Porphyrias is a heterogeneous group of 8 heme biosynthesis disorders that are either inherited or acquired as a result of the defective activity of certain enzymes involved in the biosynthesis of haem. The defects in this pathway leads to the accumulation of intermediates known as porphyrins or porphyrin precursors.. The excess amounts of porphyrins and their precursors accumulate in the body causing clinical abnormalities. It is usually due to an inherited mutation in the gene for that specific enzyme except in porphyria cutanea tarda (PCT), the most common of the porphyrias which is acquired. Effects can vary from minor porphyria attacks to asymptomatic presentations but can be life threatening to others. Many people live their lives never knowing they have it.

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PORPHYRIA
SUBMITTED BY:
RHEA ANN EXPIDITE (20MSG0059)

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INTRODUCTION
● Porphyrias is a heterogeneous group of 8 heme biosynthesis
disorders that are either inherited or acquired as a result of
the defective activity of certain enzymes involved in the
biosynthesis of haem.
● The defects in this pathway leads to the accumulation of
intermediates known as porphyrins or porphyrin precursors..
The excess amounts of porphyrins and their precursors
accumulate in the body causing clinical abnormalities.
● It is usually due to an inherited mutation in the gene for that
specific enzyme except in porphyria cutanea tarda (PCT), the
most common of the porphyrias which is acquired.
● Effects can vary from minor porphyria attacks to
asymptomatic presentations but can be life threatening to
others. Many people live their lives never knowing they have it.

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TYPES OF PORPHYRIA:
PREVALENCE OF THE DISEASE:
● The prevalence of Porphyria globally can range from 1 in every 500 to 1 in every 50,000
individuals.
● Porphyria Cutanea Tarda (PCT) is found to be approximately 1 in every 5000-10000 individuals. Acute
Intermittent Porphyria (AIP) is found almost one in every 20,000 individuals.
● More commonly seen in countries in the Northern European regions, United Kingdom, smaller
countries like Sweden.

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INHERITANCE:
● Some types of porphyria are inherited in an autosomal dominant pattern.
● This single mutation is sufficient to reduce the activity of an enzyme needed for
heme production, which increases the risk of developing signs and symptoms
of porphyria.
● Autosomal dominant porphyrias include acute intermittent porphyria, most
cases of erythropoietic protoporphyria, hereditary coproporphyria, and
variegate porphyria.
● Other types of porphyria are inherited in an autosomal recessive pattern which
means both copies of the gene in each cell have mutations.
● Most often, the parents of an individual with an autosomal recessive condition
each carry one copy of the mutated gene, but do not show signs and
symptoms of the condition.
● Porphyrias with an autosomal recessive pattern of inheritance include ALAD
deficiency porphyria, congenital erythropoietic porphyria, and some cases
of erythropoietic protoporphyria.

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GENES INVOLVED:
● Each form of porphyria results from mutations in one of these genes: ALAD,
ALAS2, CPOX, FECH, HMBS, PPOX, UROD, or UROS.
● About 20 percent of cases are related to mutations in the UROD gene. The
remaining cases are not associated with UROD gene mutations and are classified
as sporadic.
● Mutations in most of these genes reduce enzyme activity, which limits the
amount of heme the body can produce. As a result, compounds called
porphyrins and porphyrin precursors, which are formed during the process of
heme production, can build up abnormally in the liver among other organs.
● Mutations in the UROD gene are related to both porphyria cutanea tarda and
hepatoerythropoietic porphyria. Individuals who inherit one altered copy of the
UROD gene are at increased risk for porphyria cutanea tarda.
● People who inherit two altered copies of the UROD gene in each cell develop
hepatoerythropoietic porphyria.

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● When erythropoietic protoporphyria is caused by mutations in the
ALAS2 gene, it has an X-linked dominant pattern of inheritance. The
ALAS2 gene is located on the X chromosome.
● In females (2 X chromosomes), a mutation in one of the two copies of
the gene in each cell may be sufficient to cause the disorder. In males (
one X chromosome), a mutation in the only copy of the gene in each cell
causes the disorder. Males may experience more severe symptoms of
the disorder than females. A characteristic of X-linked inheritance is that
fathers cannot pass X-linked traits to their sons.

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CLINICAL MANIFESTATIONS of ACUTE PORPHYRIAS:
▪ The clinical manifestations/ signs and symptoms of porphyrias are often non specific and may
coincide with other commonly seen diseases making it difficult to be diagnosed.
▪ Acute porphyrias usually have effects on the nervous system in the form of acute attacks.
TYPE SYMPTOMS
AIP • Occurrence of acute neurovisceral attacks. Attacks affect the visceral, peripheral, ANS and CNS.
• Severe abdominal pain, nausea, vomiting, tachycardia, hypertension, hyponatremia, anxiety, agitation.
• Most patients present with latent/ pre-symptomatic AIP- difficult to diagnose
HCP • Symptoms of the attack are similar to AIP, almost indistinguishable.
• Number of attacks fewer as compared to AIP.
VP • Adult onset cutaneous blistering lesions (bullae, subepidermal vesicles, etc) most commonly seen on
sun exposed skin of the face and hands. Scarring, thickening, increased and decreased skin
pigmentation.
• Acute neurovisceral symptoms are highly variable but may be similar to the ones observed in cases of
AIP.
ADP • No cutaneous manifestations, only neurovisceral symptoms.
• ALAD activity is decreased by 50% in ADP patients.

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CLINICAL MANIFESTATIONS of CUTANEOUS PORPHYRIAS:
▪ Cutaneous Porphyrias usually show clinical manifestations in the form of cutaneous
symptoms such as skin fragility and phototoxicity. The commonly seen symptoms for each
type of cutaneous porphyria has been mentioned below:
TYPE SYMPTOMS
PCT • Skin abnormalities, photosensitivity leading to blistering skin lesions and skin fragility (peeling skin)
• Scarring, hyperpigmentation, hypopigmentation, hypertrichosis, milia
• Liver dysfunction in the form of hepatic siderosis, steatosis, periportal fibrosis, etc
CEP • Symptoms start in infancy/childhood. Extreme photosensitivity (skin lesions in the form of bullae,
vesicles). Red urine is a common symptom of CEP.
• Anemia, Hemolysis, Splenomegaly, Erythrodontia, Erythema, Edema, Hypertrichosis.
EPP • Hypersensitivity of skin to sunlight- swelling, burning, itching sensations and redness of skin
• Blistering is not commonly observed delaying diagnosis
• Rare cases- biliary system is affected (gallbladder and bile ducts) causing gallstones, cholestasis,
cholecystitis, etc.
HEP • Clinical manifestations usually during infancy itself- extreme photosensitivity (scarring and erosions)
• Pink to red coloured urine is a common symptom of HEP in infants.
• Mild to severe anemia.

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SCREENING TESTS:
● Porphyria is caused due to the accumulation of large amounts of porphyrin
precursors and porphyrins in the body. They accumulate first in the liver and
bone marrow followed by appearance in blood and finally excreted out in the
urine and feces.
● Therefore the primary tests for Porphyrias is testing for the presence of excess
amount of porphyrins and its precursors in the blood, urine and feces.
● Before carrying out diagnostic tests, sensitive and specific screening tests are
usually performed which are more cost effective and can help avoid
unnecessary diagnostic medical tests as in most cases the symptoms presented
may not always be a result of porphyria.
✔PBG measurement tests:
Measurement of porphobilinogen in urine is used for testing the presence of
acute porphyrias.
✔Urine ALA + PBG measurement tests:
Often account for ADP if the results shows increased ALA and decreased PBG.
✔Total plasma porphyrins:
Can be used for screening patients with skin photosensitivity and used to test for
cutaneous porphyrias in most cases.

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DIAGNOSTIC TESTS:
● Fecal Porphyrins:
HPLC techniques are used diagnostically for measuring fecal porphyrins in order to detect HCP and
VP types of Porphyria. This form of measurement is done less for diagnosis of PCT or EPP.
● Blood Tests:
Serum and plasma from blood is also commonly used for diagnosing Porphyrias. Types of
Porphyrias associated to photosensitivity are differentiated using plasma total porphyrin
measurement by fluorescence scanning (differentiates between skin blistering forms of VP and PCT)
● Erythrocyte Porphyrin Measurement:
EPP can be diagnosed successfully by measuring the amount of erythrocyte porphyrins in the blood
sample. An EPP diagnosis is usually confirmed with the help of an ethanol extraction procedure
indicating increased erythrocyte protoporphyrin.
● Erythrocyte Enzymes Tests:
Assays for enzymes of the heme biosynthetic pathways such as PBGD, ALAD, UROD are used in
cases of family studies wherein deficiency of certain enzymes has already been established in the
index patients.
● DNA Tests/ Genetic Testing:
DNA Tests for specific mutations can also be carried out for determining the presence of carriers of
the disease in the family. Presence of the PBGD gene mutation can act as an ultimate form of
diagnosis for Porphyrias.

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TREATMENT OF ACUTE PORPHYRIAS:
Acute attacks often require symptomatic treatment for the varied manifestations
of the condition.
● Heme preparations are the treatment of choice for acute attacks.
● Heme arginate and lyophilized hematin are usually infused daily (3–4 mg/kg).
● An adequate intake of calories should be ensured, given orally as
carbohydrate-rich food supplements or infused as normal saline with 5%
dextrose, during severe vomiting to downregulate the activity of ALA synthase
and prevent fasting.
● High doses of opiates in combination with an antiemetic and a phenothiazine,
such as chlorpromazine for anxiety and restlessness.
● Therapy with Beta-blockers for tachycardia and hypertension.
● Gene therapies, such as Givlaari™ (givosiran).
● Any precipitating factors—especially drugs (including oestrogens and
progesterone)—must be avoided.
● Sun avoidance, use of protective clothing, use of opaque sunscreens are
crucial to skin symptoms in VP and HCP.

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TREATMENT OF CHRONIC PORPHYRIAS:
● Predisposing factors such as alcohol and oestrogen intake should be eliminated.
● In PCT, phlebotomy is the treatment of choice, particularly in patients with iron
overload.
● Chloroquine treatment (100–200 mg twice per week).
● Few cases of PCT with chronic renal failure have been supplemented with
erythropoietin during phlebotomies.
● For HEP patients, the treatment is based on sun avoidance measures and
phlebotomy, chloroquine are not effective.
● Protection from sunlight is the mainstay of EPP and photo-intolerance can be
improved with UVB phototherapy.
● Afamelanotide has been proposed as a way to induce the production of photo-
protective epidermal melanin.
● Oral ß carotene (75–200 mg per day) increases light tolerance.
● CEP is also centered on complete total sun and UV protection, as well as diligent
skin care.
● The sole curative treatment is allogeneic bone marrow transplantation

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GENETIC COUNSELING:
● If a person tests positive for porphyria, it is
recommended to meet a physician and genetic
counselor.
● They will discuss your test results and talk to you
about the inheritance of the disease, the type of
testing to diagnose it, and how the disease could
affect your life.
● For example, they could advise us to avoid sunlight
if we have one of the cutaneous (skin) porphyrias.
● They could also talk to you about medications to
avoid if you have acute porphyria.

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WHY GENETIC COUNSELING?
● It can help them learn more about their disease type and guide them in
understanding how the disease might affect your life and that of their family.
● Make them more aware of the disease progression and treatment options.
● Genetic counselors analyze personal and family health history, so that they
can find out the probability of a recessive condition.
● Analyze any symptoms and any test results they might already have had and
then calculate the odds of the potentially of having a form of porphyria.
● These information helps them to decide whether to go for a genetic testing.
● If a genetic test is already conducted, genetic counselor will discuss its results
with you, and what follow-up testing you may need.
● Help to put test results into practical terms, including what they mean for your
life ahead.
● A genetic counselor can also help you to find a support network that can give
you encouragement and advice on how to live with porphyria

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WHEN IS IT REQUIRED?
● When we are planning to have children but we are
affected with porphyria or if it is running in the family, we
can speak with a counselor about the risk of your
children inheriting the disease.
● If a person or his child are showing the symptoms of
porphyria.
● When a person or his family member are tested positive
for the disease, genetic counseling helps us to have
more idea of disease progression and if genetic testing is
needed.
● They can also work with your physician to help you
decide on treatment options to manage
● If we feel anxious, sad, or depressed — a type of
“survivor’s guilt ” especially if another family member has
tested positive.
● If you are experiencing any of these feelings, you should
discuss them with your physician, genetic counselor, or
therapist.

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GENETIC TESTING:
● Genetic testing is rarely required to make a diagnosis of porphyria and, by itself, may
be misleading if a mutation is not found or unclassified variants are identified.
● It helps us to choose a lifestyle that reduces the risk of manifesting the disease and
allows for awareness of potential long-term complications.
● Genetic testing should be done to avoid known triggers, because several drugs and
behavioral factors are potential attack inducers.
● Genetic testing is being done in the case of the autosomal dominant acute
porphyrias to identify presymptomatic carriers of the family specific pathogenic
mutation.
● At present the additional genetic factors that influence penetrance are not known,
and all patients are treated as equally at risk.
● Genetic testing in the erythropoietic porphyrias is focused on predictive and
preconceptual counselling, prenatal testing and genotype-phenotype correlation
● Recent advances in analytical technology have resulted in increased sensitivity of
mutation detection with success rates of greater than 90% for most of the genes.
● Current research into genetic factors that affect penetrance is likely to lead to a
more refined approach to counselling for presymptomatic gene carriers.

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Challenges faced during diagnosis and treatment of
Porphyria
● Porphyrias are usually accompanied by high degree of symptom variance. Hence a high index of
suspicion is needed to suspect the disease, but the diagnosis is readily established by testing for
increased PBG.
● AIP presents exclusively with neurological symptoms that develop after puberty, including abdominal
pain.
● Certain drugs, steroid hormones, alcohol, and reduced food intake are among the factors that can
provoke attacks of AIP.
● It is likely that empiric use of harmful drugs (including diclofenac, metronidazole, diazepam, and
phenytoin) in the absence of a specific diagnosis and reduced food intake contributed to progression
of the disease in patients.
● Biochemical testing showing a substantial increase in PBG is a simple, sensitive, and specific
method for diagnosis of the three most common acute porphyrias, including AIP
● Haem arginate, used to cure AIP, variegate porphyria,and hereditary coproporphyria is an orphan
drug . It is rare and can be procured only by government assistance.
● It is very expensive and not easy to procure as it is only manufactured in the US and Europe.
● Liver transplantation which is currently the only effective treatment available for the most seriously
affected patients is a high-risk procedure and should be considered only as a last resort in patients
with severe recurrent attacks.

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GIVOSIRAN, a novel treatment for acute hepatic porphyrias
● Givosiran is synthetic small interfering RNA (siRNA) molecule directed against 5-
aminolevulinic acid synthase(the first and rate limiting enzyme in the heme
biosynthetic pathway) that is used to treat acute hepatic porphyria.
● The accumulation ALA/PBG induces porphyria symptoms
● Givosiran results in reduction of ALAS1 mRNA and lowers ALA/PBG accumulation
to prevent attacks and disease symptoms
● By interfering with ALAS1 expression, givosiran prevents the buildup of delta-
aminolevulinic acid (ALA) and porphobilinogen (PBG), the accumulation of
which is central to the pathogenesis of acute attacks and chronic symptoms in
acute hepatic porphyria.
● The Food and Drug Administration (FDA) has approved the treatment of adult
patients with AHP, and it received also approval in the E.U. in 2020 for the
treatment of AHP in adults and adolescents aged 12 years and older. Until
recently, IV hemin was the only definitive treatment option available.

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● The drug can cause elevated liver enzymes, elevations in serum creatinine, and injection site
reactions. Single doses, given to asymptomatic persons with AIP who are chronic high
excretors of ALA and porphobilinogen caused decreases in CYP1A2 and CYP2D6 activity,
raising concern for drug interactions.
● The acute hepatic porphyrias are rare, and the pivotal trials of givosiran were conducted in
rather small numbers of patients, so the full spectrum of hepatotoxicity may not be fully
known.
● To minimize risks in pregnancy, the use of a highly effective method of birth control while
women are taking givosiran is required in all protocols.
● Nevertheless, in the registration controlled trials, serum aminotransferase elevations arose in
13% of givosiran- versus 2% of placebo-recipients, but rose to levels above 5 times the upper
limit of normal only rarely.
● Givosiran Treatment Led to Rapid Reduction of Attacks Sustained Over Time a Month
➔ Patients who continued givosiran treatment had sustained or enhanced reduction in
average attacks per month over time
➔ Continued givosiran treatment led to sustained reductions in hemin use with 70% of
patients requiring zero days of hemin.
➔ Continued givosiran treatment led to a further decrease in patient-reported daily worst pain
score

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ADVANTAGES
● Breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) and European
Medicines Agency.
● Showed significantly lower rate of attacks in patients with acute intermittent porphyria.
● Annualized rates of porphyria attacks and hemin use is seen to be reduced drastically.
● It could reduce the toxic metabolite levels and also the need of hemin treatment upto 83 percent
● Only mild to moderate reversible adverse effects could be seen in patients undergone treatment with
Givosiran.
● Once-monthly treatment with givosiran resulted in sustained reductions in ALAS1 mRNA, ALA, and PBG
levels to near normal.
● Exposure levels of givosiran in extrahepatic tissues is shown to be so low that they would not be
expected to result in pharmacodynamic activity.
DISADVANTAGES
● Treatment with Givosiran shown to have a higher frequency of hepatic and renal adverse events,
including chronic kidney disease.
● patients who received givosiran were more likely to have nausea, chronic kidney disease [CKD], a
decreased estimated glomerular filtration rate, rash, liver damage, and fatigue than were those who
received placebo
● Serious adverse events included worsening of [CKD] and abnormal liver-function results; the latter led to
the discontinuation of givosiran by one patient

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NEXT GENERATION SEQUENCING FOR THE
DETECTION OF PORPHYRIA
● In the case of patients who have not yet shown any symptoms, it is not likely to see any
biochemical abnormalities in porphyrin precursors,, aminolevulinic acid and
porphobilinogen etc.
● Hence it becomes difficult to diagnose different forms of porphyria.
● In such cases genetic analysis becomes an apt method to diagnose porphyrias.
● In a research conducted, For carrying out the mutational analysis of dominant acute hepatic
porphyrias, a panel containing the four genes ALAS1, HMBS, CPOX and PPOX was created
.
● This panel panel covered 92% of the exons of the four genes, and 100% of the HMBS
gene specifically.
● This method is able to replace the sanger method in AIP diagnosis
● The NGS technique requires very less sample of DNA and genetic analysis can also be
carried out in biopsy samples.
● It takes less time and is more sensitive
● The sanger sequencing results and NGS results were shown to have a 98 % similarity.
● As a next step researchers are planning to integrate the AHP panel to diagnostic
routine.

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Gene Therapy for AIP using rAAV Vector
● A recombinant adeno-associated vector (rAAV 2/5- PBGD) with a liver specific
promoter was developed for increasing the PBGD expression as a gene
therapy for treatment of AIP.
● The vector consists of AAV serotype 2 genome elements and AAV serotype 5
capsid proteins.
● The vector expresses itself under the control of a liver specific promoter, codon
optimised PBGD gene.
● Studies conducted in AIP mice demonstrated that increasing the expression
of 5-10% of hepatocytes was sufficient in preventing ALA and PBG
accumulation.
● Further human phase-1 trial revealed a cross metabolization of haem
precursors from non transduced neighbouring cells and overexpressing
PBGD hepatocytes thereby preventing the blood secretion of ALA and PBG.

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Gene Therapy for AIP using rAAV Vector
(contd...)
● The human phase 1 clinical trial confirmed the safety and tolerability of AAV-
vector gene therapy but higher doses and/or more efficient vectors are needed
to achieve therapeutic expression of the transgene.
● These studies support the inclusion of two ADRES elements before the AAT
promoter in gene therapy vectors for AIP as an enhancer element of
therapeutic PBGD expression
● The insertion of two tandem ADRES elements in the promoter driving the
expression of the PBGD transgene of an AAV vector allows the effective dose to
be lowered by ten while maintaining protection against acute attack.
● Therefore, an AAV-PBGD vector carrying this regulatory element would be
expected to markedly increase therapeutic transgene expression in clinical
trials of AAV-mediated gene therapy for AIP or, analogously, for the other acute
porphyrias.

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CRISPR
● A potential method for correction of defective genes leading to Porphyria is the
utilization of the CRISPR system, in order to edit the genes directly inside the cell.
● In CRISPR the exact location of the affected gene is identified by taking a cell
sample from the patient and the mutated gene is compared to wild type genes
which help in identifying the potential disease causing mutations in it.
● A wild type gene can be artificially mutated and inserted into the somatic cell
once the location of the potential nucleotide mutation has been identified. In
case of Porphyria, the levels of porphyrin precursors in the cells act as an
indicator of the disease causing mutation.
● Guide RNAs complementary to the area of the gene mutations are then utilized
to lead the CRISPR attached to the Cas9 to the mutation site wherein Cas9 helps
in precisely cutting the mutated nucleotides. This nullifies the effect of the
disease causing mutation permanently.

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CRISPR contd...
● A 2019 study was conducted using a Cas9 nuclease induced double-strand break DNA (DSB) at
the UROS locus to model and correct congenital erythropoietic porphyria(CEP) which is caused
by a profound deficiency in the enzymatic activity of uroporphyrinogen III synthase(UROS)
gene.
● The results obtained revealed a higher number of on-target indels, causing unwanted
dysfunctional protein characteristics as well as unexpected chromosomal truncations.
● The on-target Non homologous end joining (NHEJ) activated in response to DNA DSBs is a major
limiting factor for Precise Genome Editing (PGE).
● Altogether, these side effects limited the promising perspectives of the CRISPR-Cas9 nuclease
system for disease modeling and gene therapy.
● For this reason, another approach demonstrating the use of a single nickase method for
homozygous mutation modelling in CEP was used.
● This approach allows PGE at the locus with all regulatory elements of the promoters and an ideal
physiological enzymatic rescue. It strongly reduced genotoxic terminal chromosomal deletion
mediated by DSB in two cell lines.
● Importantly, this approach is devoid of off-target indels and should be preferred to DSB nuclease
approach.

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CRISPR contd...
● Another recent study proposed the correction of two heterozygous
mutation in the UROS gene of a CEP patient using the CRISPR/Cas9
gene editing technology. (Prat, Florence et al., 2020)
● A comparison of the editing efficiency and genotoxicity by biallelic
gRNA versus allele-specific gRNA was involved in this study.
● It showed that a mutant allele-specific guide was mandatory to
perfectly correct cells without on-target indels and obtain efficient
correction of CEP recessive disease with compound heterozygous
mutations.
● This study proposes a potential design for avoiding genotoxicity and
obtaining on-target scarless gene correction for recessive disease with
frequent cases of compound heterozygous mutations.

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CONCLUSION
● In conclusion, the current treatment measures majorly focus on symptom interventions
and management of the condition.
● Although diagnosis and symptom management is crucial to porphyria control, further
emphasis should be placed on finding effective cures to the disease.
● As porphyria is genetic, the only way to completely cure the disease is to repair the
gene itself.
● Methods such as viral gene therapy, siRNA therapy (Givosiran) and CRISPR
(clustered regularly interspaced short palindromic repeats) Cas9 protein could
potentially be utilized to cure porphyria in patients.
● These potential methods are either conceptual or still under experimental investigation
and have many issues to be resolved before they can be used clinically.

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