Introduction

Creutzfeldt–Jacob disease (CJD) is the most common human prion disease, characterized by rapid cognitive decline, psychiatric and behavioral disturbances, cerebellar, pyramidal and extrapyramidal involvement, visual disturbances, myoclonus and epileptic seizures [1]. The disease is etiologically classified into sporadic, familial and acquired forms [2].

The largest cluster of familial CJD (fCJD) which is transmitted as an autosomal-dominant trait exists in Israel in Jews of Libyan ancestry carrying an E200K (Glu to Lys) mutation in the gene encoding for the prion protein (PRNP) [3, 4]. Most patients are heterozygoteus for the mutation, although homozygous cases have been described as well [5]. The disease course of homozygous patients with autosomal-dominant disorders is expected to be more aggressive compared with heterozygous patients due to dysfunction of both alleles, a phenomenon that has been demonstrated in several other autosomal-dominant disorders [6]. A well-known example is alpha thalassemia in which patients who are homozygous to the mutated allele die in utero (“Hydrops Fetalis”) or soon after delivery, whereas heterozygous patients develop mild hypochromic microcytic anemia. Another example is familial hypercholestolemia where heterozygous patients usually develop mild disease, whereas homozygous patients are severely affected [7]. A more aggressive disease has been described in homozygous patients with dominant neurological disorders as well: Charcot-Marie-Tooth 1A homozygous trait leads to a more severe disorder [8] and homozygous Machado–Joseph disease is characterizes by early onset and more aggressive disease course [9]. On the other hand, homozygous and heterozygous patients with Huntington's disease are similarly affected [10]. There are limited data on CJD patients homozygous to the E200K mutation. Simon et al. [5] compared 5 patients homozygous to E200K mutation to 65 heterozygous patients. The homozygous patients had a younger age of onset but no differences were found in other clinical features. In the present study, we reviewed a larger population of E200K homozygous CJD patients to further characterize them.

Methods

The Israeli National CJD database consists of the medical records of patients diagnosed with CJD according to WHO criteria [11] in Israel since 1968 [12]. The database which includes demographic, clinical and laboratory data including genetic tests for mutations in the PRNP gene was screened for patients homozygous for the E200K mutation. Demographic data (age, gender), clinical presentation, neurological features, tau protein levels in the cerebrospinal fluid (CSF) and EEG reports were evaluated. Clinical presentation was defined as the first symptom related to the disease. Age of onset was defined as the patient's age at the time of clinical presentation. Based on the neurological examination, we calculated the CJD neurological status scale (CJD-NS) score [13]. In the CJD-NS score, each sign in the neurological examination is assigned to one of eight neurological systems (vision and ocular motility, brainstem, cerebellar, extrapyramidal, pyramidal, frontal releasing signs, peripheral neuropathy and cortical systems). The System-Involved Score (SIS) is the sum of affected systems. The SIS, therefore, ranges from 0 (no neurological system involved, apparently unaffected individual) to 8 (all systems involved). Data of homozygous patients were compared to those of heterozygous E200K patients. Parametric variables were compared using ANOVA and the non-parametric variables were compared using Fisher exact test.

Results

Among 238 fCJD patients with available genetic data, we identified 10 (80% males) homozygous and 228 (47% males) heterozygous to the E200K mutation. Homozygous patients (Table 1) had an average age of onset of 47.5 ± 6.1 years (range 40–56) and a median age of onset of 49 years. Average age of death was 49.3 ± 7. 7 years (range 42–63, median 51 years) and average disease duration was 27.7 ± 9.7 months (range 2–97, median 10 months). The most common presenting symptom was behavioral changes in homozygous patients and cognitive decline in heterozygous patients (Table 2). Throughout the course of the disease, the abnormal neurological signs in descending order included cerebellar (70%), brainstem (60%), extrapyramidal (50%), pyramidal (50%), frontal lobe (30%) signs, and disturbances of ocular motility (30%). In comparison with the 228 heterozygous patients, homozygous patients were significantly younger at disease onset (47.2 vs 59.1 years, p < 0.001) and had a longer disease duration (27.7 vs 8.5 months) (p < 0.001) (Table 3). Behavioral changes as a presenting symptom were more common in the homozygous patients (Table 3). Mean SIS in the homozygous group was 3.6 ± 1.43 (range 1–6). Low SIS (< 4) was associated with normal EEG (p = 0.02). However, SIS was not associated with gender, age of onset, disease duration or distribution of symptoms. Tau protein levels were available in 40/228 heterozygous patients with an average level of 1211 pg/ml and in 3/10 homozygous patients with an average level of 1216 pg/ml with no significant difference between the groups (Table 3).

Table 1 Demographic data of the ten homozygous patients with CJD
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Table 2 Most common initial clinical presentation in homozygote and heterozygote patients
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Table 3 Demographic and clinical data of E200K homozygous vs. heterozygous CJD patients
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Discussion

Homozygous trait in some autosomal-dominant genetic disorders such as alpha thalassemia or Machado-Joseph disease [9] is characterized by younger age of onset and more aggressive disease course compared to the heterozygous trait. Our study shows that CJD patients homozygous to the E200K mutation are younger at disease onset but have longer disease duration than heterozygous patients (although in some homozygous patients, disease duration was similar to the heterozygous patients), with similar clinical features in both groups. In E200K fCJD patients, the PRNP mutated gene encodes a normal functioning Prpc protein, but due to the substitution of Glu with Lys, there is a higher risk of conversion of Prpc to the pathogenic isoform of PrpSc. The lifetime risk of this conversion is very high, reaching 96% after age 80 [14, 15]. The load of the susceptible Prpc protein in homozygous carriers is double, carrying a higher risk of earlier conversion to the pathogenic PrpSc protein than in heterozygous subjects. This might explain the younger age of disease onset in homozygous patients. However, once the conversion occurred and the vicious cycle had started, the process is similar in homozygote and heterozygote patients leading to similar expression of the disease. Another interesting finding in our study is the longer duration of the disease in homozygous patients, as already described previously in a smaller cohort [5]. Actually, longer disease duration has been reported in patients with variant CJD which is characterized by younger age of onset [16], as well as in young-onset sporadic CJD patients [17]. Possible explanations include more dedicated palliative care in young people and the increased frailty of elderly people [16]. The effect of various age-related disease modulating factors that may lead to prolonged disease course at younger age is also a possibility. An alternative explanation is that the mutation in the PRNP gene exposes the patient to an increased tendency of spontaneous conversion to the pathologic form compared to the wild type one. Patients homozygous to the mutation have double load of the mutant Prpc protein with higher risk for the spontaneous conversion to PrpSc than heterozygous patients, therefore, the age of onset is earlier in the homozygous patients. However, the infective process, in which the PrPSc interacts with PrpC and converts it to the pathologic form of PrpSc, is less effective in the mutant PrpSc, therefore, disease duration is longer in the homozygous patients.

In summary, homozygous E200K patients present characteristic disease course with younger age of onset, prolonged disease duration and behavioral changes as the most common initial presenting symptom, but otherwise typical phenotype.