[Delayed diagnosis in a patient with Creutzfeldt-Jakob disease in a psychiatric hospital]. / Late diagnose bij een patiënt met de ziekte van Creutzfeldt-Jakob in een psychiatrisch ziekenhuis.

A 51-year-old female teacher of dance was referred to the diagnostic unit of our psychiatric hospital with symptoms of anxiety and depression. The clinical image was suggestive of organic pathology, but this could not be determined with certainty until a late stage. We discuss the course of the patient's illness. Her symptoms appeared to be psychiatric and closely resembled those of Creutzfeldt-Jakob disease. We comment on some of the signs that could have led to an earlier diagnosis and we discuss the tools that are needed.

Progressive myoclonic epilepsy as an adult-onset manifestation of Leigh syndrome due to m.14487T>C.

BACKGROUND: m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported. OBJECTIVES: To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family. METHODS: A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies. RESULTS: Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue. INTERPRETATION: m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.

Opsoclonus-myoclonus syndrome: a clinicopathological confrontation.

Opsoclonus-myoclonus syndrome (OMS), a movement disorder characterised by chaotic eye movements and myoclonus, is a rare clinical entity. We present two cases of opsoclonus-myoclonus syndrome of paraneoplastic origin. In the first patient the syndrome was associated with a breast carcinoma and in the second patient with a non small cell lung carcinoma. However none of the commonly associated antibodies were found in these cases. From the neuropathological findings from the first patient we find arguments that support the current hypothesis on the pathophysiology of OMS namely a dysfunction in brainstem and cerebellum. We conclude that in adults with OMS one has to be very suspicious of a possible neoplastic origin of the syndrome. The antibodies associated with some cases of OMS are thought to play a role in the pathophysiology of the syndrome although the exact immunologic mechanism remains unknown. Research into the neuropathological substrate of OMS yields a broad range of abnormalities in brain stem and cerebellum. However none of these findings seem to be pathognomonic. As for the possible therapy of OMS, several immunomodulating strategies can be used with varying success. At present there is no established standard therapy.

Antigen retrieval in prion protein immunohistochemistry.

Transmissible spongiform encephalopathies are a group of neurodegenerative diseases occurring in both humans and animals and are most likely caused by prions. Neuropathological confirmation of the clinical diagnosis has been a problem because of the difficulty in epitope retrieval from formalin-fixed, paraffin-embedded brain specimens. Many different protocols for the detection of prions in brain tissue have been used. Thus far, picric and/or formic acid, steam autoclaving at 121C of sections, microwave treatment, and 4 M guanidine thiocyanate treatment have been suggested. The objective of our experiment was to obtain the standard pretreatment(s) resulting in optimal immunostaining. In the experiment, successive tissue slides of brain specimens of several Creutzfeldt-Jakob disease and control patients were stained using different combinations of pretreatments. Using densitometric analysis, several well-defined locations per section were examined and prion immunostaining was quantified. The results showed that autoclaving is necessary for antigen retrieval and cannot be substituted by microwave treatment. The best results were obtained when the following combination was used in the specified order: 15 min saturated picric acid, 10 min steam autoclaving at 121C, 5 min 88% formic acid, and 2 hr 4 M guanidine thiocyanate at 4C. (J Histochem Cytochem 47:1465-1470, 1999)

Influence of the prion protein and the apolipoprotein E genotype on the Creutzfeldt-Jakob Disease phenotype.

We investigated the risk associated with the codon 129 polymorphism in the prion protein gene (PRNP) and apolipoprotein E gene (APOE) isoforms for development of Creutzfeldt-Jakob disease (CJD) (n=126) and the possible influences on the disease pathology and its most important clinical characteristics. The PRNP M129V (PRNP129) polymorphism was determined using both DNA extracted from formalin fixed and paraffin embedded brain tissue (n=59) and leukocyte extracted DNA (n=67). In the latter group also the PRNP open reading frame and the APOE genotype were analysed and compared to a neurologically unaffected, age and sex matched control group (n=79). We found that methionine homozygosity of the PRNP129 increases the risk for developing CJD. PRNP129 also influenced the prion accumulation patterns in brain. The APOE 4 allele was an independent risk factor for developing CJD. We further observed a significant dose dependent APOE 4 effect on the number and type of amyloid-beta plaques in the brain of CJD patients.

Creutzfeldt-Jakob disease and blood transfusion.

Experimental data suggest that blood components from patients with CJD may carry infectivity. However, most of the studies have been made on the classic form of CJD. Further studies are needed to discern whether infectivity levels in blood from patients with the nvCJD differ from those with the classic form. Possibility of transmission of CJD by blood or blood products can not be excluded and therefore adequate surveillance should be implemented. People who have been exposed to contaminated blood should be followed, while recommendations are being adapted according to new scientific data on infectivity.

The many faces of human prion diseases in Belgium and the world.

Prion diseases are rare neurodegenerative disorders that always lead to death and that can be transmissible under certain conditions. Although sporadic Creutzfeldt-Jakob's disease (CJD) is the best known human variant of these transmissible spongiform encephalopathies with an incidence of about 1 in 106 inhabitants, several other types of human prion disease have been described (e.g. Familial CJD, Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia,...). In 1996, a variant of CJD has been linked to the epidemic of bovine spongiform encephalopathy (BSE). Therefore, vigilance concerning prion diseases was increased throughout the whole of Europe. In Belgium, a comprehensive, nation-wide study has been conducted both retrospectively (1960-1997) and prospectively (1998-...) to identify prion disease patients. In 1998, a surveillance system has also been created to monitor the incidence of CJD and other prion diseases. Using data from both studies and the surveillance program, the occurrence and phenotype of all types of prion diseases in Belgium was investigated. The sporadic type of CJD was identified in 116 patients, while 4 suffered from a hereditary form. In our series, we could find no evidence for variant or iatrogenic CJD, neither for the more rare types of prion diseases.

[Safety measures for handling laboratory specimen and patients with Creutzfeldt-Jakob disease]. / Voorzorgsmaatregelen bij omgang met patiënten en laboratoriummonsters besmet met de ziekte van Creutzfeldt-Jakob.

Creutzfeldt-Jakob disease (CJD) is a transmissible subacute spongiform encephalopathy that invariably leads to death. The presumed causative agent, the prion protein, is highly resistant to inactivation and has a long incubation period. Physical contact with CJD patients (as in clinical care) entails no risk of transmission. During procedures such as lumbar puncture where contact with infected material is possible, precautions are necessary. Precautions are: the use of gloves, maximal protection of people who come in contact with contaminated tissue (e.g. pathologist and histological laboratory worker) and transportation of samples in a closed and labelled container. For laboratory research the tissue must be submerged in 92-98% formic acid for 1 hour. All used materials and instruments must be decontaminated properly, using for instance NaOH, NaClO, guanidine thiocyanate or steam autoclaving. If adequate precautions are taken contact with contaminated materials can be safe.

Progranulin variability has no major role in Parkinson disease genetic etiology.

BACKGROUND: Different loss-of-function mutations were identified underlying PGRN haploinsufficiency in patients with frontotemporal lobar degeneration. PGRN mutations were also identified in other neurodegenerative brain diseases such as amyotrophic lateral sclerosis and Alzheimer disease, though their biologic contribution to these diseases remains elusive. Because of its apparent role in neuronal survival, we argued that PGRN might also contribute to Parkinson disease (PD) pathogenesis. METHODS: We screened PGRN exons for mutations in 255 patients with PD and 459 control individuals by direct genomic sequencing. Genetic association of PGRN with risk for PD was assessed using single nucleotide polymorphisms (SNPs) across the gene. RESULTS: In patients we identified four missense mutations of which p.Asp33Glu and p.Arg514Met were absent in control individuals. Single SNP and haplotype analyses did not detect significant associations with PD. CONCLUSIONS: Our results do not support a major role for PGRN in the genetic etiology of Parkinson disease (PD). At this stage and in the absence of functional data, it remains unclear whether p.Asp33Glu and p.Arg514Met are biologically relevant to PD pathogenesis in the mutation carriers.

Lrrk2 R1441C parkinsonism is clinically similar to sporadic Parkinson disease.

OBJECTIVE: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C. METHODS: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis. RESULTS: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation. CONCLUSIONS: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.

Retrospective study of Creutzfeldt-Jakob disease in Belgium: neuropathological findings.

Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that affects about 1 in 10(6) inhabitants in most countries. Recently, a new variant of CJD has been linked to the epidemic of bovine spongiform encephalopathy. Therefore, vigilance concerning the disease's incidence has been increased. We conducted a comprehensive, nation-wide and retrospective study. In 79 Belgian autopsies, we found the characteristic triad of spongiosis, neuronal loss and reactive gliosis. The occipital cortex was most affected, while the cerebellum was mostly spared. Immunohistochemistry was performed using hydrated autoclave pretreatment and several monoclonal antibodies directed against the prion protein. We identified prion-immunoreactive patterns and locations reflecting the important heterogeneity, independently of the antibody that was used. Granular prion immunoreactivity was observed in astrocytes. We studied the regional intensity of the prion immunostaining and determined that the frontal cortex with 95% positive immunoreactivity was best suited for a biopsy. We studied the disease duration in sporadic CJD patients who showed neuropathological lesions of other neurodegenerative disorders (such as Alzheimer's disease). The study shapes the framework in which a prospective neuropathological registry will be able to function.

A retrospective study of Creutzfeldt-Jakob disease in Belgium.

Using data from Belgian neuropathological archives, completed with the results of a comprehensive study of available medical records, we found 100 patients who fulfilled diagnostic criteria for probable or definite Creutzfeldt-Jakob d1551isease (CJD). Mean age at death was 63 years. The median disease duration was 9 months. Progressive mental deterioration was present in all cases, whereas signs of cerebellar dysfunction and myoclonus were found in approximately 80% of the patients. In 50% of the population, the EEG revealed characteristic abnormalities. Ninety-six patients suffered from the sporadic type of CJD, while 4 suffered from a hereditary form. In our series, we could find no evidence for the new variant, neither for an iatrogenic cause.

Phosphorylated tau in cerebrospinal fluid as a marker for Creutzfeldt-Jakob disease.

OBJECTIVE: To determine the concentrations of microtubule associated protein tau and multiple phosphorylated tau epitopes in the cerebrospinal fluid of patients with sporadic Creutzfeldt-Jakob disease (sCJD), dementias, and controls, in order to evaluate their diagnostic use and clinical relevance. METHODS: The CSF concentrations of total tau and phosphorylated tau at epitope 181 were determined by enzyme linked immunosorbent assay in 66 definite and nine probable sCJD patients, and in 97 controls. Other phosphorylated tau epitopes were investigated by western blot. RESULTS: In the sCJD population, determination of 14-3-3 protein and total tau protein concentrations was of the highest diagnostic value, with a sensitivity of 96% and 92%, respectively, and a specificity of 94% and 97%. Two distinct subgroups could be identified among the 75 sCJD patients based on the detection of phosphorylated tau at threonine 181 and serines 199, 202, and 404. A high phosphorylated tau concentration was clinically correlated with a significantly shorter disease duration, early onset of akinetic mutism, and a higher rate of typical EEGs (p < 0.05). CONCLUSIONS: Although the determination of phosphorylated tau levels cannot be used as a diagnostic biomarker, it may prove useful for estimating the prognosis of an sCJD patient. These experiments reconfirm that sCJD is a disease with a complex pathology.