B. Ghetti

Gerstmann-Sträussler-Scheinker disease. II: Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family

Azzarelli et al reported an Indiana kindred affected by a hereditary disorder, characterized clinically by ataxia, parkinsonism, and dementia. Recently, we studied neuropathologically the 3rd and 4th cases that came to autopsy among the patients of this family. As in 2 patients examined previously, amyloid plaques were widespread throughout the cerebrum and the cerebellum, whereas neurofibrillary tangles were numerous in the cerebral cortex, the hippocampus, and the substantia innominata. Amyloid plaques were not recognized by polyclonal antibodies against the Alzheimers disease amyloid A4 protein, but did contain epitopes recognized by antibodies against a prion protein. Spongiform changes were occasionally observed and were mild. Our findings indicate that this familial disorder is a form of or is related to Gerstmann-Sträussler-Scheinker disease. The consistent presence of numerous neurofibrillary tangles may be important in differentiating a distinct subgroup of patients with familial Gerstmann-Sträussler-Scheinker disease, and indicates that a disturbance of the cytoskeleton might be part of the neuronal pathology of Gerstmann-Sträussler-Scheinker disease.

Gerstmann‐Sträussler‐Scheinker disease. I. Extending the clinical spectrum

We present the clinical findings in affected members of a large kindred with Gerstmann-Sträussler-Scheinker disease. Sixty-four patients exhibited progressive ataxia, dementia, and parkinsonian features. Inheritance appears to be autosomal dominant. Impaired smooth-pursuit eye movements, defective short-term memory, clumsiness of the hands, and ataxia of gait develop in the late 30s to early 60s. Eye movement abnormalities are characteristic of cerebellar dysfunction. Dementia progresses gradually over several years. Later, rigidity and bradykinesia appear and, at this stage, there is often psychosis or severe depression with rapid weight loss. Death occurs in 6 months to 2 years after onset of rigidity. Magnetic resonance imaging in 2 affected individuals showed cerebellar atrophy. There is decreased T2 signal in the basal ganglia, consistent with iron deposition.

Insomnia associated with thalamic involvement in E200K Creutzfeldt–Jakob disease

BackgroundInsomnia with predominant thalamic involvement and minor cortical and cerebellar pathologic changes is not characteristic of familial Creutzfeldt–Jakob disease (CJD) but is a hallmark of fatal familial insomnia. ObjectiveTo report a 53-year-old woman with intractable insomnia as her initial symptom of disease. MethodsThe authors characterized clinical, pathologic, and molecular features of the disease using EEG, polysomnography, neurohistology, Western blotting, protein sequencing, and prion protein (PrP) gene (PRNP) analysis. ResultsThe patient developed dysgraphia, dysarthria, bulimia, myoclonus, memory loss, visual hallucinations, and opisthotonos, as well as pyramidal, extrapyramidal, and cerebellar signs. Polysomnographic studies showed an absence of stages 3 and 4, and REM. She died 8 months after onset. On neuropathologic examination, there was major thalamic involvement characterized by neuronal loss, spongiform changes, and prominent gliosis. The inferior olivary nuclei exhibited chromatolysis, neuronal loss, and gliosis. Spongiform changes were mild in the neocortex and not evident in the cerebellum. PrP immunopositivity was present in these areas as well as in the thalamus. PRNP analysis showed the haplotype E200K-129M. Western blot analysis showed the presence of proteinase K (PK)–resistant PrP (PrPsc) with the nonglycosylated isoform of approximately 21 kd, corresponding in size to that of type 1 PrPsc. N-terminal protein sequencing demonstrated PK cleavage sites at glycine (G) 82 and G78, as previously reported in CJD with the E200K-129 M haplotype. ConclusionsInsomnia may be a prominent early symptom in cases of CJD linked to the E200K-129M haplotype in which the thalamus is severely affected.

Creutzfeldt-Jakob disease in a husband and wife

A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein (prion protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.

Aluminum encephalopathy: Experimental vs human

Aluminum (Al) is one of the most common components of the natural milieu. Although food and drinking water are reasonably rich in aluminum [1], primates do not accumulate large amounts of the metal within the body fluids and tissues. The slight increase in the aging brain [2, 3] is probably biologically irrelevant. These facts explain why aluminum is toxic only to animals artificially exposed to abnormal amounts of the metal. In such circumstances, the brain is one of the main targets of Al toxicity. Signs of neurological involvement develop in animals that receive substantial amounts of aluminum, whatever the route of administration. In laboratory animals the most severe encephalopathy is obtained by injecting aluminum within the brain or the cerebrospinal fluid. In humans a neurological disease has been observed in uremic patients on dialysis exposed to high concentrations of the metal in the dialysate. Epilepsy is common to all individuals suffering from Al encephalopathy. In some species neurons develop neurofibrillary tangles.

Clinical, Pathological, and Molecular Characterization of Gerstmann-Sträussler-Scheinker Disease in the Indiana Kindred (PRNP F198S)

An adult-onset, autosomal dominant neurodegenerative disorder characterized clinically by cerebellar ataxia, parkinsonism and dementia, has been studied in a large Indiana kindred (IK)1–3. The clinical signs of affected individuals have similarities with those observed in patients from an Austrian family (“H” family) described by Gerstmann Straussler and Scheinker4 and further characterized by Braunmuhl5, Seitelberger6,7, Budka et al.8, and Kretzschmar et al9. In the “H” family, the salient clinical features were adult-onset ataxia, pyramidal signs and dementia. The disease in the “H” family was inherited as an autosomal dominant trait. Neuropathologically, amyloid deposits in cerebellum and cerebrum as well as atrophy in spinal cord, brain stem and cerebellum, were consistently observed.