統合失調症の治療 母のチカラ

1年前にに息子が破瓜型の統合失調症と診断されましたが、息子には病識がまったくありません。薬の副作用で過食になり1年間で体重が20キロも増えてしまいました。母として出来る事を模索していきます。

統合失調症が遺伝子変異に起因している場合、遺伝子治療に期待したい。
以下は理研のHPより
http://www.riken.jp/pr/press/2017/20170301_1/digest/

2017年3月1日

理化学研究所
筑波大学
東京大学

統合失調症研究に新たな視点

-マウス成熟個体において認知機能を回復させることに成功-

遺伝子治療により新しい統合失調症モデルマウスの作業記憶が改善の図

図 遺伝子治療により新しい統合失調症モデルマウスの作業記憶が改善

統合失調症は、およそ100人に1人の割合で発症する身近な精神疾患です。主な症状には、幻聴や妄想などの「陽性症状」、意欲の低下・感情の平板化などの「陰性症状」、記憶力・注意力・情報処理能力などの機能が低下する「認知機能障害」があります。従来の治療薬は、陽性症状の治療には有効ですが、陰性症状と認知機能障害に対しては十分な治療効果が得られず、患者の社会復帰を妨げる要因となっています。そのため、新たな治療法の探索に向けて、統合失調症のモデル動物の開発が求められていました。また、発症には「NMDA型グルタミン酸受容体(NMDA受容体)」の機能低下が関わっていることが、古くから提唱されてきましたが、そのメカニズムは不明でした。

今回、共同研究グループは、脳の深部にある「視床髄板内核(ILN)」におけるNMDA受容体の機能が生まれつき低下している遺伝子改変マウス(ILN変異マウス)を作製しました。作製したILN変異マウスにモリス水迷路試験、Y字迷路試験、5選択反応時間課題、プレパルス抑制試験を行ったところ、どれにも異常がみられ、記憶力・注意力・情報処理能力などの認知機能に障害を示すことが分かりました。また、歩行活動量を調べたところ、活動量過多という陽性症状の一部に類似した症状を示すことが分かりました。さらに、統合失調症患者にみられるノンレム睡眠(深い眠り)が減少するという睡眠覚醒の障害と神経オシレーション活動の異常を示すことも分かりました。神経オシレーション活動とは、脳波の測定でみられる多数の神経細胞の活動の総和としての振動のことです。これらの結果から、NMDA受容体の機能低下を引き金としたILN領域の機能異常が、統合失調症の病態に深く関わることが明らかになり、ILN変異マウスを新たな「統合失調症モデルマウス」として確立しました。

さらにモデルマウスの成熟個体への遺伝子治療によりNMDA受容体の機能を正常に戻すことで、認知機能を“可逆的に”回復させることに成功しました(図参照)。これまで、精神疾患の多くは脳の発達期に生じた不可逆的な要因が関与すると考えられていましたが、NMDA受容体の機能を後天的に回復させることが統合失調症の治療改善につながる可能性を示しました。

今後、モデルマウスを用いてILNの役割を明らかにすることにより、統合失調症の発症機序をより深く理解し、LINのNMDA受容体を標的とした薬や遺伝子治療その他の手法による治療法の探索に役立つ知見が得られると期待できます。

理化学研究所 
脳科学総合研究センター 行動遺伝学技術開発チーム 
チームリーダー 糸原 重美 (いとはら しげよし) 

が原因である場合もあると。。。

以下はWikiより

 

1q21.1 duplication syndrome

From Wikipedia, the free encyclopedia

1q21.1 duplication syndrome or 1q21.1 (recurrent) microduplication is a rare aberration of chromosome 1. the international rare chromosome disorder group, has 57 genetically confirmed registered cases of this duplication worldwide (October 2012).

In a common situation a human cell has one pair of identical chromosomes on chromosome 1. With the 1q21.1 duplication syndrome one chromosome of the pair is over complete, because a part of the sequence of the chromosome is duplicated twice or more. In 1q21.1, the '1' stands for chromosome 1, the 'q' stands for the long arm of the chromosome and '21.1' stands for the part of the long arm in which the duplication is situated.

Next to the duplication syndrome, there is also a 1q21.1 deletion syndrome. While there are two or three copies of a similar part of the DNA on a particular spot with the duplication syndrome, there is a part of the DNA missing with the deletion syndrome on the same spot. Literature refers to both the deletion and the duplication as the 1q21.1 copy-number variations (CNV).

The CNV leads to a very variable phenotype and the manifestations in individuals are quite variable. Some people who have the syndrome can function in a normal way, while others have symptoms of mental retardation and various physical anomalies.


Meiosis is the process of dividing cells in humans. In meiosis, the chromosome pairs splits and a representative of each pair goes to one daughter cell. In this way the number of chromosomes will be halved in each cell, while all the parts on the chromosome (genes) remain, after being randomized. Which information of the parent cell ends up in the daughter cell is purely decided by chance. Besides this random process, there is a second random process. In this second random process the DNA will be scrambled in a way that pieces are omitted (deletion), added (duplication), moved from one place to another (translocation) and inverted (inversion). This is a common process, which leads to about 0.4% variation in the DNA. It explains why even identical twins are not genetically 100% identical.

The second random process can give rise to genetic mistakes. In the deletion and duplication process, the chromosomes that come together in a new cell may be shorter or longer. The result of this spontaneous change in the structure of DNA is a copy number variation. Due to the copy number variation chromosomes of different sizes can be combined in a new cell. If this occurs around conception, there is the first cell of a human with a genetic variation. This can be either positive or negative. In positive cases this new human will be capable of a special skill that is assessed positively, for example, sports or science. In negative cases, you have to deal with a syndrome or a severe disability, as in this case the 1q21.1 duplication syndrome.

Based on the meiotic process, the syndrome may occur in two ways.

  • 1. a spontaneous deviation (a 'novo' the situation): two chromosomes come together of which one has a copy number variation as a result of the meiosis process.
  • 2. a parent is unknowingly carrier of a chromosome with a copy number variation and passes itthrough at conception to the child, with different consequences for the child.

Due to this genetic misprint the embryo may experience problems in the development during the first months of pregnancy. Approximately 20 to 40 days after fertilization, something goes wrong in the construction of the body parts and brain, which leads to a chain reaction.[1]

The structure of 1q21.1

Structure of 1q21.1[edit]

The structure of 1q21.1 is complex. The area has a size of approximately 6 Megabase (Mb) (from 141.5 Mb to 147.9 Mb). Within 1q21.1 there are two areas where a duplication or deletion can be found: the TAR-area for the TAR syndrome and the distal area for other anomalies. The 1q21.1 duplication syndrome will commonly be found in the distal area, but an overlap with the TAR-area is possible. 1q21.1 has multiple repetitions of the same structure (areas with the same color in the picture have equal structures) Only 25% of the structure is unique. There are several gaps in the sequence. There is no further information available about the DNA-sequence in those areas up till now. The gaps represent approximately 700 Kilobase. New genes are expected in the gaps. Because the gaps are still a topic of research, it is hard to find the exact start and end markers of a deletion. The area of 1q21.1 is one of the most difficult parts of the human genome to map.

Symptoms

Recognised symptoms up till now are:

  • Autism or autistic behaviors
  • ADHD
  • Learning disability
  • Large head
  • Dysmorphic facial appearance - mild
  • Prominent forehead
  • Wide-set eyes (hypertelorism)
  • Schizophrenia
  • Loose joints
  • GERD
  • Sleep disturbances
  • Sleep Apnea
  • Underdeveloped parts of brain - corpus callosum and cerebellar vermis
  • Neuroblastoma
  • Speech & developmental delays
  • Chiari malformation of the brain
  • Congenital heart defects
  • Hypotonia


It is not clear whether the list of symptoms is complete. Very little information is known about the syndrome. The symptomology may be different among individuals, even in the same family.

Related genes

Genes related to 1q21.1 deletion in the TAR area are HFE2TXNIPPOLR3GLLIX1LRBM8APEX11BITGA10ANKRD35PIAS3NUDT17POLR3CRNF115CD160PDZK1, and GPR89A
Genes related to 1q21.1 deletion in the distal area are HYDIN2PRKAB2FMO5CHD1LBCL9ACP6GJA5GJA8, and GPR89B.

Diagnostics[edit]

A 'de novo'-situation appears in about 75% of the cases.In 25% of the cases, one of the parents is carrier of the syndrome, without any effect on the parent. Sometimes adults have mild problems with the syndrome. To find out whether either of the parents carries the syndrome, both parents have to be tested. In several cases, the syndrome was identified with the child, because of an autism disorder or another problem, and later it appeared that the parent was affected as well. The parent never knew about it up till the moment that the DNA-test proved the parent to be a carrier.

In families where both parents have been tested negative on the syndrome, chances on a second child with the syndrome are extremely low. If the syndrome was found in the family, chances on a second child with the syndrome are 50%, because the syndrome is autosomal dominant. The effect of the syndrome on the child cannot be predicted.

The syndrome can be detected with fluorescence in situ hybridization and Affymetrix GeneChip Operating Software.

For parents with a child with the syndrome, it is advisable to consult a physician before a next pregnancy and to do prenatal screening.

Research

Several researchers around the world are studying on the subject of 1q21.1 duplication syndrome. The syndrome was identified for the first time in people with heart abnormalities. The syndrome was later observed in patients who had autism or schizophrenia.

It appears that there is a relation between autism and schizophrenia. Literature shows that nine locations have been found on the DNA where the syndromes related to autism or schizophrenia can be found, the so-called "hotspots": 1q21.1, 3q29, 15q13.3, 16p11.2, 16p13.1, 16q21, 17p12, 21q11.2 and 21q13.3. With a number of hotspots both autism and schizophrenia were observed at that location. In other cases, either autism or schizophrenia has been seen, while they are searching for the opposite.

Statistical research showed that schizophrenia is significantly more common in combination with 1q21.1 deletion syndrome. On the other side, autism is significantly more common with 1q21.1 duplication syndrome. Similar observations were done for chromosome 16 on 16p11.2 (deletion: autism/duplication: schizophrenia), chromosome 22 on 22q11.21 (deletion (Velo-cardio-facial syndrome): schizophrenia/duplication: autism) and 22q13.3 (deletion (Phelan-McDermid syndrome): schizophrenia/duplication: autism). Further research confirmed that the odds on a relation between schizophrenia and deletions at 1q21.1, 3q29, 15q13.3, 22q11.21 en Neurexin 1 (NRXN1) and duplications at 16p11.2 are at 7.5% or higher.[2][3]

Expected relation within 1q21.1

Common variations in the BCL9 gene, which is in the distal area, confer risk of schizophrenia and may also be associated with bipolar disorder and major depressive disorder.[4]

Research is done on 10-12 genes on 1q21.1 that produce DUF1220-locations. DUF1220 is an unknown protein, which is active in the neurons of the brain near the neocortex. Based on research on apes and other mammals, it is assumed that DUF1220 is related to cognitive development (man: 212 locations; chimpanzee: 37 locations; monkey: 30 locations; mouse: 1 location). It appears that the DUF1220-locations on 1q21.1 are in areas that are related to the size and the development of the brain. The aspect of the size and development of the brain is related to autism (macrocephaly) and schizophrenia (microcephaly). It is assumed that a deletion or a duplication of a gene that produces DUF1220-areas might cause growth and development disorders in the brain [5]

Another relation between macrocephaly with duplications and microcephaly with deletions has been seen in research on the HYDIN Paralog or HYDIN2. This part of 1q21.1 is involved in the development of the brain. It is assumed to be a dosage-sensitive gene. When this gene is not available in the 1q21.1 area it leads to microcephaly. HYDIN2 is a recent duplication (found only in humans) of the HYDIN gene found on 16q22.2.[6]

GJA5 has been identified as the gene that is responsible for the phenotypes observed with congenital heart diseases on the 1q21.1 location. In case of a duplication of GJA5 tetralogy of Fallot is more common. In case of a deletion other congenital heart diseases than tetralogy of Fallot are more common.[7]

References

  1. Jump up^ A. Ploeger; 'Towards an integration of evolutionary psychology and developmental science: New insights from evolutionary developmental biology'
  2. Jump up^ Levinson DF, Duan J, Oh S, et al. (March 2011).  Am J Psychiatry168 (3): 302–16. 
  3. Jump up^ Ikeda M, Aleksic B, Kirov G, et al. (February 2010).Biol. Psychiatry67 (3): 283–6.
  4. Jump up^ Li J, Zhou G, Ji W, et al. (March 2011).  Arch. Gen. Psychiatry68 (3): 232–40. 
  5. Jump up^ Dumas L, Sikela JM (2009).  Cold Spring Harb. Symp. Quant. Biol74: 375–82. 
  6. Jump up^ Doggett NA, Xie G, Meincke LJ, et al. (Dec 2006).  Genomics88 (6): 762–71.
  7. Jump up^ Soemedi, R.; et al. (2011).  Hum. Mol. Genet21: 1513–1520. 

Further reading

  • Mefford HC, Sharp AJ, Baker C, et al. (October 2008).  N. Engl. J. Med359 (16): 1685–99.
  • Brunetti-Pierri N, Berg JS, Scaglia F, et al. (December 2008). . Nat. Genet40 (12): 1466–71. 
  • Crespi B, Stead P, Elliot M (January 2010).  Proc. Natl. Acad. Sci. U.S.A107 (Suppl 1): 1736–41. 

 1994 Aug;151(8):1234-6.

Amelioration of negative symptoms in schizophrenia by glycine.

Abstract

Phencyclidine induces a psychotomimetic state by blocking neurotransmission at N-methyl-D-aspartic acid (NMDA) receptors. In a double-blind, placebo-controlled fashion, 14 medicated patients with chronic schizophrenia were treated with glycine, a potentiator of NMDA-receptor-mediated neurotransmission. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia.

 1996 Nov;169(5):610-7.

Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.

Abstract

BACKGROUND:

It has been proposed that schizophrenia is associated with underactivity of brain glutamatergic neurotransmission, especially at the level of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Glycine potentiates NMDA receptor-mediated neurotransmission, indicating that it may serve as an effective therapeutic agent in the treatment of schizophrenia.

METHOD:

Eleven treatment-resistant patients with chronic schizophrenia completed a double-blind, placebo-controlled, six-week, randomly assigned, crossover treatment trial of 0.8 g/kg body weight/day of glycine, added to their prior antipsychotic treatment.

RESULTS:

Glycine was well tolerated, resulted in significantly increased serum glycine levels and induced a mean 36 (7%) reduction in negative symptoms (P < 0.0001). Significant improvements were also induced in depressive and cognitive symptoms. The greatest reduction in negative symptoms was registered in the patients who had the lowest baseline serum glycine levels.

CONCLUSIONS:

These results extend previous findings and suggest an additional approach to the pharmacotherapy of negative symptoms and cognitive deficits in schizophrenia.

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