Familial prion diseases are rapidly progressive neurodegenerative disorders with autosomal dominant inheritance. Three main clinical and pathological phenotypes are commonly distinguished:

1. familial Creutzfeldt–Jakob Disease (fCJD; MIM #123400), presenting with rapidly progressive dementia and two of the following four disorders: myoclonus, visual or cerebellar symptoms, pyramidal or extrapyramidal signs, or akinetic mutism;

2. Gerstmann–Straussler–Scheinker disease (GSS; MIM #137440), presenting with limb and truncal ataxia, dysathria and—in the later course of the disease—cognitive decline;

3. fatal familial insomnia (FFI; MIM #600072), presenting with untreatable insomnia, signs of dysautonomia and memory loss.

Until very recently, one of the most common mutations in the prion protein gene (PRNP)—an aspartic-acid-to-asparagine exchange at codon 178 in coupling with methionine at codon 129 (D178N-129M)—was held to cause FFI. Recent phenotype–genotype correlation studies, however, revealed a considerable clinical and pathological overlap between FFI and CJD phenotypes among patients homozygous for D178N-129MM, suggesting that FFI and CJD are the extremes of a spectrum rather than two discrete and separate entities and that, moreover, other genetic or environmental factors apart from the polymorphism in codon 129 contribute to the phenotypic expression of the D178N mutation in the PRNP gene.1 2

Here we add further evidence to this thesis from a large German prion pedigree with D178N mutation in the PRNP gene. We found a wide variability in age of disease onset and phenotype with substantial impact for genetic counselling in hereditary prion diseases.

CASE REPORT

A 43-year-old man of German origin presented with a 15-month history of rapidly progressive ataxia, pronounced cerebellar dysartrhia, double vision and pyramidal signs (hyper-reflexia, spasticity of lower limbs). Disability was advanced with severe affection of all effectors and dependency for all activities of daily living. Scoring by the Scale for the Assessment and Rating of Ataxia (SARA;3) yielded 27 out of 40 points.

Family history on the paternal side was positive for rapidly progressive and lethal neurological disorders in four generations apparently following an autosomal dominant trait (see fig 1). Affected family members received different diagnoses, varying from “meningitis” or “early calcification” to “atypical Alzheimer disease” or “Friedreich ataxia,” thus indicating a highly variable phenotype within this pedigree. Additionally, the age of disease onset was highly variable: while the brother of the patient (IV-4) became symptomatic in the age of 19, another ancestor did not become sick before the age of 72 (II-4), and the father of the patient (III-5) presents as an asymptomatic carrier of the heterozygous D178N mutation (and two M129 alleles) at 73 years of age as confirmed by personal examination (MS) and genetic testing.

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Figure 1 D178M pedigree illustrating variable disease duration, disease phenotype (indicated by the medical diagnoses given at the respective point of time) and, in particular, highly variable age of disease onset. One 73-year-old gene carrier is still asymptomatic (dotted symbol; III-5), thus suggesting a reduced penetrance. Circles, women; squares, men; filled symbols, affected members; slashed symbols, deceased; dd, disease duration; cross, age of death; *current age.

Due to the primarily ataxic phenotype and positive family history, spinocerebellar ataxia was suspected in the index patient, but the genetics for SCA2 and SCA3 were negative. Hyperhidrosis and arterial hypertension were of only moderate level and readily explained by the hot summer weather, respectively controlled by a low-dosed beta-blocker. No signs of insomnia or other sleep disturbance were present. Detailed neuropsychological testing was inconclusive since the severe dysathria and ataxia confounded most results of the applied test batteries; clinical observations based on his behaviour, facial reactions and residual speech capacity, however, did not reveal any signs of significant cognitive or behavioural disturbances as were previously described in patients with D178N mutations (eg, aggression, apathy, depression, memory loss1).

Magnetic resonance imaging of the brain including DWI sequences revealed mild cerebral and cerebellar atrophy, but no other signs suggestive of spongiform encepalopathy. No periodic sharp- or slow-wave complexes were seen in serial EEG tracings, and repeated CSF investigations did not show elevated NSE levels or detect protein 14-3-3 (therefore prion disease was excluded in other hospitals). Due to rapid disease progression and positive family history, a genetic analysis of the PRNP gene was initiated, revealing a heterozygous D178N mutation (sequence variant: c.532G>A) in combination with the polymorphism M129V (sequence variant: c.385A>G).

DISCUSSION

The clinico-genetic study of this German prion disease pedigree reveals new insights with an important impact for both genetic diagnostics and clinical practice. D178N mutations present with a large variability in clinical phenotype not only between different families, but also within one and the same family.4 5 In particular, a GSS-like phenotype (found in the patient himself and most probably in his brother who was diagnosed as having “Friedreich ataxia”) can be caused by a D178N mutation. Thus, the recently described continuous spectrum between FFI, familial CJD2 and sporadic CJD phenotypes1 must be expanded to the GSS phenotype. As the phenotype is highly variable, and MRI as well as 14-3-3 protein were negative in repeated investigations in our patient, genetic testing for PRNP-gene mutations is the only reliable way to diagnose familial prion disease. As demonstrated by the early disease onset in the brother of the index patient, familial prion disease must be considered in rapidly progressive ataxia independently of age at onset.

D178N mutations present with huge variability in age of onset not only between different families, but also within one and the same family. In fact, the high intrafamilial variability in age of disease onset (ranging from 19 to 72 years) reported here even exceeds the range of previously described high interfamilial variability.1 2 Even more interestingly, the finding of an asymptomatic 73-year-old gene carrier suggests that this mutation exhibits a reduced penetrance (if defined as the absence of disease in a 70-year-old carrier of a mutation gene). Importantly, this finding is of academic interest for understanding prion genetics but also bears essential consequences for clinical practice and genetic counselling: the fact that disease onset might begin not until the mid-seventies (if it begins at all) allows for the possibility that patients with symptoms might have unaffected parents, thus presenting with a supposedly “negative family history,” and that, moreover, at-risk persons might live unaffected until old age and die due to causes other than the prion disease. Thus, genetic testing might deliver only limited information for an at-risk person at the individual level.