Machado-Joseph病（マシャド・ジョセフ病、Machado-Joseph disease、MJD）は常染色体優性遺伝形式の遺伝性脊髄小脳変性症の一型である。世界的にみても頻度が高いものである。脊髄小脳変性症3型（SCA3）ともいわれる。MJDは多彩な臨床病型をとることが知られている。かつてはMJDとSCA3は臨床像が異なると考えられていたがMJDの原因遺伝子が同定されSCA3とMJDの原因遺伝子が同じものと明らかになってからは区別されなくなった。
目次
- 1 歴史的経緯
- 2 臨床症状
- 3 画像検査
- 4 遺伝子検査
- 5 病理検査
- 6 病因
- 7 参考文献
歴史的経緯
1972年にポルトガルでアゾレス諸島に先祖をもつ2つの家系が報告された。１つは50歳代発症の進行性小脳性運動失調と筋萎縮・末梢神経障害を呈するMachado家系を報告したものであり、もうひとつは30～50歳代に発症する進行性の失調、外眼筋麻痺、顔面や舌の線維束攣縮と痙縮および四肢の固縮を呈するThomas家系を報告したものである。1976年にはRosenbergらが20～30歳代発症の進行性の痙縮、眼球運動障害、構音障害、全身性のジストニアを特徴とするポルトガルに先祖を持つJoseph家系を報告した。1978年にアゾレス諸島での調査によりこれらは単一の常染色体優性遺伝形式をとる神経疾患の部分症であるという報告がなされ、臨床的特徴からⅠ型からⅢ型に分類された。当初はポルトガルを起源にもつ稀な疾患と考えられていたがその後世界中で普遍的に分布する疾患であることが認識されるようになった。
臨床症状
MJDは発症年齢によって非常に多彩な臨床症状を示す。ATXN3遺伝子のCAGリピート数が発症年齢に影響を与えている。古典的な分類ではI〜III型の分類で行われる。I型はJoseph家系に相当するものであり下肢痙性や腱反射亢進といった錐体路徴候、ジストニアなどの錐体外路徴候、顔面や舌の線維束攣縮様運動、外眼筋麻痺を伴う眼振などが25歳前後から出現するというものである。しばしば小脳性運動失調は目立たない。II型はI型の症状に加えて四肢、体幹の小脳性体幹失調が加わりジストニアなどはあまり目立たなくなる。30歳前半から症状が出現するものであり症状の進行はI型よりも遅い。III型はMachado家系に相当するものである。高齢発症であって小脳性運動失調と末梢神経障害（腱反射消失、筋緊張低下、遠位部感覚低下、遠位筋の筋萎縮など）が前景に立つものであり錐体路症状は目立たなくなる。遺伝性パーキンソン症候群と末梢神経障害をしめすものをIV型に分類することもあるが、IV型は極めて稀である。また非典型例として痙性対麻痺型や純小脳失調型なども報告されている。
実際には症状は複雑に入り組み症状の進行によっても臨床像は変化する。症状の進行に伴い眼球運動障害も目立つようになり複視が出現するようになる。症状の進行とともに眼振も高度になっていくが、やがて律動性眼球運動の障害の進行により眼振は再びめだたなくなっていく。びっくり眼はMJDの症状としてよく知られているが特異的なものではない。15年程度で車椅子などを要するようになり発症から死に至るまでは平均21年と言われている。しかしリピート数の影響などもありばらつきは大きい。
| |
I型 |
II型 |
III型 |
IV型 |
| 発症年齢 |
20〜30歳 |
20〜45歳 |
40〜65歳 |
まれ |
| 臨床症状 |
錐体路症状、錐体外路症状、痙性 |
小脳症状、錐体路症状 |
小脳症状、末梢神経障害、筋萎縮 |
パーキンソン症候群、末梢神経障害 |
| リピート数 |
79.4±1.0 |
74.6±0.5 |
72.6±1.1 |
|
画像検査
MRIでは小脳皮質の萎縮はないかあっても軽度である。一方、歯状核・赤核系の変性を反映して第4脳室の拡大は高率に認められる。脳幹は被蓋部、底部いずれも萎縮する。
遺伝子検査
1993年に滝山らがMJDの責任遺伝子が14q24.3-q32に連鎖していることを報告した。次いで1994年に川口らが新規遺伝子ATXN3（またはMJD1）にCAGリピート伸長を認め、責任遺伝子に同定した。これにより遺伝子診断に基づく診断が可能となりMJDが人種を問わず普遍的に認められることが確認できた。
このCAGリピートは正常アレルでは14から44である伸長アレルは56から86であり両者の間のオーバーラップは存在しないと言われている。非典型例であるがリピート長53で錐体外路症状と末梢神経障害の合併という臨床病型の報告がある。そのためリピート長は53以上が異常域とする意見もある。
リピート長は臨床病型に関連し佐々木らの報告ではI型の平均リピート数は80、II型は76、III型は73であったとしている。川口らはCAGリピート伸長と発症年齢には負の相関があることを報告している。他のポリグルタミン病と同様に表現促進現象があり、父から遺伝する場合の方が母から遺伝する場合よりも顕著である。父親由来では平均3.2リピート、母親由来では1.2リピートの伸長があり発症年齢は父親由来では平均14.7年、母親由来では平均6.5年の早くなるという報告がある。また父親からの遺伝の場合は73％の子が発症するためメンデル遺伝からずれておりmeiotic draiveと言われている。この現象は筋緊張性ジストロフィーやDRPLAでも認められている。またホモ接合体症例は同じリピート数を有するヘテロ接合体症例とくらべては発症年齢がはやく重篤である。
CAGリピート長が発症年齢や臨床病型以外に及ぼす影響が知られている。例えばICARSやSARA[1]など半定量スケールで評価した場合の病勢進行速度に関してCAGリピート長と相関することが知られている。しかしその相関はあまり強くない。
病理検査
病理学的には小脳歯状核、大脳基底核、脳幹、脊髄特に胸髄の変性は認められるが、小脳皮質は比較的保たれる。歯状核神経細胞は萎縮し、プルキンエ細胞の神経終末の二次的変性であるグルモース変性が認められる。この変性は小脳皮質が比較的保たれ、かつ歯状核神経細胞の萎縮があるときに認められる所見である。抗ポリグルタミン抗体IC2陽性の核内封入体を認める。淡蒼球は内節優位に障害されるため淡蒼球外節優位に障害されるDRPLAとは異なるが両者の区別は遺伝子検査が有用である。
病因
正常ATXN3遺伝子の転写産物であるATXN3蛋白質（ataxin-3）は様々なタンパク分解酵素サブユニットやユビキチン化蛋白質と結合し、ユビキチン分解酵素であると考えられている。このATXN3遺伝子のCAGリピートはコーディング領域のC末端に近いところに存在している。CAGリピート伸長が生じるとATXN3タンパク質の伸長ポリグルタミン鎖を含むC末端側フラグメントが難溶性重合体を形成しそこに正常ATXN3タンパク質が巻き込まれる。正常ATXN3タンパク質の細胞内濃度が低下することで細胞障害につながるという仮説がある。この仮説ではなぜ神経細胞だけで重合体形成が起こるのかを説明することができない。
参考文献
- Spinocerebellar Degenerations ISBN 9780750675031
- 脊髄小脳変性症の臨床 ISBN 9784880022703
- 小脳と運動失調 小脳はなにをしているのか ISBN 9784521734422
- Clinical Neuroscience Vol.27 (2009年) 01月号 脊髄小脳変性症―What's new？
- 最新医学 67巻5号(通巻849号）特集 脊髄小脳変性症(SCD)のUp-To-Date
- ^ Neurology. 2006 66 1717-20. PMID 16769946
| Machado-Joseph disease |
| Classification and external resources |
| ICD-10 |
G11.1 |
| ICD-9 |
334.2 |
| OMIM |
109150 |
| DiseasesDB |
31961 |
| MeSH |
D017827 |
Machado–Joseph disease (MJD), also known as Machado–Joseph Azorean disease or Joseph's disease or Spinocerebellar ataxia type 3 (SCA3), is a rare autosomal, dominantly inherited neurodegenerative disease that causes progressive cerebellar ataxia,[1] [2]which results in a lack of muscle control and coordination of the upper and lower extremities.[3] The symptoms are caused by a genetic mutation that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene [1] that results in an abnormal form of the protein ataxin which causes degeneration of cells in the hindbrain.[3] Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness and/or Parkinson's disease.
Machado–Joseph disease is a type of spinocerebellar ataxia and is the most common cause of autosomal-dominant ataxia.[1] MJD causes ophthalmoplegia and mixed sensory and cerebellar ataxia.
Contents
- 1 History
- 2 Symptoms
- 3 Treatment
- 4 Prognosis
- 5 Pathophysiology
- 6 Classification
- 7 Diagnosis
- 8 Notable cases
- 9 Ethical Consideration
- 10 References
- 11 External links
History
The disease was first identified in 1972.[4]
Unlike many other medical conditions, Machado–Joseph disease isn't named after researchers. It is named after two men ("William Machado" and "Antone Joseph") who were the patriarchs of the families in which the condition was initially described.[5] The above families are of Azorean descent, an ethnic group in which the disease is most prevalent. The highest prevalence of the condition is on the Azorean island of Flores where around 1 in 140 individuals in the population are diagnosed with MJD.[6]
Symptoms
Symptoms of MJD are memory deficits,[7] spasticity, difficulty with speech and swallowing, weakness in arms and legs, clumsiness, frequent urination and involuntary eye movements. Symptoms can begin in early adolescence and they get worse over time. Eventually, MJD leads to paralysis; however, intellectual functions usually remain the same.
Treatment
There is no cure for Machado-Joseph Disease. However, treatments are available for some symptoms.[1][3] For example, spasticity can be reduced with antispasmodic drugs, such as baclofen. The Parkinsonian symptoms can be treated with levodopa therapy. Prism glasses can reduce diplopic symptoms.[3] Physiotherapy/Physical Therapy and/or occupational therapy can help patients by prescribing mobility aids to increase the patients' independence, providing gait training, and prescribing exercises to maintain the mobility of various joints and general health to decrease the likelihood of falls or injuries as a result of falls. Walkers and wheelchairs can greatly help the patient with everyday tasks. Some patients will experience difficulties with speech and swallowing, therefore a Speech-Language Pathologist can assist the patients to improve their communicating abilities and their issues with swallowing.[3]
Prognosis
Life expectancy ranges with people who have the disease. A normal life expectancy is expected in patients with a mild form of MJD.[3] Those with severe forms of MJD are expected to live only to their mid-thirties.[3] The cause of death of those who die early is often aspiration pneumonia.[3]
Pathophysiology
The disease is caused by a mutation in the ATXN3 gene, which is located on chromosome 14q. The gene contains lengthy irregular repetitions of the code "CAG", producing a mutated protein called ataxin-3. (Normally, the number of copies is between 13 and 41.)[8] MJD is an autosomal dominant disease, meaning that if either parent gives the defective gene to a child, the child will show symptoms of the disease. Therefore, if one parent suffers from this disease and the other parent does not, then if they decide to have children, there will be a 50% chance of their child inheriting the disease.[3]
The pons (a structure located on the brain stem) is one of the areas affected by MJD. The striatum (a brain area connected to balance and movement) is also affected by this disease, which could explain both of the main motor problems cause by MJD: the tightening and twisting of the limb and the abrupt, irregular movements.[9]
In affected cells, this protein builds up and assembles intranuclear inclusion bodies. These insoluble aggregates are hypothesized to interfere with the normal activity of the nucleus and induce the cell to degenerate and die.[citation needed]
Classification
There are five sub-types of MJD [1] that are characterized by the age of onset and range of symptoms. The sub-types illustrate a wide variety of symptoms that patients can experience.[1] However, assigning individuals to a specific sub-type of the disease is of limited clinical significance.[1]
- Type I is distinguished by arrival between the ages of 10 and 30 and represents approximately 13% of individuals.[1] It usually has fast development and severe rigidity and dystonia.
- Type II is the most common sub-type (approximately 57% of individuals with MJD [1]) and typically begins between 20 and 50 years of age . It has an intermediate progression and causes symptoms that include spasticity, exaggerated reflex responses and spastic gait, ataxia [1] and upper motor neuron signs.[1]
- Type III MJD has a slow progression. Patients typically have an onset between the ages of 40 and 70 and represent approximately 30% of MJD patients.[1] Symptoms include muscle twitching, tingling, cramps, unpleasant sensations such as numbness, pain in the feet, hands and limbs and muscle atrophy. Nearly all patients experience a decline in their vision such as blurred vision, double vision, inability to control eye movements, and loss of capability to distinguish color. Some patients also experience Parkinsonian symptoms.
- Type IV is distinguished by Parkinsonian symptoms that respond particularly well to levodopa treatment.[1]
- Type V appears to resemble Hereditary Spastic Paraplegia; however, more research is needed to conclude the relationship between Type V MJD and hereditary spastic paraplegia.[1]
Diagnosis
MJD can be diagnosed by recognizing the symptoms of the disease and by taking a family history. Physicians ask patients questions about the kind of symptoms relatives with the disease had, the progression and harshness of symptoms, and the ages of onset in family members.
Presymptomatic diagnosis of MJD can be made with a genetic test.[10] The direct detection of the genetic mutation responsible for MJD has been available since 1995.[11] Genetic testing looks at the number of CAG repeats within the coding region of the MJD/ATXN3 gene on chromosome 14. The test will show positive for MJD if this region contains 61-87 repeats, as opposed to the 12-44 repeats found in healthy individuals. A limitation to this test is that if the number of CAG repeats in an individual being tested falls between the healthy and pathogenic ranges (45-60 repeats), then the test cannot predict whether an individual will have MJD symptoms.[10]
Notable cases
Brazilian comedian, actor and TV personality Guilherme Karan was diagnosed with Machado–Joseph disease.[12]
Ethical Consideration
Ethicists have used Machado–Joseph disease as a paradigmatic illness to discuss the rights of a community of patients to control "ownership" of their disease, particularly when it comes to research on genetic testing.[13] Also, as there currently is no clinical intervention to prevent the onset of the disease symptoms, there is discourse over the whether individuals should get tested or not.[11] The benefits of having MJD testing include a reduction in anxiety and uncertainty, and the ability to plan for the future. Some disadvantages include the anticipation of negative results and the individual's difficulties in adapting to this outcome.
For an ethnographic case study exploring some of the social and ethical consequences of living with Machado–Joseph disease, see João Biehl's Vita: Life in a Zone of Social Abandonment (Berkeley: University of California Press, 2006).
References
- ^ a b c d e f g h i j k l m n Paulson, H. (2011, March 8). Spinocerebellar Ataxia Type 3. In R. A. Pagon, T. D. Bird, C. R. Dolan, & K. Stephens (Eds.), GeneReviews. Seattle, WA: University of Washington. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK1196/
- ^ Bettencourt, Conceição; Lima, Manuela (2011). "Machado-Joseph Disease: from first descriptions to new perspectives". Orphanet Journal of Rare Diseases 6: 35. doi:10.1186/1750-1172-6-35. PMID 21635785. Retrieved 12 April 2015.
- ^ a b c d e f g h i Machado-Joseph Disease Fact Sheet. 11 December 2007. National Institute of Neurological Disorder & Stroke. 24 Mar. 2008 <http://www.ninds.nih.gov/disorders/machado_joseph/detail_machado_joseph.htm>
- ^ Nakano KK, Dawson DM, Spence A (1972). "Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts". Neurology 22 (1): 49–55. doi:10.1212/wnl.22.1.49. PMID 5061839.
- ^ "SCA-3 - Ataxia Center in the Medical School at the University of Minnesota".
- ^ "Machado-Joseph Disease Fact Sheet". Retrieved 2011-05-09.
- ^ Kawai Y, Takeda A, Abe Y, Washimi Y, Tanaka F, Sobue G (November 2004). "Cognitive impairments in Machado-Joseph disease". Arch. Neurol. 61 (11): 1757–60. doi:10.1001/archneur.61.11.1757. PMID 15534186.
- ^ Lima M, Costa MC, Montiel R et al. (2005). "Population genetics of wild-type CAG repeats in the Machado-Joseph disease gene in Portugal". Hum. Hered. 60 (3): 156–63. doi:10.1159/000090035. PMID 16340213.
- ^ http://www.cienciahoje.pt/index.php?oid=26002&op=all
- ^ a b Maciel P, Costa MC, Ferro A et al. (November 2001). "Improvement in the molecular diagnosis of Machado-Joseph disease". Arch. Neurol. 58 (11): 1821–7. doi:10.1001/archneur.58.11.1821. PMID 11708990.
- ^ a b Rolim, L., Zagalo-Cardoso, J.A., Paul, C., Sequeiros, J., & Fleming, M. (2006). The perceived advantages and disadvantages of presymptomatic testing for Machado-Joseph Disease: development of a new self-response inventory. Journal of Genetic Counseling,15(5):375-391.
- ^ [1]
- ^ Appel J, Friedman JH (January 2004). "Genetic markers and the majority's right not to know". Mov. Disord. 19 (1): 113–4. doi:10.1002/mds.20014. PMID 14743372.
External links
- -234487767 at GPnotebook
- machado_joseph at NINDS
- eNotes
- Machado–Joseph disease at DMOZ
|
Non-Mendelian inheritance: anticipation
|
|
| Trinucleotide |
|
Polyglutamine (PolyQ), CAG
|
- Dentatorubral-pallidoluysian atrophy
- Huntington's disease
- Kennedy disease
- Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease)
|
|
|
Non-polyglutamine
|
- CGG (Fragile X syndrome)
- GAA (Friedreich's ataxia)
- CTG (Myotonic dystrophy type 1)
- CTG (Spinocerebellar ataxia 8)
- CAG (Spinocerebellar ataxia 12)
|
|
|
| Tetranucleotide |
- CCTG (Myotonic dystrophy type 2)
|
|
| Pentanucleotide |
- ATTCT (Spinocerebellar ataxia 10)
|
|
|
Disorders of translation and posttranslational modification
|
|
| Translation |
- Ribosome: Diamond–Blackfan anemia
- FMR1
- Fragile X syndrome
- Fragile X-associated tremor/ataxia syndrome
- Premature ovarian failure 1
- Initiation factor: Leukoencephalopathy with vanishing white matter
- snRNP: Retinitis pigmentosa 33
|
|
| Posttranslational modification |
| Protein folding |
- Alzheimer's disease
- Huntington's disease
- Creutzfeldt–Jakob disease
- chaperonins: 3-Methylglutaconic aciduria 5
|
|
| Protein targeting |
|
|
| Ubiquitin |
- E1: X-linked spinal muscular atrophy 2
- E3: Johanson–Blizzard syndrome
- Von Hippel–Lindau disease
- 3-M syndrome
- Angelman syndrome
- Deubiquitinating enzyme: Machado–Joseph disease
- Aneurysmal bone cyst
- Multiple familial trichoepithelioma 1
|
|
| SUMO |
|
|
| Other |
- Multiple sulfatase deficiency
- Hyperproinsulinemia
- Ehlers–Danlos syndrome 6
|
|
|
|
Index of genetics
|
|
| Description |
- Gene expression
- DNA
- replication
- cycle
- recombination
- repair
- binding proteins
- Transcription
- factors
- regulators
- nucleic acids
- RNA
- RNA binding proteins
- ribonucleoproteins
- repeated sequence
- modification
- Translation
- ribosome
- modification
- nexins
- Proteins
- domains
- Structure
- primary
- secondary
- tertiary
- quaternary
|
|
| Disease |
- Replication and repair
- Transcription factor
- Transcription
- Translation
|
|
|
