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NCBI Bookshelf. Huntington disease HD is a progressive disorder of motor, cognitive, and psychiatric disturbances.

The mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset. The diagnosis of HD rests on positive family history, characteristic clinical findings, and the detection of an expansion of 36 or more CAG trinucleotide repeats in HTT. Treatment of manifestations: Pharmacologic therapy including typical neuroleptics haloperidol , atypical neuroleptics olanzapine , benzodiazepines, or the monoamine depleting agent tetrabenazine for choreic movements; anti-parkinsonian agents for hypokinesia and rigidity; psychotropic drugs or some types of antiepileptic drugs for psychiatric disturbances depression, psychotic symptoms, outbursts of aggression ; valproic acid for myoclonic hyperkinesia.

Supportive care with attention to nursing needs, dietary intake, special equipment, and eligibility for state and federal benefits. Prevention of secondary complications: Attention to the usual potential complications in persons requiring long-term supportive care and the side effects associated with pharmacologic treatments. Other: Children and adolescents with a parent with HD may benefit from referral to a local HD support group for educational materials and psychological support.

HD is inherited in an autosomal dominant manner. Predictive testing in asymptomatic adults at risk is available but requires careful thought including pre- and post-test genetic counseling as there is currently no cure for the disorder. However, asymptomatic individuals at risk may be eligible to participate in clinical trials. Predictive testing is not considered appropriate for asymptomatic at-risk individuals younger than age 18 years.

Prenatal testing by molecular genetic testing is possible. Note: The appearance and sequence of motor, cognitive, and psychiatric disturbances can be variable in HD see Clinical Description. The diagnosis of HD is confirmed in a proband with clinical signs and symptoms of HD by identification of a heterozygous expansion of a CAG trinucleotide repeat in HTT by molecular genetic testing see Table 1.

Allele sizes. View in own window. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. Detects CAG trinucleotide repeat number. Other methods may occasionally be useful to identify large CAG repeat tracts associated with juvenile-onset HD or to confirm an apparent homozygous genotype obtained by conventional PCR analysis. See Benjamin et al [] for further considerations for predictive testing related to HD.

MacDonald et al []. During the prodromal phase of Huntington disease HD individuals may have subtle changes in motor skills, cognition, and personality Figure 1 [ Tabrizi et al , Ross et al , Liu et al ]. These subtle changes can occur as early as years prior to the clinical onset of manifest HD. Natural history of Huntington disease HD. Presymptomatic individuals are free from signs and symptoms of HD. During the prodromal phase, subtle signs and symptoms may be present prior to the diagnosis of HD, which is usually based on motor symptoms.

Reilmann et al [] present guidelines for the diagnostic criteria of presymptomatic, prodromal, and manifest HD; see Table 2. This table can be used to place individuals into different diagnostic categories, which may have clinical management implications over time.

For example, awareness of presymptomatic and prodromal HD may allow for preventive rather than symptomatic therapies. Note the clear differentiation of genetically confirmed HD in the classification system.

Adapted from Reilmann et al [] ; used with permission. The mean age of onset for HD is approximately 45 years [ Bates et al ].

About two thirds of affected individuals first present with neurologic manifestations; others present with psychiatric changes. In the early stages following diagnosis, manifestations include subtle changes in eye movements, coordination, minor involuntary movements, difficulty in mental planning, and often a depressed or irritable mood see Table 3.

Affected individuals are usually able to perform most of their ordinary activities and to continue work [ Ross et al , Bates et al ]. These individuals have chorea, gait disturbances, and dysphagia, but a more prolonged and benign course than the typical individual. In the next stage, chorea becomes more prominent, voluntary activity becomes increasingly difficult, and dysarthria and dysphagia worsen.

Most individuals are forced to give up their employment and depend increasingly on others for help, although they are still able to maintain a considerable degree of personal independence.

The impairment is usually considerable, sometimes with intermittent outbursts of aggressive behaviors and social disinhibition. In late stages of HD, motor disability becomes severe and the individual is often totally dependent, mute, and incontinent. The average age at death is 54 to 55 years [ Bates et al ]. Abnormalities of movement. Disturbances of both involuntary and voluntary movements occur in individuals with HD. Chorea, an involuntary movement disorder consisting of non-repetitive, non-periodic jerking of limbs, face, or trunk, is the major sign of the disease.

The choreic movements are continuously present during waking hours, cannot be suppressed voluntarily, and are worsened by stress. With advancing disease duration, other involuntary movements such as bradykinesia, rigidity, and dystonia occur. Impairment in voluntary motor function is an early sign. Affected individuals and their families describe clumsiness in common daily activities. Motor speed, fine motor control, and gait are affected.

Oculomotor disturbances occur early and worsen progressively. Dysarthria occurs early and is common. Dysphagia occurs in the late stages. Abnormalities of cognition. A global and progressive decline in cognitive capabilities occurs in all individuals with HD. Cognitive changes include forgetfulness, slowness of thought processes, impaired visuospatial abilities, and impaired ability to manipulate acquired knowledge.

Several studies have identified subtle but definite cognitive deficits prior to the onset of motor symptoms [ Bourne et al , Montoya et al , Paulsen et al , Tabrizi et al , Rupp et al ]. The initial changes often involve loss of mental flexibility and impairment of executive functions such as mental planning and organization of sequential activities.

Memory deficits with greater impairment for retrieval of information occur early, but verbal cues, priming, and sufficient time may lead to partial or correct recall. Early in the disease the memory deficits in HD are usually much less severe than in Alzheimer disease. The overall cognitive and behavioral syndrome in individuals with HD is more similar to frontotemporal dementia than to Alzheimer disease. Attention and concentration are involved early [ Peinemann et al ], resulting in easy distractibility.

Language functions are relatively preserved, but a diminished level of syntactic complexity, cortical speech abnormalities, paraphasic errors, and word-finding difficulties are common in late stages. Neuropsychologic testing reveals impaired visuospatial abilities, particularly in late stages of the disease. Lack of awareness, especially of one's own disabilities, is common [ Ho et al , Bates et al ].

Psychiatric disturbances. Individuals with HD develop significant personality changes, affective psychosis, or schizophrenic psychosis [ Rosenblatt ]. Prior to onset of HD, they tend to score high on measures of depression, hostility, obsessive-compulsiveness, anxiety, and psychoticism [ Duff et al ]. Unlike the progressive cognitive and motor disturbances, the psychiatric changes tend not to progress with disease severity [ Epping et al ].

Behavioral disturbances such as intermittent explosiveness, apathy, aggression, alcohol abuse, sexual dysfunction and deviations, and increased appetite are frequent. Delusions, often paranoid, are common. Hallucinations are less common. Depression and suicide risk. The incidence of depression in preclinical and symptomatic individuals is more than twice the general population [ Paulsen et al b , Marshall et al ].

The etiology of depression in HD is unclear; it may be a pathologic rather than a psychological consequence of having the disease [ Slaughter et al , Pouladi et al ]. Suicide and suicide ideation are common in persons with HD, but the incidence rate changes with disease course and predictive testing results [ Larsson et al , Robins Wahlin , van Duijn et al ].

The critical periods for suicide risk were found to be just prior to receiving a diagnosis and later, when affected individuals experience a loss of independence [ Baliko et al , Paulsen et al a , Eddy et al ].

It is also common for persons with HD to demonstrate increased appetite and energy expenditure [ Pratley et al , Trejo et al , Gaba et al ]. Insomnia and daytime somnolence may also be present, although this is more commonly due to psychiatric changes, depression, or chorea [ Videnovic et al ]. The primary neuropathologic feature of HD is degeneration of neurons in the caudate and putamen as well as the cerebral cortex [ Waldvogel et al ].

The preferential degeneration of enkephalin-containing, medium spiny neurons of the indirect pathway of movement control in the basal ganglia provides the neurobiologic basis for chorea [ Galvan et al ].

The additional loss of substance P-containing medium spiny neurons of the direct pathway results in akinesia and dystonia [ Galvan et al ]. Region-specific patterns of neuronal loss in the basal ganglia and cortex may underlie the most evident symptoms in affected individuals and could contribute to the phenotypic variability among individuals [ Thu et al , Hadzi et al , Kim et al , Waldvogel et al , Mehrabi et al ].

Intraneuronal inclusions containing huntingtin, the protein expressed from HTT , are also a prominent neuropathologic feature of the disease. Imaging studies provide additional support for the clinical diagnosis of HD and are valuable tools for studying progression of the disease [ Biglan et al , Paulsen , Tabrizi et al , Tabrizi et al , Tabrizi et al ].

In addition to significant striatal atrophy in symptomatic individuals, regional and whole-brain gray and white matter changes have been detected [ Majid et al , Tabrizi et al , Tabrizi et al , Tabrizi et al ]. Furthermore, MRI studies have revealed progressive gray and white matter atrophy many years prior to predicted disease onset [ Tabrizi et al , Tabrizi et al , Tabrizi et al ]. Numerous studies in recent years have used neuroimaging to elucidate the clinical progression of HD, with the specific interest of using these objective measures in clinical trials for testing efficacy of experimental therapeutics [ Tabrizi et al , Tabrizi et al ].

The motor, cognitive, and psychiatric disturbances observed in adult HD are also observed in juvenile HD, but the clinical presentation of these disturbances is different. Intermediate alleles IA. An individual with a CAG repeat in the range is not believed to be at risk of developing HD but, because of instability in the CAG tract, may be at risk of having a child with an allele in the pathogenic CAG range [ Semaka et al , Kay et al ]. Limited data suggest that individuals with IAs may exhibit behavioral changes as well as motor and cognitive impairments, although more research is required in this regard [ Killoran et al , Cubo et al ].

A significant inverse correlation exists between the number of CAG repeats and the age of onset of HD [ Langbehn et al , Langbehn et al ]. See Molecular Genetics. For data on the age-specific likelihood of onset by trinucleotide repeat size, see cmmt. In addition to age at clinical onset, CAG repeat length has also been shown to predict age at death, but not the duration of the illness [ Keum et al ]. The rate of deterioration of motor, cognitive, and functional measures increases with larger CAG repeat sizes [ Aziz et al , Chao et al ].

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Mariana Moscovich I ; Renato P. Teive I. Huntington's disease HD is a neuro degenerative disorder with an autosomal dominant inheritance pattern, resulting from an expanded and unstable trinucleotide repeat in the IT15 gene on chromosome 4 that encodes a protein called huntingtin 1,2. The prevalence of HD in the Caucasian population ranges from 0.

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These images are a random sampling from a Bing search on the term "Huntingtons Chorea. Search Bing for all related images. Huntington's disease HD is an inherited disease that causes certain nerve cells in the brain to waste away. People are born with the defective gene, but symptoms usually don't appear until middle age. Early symptoms of HD may include uncontrolled movements, clumsiness, and balance problems.

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