fragile X syndrome

脆弱X症候群

WordNet

1. vulnerably delicate; "she has the fragile beauty of youth"
2. a pattern of symptoms indicative of some disease
3. a complex of concurrent things; "every word has a syndrome of meanings"
4. the 24th letter of the Roman alphabet (同)x, ex

PrepTutorEJDIC

1. 『壊れやすい』,もろい / (体質が)虚弱な(weak);《おどけて》調子が悪い / (幸福などが)はかない
2. (疾患の徴候となる一群の)症徴候,症候群 / (事件・社会的状態などのパターンを示す)徴候形態
3. Christ / Christian
4. x-axis

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/03/05 10:42:31」(JST)

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Fragile X syndrome
Classification and external resources
Location of FMR1 gene
ICD-10	Q99.2
ICD-9	759.83
OMIM	300624
DiseasesDB	4973
eMedicine	ped/800
MeSH	D005600

Fragile X syndrome (FXS), Martin–Bell syndrome, or Escalante's syndrome (more commonly used in South American countries), is a genetic syndrome that is the most common known single-gene cause of autism and the most common inherited cause of intellectual disability. It results in a spectrum of intellectual disability ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and larger testes (macroorchidism), behavioral characteristics such as stereotypical movements (e.g. hand-flapping), and social anxiety.

Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development. Depending on the length of the CGG repeat, an allele may be classified as normal (unaffected by the syndrome), a premutation (at risk of fragile X associated disorders), or full mutation (usually affected by the syndrome). A definitive diagnosis of fragile X syndrome is made through genetic testing to determine the number of CGG repeats. Testing for premutation carriers can also be carried out to allow for genetic counseling.

There is currently no drug treatment that has shown benefit specifically for fragile X syndrome. However, medications are commonly used to treat symptoms of attention deficit and hyperactivity, anxiety, and aggression. Supportive management is important in optimizing functioning in individuals with fragile X syndrome, and may involve speech therapy, occupational therapy, and individualized educational and behavioral programs.

J. Purdon Martin and Julia Bell in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism (larger testicles). In 1969 Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability. In 1970 Frederick Hecht coined the term "fragile site".

Signs and symptoms

Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone.

Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone. Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include stereotypical movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism.

Males with a full mutation display virtually complete penetrance and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome. Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males.

Physical phenotype

• Large, protruding ears (one or both)
• Long face (vertical maxillary excess)
• High-arched palate (related to the above)
• Hyperextensible finger joints
• Double-jointed thumbs
• Flat feet
• Soft skin
• Postpubescent macroorchidism (Larger testes in men after puberty)
• Hypotonia (low muscle tone)

Intellectual development

Individuals with FXS may present anywhere on a continuum from learning disabilities in the context of a normal intelligence quotient (IQ) to severe intellectual disability, with an average IQ of 40 in males who have complete silencing of the FMR1 gene. Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with FXS are with working and short-term memory, executive function, visual memory, visual-spatial relationships and maths, with verbal abilities being relatively spared.

Data on intellectual development in FXS are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 2.2 times slower than unaffected children.

When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.

Social interaction

FXS is characterized by social anxiety, including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships. Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks. Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before.

It appears that individuals with FXS are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people. This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder.

Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal. In addition, premutation in females has been found to be associated with social anxiety. The size of DNA insertion is related to severity of attention problems and withdrawal symptoms.^{[citation needed]}

Individuals with FXS show decreased activation in the prefrontal regions of the brain. These regions are associated with social cognition.^{[citation needed]}

Psychiatric

Attention deficit hyperactivity disorder (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong.

Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with FXS, with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full. Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety. Although only a minority will meet the criteria for obsessive-compulsive disorder (OCD), a significant majority will feature obsessive-type symptoms. However, as individuals with FXS generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors.

Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration. Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression.

Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience dementia, mood, and/or anxiety disorders. Males with the FMR1 premutation and clinical evidence of FXTAS were found to have increased occurrence of somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, phobic anxiety, and psychoticism.

Hypersensitivity and repetitive behavior

Children with fragile X have very short attention spans, are hyperactive, and show hypersensitivity to visual, auditory, tactile, and olfactory stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to hyperarousal. Children with FXS pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with FXS. Behavioral therapy can be used to decrease the child’s sensitivity in some cases.

Perseveration is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches.

Vision

Ophthalmologic problems include strabismus (lazy eye). This requires early identification to avoid amblyopia. Surgery and/or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with FXS are also common.

Neurological

Individuals with FXS are at a higher risk of developing seizures, with rates between 10 and 40% reported in the literature. In larger study populations the frequency varies between 13 and 18%, consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures. The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication.

Individuals who are carriers of premutation alleles are at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease. It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of tremor occurs in the sixth decade of life, with subsequent progression to ataxia (loss of coordination) and gradual cognitive decline.

Working memory

From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of working memory. Working memory involves the temporary storage of information 'in mind', while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the phonological loop. The CGG length is significantly correlated with central executive and the visual–spatial memory. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.

Fertility

About 20% of women who are carriers for the fragile X premutation are affected by fragile X-related primary ovarian insufficiency (FXPOI), which is defined as menopause before the age of 40. The number of CGG repeats correlates with penetrance and age of onset. However, it is interesting to note that premature menopause is more common in premutation carriers than in women with the full mutation, and for premutations with more than 100 repeats the risk of FXPOI begins to decrease.

Causes

Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.

In unaffected individuals, the FMR1 gene contains 5-44 repeats of the CGG codon, most commonly 29 or 30 repeats. Between 45 and 54 repeats is considered a "grey zone", with a premutation allele generally considered to be between 50 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the FMR1 allele, with over 200 repeats of the CGG codon. The FMR1 gene generally refers to the protein-coding sequence that produces the fragile X mental retardation protein (FMRP). In addition to this gene, there are a number of non-coding RNAs (ncRNAs) that have been shown to be transcribed from the same location in the genome. Two studies have found antisense RNA transcripts originating in the 5’ region of FMR1 whose expression is increased in premutation allele carriers, and is silenced in full mutation alleles. Other antisense transcripts have been detected which are expressed at similar levels in all FMR1 alleles, regardless of mutation status. In addition to the previously mentioned long ncRNAs, small (~20 nucleotides in length) RNAs were shown to be expressed similarly in normal and patient cells.

FMR1 methylation

In those individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1 promoter, leading to the silencing of the FMR1 gene and a lack of its product, FMRP. Recent studies have examined the specific pattern of methylation that occurs, and where along the FMR1 gene locus these changes are located. Upstream of FMR1, there is a stretch of heterochromatin. In normal individuals, there is a pattern of histone modification in this zone similar to regions of the genome that are normally repressed during development; these modifications include H3K9Me2 and H3K27Me3. However, individuals with silenced FMR1 have a different complement of modifications. H3K9Me2 and H3K27Me3 were found to be elevated in the upstream region, in exon 1 and in intron 1 of FMR1. In addition, elevated levels of H3K9Me3 and H4K20Me3 were found in exon 1 of FMR1 (which contains the CGG repeat region), but lower levels noted in the upstream region 5' to exon 1 and in the intron at the 3' end. The presence of H3K9Me3 and H4K20Me3 modifications are typical of other repetitive sequences, such as those that make up satellite DNA.

This methylation of FMR1 in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name.

Transmission

Fragile X syndrome is an X-linked dominant condition with variable expressivity and possibly reduced penetrance. It does not follow the usual pattern of inheritance for an X linked condition.

Before the FMR1 gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that genetic anticipation was occurring. This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985.

The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the FMR1 CGG repeat typically not increasing during meiosis. Incidentally, males with a full mutation only pass on premutations to their daughters. However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected. In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected.

Pathophysiology

FMRP is found throughout the body, but in highest concentrations within the brain and testes. It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the synapses of neurons. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines, which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning.

In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning. The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect dopamine pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS. The downregulation of GABA pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.

Diagnosis

Cytogenetic analysis for fragile X syndrome was first available in the late 1970s when diagnosis of the syndrome and carrier status could be determined by culturing cells in a folate deficient medium and then assessing for "fragile sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome. This technique proved unreliable, however, as the fragile site was often seen in less than 40% of an individual's cells. This was not as much of a problem in males, but in female carriers, where the fragile site could generally only be seen in 10% of cells, the mutation often could not be visualised.

Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using polymerase chain reaction (PCR) and methylation status using Southern blot analysis. By determining the number of CGG repeats on the X chromosome, this method allows for more accurate assessment of risk for premutation carriers in terms of their own risk of fragile X associated syndromes, as well as their risk of having affected children. Because this method only tests for expansion of the CGG repeat, individuals with FXS due to missense mutations or deletions involving FMR1 will not be diagnosed using this test and should therefore undergo sequencing of the FMR1 gene if there is clinical suspicion of FXS.

Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.

Early diagnosis of fragile X syndrome or carrier status is important for providing early intervention in children with the syndrome, and allowing genetic counselling with regards to the potential for a couples future children to be affected.

Autism and fragile X syndrome

Fragile X syndrome is the leading known genetic cause of autism, accounting for about 5% of cases. This finding has resulted in screening for FMR1 mutation to be considered mandatory in children diagnosed with autism. Of those with fragile X syndrome, prevalence of concurrent autism spectrum disorder (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD.

Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to severe ASD. When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.

Genetic mouse models of FXS have also been shown to have autistic-like behaviors.

Management

Pharmacological

Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor. While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes will lead to new therapies.

ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants. However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability. Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. Atypical antipsychotics can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to extrapyramidal side effects such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with anticonvulsants.

Non-pharmacological

Management of FXS may include speech therapy, behavioral therapy, sensory integration occupational therapy, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.

Research

The increased understanding of the molecular mechanisms of disease in FXS has led to the development of therapies targeting the affected pathways. Evidence from mouse models shows that mGluR5 antagonists (blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS. Two new drugs, AFQ-056 (mavoglurant) and dipraglurant, as well as the repurposed drug fenobam are currently undergoing human trials for the treatment of FXS. There is also early evidence for the efficacy of arbaclofen, a GABA_B agonist, in improving social withdrawal in individuals with FXS and ASD.

In addition, there is evidence from mouse models that minocycline, an antibiotic used for the treatment of acne, rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from controlled trials to support its use.

References

External links

• CDC’s National Center on Birth Defects and Developmental Disabilities
• FraXA.org – The Fragile X Research Foundation
• Fragilex.org.uk – The United Kingdom National Fragile X charity
• FragileX.org The National Fragile X Foundation (US) – Support, Awareness, Education, Research and Advocacy since 1984
• FragileX.org.au – Fragile X Association of Australia – charity – news, forums, support, information, clinics
• The Colorado Fragile X Consortium
• Gene Reviews
• Closely linked to Nicolaides-Baraitser syndrome

UpToDate Contents

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• 1. 小児および思春期における脆弱X症候群の臨床的特徴および診断 clinical features and diagnosis of fragile x syndrome in children and adolescents
• 2. 脆弱Ｘ症候群の出生前スクリーニングおよび診断 prenatal screening and diagnosis for fragile x syndrome
• 3. 小児および思春期における脆弱X症候群のマネージメント management of children and adolescents with fragile x syndrome
• 4. 原発性早期卵巣障害（早期卵巣機能不全）の病因と原因 pathogenesis and causes of spontaneous primary ovarian insufficiency premature ovarian failure
• 5. 知的障害（精神遅滞）をもつ成人のプライマリケア primary care of the adult with intellectual disability mental retardation

English Journal

• Males but not females show differences in calbindin immunoreactivity in the dorsal thalamus of the mouse model of fragile X syndrome.

• Giráldez-Pérez RM, Avila MN, Feijóo-Cuaresma M, Heredia R, De Diego-Otero Y, Real MÁ, Guirado S.SourceUniversity of Málaga, Department of Cell Biology, Genetics, and Physiology, Málaga, Spain.
• The Journal of comparative neurology.J Comp Neurol.2013 Mar 1;521(4):894-911. doi: 10.1002/cne.23209.
• Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of the Fmr1 gene product, fragile X mental retardation protein. Here we analyze the immunohistochemical expression of calcium-binding proteins in the dorsal thalamus of Fmr1 knockout mice of both se
• PMID 22886886

• Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice.

• Gantois I, Pop AS, de Esch CE, Buijsen RA, Pooters T, Gomez-Mancilla B, Gasparini F, Oostra BA, D'Hooge R, Willemsen R.SourceLaboratory of Biological Psychology, Faculty of Psychology and Educational Sciences, KU Leuven, Tiensestraat 102, 3000 Leuven, Belgium. Electronic address: ilsegantois@yahoo.com.
• Behavioural brain research.Behav Brain Res.2013 Feb 15;239:72-9. doi: 10.1016/j.bbr.2012.10.059. Epub 2012 Nov 6.
• Fragile X syndrome is caused by lack of FMR1 protein (FMRP) leading to severe symptoms, including intellectual disability, hyperactivity and autistic-like behaviour. FMRP is an RNA binding protein involved in the regulation of translation of specific target mRNAs upon stimulation of metabotropic glu
• PMID 23142366

Japanese Journal

• Carotid Blowout Syndromeに対する血管内治療

• 足立 明彦,小林 英一,渡邉 義之,米山サーネキー 智子,早坂 典弘,鈴木 誉,岡本 美孝,佐伯 直勝
• 脳神経外科ジャーナル 20(8), 597-603, 2011-08-20
• … blowout syndrome)は,頭頚部腫瘍に対する放射線治療後に,遅発性に動脈破裂をきたす致死的疾患として知られている.今回,放射線治療後36年および2年を経て大量出血で発症し,血管内治療で良好な結果が得られた2例を報告する.1例目は,瘤内塞栓をしたものの,2週間後に再出血し,母動脈を閉塞した.2例目は,虚血耐性を確認できたため,同様にtrappingにて止血を得た.大量出血で発症するCBSは緊急の止血処置を要する.将来的 …
• NAID 110008713067

• ADHD and genetic syndromes

• LO-CASTRO Adriana,D'AGATI Elisa,CURATOLO Paolo
• Brain & development 33(6), 456-461, 2011-06-06
• NAID 10029561872

Related Links

• 脆弱X症候群 - Wikipedia

移動： 案内、 検索. 脆弱X症候群（ぜいじゃくエックスしょうこうぐん、フラジャイル エックスしょうこうぐん）は、2006年現在唯一遺伝性であることが確認されている精神 発達障害である。英語ではfragile X syndrome。「フラジャイル」はfragile（脆い、の意） のカタカナ ...

Related Pictures

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★リンクテーブル★

リンク元	「トリプレットリピート病」「脆弱X症候群」「X連鎖劣性遺伝病」「過成長症候群」「ぜい弱X症候群」
関連記事	「fragile」「X syndrome」「X」「syndrome」

「トリプレットリピート病」

　　[★]

英

triplet repeat disease

同

トリヌクレオチドリピート病 trinucleotide repeat disorder、リピート伸長病 repeat expansion disease、3塩基繰り返し病、トリプレット反復病 triplet repeat disease

関

• 3塩基のリピートが翻訳領域に反復して現れることにより、発病機構は不明であるが発病する疾病を総称して言う。
• 下位の疾病概念にポリグルタミン病、CAGリピート病がある。
• ポリグルタミン病の中にハンチントン舞踏病が含まれる。

特徴

• 発症前診断
• 促通現象
• 体細胞モザイク
• gain of function
• 多くが優性遺伝で成人発症
• 神経系の変性疾患

トリプレットリピート病

• ハンチントン病 Huntington disease AD
• 脆弱X症候群 fragile X syndrome XR
• 筋強直性ジストロフィー myotonic dystrophy AD
• 優性遺伝性脊髄小脳変性症：ほとんど全て

• 脊髄小脳変性症3型 spinocerebellar ataxia type 3
• 脊髄小脳変性症6型 spinocerebellar ataxia type 6
• 歯状核赤核淡蒼球ルイ体萎縮症 dentatorubropallidoluysian atrophy DRPLA

• 球脊髄性筋萎縮症 bulbospinal muscular atrophy BSMA = Kennedy病 ケネディ・オルター・スン症候群 Kennedy-Alter-Sung syndrome XR

「脆弱X症候群」

　　[★]

英

fragile X syndrome FRAXA

同

脆弱X染色体症候群、

関

MSH 2遺伝子 MSH

• トリプレットリピート病の1つ

概念

• 定義：FMR-1遺伝子がコードしているFMR-1タンパクの低下、欠損によるX連鎖遺伝性精神遅滞(PED.219)

病因

• FMR-1遺伝子の5'末端UTR上のCGGリピートが増加することによる

Xq27.3にマップされる

CGGリピート

正常：29

前突然変異：52-200

完全突然変異：230-4000

• プロモーター領域のCpGがメチル化を受けるために、FMR-1の発現が抑制されることによる

疫学

• 原因の判明している精神遅滞の中ではダウン症候群に次いで多い
• 欧米では一般男性1/4,000人，女性1/10,000人。(♂1,500人対1人、♀2,500人対1人(PED.219)
• 脆弱X突然変異を有する人の中で男性の20%が無症状、女性の30%に軽度の知的障害が認められる。

遺伝形式

• 伴性劣性遺伝

• X連鎖劣性遺伝

• 表現促進現象

症状

• 精神遅滞，細長い顔，突出した下顎，大耳介，小児期の自閉・多動，思春期以降の巨大睾丸（80％）

• 精神遅滞の２大原因は脆弱X症候群とダウン症候群

「X連鎖劣性遺伝病」

　　[★]

英

X-linked recessive disorder

関

伴性劣性遺伝病、X連鎖遺伝病

X-linked recessive disorders (first aid step p.109)

• 脆弱X症候群 fragile X syndrome
• デュシェンヌ型筋ジストロフィー Duchenne's muscular dystrophy
• 血友病A hemophilia A
• 血友病B hemophilia B
• ファブリー病 Fabry's disease
• グルコース-6-リン酸脱水素酵素欠損症 glucose-6-phosphate dehydrogenase deficiency
• ハンター症候群 Hunter's syndrome
• 眼白子症 ocular albinism
• レッシュ・ナイハン症候群 Lesch-Nyhan syndrome
• ブルトン型無γグロブリン血症 Bruton's agammaglobulinemia
• ウィスコット・アルドリッチ症候群 Wiskott-Aldrich syndrome

Female carriers of X-linked recessive disorders are rarely affected because of random inactivation of X chromosomes in each cell.

「過成長症候群」

　　[★]

英

overgrowth syndrome

• 全身または部分的に身体が異常に成長する症候群。先天性であり、多くは出生児に認められる。ゲノム刷り込みとの関連が指摘されている。また、これらの症候群の多くでは発癌リスクが増大する。

• 神経線維腫症 neurofibromatosis
• ソトス症候群 Sotos syndrome
• ベックウィズ・ヴィーデマン症候群 Beckwith-Wiedemann syndrome
• シンプソン・ゴラビ・ベーメル症候群 Simpson-Golabi-Behmel syndrome
• ウィーバー症候群 Weaver's syndrome Weaver syndrome
• プロテウス症候群 Proteus syndrome
• スタージ・ウェーバー症候群 Sturge-Weber syndrome
• 脆弱X染色体症候群 fragile X syndrome
• 片側肥大症候群 hemihyperplasia syndrome HHS

「ぜい弱X症候群」

　　[★]

英

[[]]

同

fragile X syndrome

関

[[]]

同

fragile X syndrome

「fragile」

　　[★]

• adj.

• 脆弱な、脆弱性の、脆い、壊れやすい

関

brittle、fragility、frailty、friability、friable、vulnerability、vulnerable

　 　

「X syndrome」

　　[★]

X症候群、X染色体症候群

• fragile X syndrome

「X」

　　[★] キサントシン, xanthosine 　 　

「syndrome」

　　[★]

• n.

• 症候群