Machado-Joseph disease, also known as spinocerebellar ataxia 3, is a progressive, degenerative nervous system disorder affecting the cerebellum, brain stem, basal ganglia, thalamus and cerebral cortex. It is characterized by varying degrees of motor and non-motor symptoms and is caused by a mutation in the ATXN3 gene located on chromosome 14.
Machado-Joseph disease, also known as spinocerebellar ataxia 3, (MJD/SCA3) is a rare disease characterized by varied phenotypic features and progressive neurodegeneration. It is caused by a trinucleotide repeat expansion (CAG) related to the mutation in the ATXN3 gene located at chromosome 14q32.1 . Clinical presentation consists of motor, as well as, non-motor manifestations. Motor manifestations are noticed initially between the age of 30 and 40 years and they include cerebellar ataxia, gait instability, incoordination of limb movements, and intentional tremor . Spasticity is a common feature with lower limbs being more frequently affected . Later, other motor problems like dysphagia, dysarthria, and truncal ataxia start to develop. Diplopia is a common ocular complaint . Dystonia and parkinsonism are two movement disorders which are frequently noticed in MJD/SCA3 along with peripheral neuropathy, tactile and proprioceptive hypoesthesia   . Non-motor manifestations include chronic pain, cramps, fatigue, sleep disorders, and depression, while autonomic symptoms like nocturia, urinary incontinence, cold intolerance and hypohidrosis may also be present . A majority of MJD/SCA3 patients have excessive daytime sleepiness with impaired nocturnal sleep , insomnia , and restless legs syndrome. Sleep disorders are seen more frequently in older adults with a long-standing disease. About half of the patients complain of chronic pain, especially in the lumbar region . Minor cognitive and behavioral difficulties, but not frank dementia, are noticed in MJD/SCA3 patients .
Three types of MJD/SCA3 have been identified with onset and severity being their differentiating features:
- Type I MJD/SCA3 has an early onset in the 1st to the 3rd decades with a rapid progression. It is characterized by spastic dystonia, ataxia, athetosis, ophthalmoplegia, and exophthalmos. Mental and intellectual abilities are most frequently normal.
- Type II MJD/SCA3 has an onset between the 2nd and 5th decade with a slower progression. Ataxia and limb incoordination are its characteristic features along with spasticity.
Entire Body System
- Excessive Daytime Sleepiness
SUMMARY: Sleep disorders are frequent in MJD, and include restless legs syndrome, rapid eye movement sleep behavior disorder, excessive daytime sleepiness, insomnia, sleep apnea, periodic limb movements during sleep, parasomnia, and others. [ncbi.nlm.nih.gov]
A majority of MJD/SCA3 patients have excessive daytime sleepiness with impaired nocturnal sleep, insomnia, and restless legs syndrome. Sleep disorders are seen more frequently in older adults with a long-standing disease. [symptoma.com]
MJD/SCA3 patients had a higher frequency of arousals from slow wave sleep (P < 0.001), parasomnia complaints (confusional arousal/sleep terrors, P = 0.001; RBD, P < 0.001; and nightmares, P < 0.001), REM sleep without atonia (P < 0.001), periodic limb [ncbi.nlm.nih.gov]
Jaw & Teeth
The diplopia in SCA3/MJD cases is, therefore, attributed, at least in part, to the impairment of the vergence eye movements. [ncbi.nlm.nih.gov]
Diplopia is a common ocular complaint. Dystonia and parkinsonism are two movement disorders which are frequently noticed in MJD/SCA3 along with peripheral neuropathy, tactile and proprioceptive hypoesthesia. [symptoma.com]
[…] of age Symptoms slowly worsen over time Muscle twitching Numbness, tingling, cramps, and pain in the hands, feet, arms, and legs (neuropathy) Loss of muscle tissue (atrophy) Many individuals with MJD also have vision problems such as double vision (diplopia [rarediseases.about.com]
Most have double (diplopia) or blurred vision, loss of color vision, and inability to regulate eye movements. Some have Parkinson-like symptoms. There may be sleep disturbance, cramps, and urinary bladder dysfunction. [sci.rutgers.edu]
Symptoms Vision problems: Bulging eyes Double vision (diplopia) Blurred vision Loss of ability to distinguish color and/or contrast Involuntary eye movements Supranuclear opthalmoplegia – the inability to voluntarily move the eyes in all directions 14 [slideshare.net]
- Abnormal Eye Movement
This patient had a 4-year medical history mainly presenting severe ataxia, abnormal eye movement and pyramidal signs. [ncbi.nlm.nih.gov]
Familial cerebellar ataxia, dystonia and abnormal eye movements in a non-portuguese family. Neurology 1979, 29:559. [ Links ] 16. Healton EB, Brust JCM, Kerr DL, Resor S, Penn A. Presumably azorean disease in a presumably non-portuguese family. [scielo.br]
The shared features include nystagmus in the horizontal direction, orbicularis oculi contractions, and bilateral esotropia. The findings indicate the importance of the inherent ophthalmological features expressed in MJD. [ncbi.nlm.nih.gov]
- Retinal Pigmentation
Dystrophic changes in the retinal pigment epithelium have rarely been described but may be one of the characteristic complications of Machado--Joseph disease. [ncbi.nlm.nih.gov]
[…] disorder) MJD spinocerebellar ataxia type 3 spinocerebellar ataxia 3 Azorean disease Nigrospinodentatal Degeneration MACHADO-JOSEPH DISEASE; MJD Autosomal dominant striatonigral degeneration Nigro-spino-dentatal degeneration with nuclear ophthalmoplegia [wikidata.org]
Ataxia and limb incoordination are its characteristic features along with spasticity. [symptoma.com]
X tremor and ataxia syndrome (FXTAS) and the nonprogressive episodic forms of inherited ataxias (EAs). [ncbi.nlm.nih.gov]
- Cerebellar Ataxia
From Wikidata Jump to navigation Jump to search autosomal dominant cerebellar ataxia that is characterized by slow degeneration of the hindbrain and has material basis in expansion of CAG triplet repeats (glutamine) in the ATXN3 gene Azorean disease [wikidata.org]
cerebellar ataxia strongly suggests the diagnosis of MJD. [jnnp.bmj.com]
Recently, there have been a few reports of its potential role in the treatment of cerebellar ataxia. We report the first case of a patient with Machado-Joseph disease in which we successfully treated cerebellar ataxia. [ncbi.nlm.nih.gov]
Watanabe HTanaka FMatsumoto M et al Frequency analysis of autosomal dominant cerebellar ataxias in Japanese patients and clinical characterization of spinocerebellar ataxia type 6. Clin Genet. 1998;53:13-19. Google Scholar 17. [doi.org]
The frequency of nystagmus was calculated for the 3 groups. RESULTS: Nystagmus was present in 88% of the MJD patients. [ncbi.nlm.nih.gov]
In the five non-MJD patients standard caloric testing elicited nystagmus. The presence of caloric induced nystagmus made the irrigation of ice water unnecessary. [jnnp.bmj.com]
- Postural Instability
Postural instability is often an early feature. We discuss the distinction of this entity from the olivopontocerebellar atrophies. [ncbi.nlm.nih.gov]
Clinical features include progressive ataxia, DYSARTHRIA, postural instability, nystagmus, eyelid retraction, and facial FASCICULATIONS. DYSTONIA is prominent in younger patients (referred to as Type I Machado-Joseph Disease). [hon.ch]
- Neurologic Manifestation
Clinical presentation of MJD/SCA3 resembles other neurologic disorders like Parkinson's disease and multiple sclerosis. Therefore diagnosis based on clinical features, family history, and genetic testing, requires an experienced neurologist for interpretation. A family history of neurological disorders should be inquired about during the preliminary interview. Predictive genetic testing in the absence of symptoms can be performed in suspected cases with a positive family history . During the physical examination, gaze-evoked nystagmus, abnormal saccades, decreased smooth pursuit gain, impaired vestibulo-ocular reflex, and supranuclear vertical gaze palsy may be noticed . Lid retraction and decreased blinking may lead to the appearance of “bulging eyes" which is characteristic of MJD/SCA3 . The diagnostic test to detect MJD/SCA3 is the direct determination of the number of abnormal CAG triplets in the DNA of affected patients using genetic testing which is available in specialized laboratories.
Neuroimaging studies like magnetic resonance imaging (MRI) help to demonstrate the extent of neural degeneration. MRI may be normal in the early stages of MJD/SCA3 but typical findings include brainstem and cerebellar atrophy . Single-photon emission computed tomography (SPECT) studies of the brain have shown poor perfusion in the parietal lobes, inferior portion of the frontal lobes, medial and lateral portions of the temporal lobes, basal ganglia, and cerebellar hemispheres and vermis . Magnetic resonance spectroscopy (MRS) of the deep white matter has demonstrated changes indicative of axonal dysfunction, although MRI in the same study did not reveal any abnormalities .
Finally, engagement of at risk or presymptomatic individuals in future trials will enable major advances on treatment research for SCA3/MJD. KEYWORDS: Clinical trials; Machado-Joseph disease; SCA3; Study design; Treatment [ncbi.nlm.nih.gov]
Prognosis Prognosis is poor but patients have been reported to survive for decades after onset of symptoms. [orpha.net]
In the last one decade, the intensive scientific research devoted to the SCAs is resulting in clear advances and a better understanding on the genetic and nongenetic factors contributing to their pathogenesis which are facilitating the diagnosis, prognosis [ncbi.nlm.nih.gov]
Prognosis The frequency with which such genetic mutations trigger the clinical onset of disease is known as penetrance. [encyclopedia.com]
Prognosis Once the disease begins, it is practically unstoppable. It progresses relentlessly with the death occurring between 6 and 29 year after the initial symptoms. Not all the symptoms will develop at the same time. [ic.steadyhealth.com]
Etiology The disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21). Patients with this subtype of SCA3 tend to have larger CAG expansions than those with other subtypes. [orpha.net]
Etiology OWRD (ie, HHT) is a disorder that is inherited in an autosomal dominant fashion, [23, 24] though 20% of patients are unaware of a positive family history, partly because the lesions may be minimal and because 10% of patients have no episodes [emedicine.medscape.com]
SCAs show high clinical, genetic, molecular and epidemiological variability. [ncbi.nlm.nih.gov]
Summary Epidemiology The prevalence of this form of MJD is not known. It accounts for 13% of all SCA3 cases. Clinical description Onset is generally early (mean of 24 years) and symptoms progress rapidly. [orpha.net]
The genetic epidemiological studies presently under way in these islands are based on the genealogical reconstruction of the affected families, thus partially depending on the reference of patients using family history. [jamanetwork.com]
Machado-Joseph disease: epidemiology, genetics and genetic epidemiology. In: Lechtenberg R, ed. Handbook of Cerebellar Diseases. New York, NY: Marcel Decker; 1993:345-351 5. Sequeiros J, Coutinho P. [doi.org]
PURPOSE OF REVIEW: This article provides a description on clinical features and pathophysiology of the main sleep disorders observed in Machado-Joseph disease (MJD). [ncbi.nlm.nih.gov]
Pisa syndrome is an unusual truncal dystonia that might be related to neuroleptics and is also observed in multiple system atrophy, PD, and other neurodegenerative conditions.  The pathophysiology of Pisa syndrome is still not fully understood, and [movementdisorders.org]
Present treatments are symptomatic and do not prevent disease progression. [ncbi.nlm.nih.gov]
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- Coutinho P. Doença de Machado-Joseph: Estudo Clínico, Patológico e Epidemiologico de uma Doença Neurológica de Origem Portuguesa. Porto, Portugal: Tipografia Nunes Ltda; 1994.
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- Etchebehere EC, Cendes F, Lopes-Cendes I, et al. Brain single-photon emission computed tomography and magnetic resonance imaging in Machado-Joseph disease. Arch Neurol. 2001;58:1257–1263.
- D’Abreu A, França M, Jr, Appenzeller S, et al. Axonal Dysfunction in the Deep White Matter in Machado-Joseph Disease. J Neuroimaging. 2009;19(1):9-12.