Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation

Figures & data

Table 1. Age of onset and disease duration in the Swedish family affected by IPD with 8-OPRI

Nr in pedigree	Gender	Age of onset/ Age of death, years	Disease duration, years	PRNP polymorphic codon 129 (mutated allele)	PRNP polymorphic codon 129 (both alleles)
I:2	M	41/52	11	M	M-
II:2	F	28/42	14	M	M-
II:6	F	29/43	14	M	M-
III:1	F	23/46	23	M	MM
III:3	M	29/48	19	M	MM
III:8	F	29/42	12	M	MM
III:10	M	29/41	12	M	MM

III, 3 is the subject reported here; M, inferred polymorphism.

Figure 1. Age of onset with mean and SD in the four 8-OPRI families. *P = 0.026 only when compared with the A and Che families.

Table 2. Comparison of four 8 OPRI families

	A family	Che family	M-E family	Swedish family	All the families
n (females; males)	6 (2;4)	6 (1;5)	11 (7; 4)	7 (4;3)	30 (14; 16)
PRNP polymorphic codon 129 in mutated allele (n)	129V^6	129V^6	129M^11	129M^7	129V,^12 129M^18
PRNP polymorphic codon 129 in both alleles (nr of homozygous and heterozygous)	2 pol 129VV 1 pol 129 VM	NA	4 pol 129MM	4 pol 129 MM	1 pol 129 VM 2 pol 129VV 8 pol 129 MM
Age of onset, mean in years; SD (range; missing values)	43.3; 12.4 (21–54; 0)	43.3; 6.8 (35–54; 0)	31.8; 7.0 (21–43; 1)	29.7; 5.4 (23–41; 0)	36.1; 6.6 (21-54; 1)
Disease duration, mean in years; SD (range; number for which information is available; missing values; still alive at the time of publication)	3.6; 2.6 (0.4–6^a; 4; 0; 2)	3.3; 4.9 (0.3–13; 6; 0; 0)	3.4; 2.3 (1.3–7^b; 6; 1; 4)	15.1; 4.3 (11–23; 7; 0; 0)	6.9; 6.6 (0.3–23; 23; 1; 6)
Age of death, mean in years; SD (range; n)	53.6; 3.9 (50.4–59; 4)	46.6; 8.7 (35.3–56; 6)	40.6; 4.8 (35-47;7)	44.9; 4.0 (41–52; 7)	45.5; 6.9 (35-59; 24)

^a Two subjects were still alive at the time of report publication more than 1 and two years after disease onset. ^bOne subject was still alive more than 12 y after symptom onset. Disease duration is the longest of all the reported IPD families with 8-OPRI (P < 0.001).

Figure 2. (A) Kaplan-Meier survival curve for the 4 8-OPRI families. The Swedish family had the longest survival (log-rank test with P value = 0.004). (B) Kaplan-Meier survival curve when early age of onset is set as less than 30 y (log-rank test with P value < 0.001).

Figure 3. Pearson correlation for early age of onset and long survival (n = 23) with r = -0.642 and P value < 0.001.

Figure 4. Disease duration with mean and SD in the four 8-OPRI families. ** P = 0.004 when compared with all the three families.

Figure 5. Age of death with mean and SD in the four 8-OPRI families. ** P = 0.009 only when compared with the A family.

Table 3. Differences based on PRNP polymorphic codon 129 in the mutated allele

	129M	129V	Mean difference in years	P value and 95% CI
Age of onset mean in years, (n)	30.9 (17)	43.3 (12)	12.3	0.0002*; -18.41 to -6.371
Disease duration mean in years (n)	9.7 (13)	3.3 (10)	6.4	0.0170*; 1.262 to 11.53
Age of death mean in years (n)	42.7 (14)	49.4 (10)	6.7	0.0154*; -12.00 to -1.408

* significant value based on the Student t test at P < 0.05

Table 4. ANOVA for age of onset and disease duration for homozygous 129MM in three IPD: E200K, 6-OPRI and 8-OPRI

	E200K	P102L	6-OPRI	8-OPRI	P value
Age of onset Number of cases Mean in years (SD)	17 58 (12.8)	22 46 (12.4)	30 31.4 (5.7)	8 26.4 (3.2)	P < 0.001 (F3,73 statistics = 35.2)
Disease duration Number of cases Mean in years (SD)	17 0.6 (0.3)*	15 4.5 (2.0)*	19 11.4 (4.6) *	4 16.8 (5.2)	P < 0.001 (F3,51 statistics = 49.6)

Information obtained from Mead et al.¹⁸ other than that denoted by * which was provided by personal communication also with Professor Simon Mead.

Table 5. Comparison of homozygous 129MM in three IPD- E200K, IPD with 6-OPRI, and IPD with 8-OPRI

Homozygous 129MM	Compared PRNP mutation types	Mean difference, years (95% CI)	t statistics	P value
Age of onset	E200K and P102L	12 (3.5, 20.5)^e	2.9	0.005*
	E200K and 6-OPRI	26.6 (18.6, 34.6)^u	8.1	< 0.001*
	E200K and 8-OPRI	31.6 (20.3,42.9)^u	9.6	< 0.001*
	P102L and 6-OPRI	14.6 (7.2, 21.9)^u	5.1	< 0.001*
	P102L and 8-OPRI	19.6 (8.7 30.5)^u	6.8	< 0.001*
	6-OPRI and 8-OPRI	5.0 (-5.4, 15.5)^e	2.4	0.02
Disease duration	E200K and P102L	-3.9 (-7.1, -0.8)^u	-7.5	< 0.001*
	E200K and 6-OPRI	-10.8 (-13.8, -7.9)^u	-10.2	< 0.001*
	E200K and 8-OPRI	-16.2 (-21.1, -11.3)^u	-6.2	0.008
	P102L and 6-OPRI	-6.9 (-9.9, -3.8)^u	-5.8	< 0.001*
	P102L and 8-OPRI	-12.2 (-17.2, -7.3)^u	-4.6	0.02
	6-OPRI and 8-OPRI	-5.4 (- 10.2, -0.5)^e	-2.1	0.05

^e Equal variance, ^uunequal variance. *Significant P value, new α = 0.008 after Bonferroni correction.

Table 6. Gender differences in IPD with8-OPRI

	Males	Females	Mean difference in years	P value and 95% CI
Age of onset mean in years (n)	40.4(16)	30.7 (13)	9.8	0.0057*; 3.094 to 16.40
Disease duration mean in years (n)	6.1 (14)	8.3 (9)	2.3	0.4351; -8.158 to 3.643
Age of death mean in years (n)	48.8(14)	41.0 (10)	7.8	0.0037*; 2.824 to 12.80

* significant value based on the Student t test at P < 0.05

Table 7. Regression model for age of onset (dependent variable) in IPD with 8-OPRI

Independent variables	Coefficient (β)	95% CI	P value
PRNP polymorphic codon 129	0.52	4.26–16.24	0.002*
Gender	0.33	0.414–12.28	0.0037*

R² = 50%

Table 8. Regression model for disease duration (dependent variable) in IPD with 8-OPRI,

Independent variables	Coefficient (β)	95% CI	P value
PRNP polymorphic codon 129	- 0.56	-13.36- -1.06	0.024*
Gender	0.12	-4.67–7.82	0.605

R² = 25.3%.

Table 9. Regression models for disease duration in IPD with 8-OPRI

Independent variables	Coefficient (β)	95% CI	P value
PRNP polymorphic codon 129	-0.1	-8.11–5.52	0.69
Gender	0.32	-1.45–9.87	0.14
Age of onset	-0.76	-0.94- -0.15	0.01*

R² = 48%

Table 10. Regression models for age of death in IPD with 8-OPRI

Independent variables	Coefficient (β)	95% CI	P value
PRNP polymorphic codon 129	0.09	8.11–5.52	0.69
Gender	0.30	1.45–9.97	0.14
Age of onset	0.59	0.06–0.85	0.026*

R² = 54.6%

Table 11. Structure of the OPRI region in a normal case and in the four 8-OPRI families

Family	OPRI region	Codon 129 in the PRNP gene
Wild-type	R1-R2-R2-R3-R4	M or V
Che	R1-R2-R2-R3-R2-R2-R2-R2-R2-R2-R2-R2a-R4	V
M-E	R1-R2-R2-R3-R2-R2-R2-R2a-R2-R2-R2-R3-R4	M
A	R1-R2-R2-R3g-R3-R2-R2-R2-R2-R2-R2-R3-R4	V
Swedish	R1-R2-R2-R3g-R2-R2-R2-R3g-R3g-R2-R2-R3-R4	M

R1 encodes a nonapeptide, R2-R4 encode octapetides of similar amino acid sequence and structure. Additional repeats are in bold, R2a and R3g case are variants of R2 and R3 with a silent amino acid substitution in each.^7-10

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