los operadores con PSM
III.5.3.1 Obligación de acceso
Huntington disease is an autosomal dominant neurode- generative disorder characterized by chorea, psychiatric symptoms, and dementia. The cause is an expanded CAG trinucleotide repeat coding for a polyglutamine tract in the huntingtin (Htt) gene. The brain shows atrophy affecting the caudate nucleus, putamen, and cerebral cortex, with Htt aggregation in cytoplasmic and nuclear inclusions. Dementia usually becomes apparent after chorea and psy- chiatric symptoms have been present for a few years but precedes chorea in approximately one-fourth of cases. Impaired executive function (eg, judgment) and memory are prominent features, whereas language tends to be spared until late in the course. Huntington disease is dis- cussed further in Chapter 11, Movement Disorders.
Singer CS. Comprehensive treatment of Huntington disease and other choreic disorders. Cleve Clin J Med. 2012;79(suppl 2): S30-S34.
DeMeNtIa & aMNeStIC DISOrDerS
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CREUTZFELDT-JAKOB (PRION) DISEASE
Creutzfeldt-Jakob disease (CJD) produces rapidly progres- sive dementia with variable focal degeneration of cerebral cortex, basal ganglia, cerebellum, brainstem, and spinal cord. It is caused by a proteinaceous infectious particle (prion) and may be sporadic (approximately 85% of cases), genetic, or infectious. In the latter case, CJD can be trans- mitted via prion-contaminated tissue or surgical instru- ments (iatrogenic CJD) or by consumption of contaminated beef (variant CJD). Documented human-to-human trans- mission (by corneal transplantation, cortical electrode implantation, or administration of human growth hor- mone) is rare. The infectious agent is present in the brain, spinal cord, eyes, lungs, lymph nodes, kidneys, spleen, liver, and CSF, but not other body fluids.
The annual incidence is approximately 1 case per 1 mil- lion population. The sporadic disease usually occurs in patients older than 40 years and has a mean age at onset of approximately 60 years; in contrast, the genetically acquired disease usually has its onset before age 55 years. More than one member of a family is affected in only 5% to 10% of cases, and conjugal cases are rare.
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`Pathogenesis
Familial CJD is an autosomal dominant disorder caused by a mutation in the PRNP gene, which codes for the prion protein cellular isoform (PrPC), a protein of unknown function. In
sporadic CJD, PrPC undergoes a conformational change to
produce an abnormal prion protein (scrapie isoform, or PrPSc). PrPSc then serves as a template on which PrPC is con-
verted to additional PrPSc. In infectious CJD, PrPSc is intro-
duced into the brain from an external source. In each case, the result is accumulation of abnormal PrPSc prions in brain tis-
sue. The ability of PrPSc to induce the PrPSc conformation in
PrPC prions enables it to replicate without nucleic acids.
Prions have also been implicated in diseases of animals and in three other rare human disorders (Table 5-10)—
kuru, a dementing disease of Fore-speaking tribes of New
Guinea (apparently spread by cannibalism); Gerstmann-
Straüssler syndrome, a familial disorder characterized by
dementia and ataxia; and fatal familial insomnia, which produces disturbances of sleep and of autonomic, motor, and endocrine function.
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`Clinical Findings
The clinical picture may be that of a diffuse central nervous system (CNS) disorder or of more localized dysfunction (Table 5-11). Dementia is present in virtually all cases and may begin as mild global cognitive impairment or a focal cortical disorder such as aphasia, apraxia, or agnosia. Progression to akinetic mutism or coma typically ensues over a period of months. Psychiatric symptoms including anxiety, euphoria, depression, labile affect, delusions, hal- lucinations, and changes in personality or behavior may be prominent. Fever is absent.
Aside from cognitive abnormalities, the most frequent clinical manifestations are myoclonus (often induced by a startle), extrapyramidal signs (rigidity, bradykinesia, tremor, dystonia, chorea, or athetosis), cerebellar signs, and pyramidal signs. Visual field defects, cranial nerve palsies, and seizures occur less often.
A distinct variant of CJD results from the transmission of bovine spongiform encephalopathy (“mad cow dis-
ease”) to humans. This variant is characterized by earlier
onset (typically in the teens or young adulthood), invari- able cerebellar involvement, prominent early psychiatric abnormalities, and diffuse amyloid plaques.
Table 5-10. Prion Diseases. Human diseases
Creutzfeldt–Jakob disease (familial, sporadic, iatrogenic, new variant) Fatal familial insomnia
Gerstmann-Straüssler-Scheinker disease Kuru
Animal diseases
Bovine spongiform encephalopathy Feline spongiform encephalopathy Scrapie (sheep and goats) Transmissible mink encephalopathy Wasting disease of deer and elk
Transmissible spongiform encephalopathy of captive wild ruminants Adapted from Johnson RT, Gibbs CJ. Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med. 1998;339:1994-2004.
Table 5-11. Clinical Features of Sporadic Creutzfeldt–Jakob Disease. Feature percentage Cognitive Memory loss 100 Behavioral abnormalities 57 Other 73 Motor Myoclonus 78 Cerebellar ataxia 71 Pyramidal signs 62 Extrapyramidal signs 56 Lower motor neuron signs 12
Visual disturbances 42
Periodic EEG complexes 60
Data from Brown P, Gibbs CJ Jr, Rodgers-Johnson P, et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol. 1994;35:513.
Chapter 5
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`Investigative Studies
The electroencephalogram (EEG) may show periodic sharp waves or spikes (Figure 5-9), which are absent in the variant form described previously. CSF protein may be elevated (≤100 mg/dL), and levels of 14–3–3 protein are increased. MRI scans may show hyperintense signals in the basal ganglia on T2-weighted images (see Figure 5-9). Definitive diagnosis is by immunodetection of PrPSc in cere-
brospinal fluid, brain tissue obtained at biopsy or, in familial cases, by detection of mutant forms of PrPC in
DNA from lymphocytes.
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`Differential Diagnosis
A variety of other disorders must be distinguished from CJD. Alzheimer disease is often a consideration, especially in patients with a less fulminant course and a paucity of cerebellar and extrapyramidal signs. Where subcortical involvement is prominent, Parkinson disease, cerebellar degeneration, or progressive supranuclear palsy may be suspected. Striking focal signs raise the possibility of an intracerebral mass lesion. Acute metabolic disorders that produce altered mentation and myoclonus (eg, sedative drug withdrawal) can mimic CJD.
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`Prognosis
No treatment is currently available. The disease is usually relentlessly progressive and invariably fatal. In most sporadic cases, death occurs within 1 year after the onset of symp- toms. Depending on the specific mutation present, familial forms of the disease may have a longer course (1-5 years).
Prusiner SB. Biology and genetics of prions causing neurodegen- eration. Annu Rev Genet. 2013;47:601-623.