Machado-Joseph Disease


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Machado-Joseph Disease

  1. 1. Machado-Joseph Disease Jennifer Pagliei February 12, 2008
  2. 2. Introduction <ul><li>Machado-Joseph disease is a movement disorder. </li></ul><ul><li>It is also known as spinocerebellar ataxia (SCA) type 3. </li></ul><ul><li>It was first discovered in the 1970s. </li></ul><ul><li>It is a rare hereditary ataxia, which is a general term for lack of muscle control. </li></ul><ul><li>MJD is inherited as autosomal dominant. </li></ul><ul><li>It is the most common autosomal dominant spinocerebellar ataxia. </li></ul>
  3. 3. Origin <ul><li>The name Machado-Joseph disease comes from two families of Portuguese/Azorean descent who were among the first families described with the unique symptoms of the disease. </li></ul><ul><li>The name Machado comes from William Machado, a native of an island in the Portuguese Azores. </li></ul><ul><li>The name Joseph comes from Antone Joseph, a Portuguese sailor with the defective gene who migrated to California in 1845. </li></ul>
  4. 4. Prevalence <ul><li>The prevalence of the disease is highest among people of Portuguese/Azorean descent. </li></ul><ul><li>The prevalence of MJD is around 1 in 4,000 among immigrants of Portuguese ancestry in the US. </li></ul><ul><li>The highest prevalence in the world, around 1 in 140, occurs on the small Azorean island of Flores. </li></ul>
  5. 5. Prevalence <ul><li>Recently, researchers have identified MJD in several family groups not of obvious Portuguese descent, including: </li></ul><ul><ul><li>An African-American family from North Carolina </li></ul></ul><ul><ul><li>An Italian-American family </li></ul></ul><ul><ul><li>Several Japanese families </li></ul></ul>
  6. 6. Genetic Inheritance <ul><li>MJD belongs to a class of genetic disorders called triplet repeat diseases. </li></ul><ul><li>The MJD/SCA3 gene is located on the long arm of chromosome 14q32. </li></ul><ul><li>The gene produces a mutated protein called ataxin-3. </li></ul><ul><li>The mutant gene has an increased number of “CAG” repeats, which can range from 40 to more than 200. </li></ul><ul><li>The result in an unstable, expanded, disease-casing allele. </li></ul><ul><li>This is in contrast to the 6 to 34 repeats in the wild-type allele. </li></ul>
  7. 7. Genetic Inheritance <ul><li>The wild-type protein is located predominantly in the cytoplasm of cells. </li></ul><ul><li>In contrast, the mutant ataxin-3 protein is localized within the nucleus of neuronal cells. </li></ul><ul><li>The mutant protein accumulates in affected cells and forms intra-nuclear inclusion bodies, which are insoluble spheres located in the nucleus of the cell. </li></ul><ul><li>The spheres interfere with the normal operation of the nucleus and cause the cell to degenerate and die. </li></ul><ul><li>The cell degeneration and death occurs in the hindbrain, which includes the cerebellum, brainstem, and upper spinal cord, thus leading to deficits in movement. </li></ul>
  8. 8. Genetic Inheritance <ul><li>A trait of MJD and other triplet repeat diseases is anticipation, in which the children of affected parents: </li></ul><ul><ul><li>Develop symptoms of the disease much earlier in life </li></ul></ul><ul><ul><li>Have a faster progression of the disease </li></ul></ul><ul><ul><li>Experience more severe symptoms </li></ul></ul><ul><li>This is due to the tendency of the triplet repeat mutation to expand with the passing of genetic material from parent to offspring. </li></ul><ul><li>Thus, a longer expansion is associated with an earlier age of onset and a more severe form of the disease. </li></ul><ul><li>Nevertheless, it is not possible to predict the exact course of the disease for an individual based solely on the repeat length. </li></ul>
  9. 9. Symptoms <ul><li>Symptoms can begin any time between early adolescence and about 70 years of age. </li></ul><ul><li>The severity of symptoms is related to the age of onset. </li></ul><ul><li>Earlier onset is associated with a more severe form of the disease. </li></ul><ul><li>It is a progressive disease, therefore symptoms get worse with time. </li></ul>
  10. 10. Symptoms <ul><li>MJD is characterized by many symptoms, among these are: </li></ul><ul><ul><li>Clumsiness </li></ul></ul><ul><ul><li>Arm and leg weakness </li></ul></ul><ul><ul><li>Spasticity - continuous, uncontrollable muscle contractions. </li></ul></ul><ul><ul><li>A staggering, lurching gait, which can be mistaken for drunkenness </li></ul></ul><ul><ul><li>Frequent urination </li></ul></ul><ul><ul><li>Face or tongue twitching </li></ul></ul><ul><ul><li>Saccades – quick, simultaneous movements of both eyes in the same direction </li></ul></ul><ul><ul><li>Lid retraction that gives the impression of a persistent stare </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Diffuse joint pain </li></ul></ul><ul><ul><li>Low back pain </li></ul></ul>
  11. 11. Symptoms <ul><li>Other common symptoms include: </li></ul><ul><ul><li>Dystonia - sustained muscle contractions that cause: </li></ul></ul><ul><ul><ul><li>Twisting of the body and limbs </li></ul></ul></ul><ul><ul><ul><li>Repetitive movements </li></ul></ul></ul><ul><ul><ul><li>Abnormal postures </li></ul></ul></ul><ul><ul><ul><li>Rigidity </li></ul></ul></ul><ul><li>Some patients also experience Parkinson’s like symptoms, including: </li></ul><ul><ul><li>Slow movement </li></ul></ul><ul><ul><li>Trunk and limb rigidity or stiffness </li></ul></ul><ul><ul><li>Hand tremor </li></ul></ul><ul><ul><li>Impaired balance and coordination </li></ul></ul>
  12. 12. Symptoms <ul><li>Signs of brainstem dysfuncion: </li></ul><ul><ul><li>Dysarthria due to spastic weakness in the throat muscles. </li></ul></ul><ul><ul><li>Difficulty swallowing </li></ul></ul><ul><ul><li>Poor cough </li></ul></ul><ul><ul><li>Tongue fasciculations </li></ul></ul><ul><li>Signs of upper and lower motor neuron neuropathy: </li></ul><ul><ul><li>Tone ranging from hypotonia to rigidity </li></ul></ul><ul><ul><li>Reflexes ranging from absent to exaggerated </li></ul></ul><ul><ul><li>An extensor plantar reflex </li></ul></ul>
  13. 13. Symptoms <ul><li>Vision problems: </li></ul><ul><ul><li>Bulging eyes </li></ul></ul><ul><ul><li>Double vision (diplopia) </li></ul></ul><ul><ul><li>Blurred vision </li></ul></ul><ul><ul><li>Loss of ability to distinguish color and/or contrast </li></ul></ul><ul><ul><li>Involuntary eye movements </li></ul></ul><ul><ul><li>Supranuclear opthalmoplegia – the inability to voluntarily move the eyes in all directions </li></ul></ul>
  14. 14. Symptoms <ul><li>Cognitive impairments: </li></ul><ul><ul><li>Verbal and visual memory deficits </li></ul></ul><ul><ul><li>Impaired verbal fluency </li></ul></ul><ul><ul><li>Visuospatial and constructional dysfunction </li></ul></ul><ul><li>Autonomic dysfunction: </li></ul><ul><ul><li>Cold intolerance </li></ul></ul><ul><ul><li>Nocturia </li></ul></ul><ul><ul><li>Orthostatic dizziness </li></ul></ul>
  15. 15. Types of MJD <ul><li>MJD has been subclassified into 3 types, which are distinguished by the age of onset and range of symptoms. </li></ul><ul><li>However, many patients have clinical features of the disease that classify them into more than one type. </li></ul><ul><li>Thus, the classification system is not always clinically useful, and is becoming less frequently used. </li></ul>
  16. 16. Types of MJD <ul><li>Type I: </li></ul><ul><ul><li>Typical age of onset between 10 and 30 years. </li></ul></ul><ul><ul><li>Progresses rapidly. </li></ul></ul><ul><ul><li>Characterized by severe dystonia and rigidity. </li></ul></ul>
  17. 17. Types of MJD <ul><li>Type II: </li></ul><ul><ul><li>Begins between 20 and 50 years of age. </li></ul></ul><ul><ul><li>Has an intermediate rate of progression. </li></ul></ul><ul><ul><li>Common symptoms include: </li></ul></ul><ul><ul><ul><li>Spasticity </li></ul></ul></ul><ul><ul><ul><li>Spastic gait. </li></ul></ul></ul><ul><ul><ul><li>Exaggerated reflex responses. </li></ul></ul></ul>
  18. 18. Types of MJD <ul><li>Type III: </li></ul><ul><ul><li>Onset between 40 and 70 years of age. </li></ul></ul><ul><ul><li>Has a relatively slow rate of progression. </li></ul></ul><ul><ul><li>Is often characterized by: </li></ul></ul><ul><ul><ul><li>Muscle twitching </li></ul></ul></ul><ul><ul><ul><li>Muscle atrophy in the arms and legs </li></ul></ul></ul><ul><ul><ul><li>Uncoordinated gait that may cause stumbling or falling </li></ul></ul></ul><ul><ul><ul><li>Slurred speech </li></ul></ul></ul><ul><ul><ul><li>Unpleasant sensations: </li></ul></ul></ul><ul><ul><ul><ul><li>Numbness </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Tingling </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cramps </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pain in the hands, feet, and limbs </li></ul></ul></ul></ul>
  19. 19. Diagnosis <ul><li>The diagnosis of MJD is made by recognizing and identifying the typical symptoms of the disease. </li></ul><ul><li>It is also based upon a detailed family history of the patient, including: </li></ul><ul><ul><li>Family members who currently show symptoms of the disease. </li></ul></ul><ul><ul><li>Deceased family members who showed symptoms of the disease. </li></ul></ul><ul><ul><li>The specific symptoms the relatives have or had. </li></ul></ul><ul><ul><li>The age of onset of symptoms in family members. </li></ul></ul><ul><ul><li>The progression and severity of their symptoms. </li></ul></ul>
  20. 20. Genetic Testing <ul><li>In patients with a positive FH, genetic testing is the most efficient and definitive way to make the diagnosis. </li></ul><ul><li>Legal and ethical considerations, such as loss of health insurance and employment discrimination, may discourage some individuals with symptoms from getting tested. </li></ul><ul><li>For the same reasons, many physicians recommend against genetic testing for individuals with a family history of the disease but who do not show any symptoms. </li></ul>
  21. 21. Diagnosis <ul><li>If genetic testing is not revealing and/or a question exists about a co-existing disease process, additional studies are warranted. </li></ul><ul><li>Neuroimaging with MRI or CT scan often reveals cerebellar atrophy. </li></ul><ul><li>It is also important to rule out other causes of ataxia, including: </li></ul><ul><ul><li>Space occupying lesions </li></ul></ul><ul><ul><li>Demyelination </li></ul></ul><ul><ul><li>Vascular events </li></ul></ul>
  22. 22. Treatment <ul><li>MJD, like all other spinocerebellar ataxias, is incurable. </li></ul><ul><li>Treatments do exist, however, for some symptoms of the disease. </li></ul><ul><li>Levodopa therapy can be helpful for patients with parkinsonian features. </li></ul><ul><li>Antispasmodic drugs, such as baclofen, can help reduce spasticity. </li></ul><ul><li>Botulinum toxin: </li></ul><ul><ul><li>Can be used to treat severe spasticity as well as some symptoms of dystonia. </li></ul></ul><ul><ul><li>Should be used as a last resort due to the possibility of side effects, such as dysphagia. </li></ul></ul>
  23. 23. Treatment <ul><li>Speech therapy can aide in the treatment of dysarthria and dysphagia. </li></ul><ul><li>Prism glasses can reduce blurry vision or double vision. </li></ul><ul><li>Eye surgery can be beneficial, but only in the short-term, due to the progressive degeneration of eye muscles. </li></ul><ul><li>Physiotherapy can help patients cope with disability associated with gait problems. </li></ul><ul><li>Physical aids, such as walkers and wheelchairs, can be used to assist patients with everyday activities. </li></ul><ul><li>Medication can be used to treat other problems, such as sleep disturbances, cramps, and urinary dysfunction. </li></ul>
  24. 24. Prognosis <ul><li>Early onset and large CAG length predict shorter overall survival times. </li></ul><ul><li>Life expectancy ranges from the mid-thirties for those with severe disease to a normal life expectancy for those with mild forms of the disease. </li></ul><ul><li>For those who die early from the disease, a frequent cause of death is aspiration pneumonia. </li></ul>
  25. 25. Research <ul><li>The National Institute of Neurological Disorders and Stroke (NINDS) conducts and supports research on all diseases of the nervous system, including MJD. </li></ul><ul><li>Their goals are to learn how to better treat, cure, and prevent these diseases. </li></ul><ul><li>Ongoing research includes efforts to better understand the genetic, molecular, and cellular mechanisms that underlie triplet repeat diseases, including their characteristics of inheritance and transmission. </li></ul><ul><li>Other research areas include: </li></ul><ul><ul><li>The development of novel therapies to treat the symptoms of MJD. </li></ul></ul><ul><ul><li>Efforts to identify new diagnostic markers of the disease and to improve current diagnostic procedures. </li></ul></ul><ul><ul><li>Population studies to identify affected families. </li></ul></ul>
  26. 26. References <ul><li>Franca MC, et al. Chronic Pain in Machado-Joseph Disease. A Frequent and Disabling Symptom. Arch Neurol. Vol 64 (No. 12), Dec 2007. </li></ul><ul><li>Horimoto, Y, et al. Brainstem in Machado-Joseph disease: atrophy or small size? European Journal of Neurology 2008, 15: 102-105. </li></ul><ul><li>Kieling C, Prestes PR, Saraiva-Pereira ML, Jardim LB. Survival estimates for patients with Machado-Joseph disease (SCA 3). Clin Genet 2007: 72: 543-545. </li></ul><ul><li>Machado Joseph Disease </li></ul><ul><li>National Institute of Neurological Disorders and Stroke. Machado-Joseph Disease Fact Sheet. </li></ul><ul><li>Opal P; Zoghbi HY. The spinocerebellar ataxias. UpToDate. 2007. </li></ul>