MUTASI DINAMIKMUTASI DINAMIKMUTASI DINAMIKMUTASI DINAMIK

Kiagus Muhammad ArsyadKiagus Muhammad ArsyadBagian Biologi Kedokteran dan AndrologiBagian Biologi Kedokteran dan Andrologi

Fakultas Kedokteran UNSRIFakultas Kedokteran UNSRI

Subpokok bahasanSubpokok bahasan

1. Pendahuluan1. Pendahuluan

2. Fragile X Syndrome2. Fragile X Syndrome

3. Huntington’s Diseases3. Huntington’s Diseases

4. Myotonic Dystrophy4. Myotonic Dystrophy

5. Penyakit akibat pengulangan 5. Penyakit akibat pengulangan tak lazimtak lazim

6. Penutup6. Penutup

1.1. MutasiMutasi

2.2. Macam MutasiMacam Mutasi

3.3. Mutasi dinamikMutasi dinamik

1. PENDAHULUAN1. PENDAHULUAN

Menurut BMenurut Biology, MUTASI, MUTASI adalah setiap adalah setiap perubahan fisik pada materi perubahan fisik pada materi genetik dari suatu organisme. Hampir e. Hampir sebagian besar kasus terjadi pada sebagian besar kasus terjadi pada DNA atau atau RNA didalam inti sel. didalam inti sel.

Pada organisme multicellular ada 2 Pada organisme multicellular ada 2 macam kelas yaitu :macam kelas yaitu :

1.1. Germ line mutationGerm line mutation, dan , dan

2.2. Somatic MutationSomatic Mutation. .

Faktor penyebab:Faktor penyebab:1.1. Internal,Internal,

penyebab adalah errors pada penyebab adalah errors pada reproduksi materi genetik. reproduksi materi genetik.

2.2. ExternalExternal, yang , yang sering radiasi sering radiasi ultraviolet, , chemical chemical mutagens, atau , atau parasitic organisms (parasitic organisms (virus atau atau bacteria). ).

66 KMA MUTASI KHROMOSOM KMA MUTASI KHROMOSOM GENEGENE

77 KMA MUTASI KHROMOSOM KMA MUTASI KHROMOSOM GENEGENE

88 KMA MUTASI KHROMOSOM KMA MUTASI KHROMOSOM GENEGENE

DEFINISI DEFINISI ::

Perubahan Susunan Nukleotida DNAPerubahan Susunan Nukleotida DNA

JENIS :JENIS : Mutasi TitikMutasi Titik

DelesiDelesi

InsersiInsersi

AKIBAT AKIBAT ::

t.a.at.a.a

Fungsi Fungsi

FungsiFungsi

Tak berfungsi (inactivated)Tak berfungsi (inactivated)

LOKASI LOKASI ::

Sel benih Sel benih Peny. Keturunan Peny. Keturunan

Sel Somatik Sel Somatik Kanker Kanker

DNA Mitokondria DNA Mitokondria

(menimbulkan penyakit yang diwariskan (menimbulkan penyakit yang diwariskan garis keturunan ibu)garis keturunan ibu)

1.2. MACAM MUTASI1.2. MACAM MUTASI 1 Klas mutasi

• 1.1 Deletion mutations • 1.2 Insertion mutations • 1.3 Substitution mutations

2 Subklas Mutasi• 2.1 Morphological • 2.2 Biochemical • 2.3 Lethal • 2.4 Loss-of-function • 2.5 Gain-of-function • 2.6 Dynamic mutation • 2.7 Frame shift mutation

1. 3. MUTASI DINAMIK1. 3. MUTASI DINAMIK

Mutasi dinamik Mutasi dinamik adalah suatu elemen adalah suatu elemen heritable yang tidak stabil dimana heritable yang tidak stabil dimana probalitas dari mutasi adalah fungsi dari probalitas dari mutasi adalah fungsi dari sejumlah kopi dari mutasi.sejumlah kopi dari mutasi.

Karena itu produk replikasi dari mutasi Karena itu produk replikasi dari mutasi dinamik akanberbeda dari pewarisnya dinamik akanberbeda dari pewarisnya (predecessor). (predecessor).

Mutasi ini dicirikan dengan pengulangan Mutasi ini dicirikan dengan pengulangan sekuens pendek berkali kali, sekuens pendek berkali kali, menimbulkan berbagai penyakit termasuk menimbulkan berbagai penyakit termasuk Trinucleotide repeat disorders..

1. PENDAHULUAN1. PENDAHULUAN Robert I. Richards and Grant R. Sutherland Robert I. Richards and Grant R. Sutherland

menyebut phenomena ini, dalam kerangka menyebut phenomena ini, dalam kerangka dynamical genetics, sebagai dinamika , sebagai dinamika mutasi mutasi

Ekspansi Triplet disebabkan oleh slippage Ekspansi Triplet disebabkan oleh slippage semasa replikasi DNA. semasa replikasi DNA.

Karena pengulangan sekuens DNA pada Karena pengulangan sekuens DNA pada daerah struktur 'loop out' mungkin daerah struktur 'loop out' mungkin terbentuk semasa replikasi DNA terbentuk semasa replikasi DNA memungkinkan disintesanya penambahan memungkinkan disintesanya penambahan pasangan basa complementary base pasangan basa complementary base diantara pita ortu dan putrinya.diantara pita ortu dan putrinya.

1. PENDAHULUAN1. PENDAHULUAN Gambaran umum:Gambaran umum:

1. Kebanyakan dari penyakit penyakit ini memberikan gejala/simptom neurologik.

2. Anticipation/The Sherman paradox merujuk kearah progresitas awal dan expressi yang lebih berat dari penyakit daripada generasi sebelumnya.

1. PENDAHULUAN1. PENDAHULUAN Gambaran umum:Gambaran umum:

3. Pengulangan biasanya bersifat polymorphic pada jumlah salinan/kopi, dengan instabilitas proses mitosis dan meiosis.

4. Jumlah Copy berhubungan dengan severitas dan/atau usia onset

5. Imprinting effects 6. Reverse mutation – mutasi dapat berbalik

menjadi normal atau menjadi premutation carrier.

1. PENDAHULUAN1. PENDAHULUAN Contoh Mutasi dinamik :Contoh Mutasi dinamik :1. Fragile X syndromes 2. Huntington's Chorea 3. Myotonic dystrophy 4. Spinobulbar muscular atrophy 5. Spinocerebellar ataxia type 3 6. Friedreich ataxia 7. Ocularpharyngeal muscular dystrophy 8. Progressive myoclonus epilepsy 9. Creutzfeldt-Jakob disease

2. 2. FRAGILE X SYNDROMEFRAGILE X SYNDROME

Fragile X syndromeFragile X syndrome, atau , atau Martin-Bell Martin-Bell syndromesyndrome, adalah suatu sindroma , adalah suatu sindroma genetik dengan manifestasi beragam pada ciri2 dengan manifestasi beragam pada ciri2 fisik, intelektual, emosional dan gambaran fisik, intelektual, emosional dan gambaran perilaku dari ringan sampai berat.perilaku dari ringan sampai berat.

Fragile X syndrome adalah bentuk Fragile X syndrome adalah bentuk retardasi mental yang disebabkan oleh retardasi mental yang disebabkan oleh mutasi gen pada khromosom X. disebut mutasi gen pada khromosom X. disebut demikian karena lengan panjang demikian karena lengan panjang khromosom X tampak seperti pecah/retakkhromosom X tampak seperti pecah/retak

2.1. Sindroma2.1. Sindroma Syndroma berhubungan dengan ekspansi dari Syndroma berhubungan dengan ekspansi dari

sekuens genesekuens gene trinucleotide gene tunggal (CGG) pada (CGG) pada khromosom X, dan menyebabkan tidak terbentuknya khromosom X, dan menyebabkan tidak terbentuknya FMR1 protein yang dibutuhkan untuk perkembangan protein yang dibutuhkan untuk perkembangan normal syaraf. normal syaraf.

Terdapat 4 keadaan pada khromosom yang terkena Terdapat 4 keadaan pada khromosom yang terkena pada Fragile X syndrome yg berhubungan dengan pada Fragile X syndrome yg berhubungan dengan panjang pengulangan sekuens CGG ;panjang pengulangan sekuens CGG ;

Normal (29-31 CGG repeats) (not affected by the Normal (29-31 CGG repeats) (not affected by the syndrome), syndrome),

Premutation (55-200 CGG repeats)(not affected by Premutation (55-200 CGG repeats)(not affected by the syndrome), the syndrome),

Full Mutation (more than 200 CGG repeats)(affected), Full Mutation (more than 200 CGG repeats)(affected), and Intermediate or Gray Zone Alleles (40 - 60 and Intermediate or Gray Zone Alleles (40 - 60

repeats)repeats)

2.1. Sindroma2.1. Sindroma Martin and Bell in 1943, described a pedigree of X-linked Martin and Bell in 1943, described a pedigree of X-linked

mental disability, without considering the macroorchidism mental disability, without considering the macroorchidism (larger testicles).(larger testicles).

In 1969 Chris and Weesam first sighted an unusual "marker In 1969 Chris and Weesam first sighted an unusual "marker X chromosome" in association with mental disability.X chromosome" in association with mental disability.

In 1970 Frederick Hecht coined the term "fragile site".In 1970 Frederick Hecht coined the term "fragile site". Renpenning's syndrome is not synonymous with the Renpenning's syndrome is not synonymous with the

syndrome. In Renpenning's syndrome, there is no fragile syndrome. In Renpenning's syndrome, there is no fragile site on the X chromosome. Renpenning's cases have short site on the X chromosome. Renpenning's cases have short stature, moderate stature, moderate microcephaly, and neurological (brain) , and neurological (brain) disorders.disorders.

Escalante's syndromeEscalante's syndrome is synonymous with the fragile X is synonymous with the fragile X syndrome. This term has been used in Brazil and other syndrome. This term has been used in Brazil and other South American countrSouth American countr

2.2. Symptom 2.2. Symptom Aside from intellectual disability, prominent characteristics of the Aside from intellectual disability, prominent characteristics of the

syndrome include an elongated face, large or protruding ears, syndrome include an elongated face, large or protruding ears, flat feet, larger testicles in men (flat feet, larger testicles in men (macroorchidism), and ), and low muscle tone. Speech may include . Speech may include cluttered speech or or nervous speechnervous speech[7]. Behavioral characteristics may include . Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness, limited eye contact, memory development, particularly shyness, limited eye contact, memory problems, and difficulty with face encoding.problems, and difficulty with face encoding.

Some individuals with the fragile X syndrome also meet the Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism. Most females who have the diagnostic criteria for autism. Most females who have the syndrome experience symptoms to a lesser degree because of syndrome experience symptoms to a lesser degree because of their second X-chromosome, however they can develop just as their second X-chromosome, however they can develop just as severe symptoms. While full mutation males tend to present with severe symptoms. While full mutation males tend to present with severe intellectual disability, the symptoms of full mutation severe intellectual disability, the symptoms of full mutation females run the gamut of minimally affected to severe females run the gamut of minimally affected to severe intellectual disability, which may explain why females are intellectual disability, which may explain why females are underdiagnosed relative to males.underdiagnosed relative to males.

2.2. Symptom 2.2. Symptom

In short, similarities between X-linked In short, similarities between X-linked recessive inheritance and fragile X are:recessive inheritance and fragile X are:

Males are predominantly affected; Males are predominantly affected; Females (mothers) are obligatory carriers Females (mothers) are obligatory carriers

((i.e.i.e., are conclusively proven to be carriers) , are conclusively proven to be carriers) if a male child is affected, but not if a male child is affected, but not necessarily if female children are affected, necessarily if female children are affected, as a female child with one fragile and one as a female child with one fragile and one normal X chromosome may have inherited normal X chromosome may have inherited the fragile chromosome from the father. the fragile chromosome from the father.

Differences are:Differences are: Females may also have clinical symptoms. Females may also have clinical symptoms.

2.3. Penyebab2.3. Penyebab The fragile X syndrome is a The fragile X syndrome is a genetic disorder

caused by caused by mutation of the of the FMR1 gene on the on the X chromosome. Mutation at that site is found in 1 . Mutation at that site is found in 1 out of about every 2000 out of about every 2000 males and 1 out of about and 1 out of about every 259 every 259 females. (Incidence of the disease itself . (Incidence of the disease itself is about 1 in every 4000 females.)is about 1 in every 4000 females.)

Normally, the Normally, the FMR1 gene contains between 6-55 gene contains between 6-55 (29 in Robbins-Kumar pathology textbooks)repeats (29 in Robbins-Kumar pathology textbooks)repeats of the CGG of the CGG codon ( (trinucleotide repeats). In ). In people with the fragile X syndrome, the FMR1 people with the fragile X syndrome, the FMR1 allele has over 230-4000 repeats of this codon. has over 230-4000 repeats of this codon.[4]

Expansion of the CGG repeating codon to such a Expansion of the CGG repeating codon to such a degree results in a degree results in a methylation of that portion of of that portion of the the DNA, effectively silencing the expression of , effectively silencing the expression of the FMR1 the FMR1 protein..

2.3. Penyebab2.3. Penyebab This methylation of the FMR1 locus in This methylation of the FMR1 locus in

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

Mutation of the FMR1 gene leads to the Mutation of the FMR1 gene leads to the transcriptional silencing of the fragile X-mental transcriptional silencing of the fragile X-mental retardation protein, retardation protein, FMRP. In normal individuals, . In normal individuals, FMRP is believed to regulate a substantial FMRP is believed to regulate a substantial population of population of mRNA: FMRP plays important roles : FMRP plays important roles in learning and memory, and also appears to be in learning and memory, and also appears to be involved in development of involved in development of axons, formation of , formation of synapses, and the wiring and development of , and the wiring and development of neural circuits.neural circuits.[5]

2.4.Transmisi fragile X 2.4.Transmisi fragile X Technically, fragile X syndrome is an X-linked dominant Technically, fragile X syndrome is an X-linked dominant

condition with reduced penetrance.condition with reduced penetrance.[6] Because males normally have only one copy of the X Because males normally have only one copy of the X

chromosome, those males with significant trinucleotide chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are expansion at the FMR1 locus are symptomatic. They are intellectually disabled and may show various physical intellectually disabled and may show various physical features of the fragile X syndrome.features of the fragile X syndrome.

Females have two X chromosomes and thus have double Females have two X chromosomes and thus have double the chance of having a working FMR1 the chance of having a working FMR1 allele. Females . Females carrying one X chromosome with an expanded FMR1 gene carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be can have some signs and symptoms of the disorder or be normal. Although the extra X chromosome can serve as a normal. Although the extra X chromosome can serve as a backup, only one X chromosome is active in each cell due backup, only one X chromosome is active in each cell due to to X-inactivation..

2.4.Transmisi fragile X 2.4.Transmisi fragile X Males with the fragile X cannot transmit it to any of their Males with the fragile X cannot transmit it to any of their

sons (since males contribute a Y chromosome, not an X, to sons (since males contribute a Y chromosome, not an X, to their male offspring), but will transmit it to all of their their male offspring), but will transmit it to all of their daughters, as males contribute their X to all of their daughters, as males contribute their X to all of their daughters.daughters.

Females carrying one copy of the fragile X can transmit it to Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the anomalous pattern of inheritance is referred to as the Sherman paradox..

2.5. Physical Phenotype 2.5. Physical Phenotype 1.1. Prominent ears Prominent ears 2.2. Long face (vertical Long face (vertical

maxillary excess) maxillary excess) 3.3. High-arched palate (related High-arched palate (related

to the above) to the above) 4.4. Hyperextensible finger Hyperextensible finger

joints joints 5.5. Double-jointed thumbs Double-jointed thumbs 6.6. Flat feet Flat feet 7.7. Soft skin Soft skin 8.8. Larger testicles in men Larger testicles in men

(macroorchidism) (macroorchidism) 9.9. Low muscle tone Low muscle tone

2.6. Diagnosis 2.6. Diagnosis Fragile X syndrome was originally diagnosed by Fragile X syndrome was originally diagnosed by

culturing cells in a folate deficient medium and culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome then assessing the cultures for X-chromosome breakage by breakage by cytogenetic analysis of the long arm analysis of the long arm of the X chromosome. This technique proved of the X chromosome. This technique proved unreliable for both diagnosis and carrier testing.unreliable for both diagnosis and carrier testing.

The fragile X abnormality is now directly The fragile X abnormality is now directly determined by analysis of the number of CGG determined by analysis of the number of CGG repeats and their methylation status using repeats and their methylation status using restriction endonuclease digestion and digestion and Southern blot analysis. analysis.

2.6. Diagnosis 2.6. Diagnosis Not everyone with fragile X syndrome has Not everyone with fragile X syndrome has

the same signs and symptoms. Even the same signs and symptoms. Even affected people in the same family don’t affected people in the same family don’t show the same symptoms. The signs and show the same symptoms. The signs and symptoms fall into six categories:symptoms fall into six categories:

Intelligence and learning Intelligence and learning Physical Physical Social and emotional Social and emotional Speech and language Speech and language Sensory Sensory Disorders commonly associated or sharing Disorders commonly associated or sharing

features with Fragile X features with Fragile X

Cara Mendiagnosa Cara Mendiagnosa Fragile X syndrome is diagnosed based upon developmental delays, Fragile X syndrome is diagnosed based upon developmental delays,

behavioral characteristics, and physical traits. Your doctor will ask behavioral characteristics, and physical traits. Your doctor will ask about any family history of mental retardation. To make a definite about any family history of mental retardation. To make a definite diagnosis, a drop of blood taken from a finger can be analyzed for diagnosis, a drop of blood taken from a finger can be analyzed for the fragile X gene. If a woman is pregnant and she is a carrier, or the fragile X gene. If a woman is pregnant and she is a carrier, or there is a history of fragile X syndrome in the family, there are there is a history of fragile X syndrome in the family, there are procedures that can be performed during the pregnancy to screen procedures that can be performed during the pregnancy to screen for fragile X syndrome. With amniocentesis, a long thin needle is for fragile X syndrome. With amniocentesis, a long thin needle is inserted through the woman's abdomen and a sample of amniotic inserted through the woman's abdomen and a sample of amniotic fluid is removed. This procedure can be performed in the 15th to fluid is removed. This procedure can be performed in the 15th to 18th weeks of pregnancy. Chorionic villus sampling is a procedure 18th weeks of pregnancy. Chorionic villus sampling is a procedure performed in the 10th to 12th week of a pregnancy. A needle is performed in the 10th to 12th week of a pregnancy. A needle is inserted into the placenta to remove a small amount fetal tissue for inserted into the placenta to remove a small amount fetal tissue for study. Another technique is called percutaneous umbilical blood study. Another technique is called percutaneous umbilical blood sampling, performed at the 18th to 22nd weeks of pregnancy. This sampling, performed at the 18th to 22nd weeks of pregnancy. This procedure is also known as cordocentesis, and involves inserting a procedure is also known as cordocentesis, and involves inserting a needle through the pregnant woman's abdomen and into a blood needle through the pregnant woman's abdomen and into a blood vessel in the umbilical cord. A blood sample is drawn through the vessel in the umbilical cord. A blood sample is drawn through the cord. However, keep in mind that the presence of the fragile X cord. However, keep in mind that the presence of the fragile X chromosome does not necessarily mean the child will have any chromosome does not necessarily mean the child will have any symptoms of the disorder.symptoms of the disorder.

2.7. Pengobatan dan Hasil Riset 2.7. Pengobatan dan Hasil Riset

Recent studies have focused on a number of critical areas. The Recent studies have focused on a number of critical areas. The role of FMRP's RNA partners, many of which have now been role of FMRP's RNA partners, many of which have now been validated through validated through in vitro assays, is of primary importance. Also assays, is of primary importance. Also being examined is the function the various domains of FMRP, an being examined is the function the various domains of FMRP, an RNA-binding protein, which is still relatively unknown. One , which is still relatively unknown. One hypothesis is that many symptoms are caused by unchecked hypothesis is that many symptoms are caused by unchecked activation of activation of mGluR5, a , a metabotropic glutamate receptor, which , which was found in a 2007 study to contribute significantly to the was found in a 2007 study to contribute significantly to the pathogenesis of the disease;pathogenesis of the disease;[16] this suggests that mGluR5 this suggests that mGluR5 blockers could be used to treat fragile X syndrome.blockers could be used to treat fragile X syndrome.[17]

While there is no current cure for the syndrome, there is hope that While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes would lead to new further understanding of its underlying causes would lead to new therapies. Currently, the syndrome can be treated through therapies. Currently, the syndrome can be treated through behavioral therapy, , special education, medication, and when , medication, and when necessary, treatment of physical abnormalities. Persons with the necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who to assess the likelihood of having children who are affected, and how severe any impairments may be in affected are affected, and how severe any impairments may be in affected descendants.descendants.[18]

What is the treatment?What is the treatment? Although there is currently no cure for fragile X Although there is currently no cure for fragile X

syndrome, it can be treated through a syndrome, it can be treated through a combination of speech and language therapy, combination of speech and language therapy, occupational therapy, physical therapy, and occupational therapy, physical therapy, and psychotherapy, depending upon the child's psychotherapy, depending upon the child's symptoms. Drugs may be used to treat symptoms. Drugs may be used to treat behavioral problems, such as mood swings and behavioral problems, such as mood swings and aggressive outbursts. Your child's therapists can aggressive outbursts. Your child's therapists can also teach you techniques for reducing these also teach you techniques for reducing these problems. Anticonvulsants that are used to treat problems. Anticonvulsants that are used to treat seizures can also help with behavioral problems. seizures can also help with behavioral problems. Generally, children with fragile X benefit from Generally, children with fragile X benefit from following a regular routine and avoiding over-following a regular routine and avoiding over-stimulation. Try to keep distractions, such as stimulation. Try to keep distractions, such as noise and odors, to a minimum.noise and odors, to a minimum.

3. HUNTINGTON’S DISEASES3. HUNTINGTON’S DISEASES

Huntington's diseaseHuntington's disease or or choreachorea ( (HDHD) is ) is an incurable an incurable neurodegenerative genetic disorder that typically manifests that typically manifests itself first in middle age. It is the most itself first in middle age. It is the most common genetic cause of abnormal common genetic cause of abnormal involuntary writhing movements called involuntary writhing movements called chorea. It is much less common in people . It is much less common in people of Asian or African descent than in people of Asian or African descent than in people from Western Europe from Western Europe

3.1. PENYEBAB3.1. PENYEBAB

The disease is caused by a mutation on The disease is caused by a mutation on either of the two copies of a specific either of the two copies of a specific gene, , located on an located on an autosomal chromosome. As . As the mutation is the mutation is dominant, each child of an , each child of an affected parent has a 50% chance of affected parent has a 50% chance of inheriting the disease. In rare situations inheriting the disease. In rare situations where both parents have an affected where both parents have an affected gene, or either parent has two affected gene, or either parent has two affected copies, this chance is greatly increased. copies, this chance is greatly increased.

3.2. Tanda dan simptom 3.2. Tanda dan simptom Symptoms of Huntington's disease commonly Symptoms of Huntington's disease commonly

become noticeable between the ages of 35 and become noticeable between the ages of 35 and 44 years, but they can begin at any age from 44 years, but they can begin at any age from infancy,infancy,[1] [2] often when affected individuals often when affected individuals have had children.have had children.[1] In the early stages, there In the early stages, there are subtle changes in personality, are subtle changes in personality, cognition, or , or physical skills.physical skills.[1] The physical symptoms are The physical symptoms are usually the first to be noticed, as cognitive and usually the first to be noticed, as cognitive and psychiatric symptoms are generally not severe symptoms are generally not severe enough to be recognized on their own at the enough to be recognized on their own at the earlier stages.earlier stages.[1] Almost everyone with Almost everyone with Huntington's disease eventually exhibits similar Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms and extent of cognitive and psychiatric symptoms vary significantly between individuals.vary significantly between individuals.[3][4]

3.2. Tand dan simptom 3.2. Tand dan simptom The most characteristic initial physical symptoms are jerky, The most characteristic initial physical symptoms are jerky,

random, and uncontrollable movements called random, and uncontrollable movements called chorea..[1] Chorea Chorea may be initially exhibited as general restlessness, small may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of unintentionally initiated or uncompleted motions, lack of coordination, or slowed coordination, or slowed saccadic eye movements..[1] These minor These minor motor abnormalities usually precede more obvious signs of motor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years.dysfunction by at least three years.[3] The clear appearance of The clear appearance of symptoms such as rigidity, writhing motions or symptoms such as rigidity, writhing motions or abnormal posturing appear as the disorder progresses. appear as the disorder progresses.[5] These These are signs that the system in the brain that is responsible for are signs that the system in the brain that is responsible for movement is affected.movement is affected.[6] Psychomotor functions become functions become increasingly impaired, such that any action that requires muscle increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, abnormal facial expression, and difficulties chewing, swallowing and and speaking..[5] Eating difficulties commonly cause weight loss Eating difficulties commonly cause weight loss and may lead to malnutrition.and may lead to malnutrition.[7][8] Sleep disturbances are also are also associated symptoms.associated symptoms.[9] Juvenile HD differs from these symptoms Juvenile HD differs from these symptoms in that it generally progresses faster and chorea is exhibited in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom. briefly, if at all, with rigidity being the dominant symptom. Seizures are also a common symptom of this form of HD. are also a common symptom of this form of HD.[5]

3.2. Tanda dan simptom 3.2. Tanda dan simptom

Reported prevalences of behavioral Reported prevalences of behavioral and psychiatric symptoms in and psychiatric symptoms in Huntington's diseaseHuntington's disease[10] Irritability38–73%Irritability38–73%

Apathy34–76%Apathy34–76% Anxiety34–61%Anxiety34–61% Depressed mood33–69%Depressed mood33–69% Obsessive and compulsive10–Obsessive and compulsive10–

52%Psychotic3–11%52%Psychotic3–11%

3.2. Tanda dan simptom3.2. Tanda dan simptom Reported Reported neuropsychiatric manifestations are manifestations are anxiety, , depression, ,

a reduced display of emotions (a reduced display of emotions (blunted affect), ), egocentrism, , aggression, and , and compulsive behavior, the latter of which can , the latter of which can cause or worsen cause or worsen addictions, including , including alcoholism, , gambling, and , and hypersexuality..[10] Difficulties in recognizing other people's Difficulties in recognizing other people's negative expressions have also been observed.negative expressions have also been observed.[6] Prevalence of of these symptoms is also highly variable between studies, with these symptoms is also highly variable between studies, with estimated rates for lifetime prevalence of estimated rates for lifetime prevalence of psychiatric disorders between 33% and 76%.between 33% and 76%.[10] For many sufferers and their families For many sufferers and their families these symptoms are among the most distressing aspects of the these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason disease, often affecting daily functioning and constituting reason for for institutionalisation..[10] Suicidal thoughts and suicide attempts Suicidal thoughts and suicide attempts are more common than in the general population.are more common than in the general population.[1]

Mutant huntingtin is expressed throughout the body and Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that directly associated with abnormalities in peripheral tissues that directly caused by such expression outside the brain. These abnormalities caused by such expression outside the brain. These abnormalities include include muscle atrophy, , cardiac failure, , impaired glucose tolerance, , weight loss, , osteoporosis and and testicular atrophy..[11]

3.3. GENETIK3.3. GENETIK All humans have the All humans have the Huntingtin gene ( gene (HTTHTT), which provides ), which provides

the genetic code to produce the the genetic code to produce the protein huntingtin (HTT). (HTT). Part of this gene is a repeated section called a Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between , which varies in length between individuals and may change length between generations. individuals and may change length between generations. When the length of this repeated section reaches a certain When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHTT). The differing functions of mutant huntingtin protein (mHTT). The differing functions of these proteins are the cause of pathological changes which these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant, because either of disease mutation is genetically dominant, because either of a person's HTT genes being mutated causes the disease. It a person's HTT genes being mutated causes the disease. It is not inherited according to gender, but the length of the is not inherited according to gender, but the length of the repeated section of the gene, and hence its severity, can be repeated section of the gene, and hence its severity, can be influenced by the gender of the affected parent.influenced by the gender of the affected parent.[12]

.3.3. Mutasi Genetik .3.3. Mutasi Genetik HD is one of several HD is one of several trinucleotide repeat disorders

which are caused by the length of a repeated which are caused by the length of a repeated section of a gene exceeding a normal range.section of a gene exceeding a normal range.[13] The The HTTHTT gene is located on the gene is located on the short arm of of chromosome 4..[13] HTTHTT contains a sequence of contains a sequence of three three DNA bases—cytosine-adenine-guanine (—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...), )—repeated multiple times (i.e. ...CAGCAGCAG...), known as a trinucleotide repeat.known as a trinucleotide repeat.[13] CAG is the CAG is the genetic code for the for the amino acid glutamine, so a , so a series of them results in the production of a chain series of them results in the production of a chain of glutamine known as a of glutamine known as a polyglutamine tract (or (or polyQ tract), and the repeated part of the gene, polyQ tract), and the repeated part of the gene, the the PolyQ regionPolyQ region..[14]

3.4. PEWARISAN3.4. PEWARISAN Huntington's disease has Huntington's disease has

autosomal dominant inheritance, meaning inheritance, meaning that an affected individual typically that an affected individual typically inherits a copy of the gene with an inherits a copy of the gene with an expanded trinucleotide repeat (the mutant expanded trinucleotide repeat (the mutant allele) from an affected parent.) from an affected parent.[1] In this In this type of inheritance pattern, each offspring type of inheritance pattern, each offspring of an affected individual has a 50% chance of an affected individual has a 50% chance of inheriting the mutant allele and of inheriting the mutant allele and therefore being affected with the disorder therefore being affected with the disorder (see figure). This probability is sex-(see figure). This probability is sex-independent.independent.[17]

3.5. Mekanisme 3.5. Mekanisme The HTT protein interacts with over 100 other The HTT protein interacts with over 100 other

proteins, and appears to have multiple biological proteins, and appears to have multiple biological functions.functions.[22] The behavior of mutated mHTT The behavior of mutated mHTT protein is not completely understood, but it is protein is not completely understood, but it is toxic to certain types of cells, particularly in the toxic to certain types of cells, particularly in the brain. Damage mainly occurs in the brain. Damage mainly occurs in the striatum, but , but as the disease progresses, other areas of the as the disease progresses, other areas of the brain are also significantly affected. As the brain are also significantly affected. As the damage accumulates, symptoms associated with damage accumulates, symptoms associated with the functions of these brain areas appear. the functions of these brain areas appear. Planning and modulating movement are the main Planning and modulating movement are the main functions of the striatum, and difficulties with functions of the striatum, and difficulties with these are initial symptoms.these are initial symptoms.[12]

3.6. Diagnosis 3.6. Diagnosis Diagnosis of the onset of HD can be made following the Diagnosis of the onset of HD can be made following the

appearance of physical symptoms specific to the disease.appearance of physical symptoms specific to the disease.[1] Genetic testing can be used to confirm a physical Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an onset of symptoms, genetic testing can confirm if an individual or individual or embryo carries an expanded copy of the carries an expanded copy of the HTTHTT gene that causes the disease. gene that causes the disease. Genetic counseling is is available to provide advice and guidance throughout the available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed testing procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an diagnosis. These implications include the impact on an individual's psychology, career, family planning decisions, individual's psychology, career, family planning decisions, relatives and relationships. Despite the availability of pre-relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.HD choose to do so.[12]

3.7. Klinik 3.7. Klinik A A physical examination, sometimes combined with a , sometimes combined with a

psychological examination, can determine whether the onset of , can determine whether the onset of the disease has begun.the disease has begun.[1] Excessive unintentional movements of Excessive unintentional movements of any part of the body are often the reason for seeking medical any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or distribution, they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely the first diagnosed; they are psychiatric symptoms are rarely the first diagnosed; they are usually only recognized in hindsight or when they develop further. usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the How far the disease has progressed can be measured using the unified Huntington's disease rating scaleunified Huntington's disease rating scale which provides an overall which provides an overall rating system based on motor, behavioral, cognitive, and rating system based on motor, behavioral, cognitive, and functional assessments.functional assessments.[32][33] Medical imaging, such as , such as computerized tomography (CT) and (CT) and magnetic resonance imaging (MRI), only shows visible (MRI), only shows visible cerebral atrophy in the advanced stages in the advanced stages of the disease. of the disease. Functional neuroimaging techniques such as techniques such as fMRI and and PET can show changes in brain activity before the onset of can show changes in brain activity before the onset of physical symptoms.physical symptoms.[13]

[[edit] Genetic] Genetic

3.8. Differential diagnosis3.8. Differential diagnosis Although HD accounts for ninety percent of the cases of Although HD accounts for ninety percent of the cases of

chorea caused by genetic disorders, and an observational chorea caused by genetic disorders, and an observational diagnosis for someone with typical symptoms and a diagnosis for someone with typical symptoms and a family history of the disease is usually correct, a genetic of the disease is usually correct, a genetic test is required to rule out other disorders.test is required to rule out other disorders.[5][39] Most of Most of these other disorders are collectively labelled HD-like these other disorders are collectively labelled HD-like (HDL).(HDL).[39] The causes of most of these HDL diseases are The causes of most of these HDL diseases are unknown, but those with known causes are due to unknown, but those with known causes are due to mutations in the mutations in the prion protein gene (HDL1), the (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited (HDL2), a recessively inherited HTTHTT gene (HDL3 — only found in one family and poorly gene (HDL3 — only found in one family and poorly understood), and the gene encoding the understood), and the gene encoding the TATA box-binding protein (HDL4/ (HDL4/SCA17).).[39]

[[edit] ]

3.9. Tatalaksana 3.9. Tatalaksana There is no cure for HD, but there are treatments available to reduce the There is no cure for HD, but there are treatments available to reduce the

severity of some of its symptoms. For many of these treatments, severity of some of its symptoms. For many of these treatments, comprehensive clinical trials to confirm their effectiveness in treating comprehensive clinical trials to confirm their effectiveness in treating symptoms of HD specifically are incomplete.symptoms of HD specifically are incomplete.[40][41] As the disease As the disease progresses and a persons ability to tend to their own needs reduces, progresses and a persons ability to tend to their own needs reduces, carefully managed carefully managed multidisciplinary caregiving becomes increasingly becomes increasingly necessary.necessary.[40]

Tetrabenazine was developed specifically to reduce the severity of chorea Tetrabenazine was developed specifically to reduce the severity of chorea in HD,in HD,[40] it was approved in 2008 for this use in the US. it was approved in 2008 for this use in the US.[42] Other drugs Other drugs that help to reduce chorea include that help to reduce chorea include neuroleptics and and benzodiazepines..[2] Compounds such as Compounds such as amantadine or or remacemide are still under are still under investigation but have shown preliminary positive results.investigation but have shown preliminary positive results.[43] Hypokinesia and rigidity can be treated with and rigidity can be treated with antiparkinsonian drugs, and drugs, and myoclonic hyperkinesia can be treated with hyperkinesia can be treated with valproic acid..[2]

Psychiatric symptoms can be treated with medications similar to those Psychiatric symptoms can be treated with medications similar to those used in the general population.used in the general population.[40][41] Selective serotonin reuptake inhibitors and and mirtazapine have been have been recommended for depression, while recommended for depression, while atypical antipsychotic drugs are drugs are recommended for psychosis and behavioural problems.recommended for psychosis and behavioural problems.[41]

3.10. Prognosis 3.10. Prognosis The length of the trinucleotide repeat accounts for 60% of the variation in the age of The length of the trinucleotide repeat accounts for 60% of the variation in the age of

onset and the rate of progression of symptoms. A longer repeat results in an earlier onset and the rate of progression of symptoms. A longer repeat results in an earlier age of onset and a faster progression of symptoms.age of onset and a faster progression of symptoms.[13][48] For example, individuals For example, individuals with a trinucleotide repeat greater than sixty repeats often develop the disease with a trinucleotide repeat greater than sixty repeats often develop the disease before twenty years of age, and those with less than forty repeats may not develop before twenty years of age, and those with less than forty repeats may not develop noticeable symptoms.noticeable symptoms.[49] The remaining variation is due to environmental factors The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.and other genes that influence the mechanism of the disease.[13]

Life expectancy in HD is generally around 20 years following the onset of visible Life expectancy in HD is generally around 20 years following the onset of visible symptoms.symptoms.[5] The pathology of Huntington’s disease is not fatal, but complications The pathology of Huntington’s disease is not fatal, but complications caused by the disease's symptoms become increasingly hazardous. The largest risk caused by the disease's symptoms become increasingly hazardous. The largest risk is is pneumonia, which is the cause of death of one-third of those with HD. As the ability , which is the cause of death of one-third of those with HD. As the ability to synchronise movements deteriorates, difficulty clearing the lungs and an to synchronise movements deteriorates, difficulty clearing the lungs and an increased chance of increased chance of aspirating food or drink both increase the risk of contracting food or drink both increase the risk of contracting pneumonia. The second greatest risk is pneumonia. The second greatest risk is heart disease, which causes almost a quarter , which causes almost a quarter of fatalities of those with HD.of fatalities of those with HD.[5] Suicide is he next greatest cause of fatalities, with is he next greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are influenced by psychiatric symptoms, as unclear to what extent suicidal thoughts are influenced by psychiatric symptoms, as they may be considered to be an understandable response to avoid the later stages they may be considered to be an understandable response to avoid the later stages of the disease or help retain a sense of control of an individuals life.of the disease or help retain a sense of control of an individuals life.[50][51][52] Other associated risks include choking, Other associated risks include choking, physical injury from falls, and malnutrition. from falls, and malnutrition.[5]

3.11. Epidemiology3.11. Epidemiology The late onset of Huntington's disease means it does not usually affect reproduction.The late onset of Huntington's disease means it does not usually affect reproduction.

[12] The The prevalence is similar for men and women, but varies greatly geographically is similar for men and women, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. The rate of as a result of ethnicity, local migration and past immigration patterns. The rate of occurrence is highest in peoples of Western European descent, averaging around occurrence is highest in peoples of Western European descent, averaging around seventy per million people, but is lower in the rest of the world, e.g. one per million seventy per million people, but is lower in the rest of the world, e.g. one per million people of Asian and African descent.people of Asian and African descent.[12] Additionally, some localized areas have a Additionally, some localized areas have a much higher prevalence than their regional average.much higher prevalence than their regional average.[12] One of the highest One of the highest prevalences is in the isolated populations of the prevalences is in the isolated populations of the Lake Maracaibo region of region of Venezuela, , where HD affects up to seven thousand per million people.where HD affects up to seven thousand per million people.[12][53] Other areas of Other areas of high localization have been found in high localization have been found in Tasmania and specific regions of and specific regions of Scotland, , Wales and and Sweden..[52] Increased prevalence in some cases occurs according to a Increased prevalence in some cases occurs according to a local local founder effect, a historical migration of carriers into an area of , a historical migration of carriers into an area of geographic isolation..[52][54] Some of these carriers have been traced back hundreds Some of these carriers have been traced back hundreds of years using of years using genealogical studies. studies.[52] Genetic Genetic haplotypes can also give clues for can also give clues for the geographic variations of prevalence.the geographic variations of prevalence.[52][55]

Until the the discovery of a genetic test, statistics could only include clinical diagnosis Until the the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics and as other causes before diagnosis. These cases can now be included in statistics and as the test becomes more widely available, estimates of the prevalence and incidence the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.of the disorder are likely to increase.[52][56]

3.12. Sejarah 3.12. Sejarah Before the 19th century, some HD sufferers may Before the 19th century, some HD sufferers may

have been thought to be possessed by spirits or have been thought to be possessed by spirits or persecuted as persecuted as witches, and were , and were shunned or or exiled by society. by society.[58] A well-documented case is A well-documented case is that of , who probably suffered from HD. In 1671 that of , who probably suffered from HD. In 1671 Knapp was accused of witchcraft in Knapp was accused of witchcraft in Groton, New Hampshire, and subject to an , and subject to an torturous trial, but was not condemned.torturous trial, but was not condemned.[59][60] However, while this persecution may have However, while this persecution may have happened in some places,happened in some places,[58] other communities other communities were more accepting. The family that prompted were more accepting. The family that prompted George Huntington's description were able to 's description were able to work while healthy and accepted by their town.work while healthy and accepted by their town.[58][61]

3.12. Sejarah 3.12. Sejarah The first definite description of HD was in a letter by , published in the first The first definite description of HD was in a letter by , published in the first

edition of edition of Robley Dunglison's 's Practice of MedicinePractice of Medicine in 1842. Waters in 1842. Waters described 'a form of chorea, vulgarly called magrums', including accurate described 'a form of chorea, vulgarly called magrums', including accurate descriptions of the chorea, its progression, and the strong heredity of the descriptions of the chorea, its progression, and the strong heredity of the disease.disease.[62] In 1846 observed how prevalence seemed to occur in In 1846 observed how prevalence seemed to occur in localized regions.localized regions.[62] Both Gorman and Waters were students of Dungison Both Gorman and Waters were students of Dungison at at Jefferson Medical College..[61] Independently, also produced an early Independently, also produced an early description in 1860.description in 1860.[62] He specifically noted that in He specifically noted that in Setesdalen, a rather , a rather secluded area, there was a high prevalence of dementia associated with a secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.pattern of jerking movement disorders that ran in families.[63] The first The first widely recognized description was by George Huntington in 1872. widely recognized description was by George Huntington in 1872. Huntington was a third generation physician on Huntington was a third generation physician on Long Island. Examining the . Examining the combined medical history of several generations of a family exhibiting combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked and similar symptoms, he realized their conditions must be linked and presented his detailed and accurate definition of the disease as his first presented his detailed and accurate definition of the disease as his first paper.paper.[57][64] Sir Sir William Osler was interested in the disorder and chorea was interested in the disorder and chorea in general, and was impressed with Huntington's paper, even wishing to in general, and was impressed with Huntington's paper, even wishing to reassess the family involved a decade later.reassess the family involved a decade later.[62] Osler's interest in HD Osler's interest in HD combined with his influence in medicine circles helped to spread combined with his influence in medicine circles helped to spread knowledge of the disorder rapidly.knowledge of the disorder rapidly.[62]

3.12. Sejarah 3.12. Sejarah As As Mendelian inheritance was being rediscovered at the was being rediscovered at the

turn of the century, HD was used tentatively as an example turn of the century, HD was used tentatively as an example of autosomal dominant inheritance.of autosomal dominant inheritance.[62] In 1911 In 1911 Charles Davenport made major contributions to made major contributions to understanding of the disease, proving that it was indeed understanding of the disease, proving that it was indeed autosomal dominant, and proceeding to document most of autosomal dominant, and proceeding to document most of the inheritance variabilities like the age of onset. He also the inheritance variabilities like the age of onset. He also described the range of psychiatric and physical symptoms, described the range of psychiatric and physical symptoms, providing much of the framework for following research.providing much of the framework for following research.[62] Davenport's interest was roused by his college friend Davenport's interest was roused by his college friend Smith Ely Jelliffe's own interest in HD's strong inheritance 's own interest in HD's strong inheritance pattern.pattern.[61] Jellife collected information from across Jellife collected information from across New York State and published several articles regarding the and published several articles regarding the genealogy of HD in genealogy of HD in New England..[65] This work was This work was expanded upon in 1932 by , who traced about a thousand expanded upon in 1932 by , who traced about a thousand people with HD back to two brothers who left people with HD back to two brothers who left England in in 1630, bound for 1630, bound for Boston..[66]

3.12. Sejarah 3.12. Sejarah Research into the disorder continued progressively, and Research into the disorder continued progressively, and

was given a major boost in 1983 when the US–was given a major boost in 1983 when the US–Venezuela discovered the approximate location of a causal gene.discovered the approximate location of a causal gene.[54] This was the result of an extensive study begun in 1979, This was the result of an extensive study begun in 1979, focusing on the populations of isolated Venezuelan villages focusing on the populations of isolated Venezuelan villages of Barranquitas and Lagunetas, where there was an of Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. Among other unusually high prevalence of the disease. Among other innovations, the project developed DNA marking methods innovations, the project developed DNA marking methods which were an important step in making the which were an important step in making the Human Genome Project possible. possible.[67] In 1993 the research In 1993 the research group isolated the precise gene at 4p16.3,group isolated the precise gene at 4p16.3,[68] making this making this the first the first autosomal disease disease locus found using genetic found using genetic linkage analysis..[69][68] In the same time frame, key In the same time frame, key discoveries concerning the mechanisms of the disorder discoveries concerning the mechanisms of the disorder were being made, including the findings by were being made, including the findings by Anita Harding's 's research group on the effects of the genes length.research group on the effects of the genes length.[70]

3.12. Sejarah3.12. Sejarah A A transgenic mouse that could be made to exhibit mouse that could be made to exhibit

HD was developed in 1996. Modelling the disease HD was developed in 1996. Modelling the disease in animals enables larger scale testing, and as in animals enables larger scale testing, and as their their metabolism is faster and lifespan shorter is faster and lifespan shorter than humans, results are received sooner.than humans, results are received sooner.[71][72] The discovery that mHTT fragments The discovery that mHTT fragments misfold in 1997 led to the discovery of the in 1997 led to the discovery of the nuclear inclusions they cause. they cause.[73] These These advancements and discoveries have led to advancements and discoveries have led to increasingly extensive research into the increasingly extensive research into the interactions of HTT, mHTT, and mHTT fragments, interactions of HTT, mHTT, and mHTT fragments, potential drug treatments, care methods, and the potential drug treatments, care methods, and the gene itself.gene itself.[62][74][75]

4. MYOTONIC DYSTROPHY4. MYOTONIC DYSTROPHY Myotonic dystrophyMyotonic dystrophy ( (dystrophia myotonicadystrophia myotonica, ,

DM) is a DM) is a chronic, slowly progressing, highly , slowly progressing, highly variable inherited multisystemic variable inherited multisystemic disease that can that can manifest at any age from birth to old age. It is manifest at any age from birth to old age. It is characterized by wasting of the muscles characterized by wasting of the muscles (muscular dystrophy), posterior subcapsular (muscular dystrophy), posterior subcapsular iridescent iridescent cataracts (opacity of the lens of the (opacity of the lens of the eyes), heart conduction defects, eyes), heart conduction defects, endocrine changes and changes and myotonia (difficulty relaxing a (difficulty relaxing a muscle). Most notably, the highly variable age of muscle). Most notably, the highly variable age of onset decreases with successive generations. onset decreases with successive generations. Thus the disease shows at an earlier age in Thus the disease shows at an earlier age in successive generations, a phenomenon termed successive generations, a phenomenon termed anticipation. There are two classifications of DM, . There are two classifications of DM, each having different associated symptoms.each having different associated symptoms.

4.1. Klasifikasi 4.1. Klasifikasi Myotonic dystrophy is the most common form of Myotonic dystrophy is the most common form of

muscular dystrophy allowing adult survival and the second most allowing adult survival and the second most common form of any skeletal muscle disease after common form of any skeletal muscle disease after Duchenne muscular dystrophy. There are currently two known . There are currently two known types of adult onset DM, both identifiable by DNA analysis:types of adult onset DM, both identifiable by DNA analysis:

Myotonic dystrophy type 1 (DM1), also known as Steinert's Myotonic dystrophy type 1 (DM1), also known as Steinert's disease. DM1 has a disease. DM1 has a congenital form that can severely affect form that can severely affect babies and a childhood onset form. babies and a childhood onset form.

Myotonic dystrophy type 2 (DM2), commonly referred to as Myotonic dystrophy type 2 (DM2), commonly referred to as PROMM or proximal myotonic myopathy. PROMM or proximal myotonic myopathy.

Type 1 is by far the most common form, accounting for 98% of all Type 1 is by far the most common form, accounting for 98% of all myotonic dystrophy cases, however DM2 can be more difficult to myotonic dystrophy cases, however DM2 can be more difficult to diagnose because of unusual phenotypes and is believed to be diagnose because of unusual phenotypes and is believed to be underdiagnosed.underdiagnosed.

Other forms of myotonic dystrophy (DM3, DM4, DMX) are currently Other forms of myotonic dystrophy (DM3, DM4, DMX) are currently suspected by researchers to exist.[suspected by researchers to exist.[citation needed] One recent ] One recent case was proposed as a candidate for the "DM3" label,case was proposed as a candidate for the "DM3" label,[1] but was but was later characterized as a form of later characterized as a form of Paget's disease..[2][3]

4.2. Perbedaan DM1 dan DM2 4.2. Perbedaan DM1 dan DM2

While both diseases are considered slow While both diseases are considered slow degenerative conditions, DM2 is considered to be generally milder than conditions, DM2 is considered to be generally milder than DM1. DM1.

The severe The severe congenital form that affects babies in DM1 has form that affects babies in DM1 has not been found in DM2 and the early onset of symptoms is not been found in DM2 and the early onset of symptoms is rarely noted to appear in younger patients in the medical rarely noted to appear in younger patients in the medical literature. literature.

The repeat expansion for DM2 is considerably larger than The repeat expansion for DM2 is considerably larger than for DM1, ranging from 75 to over 11,000. for DM1, ranging from 75 to over 11,000.

Unlike DM1, the size of the repeated DNA expansion does Unlike DM1, the size of the repeated DNA expansion does not appear to make a difference in the age of onset or not appear to make a difference in the age of onset or disease severity in DM2. disease severity in DM2.

Anticipation is a common feature of DM1. It appears to be is a common feature of DM1. It appears to be less significant in type 2 and most current reviews only less significant in type 2 and most current reviews only report mild anticipation as a feature of DM2. report mild anticipation as a feature of DM2.

4.3. Simptom4.3. Simptom

Presentation of symptoms varies considerably by Presentation of symptoms varies considerably by form (DM1/DM2), severity and even unusual DM2 form (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 patients often present with phenotypes. DM1 patients often present with myotonia, disabling , disabling distal weakness and severe weakness and severe cognitive problems. DM2 patients commonly cognitive problems. DM2 patients commonly present with muscle pain, present with muscle pain, stiffness, , fatigue, or the , or the development of proximal lower extremity development of proximal lower extremity weakness (Day & al, 2003). The characteristic weakness (Day & al, 2003). The characteristic pattern of weakness is different for DM1 and pattern of weakness is different for DM1 and DM2: In DM1, it is noted in face and jaw muscles, DM2: In DM1, it is noted in face and jaw muscles, the drooping of the eyelids (the drooping of the eyelids (ptosis), weakness of ), weakness of the neck muscles, hands and lower legs. In DM2, the neck muscles, hands and lower legs. In DM2, the weakness is more evident in proximal the weakness is more evident in proximal muscles, those closer to the trunk of the body: muscles, those closer to the trunk of the body: neck, shoulders, hip flexors and upper legs.neck, shoulders, hip flexors and upper legs.

4.4. Genetik 4.4. Genetik DM is a DM is a genetic condition condition

which is inherited in an which is inherited in an autosomal dominant pattern, meaning that pattern, meaning that inheriting a mutant gene inheriting a mutant gene from one parent will result from one parent will result in the condition. There is a in the condition. There is a 50% chance of inheriting 50% chance of inheriting DM from an affected DM from an affected parent.parent.

DM is one of several known DM is one of several known trinucleotide repeat disorders. Certain areas of . Certain areas of DNA have repeated sequences have repeated sequences of two or three of two or three nucleotides..

DM1DM1 In DM1, the affected gene is called In DM1, the affected gene is called DMPK ( (

myotonic dystrophy protein kinase) which codes for a myosin ) which codes for a myosin kinase expressed in skeletal muscle. The gene is located on the kinase expressed in skeletal muscle. The gene is located on the long arm of long arm of chromosome 19..

In DM1, there is a triplet repeat of In DM1, there is a triplet repeat of Cytosine - - Thymine - - Guanine (CTG) in the DMPK gene. The number of repeats varies greatly (CTG) in the DMPK gene. The number of repeats varies greatly from person to person, but the average number in a healthy from person to person, but the average number in a healthy person is between 5 and 37. Sometimes when repetitive person is between 5 and 37. Sometimes when repetitive sequences of DNA are replicated during sequences of DNA are replicated during cell division the cellular the cellular machinery slips and an extra copy of the triplet repeat is added to machinery slips and an extra copy of the triplet repeat is added to the sequence. Once there are more than 37 triplet repeats in the the sequence. Once there are more than 37 triplet repeats in the DMPK gene the sequence becomes unstable and slippage DMPK gene the sequence becomes unstable and slippage becomes a lot more likely to happen. People affected with DM1 becomes a lot more likely to happen. People affected with DM1 have over 50 and can have as many as 2000 repeats.have over 50 and can have as many as 2000 repeats.

The result of this is that the repeat size of an individual with DM1 The result of this is that the repeat size of an individual with DM1 will become larger usually during gametogenesis or early will become larger usually during gametogenesis or early embrionic development. This explains the embrionic development. This explains the phenomenon of of anticipation, as each child of an affected adult will have a larger , as each child of an affected adult will have a larger expansion than their parent due to slippage during expansion than their parent due to slippage during gametogenesis. Individuals with larger expansions have an earlier onset of the . Individuals with larger expansions have an earlier onset of the disorder and a more severe disorder and a more severe phenotype..

DM2DM2 DM2 is similarly caused by a defect of the DM2 is similarly caused by a defect of the

ZNF9 gene on gene on chromosome 3q21.21. The repeat expansion for DM2 is much The repeat expansion for DM2 is much

larger than for DM1, ranging from 75 to larger than for DM1, ranging from 75 to over 11000 repeats. Unlike DM1, the size over 11000 repeats. Unlike DM1, the size of the repeated DNA expansion does not of the repeated DNA expansion does not appear to make a difference in the age of appear to make a difference in the age of onset or disease severity in DM2. onset or disease severity in DM2. Anticipation appears to be less significant Anticipation appears to be less significant in DM2 and most current reviews only in DM2 and most current reviews only report mild anticipation as a feature of report mild anticipation as a feature of DM2.DM2.

It involves the repeat of four nucleotides, It involves the repeat of four nucleotides, and therefore is not a trinucleotide repeat and therefore is not a trinucleotide repeat disorder.[4]disorder.[4]

4.5. Diagnosis4.5. Diagnosis

The diagnosis of DM1 and DM2 can be The diagnosis of DM1 and DM2 can be difficult and may be delayed due to the difficult and may be delayed due to the large number of neuromuscular disorders, large number of neuromuscular disorders, most of which are very rare.most of which are very rare.

Neuromuscular disorders can cover more Neuromuscular disorders can cover more than 40 different diseases and additional than 40 different diseases and additional forms of these bring the number of distinct forms of these bring the number of distinct disorders close to 100.disorders close to 100.

4.6. Tatalaksana 4.6. Tatalaksana There is currently no cure for or treatment There is currently no cure for or treatment

specific to myotonic dystrophy. Heart problems, specific to myotonic dystrophy. Heart problems, cataracts, and other abnormalities associated cataracts, and other abnormalities associated with the condition can be treated but not cured. with the condition can be treated but not cured. However there are medical interventions and However there are medical interventions and medications that may relieve some of the medications that may relieve some of the symptoms such as myotonia, pain and excessive symptoms such as myotonia, pain and excessive sleepiness. Some treatments have been subject sleepiness. Some treatments have been subject to systematic review for safety and efficacy to systematic review for safety and efficacy through the Cochrane Reviews for symptoms through the Cochrane Reviews for symptoms such as hypersomnia (excessive daytime such as hypersomnia (excessive daytime sleepiness), myotonia, strength training and sleepiness), myotonia, strength training and aerobic exercise training and foot drop.aerobic exercise training and foot drop.

4.7. Seleksi 4.7. Seleksi

Screening for the DMPK gene for DM1 is Screening for the DMPK gene for DM1 is targeted at chromosome 19 while the targeted at chromosome 19 while the ZNF9 gene for DM2 is found on ZNF9 gene for DM2 is found on chromosome 3. Genetic tests, including chromosome 3. Genetic tests, including prenatal testing, are available for both prenatal testing, are available for both confirmed forms. Molecular testing is confirmed forms. Molecular testing is considered the gold standard of diagnosis. considered the gold standard of diagnosis. Further forms of myotonic dystrophy Further forms of myotonic dystrophy (DM3, DM4, DMX) are suspected by (DM3, DM4, DMX) are suspected by researchers with possible defects on researchers with possible defects on chromosome 16 and chromosome 21.chromosome 16 and chromosome 21.

TUGAS TULISTUGAS TULIS

1. Spinobulbar muscular atrophy 2. Spinocerebellar ataxia type 3 3. Friedreich ataxia 4. Ocularpharyngeal muscular

dystrophy 5. Progressive myoclonus epilepsy 6. Creutzfeldt-Jakob disease