ASSIGNMENT

Subject Code: PDA303T

Subject Name: Pharmacotherapeutics II
Programme/Course: Pharm D
Department: Pharmacy Practice
Faculty: pharmacy

Name of the Student: J. ANTO AMITH BIJU

Reg. No:16PHPH010005
Semester/Year: 3rdyear
Subject Leader/s: Mr. Subeesh K Viswam

M. S. Ramaiah University of Applied Sciences

University House, Gnanagangothri Campus, New BEL Road,
M S R Nagar, Bangalore, Karnataka, INDIA - 560 054.

i
 Declaration Sheet
Student Name ANTO AMITH BIJU .J
Reg. No 16PHPH010005
Programme/Course Pharm.D Semester/Year 3rdyear
Subject Code PDA303T
Subject Title Pharmacotherapeutics II
Subject Date 20th August 2018 to 9th November 2018
Subject Leader Mr.Subeesh K Viswam

Declaration

The assignment submitted herewith is a result of my own investigations and that I have
conformed to the guidelines against plagiarism as laid out in the Student Handbook. All
sections of the text and results, which have been obtained from other sources, are fully
referenced. I understand that cheating and plagiarism constitute a breach of University
regulations and will be dealt with accordingly.

Signature of the Student Date

Submission date stamp

(by Examination & Assessment
Section)

Signature of the Subject Leader and date Signature of the Reviewer and date

<Subject Title> ii
 Faculty of Pharmacy
M. S. Ramaiah University of Applied Sciences
Department Pharmacy Practice Course/Branch Pharm D
Year /Batch III Year / 2016
Course Code PDA303T Course Title Pharmacotherapeutics II
Course Leader(s) Mr. Subeesh K Viswam

Assignment
Marks
Section

Marking Scheme Maximu First Second

m Marks Examiner Examiner
Identifying the orphan drugs
1.1 4
A 1.2 Addressing the safety and efficacy 5
1.5 References 1
Part-A Max Marks 10
Addressing the challenges of Nipah virus
1.1 4
management
Discuss the recent advancements in Nipah
B.1 1.2 5
management
1.3 References 1
B.1 Max Marks 10
2.1 Identification of disease and gene/protein 3
2.2 Discuss the roles of those protein/gene 6
B.2 2.3 References 1

B.2 Max Marks 10

 Total Assignment Marks 30

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 Course Marks Tabulation

Component-1 (B) First Second

Remarks Remarks
Assignment Examiner Examiner
A
B.1
B.2
Marks (Max 30 )
Marks (out of 15 )

Signature of First Examiner Signature of Second Examiner

Assignment

Instructions to students:
1. The assignment consists of 3 questions.
2. Maximum mark is 30
3. The assignment has to be neatly word processed as per the prescribed format.
4. The printed assignment must be submitted to the course leader.
5. Submission Date:
6. Submission after the due date will not be accepted.
7. The maximum number of pages should be restricted to 15. Part A should be limited to 3
pages of A4 size.
8. IMPORTANT: It is essential that all the sources used in preparation of the assignment
must be suitably referenced in the text.
9. Marks will be awarded only to the sections and sub-sections clearly indicated as per the
problem statement.

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Contents
____________________________________________________________________________

Declaration Sheet ................................................................................................................................. ii

Contents............................................................................................................................................... ix
List of Tables ........................................................................................................................................ x
List of Figures .......................................................................................... Error! Bookmark not defined.
Question No. 1 ................................................................................................................................... 12
1.1 Overview: ................................................................................................................................. 12
1.2 Solution to the question: ........................................................................................................... 12
1.3 Discussions /Suggestions/Views/Recommendations ................................................................. 14
1.4 Conclusions............................................................................................................................... 14
Question No. 2 ................................................................................................................................... 15
2.1 Overview: ................................................................................................................................. 15
2.2 Solution to the question: ........................................................................................................... 15
2.3 Discussions /Suggestions/Views/Recommendations ................................................................. 15
2.4 Conclusions............................................................................................................................... 17
Question No. 3 ................................................................................................................................... 18
3.1 Overview: ................................................................................................................................. 18
3.2 Solution to the question: ................................................................ Error! Bookmark not defined.
3.3 Discussions /Suggestions/Views/Recommendations ................................................................. 18
3.4 Conclusions............................................................................................................................... 20

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PART A.1-Write an essay on orphan drugs in light of literatures and discuss their efficiency and safety

Identification of orphan drug

NITISINONE
Nitisinone (2-[2-nitro-4-trifluoromethylbenzoyl] cyclohexane-1,3-dione), an effective tri ketone
herbicide, is a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase which is the second enzyme in
the tyrosine production pathway. The drug has become an effective pharmacological treatment for
hereditary tyrosinemia type 1 (HT1). It can prevent the development of liver disease, reverse and prevent
the renal tubular dysfunction, severe neurological crisis and cardiomyopathy and significantly reduce the
risk of developing hepatocellular carcinoma in HT1 patients.
HEREDITARY TYROSINEMIA TYPE 1 (HT1)
Tyrosinemia type 1 is a rare genetic disorder characterized by elevated blood levels of the amino acid
tyrosine, a building block of most proteins. This condition is caused by a shortage of the enzyme
fumarylacetoacetate hydrolase, one of the enzymes required for the multi-step process that breaks down
tyrosine. This enzyme shortage is caused by mutations in the FAH gene. Symptoms usually appear in the
first few months of life and include failure to thrive, diarrhea, vomiting, jaundice, cabbage-like odour, and
increased tendency to bleed (particularly nosebleeds). Tyrosinemia type I can lead to liver and kidney
failure, softening and weakening of the bones, problems affecting the nervous system, and an increased
risk of liver cancer. This condition is inherited in an autosomal recessive manner.
TYROSINE METABOLISM AND NITISINONE MECHANISM OF ACTION
Nitisinone, is a drug which
does not cure tyrosinemia or
decrease tyrosine levels but
inhibiting the enzyme 4-
hydroxyphenyl pyruvate
dioxygenase (4-HPPD) which
catalyzes the conversion of 4-
hydroxyphenyl pyruvate (4-
HPP) to homogentisic acid
(HGA) as part of the Tyr
degradation pathway The
same mechanism was also

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confirmed in animal toxicology studies in the rat. Inhibition of 4-HPPD led to a profound increase in plasma
Tyr levels in rats and corneal lesions similar to those detected in tyrosinemia type-1 patients. This
inhibition of 4-HPPD could inhibit the production of toxic metabolites (fumarylacetoacetate [FAA],
maloylacetoacetate [MAA] and succinylacetone [SA]) which get deposited in liver and causes liver
diseases and kidney diseases which is complications of tyrosinemia. So, nitisinone used to treat the
complication of tyrosinemia.

SAFETY AND EFFICACY

Nitisinone has received approval from both the US FDA and the EU Drug Agency in January 2002 and
February 2005, respectively, without formal phase II, III, and IV clinical trials and is marketed as Orfadin®
(Swedish Orphan, Biovitrum, Stockholm, Sweden).

EFFECTS NITISINONE AND HEREDITARY TYROSINEMIA TYPE 1

HT1 is an autosomal recessive inborn error of Tyr metabolism caused by deficiency of the last enzyme in
the Tyr degradation pathway, “FAH”. Reduced activity of FAH leads to the accumulation of upstream
metabolites such as FAA and MAA, which in turn are converted to SA. Toxic metabolites FAA, MAA, SA
and succinylacetoacetate (SAA) causes various complications. The human FAH complementary DNA has
been mapped to chromosome 15q, and various mutations have been identified in the human FAH gene.
FAH is mainly expressed in liver and kidney cells, although a basal amount has been detected in many
tissues. Liver transplantation (LT) was the only choice of treatment and a life-saving procedure, although
renal dysfunction remained, as low Tyr diet was not effective in the acute form and had limited success in
the chronic form but LT as some chronic side effects and cost effective.
The introduction of nitisinone in 1992 has radically improved the natural course of the disease. This
drug was found to be effective not only in preventing the acute life-threatening complications of the
disease (eg, acute hepatic failure and neurological crises) but also in reducing the need for LT, improving
the survival and the quality of life in HT1 patients, especially when started in the new-born at starting
dose is 1–2 mg/kg BW per day. The initial dose can be adjusted down by monitoring nitisinone levels
without risking metabolic control as judged from plasma SA levels and SA excretion.

EFFECTS OF NITISINONE ON THE HEPATIC MANIFESTATIONS OF HT1

Infants presenting with acute hepatic dysfunction can rapidly develop severe liver dysfunction with a high
risk of mortality. Nitisinone administration results in a remarkable clinical response, where 90% of the

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patients respond completely. SA and δ-ALA decrease within the hours after the first dose of nitisinone.
The majority of infants who present clinically already have established cirrhosis, and treatment could
convert them to a stable chronic liver disease. In most cases, liver function and coagulopathy improve
within 1 week of treatment.
HCC (hepatic cell carcinoma) is the most important long term complication of HT1, nitisinone decreases
the risk of HCC compared to those before nitisinone treatment, as HCC incidence was reported to be 18%–
37% among children who have survived past their second birthday. Early treatment has been shown to
decrease the risk of HCC.

ADVERSE EFFECTS OF NITISINONE

 Development of corneal lesions treated with nitisinone, which also resulted in discovery of the
drug for treatment of HT1.
 Transient ocular symptoms such as irritation, corneal erosion, and photophobia have been
reported in patients who are poorly compliant with the diet.
 HT1 patients treated with nitisinone are found to be at risk of developing impaired cognitive
function and a total intelligence quotient (IQ) score
 Attention deficit; decreased ability to verbal reasoning, comprehension, and verbal expression;
and school difficulties are describing in HT1 patients treated with nitisinone.
 Mild gastrointestinal system complaints (diarrhoea, enanthema, gastroenteritis), transient
thrombocytopenia, and leukopenia have also been reported but this has rarely necessitated
discontinuation of therapy.

CONCLUSION

Nitisinone is the licensed, well-tolerated treatment for HT1 based on the inhibition of 4-HPPD in the Tyr
degradation pathway. The drug effectively prevents acute hepatic insufficiency, neurologic crises and
cardiomyopathy, improves liver functions, but cirrhosis with high grade dysplasia or hepatocarcinoma still
develops, especially in some late treated patients. Furthermore, normal liver function can be achieved in
children with HT1 detected by new-born screening and early treated within a month of birth. The
combination of neonatal screening plus early treatment is believed to be the best medical treatment of
choice for HT1.
REFERENCE: 1) Aktuglu-Zeybek, A.C. and Zubarioglu, T., 2017. Nitisinone: a review. Orphan Drugs:
Research and Reviews, 7, pp.25-35.

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2) McKiernan, P.J., 2006. Nitisinone in the treatment of hereditary tyrosinaemia type 1. Drugs, 66(6),
pp.743-750.

B.1 Discuss the challenges and recent advancements in Nipah outbreak managements

NIPAH
Nipah is a virus which commonly affects animals like bats, pigs, dogs, horses, etc. The virus can spread
from animals to humans and can sometimes cause serious illness among humans.

NIPAH VIRUS OUTBREAKS IN INDIA

In early 2001, there was an outbreak of infectious febrile illnesses, occurred in and around of Siliguri city
of northern part of West Bengal. Eighteen patient samples were sent to National Institute of Virology,
Pune, and NiV was detected in five urine samples by RT‐PCR, while another nine serum/blood samples
were found positive for NiV by IgM and IgG immunological assay
The second outbreak of NiV was surfaced during April, 2007 at village Belechuapara, near to Bangladesh
border area in Nadia district of the West Bengal. This outbreak was limited to five persons only, but case
fatality rate was 100% as all infected persons died within a week of infection.
Third and recent outbreak was reported from Kozhikode district of Kerala in southern part of India on
19 May 2018. This was the first experience of NiV outbreak in southern part of India. The outbreak started
with the death of three individuals within a family A total 10 (19.2%) samples out of 52 samples collected
were found positive for NiV by RT‐PCR. The human‐to‐human transmission of infection occurred through
droplet infection. The two costal districts (Kozhikode and Malappuram) of Kerala state were affected due
to NiV. As per the reports of Directorate of Health Services, Kerala, there were 13 deaths out of 14
confirmed cases in Kozhikode district, and three deaths out of four confirmed cases were reported from
Malappuram district.

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MODE OF TRANSMISSION
Transmission of Nipah virus to humans may occur
after direct contact with infected bats, infected
pigs, or from other Nipah virus infected people.
Routes of transmission of Nipah virus have also
been identified from its natural reservoir to human
through drinking of raw date palm sap
contaminated with NiV. However, human to
human transmission has been attributed as one of
the major modes of transmission in the epidemic
in Siliguri and in the current outbreak in
Kozhikode (Kerala) (May, 2018), India.
PATHOGENESIS
The exact pathogenesis mechanism of Nipah infection is still not very clearly documented. Nipah infection
primarily involves the blood vessels in the form of vasculopathy and vasculitis resulting in perivascular
cellular infiltration, inflammation and necrosis. Due to high viremia it is very likely that several cytokines
and chemokines are released causing vascular damage. Severity of the clinical symptoms and organ
involvement are most likely dependent on the extent of vascular damage.
Post-mortem evaluation: gross cerebral and pulmonary edema. Cross-section of the brain and lungs
showed evidence of gross pulmonary hemorrhage and cerebral congestion.
Pathological findings include:
 Vasculopathy and necrotizing vasculitis
 Cerebral oedema, with vascular congestion and focal haemorrhages.
 Pulmonary oedema with or without associated diffuse alveolar damage and haemorrhage.
 Neurons adjacent to vasculitis vessels may show eosinophilic infiltration and nuclear viral
inclusions.
 In relapse cases, histopathology revealed cerebral oedema, inflammation, thrombosis.

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THE CHALLENGES OF NIPAH VIRUS MANAGEMENT

SAMPLE COLLECTION: The samples should be collected as early as possible (preferably within 4-5 days on
onset of illness) with all biosafety precautions and accompanied with detailed history of patients on the
Performa which can be obtained from the testing laboratory. Hence, this results any mistake or delay in
the sample collection leads to danger and difficulties in treating the patients.

MODE OF TRANSMISSION: Transmission of Nipah virus to humans may occur after direct contact with
infected bats, infected pigs, or from other Nipah virus infected people. Two routes of transmission of
Nipah virus have also been identified from its natural reservoir to human: drinking of raw date palm sap
contaminated with NiV and close physical contact with Nipah infected patients. The person-to person
transmission may occur from close physical contact, especially by contact with body fluids. This results in
difficulties in controlling and preventing the transmission of nipah virus and being a challenge to the
treatment
RESISTANCE TOWARDS THE TREATMENT REGIMEN: Currently there is no known treatment or vaccine
available for either people or animals. But antiretroviral therapy has been started for prevent the
complications of diseases and increase the mortality. But, the nipah virus can easily start resistance
towards the drug by undergoing modifications or mutations by the virus. This results in challenge to the
treating the diseases.
PERIOD OF COMMUNICABILITY: There is-no clinical studies to suggest the period for which a patient will
shed Virus in different body fluids. In the absence of evidence, it is presumed that a person may be
infective from the day of onset of symptoms till 21 days. This improper evidence will lead to variation in
the maturation
Period of virus and hence being a challenge to treat the diseases.
NON COMMON SYMPTOMS: Moderate to high grade fever, Headache, vomiting, Cough, Breathlessness,
Change in behavior/sensorium Seizures/abnormal movement, Myalgia, Fatigue In the Siliguri outbreak,
the patients initially had fever (100%), headache and myalgia (57%), vomiting (19%), altered sensorium
(confusion to coma, 97%), respiratory symptoms (tachypnea to acute respiratory distress, 51%), and
involuntary movements or convulsions (43%). In the current outbreak of Nipah virus disease in Kerala it
has been noted that most of the patients presented with moderate to high grade fever and neurological
abnormal symptoms (severe) vomiting and general weakness along with myalgia. Cough and
breathlessness were also one of the presenting complaints seen in the majority of the patients. This results

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that different outbreaks of nipah virus the symptoms are not found to be specific or common. Hence it is
also a challenge to treat the diseases.
INEFFECTIVE CLINCAL TRIALS: The clinical trials for the discovery of the treatment of nipah virus is not
much effective and it is also economically highly expensive and cost ineffective. This results in lack of
treatment for nipah virus and which tends to be challenges of the treatment of infection.
THE RECENT ADVANCEMENTS IN NIPAH MANAGEMENT
There is no confirmed effective specific treatment for NiV infection in humans to date. The guiding
principles are:
• Early implementation of infection control precautions will minimize nosocomial household spread of
disease.
• Active surveillance, contact tracing and early identification and follow up of persons at risk.
• Provision for dedicated isolation facilities for patients must be created so that laboratory confirmed
Nipah cases as well as suspect cases are either kept in individual isolation rooms or cohorted (separate
ward for keeping confirmed and suspect cases) in a well ventilated isolation ward with beds kept at-least
one meter apart.
• Community contacts and hospital contacts who have gone back to the community are kept in home
quarantine. Hospital staff may be kept in home quarantine or in separate individual isolation room facility
in a hospital.
• Suspect and probable cases should be hospitalized in isolation facility as described above.
• There should be dedicated doctors, nurses and paramedics well trained in hospital infection control
practices and following the standard, contact and droplet precautions to attend to the suspect or
confirmed cases. Reinforce standard infection control precautions for all those entering the room must
use hand washing practices, high efficiency masks, gowns, goggles, gloves, cap and shoe cover.

Symptomatic and supportive treatment:

 Patient is advised to drink plenty of fluids.

 Fluidmaintenance and electrolyte balance.
 Fluid restriction, after initial resuscitation, is advisable in order to avoid fluid overload/
complication
 Nasogastric tube feeding/ parenteral nutrition may be instituted, if necessary.
 Paracetamol is suggested for fever, myalgia and Headache-Salicylate / aspirin is strictly contra-
indicated in any Nipah patient due to its potential complications.

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  The cases would be constantly monitored for clinical / radiological evidence of lower respiratory
tract infection and for hypoxia (respiratory rate, oxygen saturation, level of consciousness).
 Patients with signs of tachypnea, dyspnea, respiratory distress and oxygen saturation less than 90
per cent should be supplemented with oxygen therapy. Types of oxygen devices to be used would
depend on the severity of hypoxemia. It can be started from oxygen cannula, simple mask, panial
re-breathing mask (mask with reservoir bag) and non-re-breathing mask. Disposable cannula only
should be used for Oxygen inhalation. In children, oxygen hood or head boxes can be used. -
 Oropharyngeal or endotracheal suction when used should mandatorily be done using a closed
suction circuit to avoid dispersal of aerosol in the environment.
 Patients with severe pneumonia and acute respiratory failure (Sp02 900/0 and Pa02 «60 mmHg
with oxygen therapy) must be supported with mechanical ventilation. Invasive mechanical
ventilation is preferred choice.
 Noninvasive ventilation is an option when mechanical ventilation not available.
 Anticonvulsants e.g., intravenous diazepam, phenobarbitone, phenytoin or levetiracetam may be
used in the standard recommended doses. Mannitol could be used in case of raised Intracranial
tension.

 Suspected cases does not require antibiotic therapy. Antibacterial agents should be administered,
if required, as per locally accepted clinical practice guidelines. If required, patients on mechanical
ventilation antibiotics should be used judiciously to prevent hospital associated infections.
 Patients requiring Vasopressors for shock may be started on noradrenaline infusion with or
without dobutamine in cases with significant cardiac dysfunction.
 Use of steroids have not been shown to be effective in managing the neurological/' respiratory
involvement.
DRUG REGIMEN THERAPY
Ribavirin:
As currently there are no strong evidence of proven therapy, it is advisable to administer Ribavirin to all
confirmed cases of Nipah virus infection as per the available limited in vitro and in vivo evidences, subject
to approval of Drug Controller General of India

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Ribavirin is not a proven treatment for Nipah, and has only single open label trial evidence from Malaysia.
But the benefit was significant with 36% reduction in mortality. Therefore, in absence of other treatments,
and considering its safety profile, quite well in short term as well as longer experiences with Hepatitis
patients it has been recommended for use in confirmed Nipah infections. The suggested doses are based
on the WHO Guidelines for other hemorrhagic fevers, such as Lassa, Crimean Congo etc.
DOSE FOR RIBAVIRIN
For Adults
 2000 mg loading (10 tabs of 200 mg)
 Day 1-4 - 1000 mg 6hrly (5 tabs of 200 mg each 4 times daily for 4 days 80 tablets)
 Day 5-10-500 mg 6hrly (200 mg each tablet 3 tab - 3 tab - 2 tab - 2 tab at 6hrs gap daily for 6 more
days 60 tablets)
For Children
 Load 30mg, Thereafter, for Day 1-4 to give15 mg/kg 6hrly
 Day 5- Day 10 to give 7.5 mg/kg 6 hrly.
 On an average each patient (adult) would require 150 capsules for a10 days course.
Parenteral dose of Ribavirin.
IV Ribavirin
 loading dose of 30 mg/ kg
 then 15 mg / kg every six hourly for 4 days
 Then 7.5 mg/kg every eight hourly for 6 days.
 Ribavirin should be diluted in 150 ml of 0.9% Normal Saline and infused slowly.
Adverse reactions of Ribavirin:
reactions Serious Reactions can include hemolytic anemia, neutropenia, thrombocytopenia, aplastic
anemia, teratogenicity, embryocide, severe depression, suicidal ideation, autoimmune disorders,
pulmonary toxicity, pancreatitis, diabetes, hypothyroidism, hyperthyroidism, myocardial infarction,
arrhythmias, colitis, retinal haemorrhage, retinal thrombosis, or rarely, hypersensitivity.
Newer experimental drugs:
• Favipravir has recently been shown to be effective against Nipah viral infections in animal model.
• Immunomodulating drugs have not been found to be beneficial in treatment of ADRS or sepsis
associated multi organ failure. High dose corticosteroids in particular have no evidence of benefit
and there is potential for harm.

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Post exposure prophylaxis
Human monoclonal antibody:
Human Monoclonal antibodies targeting the viral glycoproteins (anti-G MAb or anti-F Mab) against
Hendra and Nipah have been shown since 2009 to be highly effective for post-exposure protection on
experimental animal. Its use in emergency setting is subject to approval of DCG(I).
Vaccines
• Experimental vaccines in which NiV proteins are expressed by various virus vectors represent an
attractive approach in NiV vaccine development. VSV-vectored Ebola vaccines are currently in
Phase III efficacy trials, suggesting that a similar safety and efficacy testing pathway might be
implemented for VSV vectored NiV vaccines. However, as mentioned previously, a subunit
vaccine called Equivac HeV®. This vaccine is formulated using 100 g of sG prepared from either
293F human embryonic kidney or CHO cells with a proprietary immunostimulatory complex
adjuvant. Currently, the vaccine is administered to horses by the intramuscular route as two
immunizations, three to six weeks apart followed by boosting at six month intervals.
• Other vaccines are composed of vector viruses (canary pox virus, Newcastle disease virus, and
vesicular stomatitis virus) expressing NiV glycoprotein and/or fusion protein. The recombinant
vesicular stomatitis virus vaccine also includes a Zaire ebolavirus glycoprotein, allowing the vaccine
to adequately elicit neutralizing antibodies to NiV after one dose, giving it an advantage during
possible emergency vaccination scenarios.
REFERENCES:
1) Marsh GA, de Jong C, Barr JA, , Tachedjian M, Smith C, Middleton D, Yu M, Todd S, Foord AJ,Haring V,
Payne J, Robinson R, Broz I, Crameri G, Field HE, Wang LF. Cedar virus: A novel Henipavirus isolated from
Australian bats. Plos Pathog. 2012;8(8).
2) Sample Collection and Transport Guidelines for laboratory diagnosis of Nipah virus infection
3) https://ncdc.gov.in/showfile.php?lid=241

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4) Satterfield, B.A., Dawes, B.E. and Milligan, G.N., 2016. Status of vaccine research and development of
vaccines for Nipah virus. Vaccine, 34(26), pp.2971-2975.

5) Field, H., Young, P., Yob, J.M., Mills, J., Hall, L. and Mackenzie, J., 2001. The natural history of Hendra
and Nipah viruses. Microbes and infection, 3(4), pp.307-314.

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B.2 In this context, identify any genetically acquired disease of your interest and identify the
proteins/genes (four) which is affected by that disease. Correlate the functions of those genes/diseases
with the disease characteristics.

AICARDI GOUTIERES SYNDROME

Aicardi Goutières syndrome is inherited as an autosomal recessive trait, although autosomal dominant
inheritance has been described in a few cases. The disorder is characterized by a combination of basal
ganglia calcification, leukodystrophy and cerebrospinal fluid (CSF) lymphocytosis. Pregnancy, birth and
the neonatal period are usually unremarkable, although onset within the first days is seen in around 20%.
The remaining cases present after a period of normal development with a severe, subacute
encephalopathy with feeding problems, irritability and psychomotor regression or delay. Associated
symptoms include epilepsy, chilblain skin lesions on the extremities and episodes of aseptic febrile illness.
The disorder progresses over several months, and microcephaly, pyramidal signs and psychomotor
retardation.
Some people with Aicardi-Goutières syndrome
have features characteristic of autoimmune
disorders, which occur when the immune system
malfunctions and attacks the body's own systems
and organs. Some of these features overlap with
those of another disorder called systemic lupus
erythematosus (SLE). A feature of SLE that also
occurs in about 40 percent of people with Aicardi-Goutières syndrome is a skin problem called chilblains.
Chilblains are painful, itchy skin lesions that are puffy and red, and usually appear on the fingers, toes,
and ears.
CAUSES

Genes Chromosomal location

 TREX 1 3p21.31, the short (p) arm of chromosome 3 at position 21.31
 RNASEH2A 19p13.13, the short (p) arm of chromosome 19 at position 13.13
 RNASEH2B 13q14.3, the long (q) arm of chromosome 13 at position 14.3
 RNASEH2C 11q13.1, the long (q) arm of chromosome 11 at position 13.1

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  SAMHD1 20q11.23,the long (q) arm of chromosome 20 at position 11.23
 ADAR 1q21.3, the long (q) arm of chromosome 1 at position 21.3
 IFIH1 2q24.2, the long (q) arm of chromosome 2 at position 24.2
Mutations in several genes can cause Aicardi-Goutières syndrome. Several genes like

ROLES OF THE GENE AND CAUSES DUE TO MUTATION

A) RNASEH2B (RIBONUCLEASE H2 SUBUNIT B)

Normal function
The RNASEH2B gene provides instructions for making one part (subunit) of a group of proteins called the
RNase H2 complex. This complex is a ribonuclease, which means it is an enzyme that helps break down
molecules containing RNA, a chemical cousin of DNA. In particular, the RNase H2 complex normally helps

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break down molecules in which one strand of RNA is combined with one strand of DNA (RNA-DNA hybrids)
when these molecules are no longer needed. RNA-DNA hybrids are formed during DNA copying
(replication) and are found in all cells. The RNase H2 complex is also thought to be involved in DNA
replication, error repair, and other cellular processes, including helping to prevent inappropriate immune
system activation.
In AGS
The RNASEH2B gene mutations that cause Aicardi-Goutières syndrome likely result in a dysfunctional
RNase H2 complex. Abnormal functioning of this complex may disrupt transcription, DNA replication,
DNA repair, cell death (apoptosis), or other processes. Such disruptions are thought to lead to the
accumulation of unneeded DNA and RNA in cells. These DNA and RNA fragments may be mistaken for
the genetic material of viral invaders, triggering immune system reactions in multiple body systems that
cause severe brain dysfunction (encephalopathy), skin lesions, and other signs and symptoms of Aicardi-
Goutières syndrome.

B) TREX 1 (THREE PRIME REPAIR EXONUCLEASE 1)

Normal function
The TREX1 gene provides instructions for making the 3-prime repair exonuclease 1 enzyme. This enzyme
is a DNA exonuclease, which means that it trims molecules of DNA by removing DNA building blocks
(nucleotides) from the ends of the molecules. In this way, it breaks down unneeded DNA molecules or
fragments that may be generated during copying (replication) of cells' genetic material in preparation for
cell division. These fragments may also be generated during DNA repair, cell death (apoptosis), and other
processes.
In AGS
Most of these mutations are believed to prevent the production of the 3-prime repair exonuclease 1
enzyme. Researchers suggest that the absence of this enzyme results in an accumulation of unneeded
DNA and RNA in cells. These DNA and RNA molecules may be mistaken by cells for the genetic material of
viral invaders, triggering immune system reactions that damage the brain, skin, and other organs and
systems and result in the signs and symptoms of Aicardi-Goutières syndrome.
c)SAMHD1 (SAM AND HD DOMAIN CONTAINING DEOXYNUCLEOSIDE TRIPHOSPHATE
TRIPHOSPHOHYDROLASE 1)
normal function

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The SAMHD1 gene provides instructions for making an enzyme that helps cut (cleave) molecules called
deoxynucleoside triphosphates (dNTPs) into their deoxynucleoside and triphosphate components. The
dNTP molecules are needed for the replication and maintenance of the genetic material (DNA) in the
body's cells, and the amount of available dNTPs must be tightly controlled for these functions to proceed
normally. Invading viruses such as the human immunodeficiency virus (HIV) also need dNTPs in order to
replicate themselves. The SAMHD1 enzyme helps regulate the amount of available dNTPs to both meet
the needs of the body's cells and control viral infections.
In AGS
Research suggests that mutations in this gene may lead to production of a SAMHD1 protein that does not
properly regulate the amount of available dNTPs. As a result, DNA maintenance is impaired, allowing DNA
damage to accumulate in cells. Research suggests that this DNA damage may lead to cell signaling that
inappropriately activates an immune response. As a result, the immune system attacks the body's own
tissues and organs, causing inflammatory damage to the brain, skin, and other body systems that lead to
the characteristic features of Aicardi-Goutières syndrome.

D) IFIH1 GENE (INTERFERON INDUCED WITH HELICASE C DOMAIN 1)

normal function
IFIH1 gene provides instructions for making the MDA5 protein, which plays an important role in innate
immunity, the body's early, nonspecific response to foreign invaders (pathogens) such as viruses and
bacteria. In particular, the MDA5 protein recognizes a molecule called double-stranded RNA (a chemical
cousin of DNA), which certain viruses, including rhinovirus, respiratory syncytial virus (RSV), and the
influenza (flu) virus, have as their genetic material or produce when they infect cells and copy (replicate)
themselves. When pieces of viral RNA are present inside a cell, multiple MDA5 proteins attach to it, one
after another, forming a filament. Filament formation stimulates signals that turn on the production of
immune system proteins called interferons. Interferons control the activity of genes that help block the
viruses from replicating themselves and stimulate the activity of certain immune system cells to fight
infection. Interferons also help regulate inflammation, which is another part of the body's innate immune
response.
In AGS
IFIH1 gene mutations involved in Aicardi-Goutières syndrome are described as "gain-of-function" because
they lead to production of an MDA5 protein with enhanced activity. The altered protein may more readily
attach to RNA, even pieces of RNA that are not from viruses, or to other MDA5 proteins to form filaments.

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Alternatively, filaments containing the altered protein may not be broken down when immune signaling
is no longer needed. As a result of these changes, interferon production is abnormally turned on, leading
to excessive immune system activity and inflammation.
Constant inflammation is thought to disrupt the way calcium is handled in the body, leading to calcium
deposits in people with Aicardi-Goutières syndrome. Excessive inflammation is also thought to damage
cells in the brain and skin, leading to the abnormalities in these tissues characteristic of this disorder.

REFERENCES:
1) Crow, Y.J. and Rehwinkel, J., 2009. Aicardi-Goutieres syndrome and related phenotypes: linking nucleic
acid metabolism with autoimmunity. Human molecular genetics, 18(R2), pp. R130-R136.
2) Chon H, Vassilev A, DePamphilis ML, Zhao Y, Zhang J, Burgers PM, Crouch RJ, Cerritelli SM. Contributions
of the two accessory subunits, RNASEH2B and RNASEH2C, to the activity and properties of the human
RNase H2 complex. Nucleic Acids Res. 2009 Jan;37(1):96-110.

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