The Nature and Natural History of Posterior Cortical Atrophy Syndrome: A Variant of Early-onset Alzheimer Disease.

A prospective longitudinal evaluation of 12 patients over a 16-year interval using clinical neurological and imaging data to determine whether posterior cortical atrophy syndrome (PCA) related to early-onset Alzheimer disease (AD) and to examine its natural history. Our 12 patients had a median age of onset of 56 years (range, 48 to 63 y) and were followed for a median of 6 years (range, 3 to 9 y). Patients either presented with complex visual phenomena or developed them with time. Six patients underwent flurodeoxyglucose and Pittsburgh investigational compound B imaging which showed a mismatch between metabolic activity and amyloid deposition with reduced metabolism in parieto-occipital regions on flurodeoxyglucose positron emission tomography and diffuse neocortical uptake of amyloid without occipital predominance. All patients progressively deteriorated using a quality of life and total functional capacity assessments and this change is similar to the natural history of other early-onset AD variants (typical amnestic presentation, logopenic, and frontal). Two patients had neuropathologic assessments and were shown to have AD using standard pathologic criteria. Of interest, 5 of our 12 patients had occupations strongly dependent on visuospatial functioning. PCA is a syndrome that is most likely a variant of early-onset AD and our correlative clinical, structural, functional, and amyloid imaging data, along with neuropathologic studies in 2 patients, support this concept. The natural history of PCA shows progression with time and this trajectory seems to reflect that of other variants of early-onset AD.

Codon 200 mutation of the prion gene: genotype-phenotype correlations.

Genetic mutations as a cause of prion diseases are rare. We describe a large family with multiple affected members with the codon E200K prion mutation. To improve understanding of the genotype-phenotype correlations of prion gene mutations, clinical, genetic and neuropathological data were obtained from family members over 15 years. Six patients with the codon E200K mutation and 2 patients without the codon 200 mutation from this family were followed. The 6 patients with the codon 200 mutation had a mean age onset of 58.83 years (SD 7.2; lower 95 % CI 51.0; upper 95 % CI 66.4). The most common symptoms at onset were memory loss, walking difficulties and hallucinations. The most frequent neurological phenomena were a rapidly progressive dementia, eye movement abnormalities and ataxia. The mean duration of onset of symptoms to death was 3.9 months (SD 1.1; lower 95 % CI 2.8; upper 95 % CI 5.1). Two male patients developed neurodegenerative disorders unrelated to the prion codon 200 mutation: progressive supranuclear palsy and olivopontocerebellar degeneration. Their mean survival was 96 months (SD 33.9; p < 0.0001). Individuals from families with the prion codon 200 mutation may have a rapidly progressive dementia. Members of families with inherited prion mutations may be at risk of other neurodegenerative disorders unrelated to the prion mutation.

The neurology and natural history of patients with indeterminate CAG repeat length mutations of the Huntington disease gene.

OBJECTIVE: This study aims to understand the neurological manifestations of patients with an indeterminate CAG repeat length (36-39) of the Huntingtin gene, HTT. METHODS: A longitudinal evaluation of 10 patients was performed. Duration of follow-up was mean=4.23 years (standard deviation 1.068; 95% CI 3.466-4.994; range 3-6.4 years). Three patients had a CAG repeat length of 37, three 38 and four 39. Mean CAG repeat length=38 (standard deviation 0.88; 95% CI 37.47-38.73; range 37-39). Data from clinical histories, neurological examinations, the United Huntington's Disease Rating Scale (UHDRS) and MRI imaging were collected. RESULTS: Four patients developed facial chorea, ataxia, impaired tongue protrusion, abnormal saccades and intermittent eye pursuits, dysarthria and impaired Luria 3 hand test. Early in its natural history the neurological syndrome is dominated by perioral chorea, subtle cognitive deficits and mild ataxia. Three patients developed a formal diagnosis of HD within 5 years. The illness progression was variable and associated with different co-morbidities. MRI scans showed ventricular dilatation as a common finding. Scores from UHDRS, Total Functional Capacity (TFC) and mini-mental state examination (MMSE) suggested significant behavioural and functional impairment with compromised cognitive abilities. Two patients had subtle manifestations and four remained asymptomatic (3 patients CAG=37; 1 patient CAG=39). CONCLUSIONS: This study documents the disease manifestations and natural history of people with CAG repeat lengths within the indeterminate range. The findings reveal heterogeneity in disease progression and have implications on the advice that should be given to patients and families on risk assessment and prognosis. Long-term follow up of such patients is essential as the neurological presentation of indeterminate CAG repeat length mutation might be accelerated by associated medical disorders and treatments, environmental and modifying genetic factors.