Familial Disease

Pathogenesis and Pathophysiology. The molecular genetic basis for inherited disease remains to be defined. It seems probable that mutation-induced alterations in the primary amino acid structure of PrP facilitate its transition from an alpha helix to a beta-pleated sheet configuration. If the magnitude of facilitation were a million-fold, the one per million occurrence of sporadic disease would assume the appearance of a fully penetrant inherited disease linked to the mutation. y This explanation is unencumbered by any experimental evidence but is nonetheless consistent with the observed frequencies of the two forms of disease.

Epidemiology and Risk Factors. About 10 percent of cases of spongiform encephalopathy are familial and are associated with one of more than 20 mutations so far identified in the gene that encodes the amyloidogenic prion protein (.Fig, 4314 ). All are inherited in an autosomal dominant genetic pattern, and all are experimentally transmissible.

Like sporadic disease, familial disease affects men and women equally, but its temporospatial distribution is determined by the origins and migrations of affected families. All "case clusters" of spongiform encephalopathy have a familial basis, for example those in rural Slovakia and among Sephardic Jews, whose migrations have created high incidence pockets of disease in Israel, North Africa, and (via the Spanish Inquisition), Chile. More typically, in the highly mobile world of today, familial cases are geographically scattered, and individual patients may have lost all contact with and knowledge of their ancestors, leading to the mistaken appearance of sporadic mutation-positive cases.

Clinical Features and Associated Disorders. y Familial disease can present as CJD, GSS, FFI, or as atypical Alzheimer-like syndromes, depending on which of the mutations is present in the family. For example, point mutations at codons 200 or 210 usually produce an illness that begins 5 to 10 years earlier but in other respects is indistinguishable from sporadic CJD, whereas repetitive octapeptide encoding insert mutations cause illnesses that may begin as early as the third or fourth decade of life and produce a very slowly evolving dementia that ends in death after a period of 10 to 15 years with little or no brain pathology. y Other mutations can produce a wide spectrum of intermediate disease syndromes.

GSS typically begins in members of affected families between the ages of 40 and 55 years as a slowly evolving ataxia, sometimes with associated mental deterioration, and progresses through a multisystem array of symptoms, including dementia and myoclonus, finally terminating fatally after an average duration of 5 to 10 years. It is characterized neuropathologically by a profusion of multifocal amyloid plaques in the cerebellum, with or without spongiform change. The classic syndrome (including Gerstmann's original case) is associated with a point mutation at codon 102, y but more recently, variants of GSS have been described with mutations at codon 105 (with spastic paraparesis), y at codon 117 (with pseudobulbar signs), y and at codons 145, 198, or 217 (with neuropathological features of both GSS and Alzheimer's disease).y , y

FFI is the most recently admitted member of the spongiform encephalopathy group and is unusual in that patients

Figure 43-4 Mutations in the chromosome 20 PRNP gene that are known to be associated with familial spongiform encephalopathy. Three polymorphisms are also shown: an octapeptide-encoding deletion between codons 51 and 91; a methionine-valine alternative at codon 129; and a glutamic acid-lysine alternative at codon 219. The one, two, and four octapeptide-coding insert mutabooken line boxes) have been identified in individuals with Creutzfeldt-Jakob disease in whom familial disease has not been established. CJD, Creutzfeldt-Jakob disease; GSS, Gerstmann-Straussler-Scheinker disease; FFI, fatal familial insomnia; Alz, Alzheimer-like disease.

typically show early and pronounced autonomic and endocrine dysfunction, including intractable insomnia (often associated with daytime somnolence), and unexplained disorders of temperature, cardiovascular, and respiratory regulation. Later in the course of the illness, more typical features of CJD supervene (pyramidal and extrapyramidal signs, cerebellar ataxia, and myoclonus), and death occurs after an average duration of 1 to 2 years. y At autopsy, severe neuronal loss and astrogliosis are seen in the mediodorsal and anterior ventral thalamic nuclei, with variable pathology in the neocortex. The disease is caused by a mutation at codon 178, but curiously, it occurs only when the mutant allele specifies valine at polymorphic codon 129; when methionine is specified by codon 129, the pathogenic codon 178 mutation produces a CJD-like phenotype. y

From both diagnostic and genetic standpoints, it is important to remember that these clinical stereotypes have many exceptions, that significant phenotypic heterogeneity is the rule even among members of the same family, and that no matter what mutational phenotype is typical, at least one family member will have died from an illness that closely resembles sporadic CJD.

Evaluation. In addition to the EEG and CSF tests described for patients with sporadic disease, familial disease offers the possibility of identifying the specific causative mutation by molecular genetic analysis of DNA obtained from white blood cells in an anticoagulated blood specimen. Identification of the responsible mutation is not a mere academic exercise but has practical prognostic value for the patient's family: first, it permits a rough estimate of the likely age at onset and duration of illness, and second, it can have a crucial impact in counseling about the risk of disease inheritance because some mutations are not fully penetrant. For example, mutations at codons 200 and 210 have a penetrance of only 50 percent, so that although the mutation will be transmitted as an autosomal dominant trait, only half of the individuals who carry the mutation will become sick. y , y

Management, Treatment, and Prevention. The care and outlook for patients with familial disease are no different from those for patients with sporadic disease; however, familial disease can be prevented in subsequent generations through the use of molecular genetic testing of amniotic fluid and elective therapeutic abortion of fetuses found to carry a lethal mutation. y This option should be carefully explained to family members for their ethical and medical consideration.

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