Edit concept Question Editor Create issue ticket

Machado-Joseph Disease


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 [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 [2]. Spasticity is a common feature with lower limbs being more frequently affected [2]. Later, other motor problems like dysphagia, dysarthria, and truncal ataxia start to develop. Diplopia is a common ocular complaint [2]. Dystonia and parkinsonism are two movement disorders which are frequently noticed in MJD/SCA3 along with peripheral neuropathy, tactile and proprioceptive hypoesthesia [3] [4] [5]. 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 [6]. A majority of MJD/SCA3 patients have excessive daytime sleepiness with impaired nocturnal sleep [7], insomnia [8], 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 [9]. Minor cognitive and behavioral difficulties, but not frank dementia, are noticed in MJD/SCA3 patients [10].

Three types of MJD/SCA3 have been identified with onset and severity being their differentiating features:

  • 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.
  • Type III MJD/SCA3 presents between the 4th and 7th decades, has the slowest progression and is characterized by ataxia with muscular atrophy and motor polyneuropathy. Analgesia, paresthesia, incoordination and diabetes are other common features of this type.
  • The expression of acetyl histone H3 and the induction of c-Fos in response to cAMP were strongly suppressed in cells expressing the protein with the expanded polyglutamine tract.[ncbi.nlm.nih.gov]
  • 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 movements[ncbi.nlm.nih.gov]
  • 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]
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]
  • X tremor and ataxia syndrome (FXTAS) and the nonprogressive episodic forms of inherited ataxias (EAs).[ncbi.nlm.nih.gov]
  • METHODS: Efficacy analysis was performed with the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) subscores and with the subgroup of patients with independent[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]
  • We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs.[ncbi.nlm.nih.gov]
  • Ataxia and limb incoordination are its characteristic features along with spasticity.[symptoma.com]
Cerebellar Ataxia
  • 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]
  • 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 developed over time and the diagnosis of MJD was confirmed by genetic studies. MJD should be considered in the differential diagnosis of MND.[ncbi.nlm.nih.gov]
  • Only after 10 years of prolonged benefit from levodopa and different dopamine agonists (DA), the patient developed cerebellar ataxia and pyramidal signs.[ncbi.nlm.nih.gov]
  • ., cerebellar ataxia type, severe amyotrophy type, and young-onset parkinsonism type. In addition, patients with very mild symptoms (formes frustes) were encountered.[ncbi.nlm.nih.gov]
  • The frequency of nystagmus was calculated for the 3 groups. RESULTS: Nystagmus was present in 88% of the MJD patients.[ncbi.nlm.nih.gov]
  • Electronystagmographic (ENG) abnormalities included bilateral gaze nystagmus, saccadic pursuit and failure of fixation suppression suggestive of cerebellar-brainstem pathology.[ncbi.nlm.nih.gov]
  • Core clinical features described include ataxia, nystagmus, dysarthria, facial fasciculations, and lid retraction, producing a characteristic staring expression.[ncbi.nlm.nih.gov]
  • The clinical core features include gait ataxia, external ophthalmoplegia, nystagmus, and bulging eyes.[ncbi.nlm.nih.gov]
  • The patient presented with gaze-evoked nystagmus and limitations of eye movement in all directions.[ncbi.nlm.nih.gov]
Postural Instability
  • Postural instability is often an early feature. We discuss the distinction of this entity from the olivopontocerebellar atrophies.[ncbi.nlm.nih.gov]
  • We report a patient presenting at age 16 years with postural instability and falls who developed severe generalized dystonia by the age of 20 years. He was the product of a consanguineous marriage.[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]
  • 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
  • Machado-Joseph disease is a form of progressive spino-cerebellar ataxia with both bulbar and peripheral neurological manifestations. To date, anesthesia for patients affected by this disease has not been described.[ncbi.nlm.nih.gov]
  • Manifestations Genetic Diseases, Inborn[clinicaltrials.gov]


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 [11]. 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 [12]. Lid retraction and decreased blinking may lead to the appearance of “bulging eyes" which is characteristic of MJD/SCA3 [2]. 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 [10]. 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 [13]. 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 [14].


  • 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]
  • This swimming phenotype provides a valuable readout for drug treatment studies.[ncbi.nlm.nih.gov]
  • However, VPA chronic treatment was able to increase GRP78 protein levels at 30 weeks of age, one of its known neuroprotective effects, confirming target engagement.[ncbi.nlm.nih.gov]
  • Our results do not support lithium chronic treatment as a promising strategy for the treatment of Machado-Joseph disease (MJD).[ncbi.nlm.nih.gov]
  • Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84).[ncbi.nlm.nih.gov]


  • 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 Prognosis is poor but patients have been reported to survive for decades after onset of symptoms.[orpha.net]
  • Prognosis The frequency with which such genetic mutations trigger the clinical onset of disease is known as penetrance.[encyclopedia.com]
  • Part I explores basic techniques to researching machado-joseph disease (e.g. finding guidelines on diagnosis, treatments, and prognosis), followed by a number of topics, including information on how to get in touch with organizations, associations, or[amazon.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 The disease is associated with a CAG repeat expansion mutation in the ATXN3 gene (14q21) with anticipation phenomenon. The normal repeat length is 13-41 whereas repeat lengths causing SCA3 are greater than 56.[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]


  • The correlation between the epidemiological representation of MJD in each district and the frequency of small, medium and large normal alleles was not significant.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • Summary Epidemiology Prevalence is estimated to be 1-2 in 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), intermediate prevalence rates in Portugal, Germany, the[orpha.net]
Sex distribution
Age distribution


  • 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]
  • Abstract Animal models are an important tool to study the pathophysiology of Machado-Joseph Disease (MJD).[ncbi.nlm.nih.gov]
  • CONCLUSION: Increase in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism. Copyright 2013 Elsevier Ltd. All rights reserved.[ncbi.nlm.nih.gov]
  • Machado-Joseph disease still has no specific therapy to arrest progression, but the unclear pathophysiological mechanism, features related to genetic characteristics, phenotype variability, apparently global involvement of the nervous system in the disease[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. [5] 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]
  • Potential therapeutic targets for MJD and polyQ diseases can be divided into (i) those that are aimed at the polyQ proteins themselves, namely gene silencing, attempts to enhance mutant protein degradation or inhibition/prevention of aggregation; and[ncbi.nlm.nih.gov]
  • Artificially blocking the autophagy pathway prevents the removal of human ataxin-3 and improved movement produced by calpeptin treatment.[ncbi.nlm.nih.gov]
  • Onset is most frequently during the reproductive years, and genetic counseling is its only means of prevention. The causative mutation--an expansion of a (CAG)n on chromosome 14q32.1--can now be directly detected.[ncbi.nlm.nih.gov]
  • Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and[ncbi.nlm.nih.gov]



  1. Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994;8:221–228
  2. Coutinho P. Doença de Machado-Joseph: Estudo Clínico, Patológico e Epidemiologico de uma Doença Neurológica de Origem Portuguesa. Porto, Portugal: Tipografia Nunes Ltda; 1994.
  3. Rosenberg RN. Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord. 1992;7:193–203.
  4. Jardim LB, Pereira ML, Silveira I, Ferro A, Sequeiros J, Giugliani R. Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)n. Arch Neurol. 2001;58:899–904.
  5. Klockgether T, Schols L, Abele M, et al. Age-related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). J Neurol Neurosurg Psychiatry. 1999;66:222–224.
  6. Yeh TH, Lu CS, Chou YH, et al. Autonomic dysfunction in Machado-Joseph disease. Arch Neurol. 2005;62:630–636.
  7. Friedman JH, Fernandez HH, Sudarsky LR. REM behavior disorder and excessive daytime somnolence in Machado-Joseph disease (SCA-3) Mov Disord. 2003;18:1520–1522.
  8. D’Abreu A, Franca MC Jr, Conz L, et al. Sleep symptoms and their clinical correlates in Machado-Joseph Disease. Acta Neurol Scand. 2009;119(4):277–280.
  9. Franca MC Jr, D’Abreu A, Friedman JH, Nucci A, Lopes-Cendes I. Chronic pain in Machado-Joseph disease: a frequent and disabling symptom. Arch Neurol. 2007;64:1767–1770.
  10. D'Abreu A, Franca MC, Paulson HL, Lopes-Cendes I. Caring for Machado-Joseph disease: current understanding and how to help patients. Parkinsonism Relat. Disord. 2010;16(1):2
  11. Cannella M, Simonelli M, D’Alessio C, et al. Presymptomatic tests in Huntington’s disease and dominant ataxias. Neurol Sci. 2001;22:55–56.
  12. Gordon CR, Joffe V, Vainstein G, Gadoth N. Vestibulo-ocular arreflexia in families with spinocerebellar ataxia type 3 (Machado-Joseph disease) J Neurol Neurosurg Psychiatry. 2003;74:1403–1406.
  13. 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.
  14. 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.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 20:48