What is it?
Machado-Joseph disease (MJD) is a progressive neurodegenerative disease. It belongs to the family of polyglutamine diseases, a group of disorders characterized by CAG (cytosine-adenine-guanine) trinucleotide expansion in specific genes. In the case of MJD, this mutation is on the long arm of chromosome 14. It causes the accumulation of the protein ataxin and this, in turn, leads to the destruction of neurons.
It is also known as "Spinocerebellar ataxia type III," an inherited ataxia that, although considered rare, is the most common autosomal dominant ataxia worldwide. We call ataxia a neurological disorder characterized by the "slowness" of specific areas of the brain (cerebellum, brainstem, spinal cord, peripheral nerves, and the base nucleus), translating, mostly, into a lack of coordination of voluntary muscle movements and a lack of balance. Despite the progressive loss of movement, their intellect remains intact.
Diagnosis
Although family history and physical examination can help in the diagnosis, this is done with neurological tests, specific blood tests, and MRI scans, which can identify changes in the size of the brain caused by the disease.
The test that proves 100% of cases, consists of directly determining the number of suspected CAG triplets (responsible for encoding glutamine) in a patient's DNA. This can easily be done in a clinical laboratory specializing in genetic research.
Treatment
There is no cure for MJD, but some symptoms of the disease are treatable and require symptomatic and supportive care from your neurologist. For those with features of Parkinson's disease, L-dopa therapy can help for many years. Treatment with antispasmodic medications, such as baclofen, can help reduce spasticity. Botulinum toxin can also treat severe spasticity and some symptoms of dystonia. Speech problems and difficulty swallowing can be treated with medications and speech therapy. Physical therapy can help patients deal with disabilities related to gait problems. Physical aids, such as walkers and wheelchairs, help with daily activities. Last but not least, the help of a psychologist to treat conditions such as depression and sleep disorders that result from the disease.
Risk Groups
One of the main complications of the syndrome is that it is hereditary and can affect up to three generations of the same family. The chance of passing it from parent to child is about 50%, and both sexes can be affected.
It is estimated that this pathology affects 0.3 to 2 people per 100,000 worldwide, affecting 1 in every 4000 people of Portuguese ancestry. However, in some regions, the prevalence of the disease is much higher, as in the island of Flores, Azores, where for every 200 people, 1 suffers from this disease.
Origin
Machado-Joseph disease (MJD) was originally described in members of the Machado, Thomas, and Joseph families on the island of São Miguel, Azores, Portugal, in 1972.
William Machado was a Portuguese Azorean, while Antone Joseph was an Azorean who migrated to the USA in 1845.
In 1977, Paula Coutinho, a Portuguese neurologist, described a disease in Azoreans, with multiple phenotypic characteristics, which, in fact, was the same disease reported earlier in the USA, in descendants of Antone Joseph. In 1980, Paula named the disease "Machado-Joseph disease", honoring the first patients and descendants who suffered from the disease.
Causes
It is a genetic mutation that causes expansion of the ATXN3 gene, located on chromosome arm 14. The ATXN3 gene, when functional, encodes the protein ataxin-3, a protein that is involved in the degradation of damaged proteins in the body and is part of the ubiquitin-proteosome system. Central nervous system cells are very susceptible to mutations in the ATXN3 gene. The accumulation of damaged proteins that are not degraded in neurons leads to neuronal death.
Types
MJD has a variable clinical expression and age of onset, which makes diagnosis difficult and has led to the definition of the disease into four clinical subtypes.
MJD type 1 manifests early, with age of onset between 10 and 30 years of age,
and is rapidly progressive. It associates a mild cerebellar ataxic syndrome and progressive external ophthalmoplegia with predominant pyramidal and extrapyramidal signs, such as dystonia, tremors, and parkinsonism.
Type 2 is the most frequent form of the disease, characterized by ataxia associated with
progressive external ophthalmoplegia, with onset between 20 and 50 years of age and an intermediate progression. It may have pyramidal and extrapyramidal signs, but when present they are mild.
Type 3 manifests later, between the ages of 40 and 70, and has a slow progression of symptoms. It is characterized by the predominance of peripheral signs, such as peripheral neuropathy and amyotrophy.
Type 4 is the rarest clinical type and includes patients with parkinsonian symptoms associated with other more common symptoms of MJD, who may respond to L-dopa.
Symptoms
The main symptom of Machado-Joseph syndrome is loss of motor coordination, a symptom similar to that of Parkinson's disease, which can cause confusion. Other common symptoms are:
Weakness in the limbs;
Loss of balance;
Increased stiffness of the muscles;
Progressive paralysis of eye movements;
Double vision;
Exaggerated reflexes to stimuli;
Speech and swallowing problems;
Sleep problems.
Initially, symptoms are mild and usually get worse as the years go by.
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