diseases without a distinctive signature or resemblance to a specific one. Integrating the two data types identified sites of ADAR-mediated RNA editing, extending findings previously made in animal models.
The cohort is small for genomic work, the RNA sequencing was done on a subset of it, and end-stage cortex carries the consequences of disease as well as its causes. The finding of interest is the contrast between subtypes in the same tissue and pipeline rather than any individual pathway.
How does MM1 behave on CSF testing?
Well, which is why subtype-dependent failures elsewhere are easy to miss. Franceschini and colleagues compared first and second generation RT-QuIC in CSF from 239 patients with definite or probable prion disease and 100 with a definite alternative diagnosis. Second generation IQ-CSF showed high sensitivity for human prions generally, with sub-optimal sensitivity specifically for the MM2C and MM2T subtypes and low sensitivity limited to variant CJD, GSS and FFI. The second generation assay detected prions in about 80 percent of samples that the first generation assay had missed, with no difference in specificity.
Related: MM2, MV1, VV2 and diagnostics.
Sources for this page
- Parchi P and others (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects, Ann Neurol 46(2):224-233
- Cali I and others (2006) Classification of sporadic Creutzfeldt-Jakob disease revisited, Brain 129(9):2266-2277
- Parchi P and others (2009) Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification, Acta Neuropathol 118(5):659-671
- Tarozzi M and others (2022) Genomic, transcriptomic and RNA editing analysis of human MM1 and VV2 sporadic Creutzfeldt-Jakob disease, Acta Neuropathol Commun 10:181
- Franceschini A and others (2017) High diagnostic value of second generation CSF RT-QuIC across the wide spectrum of CJD prions, Sci Rep 7:10655