Machado-Joseph disease (MJD) is a rare hereditary disease that results in ataxia (a lack of muscle control). The disease affects muscles throughout the body and, in severe cases, represents a tremendous burden for affected individuals, their families, and caregivers. It is one of nearly 30 distinct genetic forms of dominantly inherited ataxia, and is perhaps the most commonly encountered form in the US. Unlike some diseases that are known by the names of physician(s) involved in their discovery, MJD is named for affected families.
- Spinocerebellar Ataxia Type 3, or SCA3
- Spinocerebellar Atrophy III
- Azorean Neurologic Disease
- Spinopontine Atrophy
- Nigrospinodentatal Degeneration
Cases of MJD can be classified according to age of onset and severity of symptoms.
Type I MJD presents between the ages of 10 and 30, symptoms develop quickly, and the symptoms include severe rigidity and dystonia (abnormal movements).
Type II MJD begins between the ages of 20 and 50; symptoms include spasticity and exaggerated reflexes. This type of MJD does not progress as quickly as Type I.
Type III MJD presents between the ages of 40 and 70 and is the least severe form. The most troublesome symptoms may be blurry vision, double vision, or loss of color vision. Movement disorders may be mistaken for Parkinson disease.
Signs and Symptoms
Affected individuals are characteristically clumsy, weak in the arms and legs, have spasticity, which is involuntary muscular contractions, and walk with a staggering lurching gait easily mistaken for drunkenness. They also have difficulty with speech and swallowing, involuntary eye movements, double vision, and frequent urination. Some individuals also have dystonia (sustained muscle contractions that cause twisting of the body and limbs, repetitive movements, abnormal postures, and rigidity) or symptoms similar to those of Parkinson's disease. Others have twitching of the face or tongue, or peculiar bulging eyes. Almost all MJD patients experience vision problems, including double vision or blurred vision, loss of the ability to distinguish color and/or contrast, and inability to control eye movements.
As a dominantly inherited disease, MJD is caused by inheritance of a variant form (i.e., a mutation) of a gene that fails to function normally. The affected gene, located on chromosome 14, in MJD is known as ataxin-3 (ATXN3), and the structural basis for abnormal functioning is the insertion of multiple copies of the nucleotides cytosine-adenosine-guanosine (CAG) in the ATXN3 gene. Normally, the ATXN3 gene has between 12 and 33 instances of the (CAG) triplet; gene sequences associated with MJD had between 66 and 78 CAG repeats. There appears to be a correlation between the number of repeats, the severity of the disease, and survival times. The mutated gene encodes a nonfunctional protein that may accumulate inside the cell, eventually resulting in a type of programmed cell death termed apoptosis.
Diagnosis is usually based on a positive family history and the presence of characteristic neurological abnormalities. In some cases, the diagnosis may be based on sequencing the ATXN3 gene to confirm (or refute) the presence of CAG repeats.
MJD is incurable, but some symptoms of the disease can be treated.
Several drugs and drug combinations have been tried in the treatment cerebellar ataxias. In MJD, conflicting results have been published regarding the efficacy of trimethoprim/sulfamethoxazole (Bactrim), for treating the associated spasticity and rigidity.
For those patients who show parkinsonian features, levodopa therapy can help for many years. Treatment with antispasmodic drugs, such as baclofen, can help reduce spasticity. Botulinum toxin can also treat severe spasticity as well as some symptoms of dystonia. Speech problems and trouble swallowing can be treated with medication and speech therapy.
Physiotherapy can help patients cope with disability associated with gait problems. Physical aids, such as walkers and wheelchairs, can assist with everyday activities.
The National Institute of Neurological Disorders and Stroke (NINDS) supports research on MJD and other neurodegenerative diseases in an effort to learn how to better treat, prevent, and even cure these diseases. Ongoing research includes efforts to better understand the genetic, molecular, and cellular mechanisms that underlie triplet repeat diseases. Other research areas include the development of novel therapies to treat the symptoms of MJD, efforts to identify diagnostic markers and to improve current diagnostic procedures for the disease, and population studies to identify affected families.
The severity of the disease is related to the age of onset, with earlier onset associated with more severe forms of the disease. Symptoms can begin any time between early adolescence and about 70 years of age. MJD is a progressive disease, meaning that symptoms get worse with time. Life expectancy ranges from the mid-thirties for those with severe forms of MJD to a normal life expectancy for those with mild forms. The cause of death for those who die early is often aspiration pneumonia.
- ↑ Paulson HL. Dominantly inherited ataxias: lessons learned from Machado-Joseph disease/spinocerebellar ataxia type 3. Semin Neurol. 2007 Apr;27(2):133-42. Abstract
- ↑ Nakano KK, Dawson DM, Spence A. Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology. 1972 Jan;22(1):49-55. Citation
- ↑ Lopes-Cendes I, Teive HGA, Cardoso F et al. Molecular characteristics of Machado-Joseph disease mutation in 25 newly described Brazilian families. Braz. J. Genet. 20: 717-724, 1997 Citation
- ↑ Ogawa M. Pharmacological treatments of cerebellar ataxia. Cerebellum. 2004;3(2):107-11. Abstract
- ↑ Kieling C, Prestes PR, Saraiva-Pereira ML, Jardim LB. Survival estimates for patients with Machado-Joseph disease (SCA3). Clin Genet. 2007 Dec;72(6):543-5. Abstract