2. Content
What is Albinism ?
The problems associated with it
Types of Albinism
Genetics of Albinism
Diagnosis
Treatment options
Gene therapy of Albinism
3. Albinism and it causes
Albinism (from Latin albus ‘’white’’) is an inherited disease, which characterized
by the partial or complete absence of the pigment melanin, that affects the
skin, hair, eyes and vision
Caused , due to absence or defect of an enzyme involved in the production of
melanin(pigment)
It vary in severity and often causing white skin, light hair, and vision problems.
Albinism is known to affect all vertebrates
All ethnic backgrounds can have it. Albinism is widespread in areas of the
globe nearer to the equator.
In sub-Saharan Africa, albinism affects one in every 5,000 to 15,000 people.
Among some groups, the rate is as high as 1 in 1,000 to 5,000. According to
the National Organization for Albinism and Hypo pigmentation, about 1 in
17,000 to 20,000 people In Europe and the United States.
4. Cont.
Albinism results from inheritance of recessive gene alleles, which is a group
of disorders caused by impaired production of the pigment melanin
albinism can result from mutations in several genes,
including TYR, OCA2, TYRP1, and SLC45A2.
Melanin production is tightly regulated in the body and occurs in specialized
ectodermally-derived cells called melanocytes. Melanocytes may be
cutaneous (hair, skin) or extracutaneous (eye, cochlea), each deriving from a
distinct ectodermal lineage
Melanin is synthesized from the amino acid Tyrosine by a Tyrosinase enzyme
.
People with albinism have been passed down a nonfunctional tyrosinase
allele, which does not allow them to produce melanin.
6. The primary symptoms of albinism can affect the
skin, hair, eye color, and vision.
Skin
The most obvious sign is a lighter skin tone, but skin tone does not
always differ substantially.
In some people, levels of melanin slowly increase over time, darkening
skin tone as the person ages.
freckles
moles, usually pink in color due to the reduced quantities of pigment
lentigines, large freckle-like spots
At higher risk than average of skin cancer risk of skin cancer • no
natural protection against the sun
7. Cont.
Hair
This can range in color from white to brown. Those of African or Asian
descent tend to have yellow, brown, or reddish hair.
As the individual ages, their hair color may slowly darken.
Eyes and Vision
Eyes color varies from very light blue to brown.
The eyes can appear slightly translucent and, in certain light, look red or
pink as the light reflects off the retina at the back of the eye.
Sensitivity to light, known as Photosensitivity/Photophobia
Nystagmus: This is an involuntary movement of the eyes, usually from
side to side but sometimes also up and down. .
Strabismus: The eyes do not function in unison.
8. Cont.
Eyes and Vision
Amblyopia: Also referred to as a "lazy eye."
Myopia or hypermetropia/Refractive error: The person may have extreme
nearsightedness or farsightedness.
Optic nerve hypoplasia: Visual impairment may result from an underdeveloped
optic nerve.
Foveal hypoplasia: The retina , the surface inside the eye that receives light,
does not develop normally before birth and in infancy.
Optic nerve misrouting: Nerve signals from the retina to the brain follow
unusual nerve routes.
Astigmatism: An abnormal inflexibility of the front surface of the eye or lens
results in blurred vision.
10. There are two main categories of albinism in humans:-
Oculocutaneous Albinism (OCA) it is an autosomal recessive disease affecting
the eyes, skin and hair. Researchers have identified multiple types of OCA, which
are distinguished by their specific skin, hair, and eye color changes and by their
genetic cause, There are 7 types of OCA :-
OCA1.
OCA2.
OCA3.
OCA4.
OCA5-OCA7
Ocular Albinism (OA) affecting the eyes only.
People having ocular albinism only lacks pigment in the eyes. They usually have
normal skin and hair color, although its typically lighter than either parent
11. Oculocutaneous Albinism type 1
OCA-1:- It is tyrosinase – related albinism results from a genetic defect in
TYR gene. There are two subtypes of OCA-1 (OCA1A and OCA1B).
OCA1-A, The enzyme is inactive and no melanin is produced, leading to
white hair and very light skin.
OCA1-B, The enzyme is minimally active and a small amount of melanin
is produced, leading to hair that may darken to blonde, yellow/orange or
even light brown, as well as slightly more pigment in the skin.
Individuals in general tend to have:
*very pale or milky skin,
*light-colored irises
* white hair. With age, some individuals skin and hair may darken.
12. Oculocutaneous Albinism type 2
OCA-2 :- results from a genetic defect in the p-protein (OCA2
gene) that helps the tyrosinase enzyme to function. Individuals
with OCA2 make a minimal amount of melanin pigment.
It also results from a defect of MC1R gene.
Type 2 is typically less severe than type 1.
*The skin is usually a creamy white color
*Typically have red hair instead of the usual
yellow or ranging from blonde to light brown.
Occurs most often in sub-Saharan Africans, African-Americans
and Native Americans.
13. Oculocutaneous Albinism type 3
OCA-3 includes a form of albinism called rufous oculocutaneous
albinism (ROCA) , which usually affects dark-skinned
people. Mostly in southern African Blacks.
It is rarely described and results from mutations in
TYRP1 gene, a protein related to tyrosinase.
Individuals with OCA3 can have substantial pigment
Affected individuals have:-
*reddish-brown skin, ginger or red hair
*hazel or brown irises.
*Milder vision abnormalities than
other forms of oculocutaneous albinism.
14. Oculocutaneous Albinism type 4
It results from a genetic defect in the SLC45A2 protein that helps the
tyrosinase enzyme to function. Individuals with OCA-4 make a minimal
amount of melanin pigment similar to persons with OCA-2
This is most common among East Asian populations.
Similar symptoms to those seen with type 2.
Other related conditions of Albinism:-
Hermansky-Pudlak syndrome: This rare variant is most common in Puerto Rico.
The symptoms are similar to oculocutaneous albinism but bowel, heart, kidney,
and lung diseases or bleeding disorders such as hemophilia, are more likely too.
Chediak-Higashi syndrome: This is a rare form of albinism, caused by a mutation
in the CHS1/LYST genes. Symptoms are similar to oculocutaneous albinism but
hair can appear silvery, and the skin can look slightly gray. There may be defects
in the white blood cells, making infections more common.
15. Ocular Albinism (OA)
Ocular albinism is a genetic condition that primarily affects the eyes. This
condition reduces the coloring (pigmentation) of the iris, which is the colored part
of the eye, and the retina, which is the light-sensitive tissue at the back of the
eye. Pigmentation in the eye is essential for normal vision.
is an X-linked disorder caused by mutations in the OA1 gene (approved gene
symbol GPR143) which is expressed in the (RPE). Plays a signaling role that is
important for pigmentation in the eye.
To have Ocular albinism, a male only need to inherit one changed copy
of the gene for OA from his carrier mother. Therefore almost all the
people with OA1 are males.
* Vision problems are present, Absence of melanin pigment in eyes
resulting in pale blue or red eyes
* hair, and skin color are generally in the normal range.
or only slightly lighter
accounts for 10%-15% of all albinism cases.
17. Inheritance
Caused by defects that affect production of the pigment,
melanin, and due to a defect in the "P" gene. People with
this type have slight coloring at birth
Organisms can be carriers of genes for albinism without
exhibiting any traits, albinistic offspring can be produced by
two non-albinistic parents.
Most forms of albinism are inherited in an autosomal
recessive inheritance pattern passed from both parents.
The exception is X-linked ocular albinism. This is passed on
an X-linked inheritance pattern. X-linked recessive
ocular albinism type I (OA1) is due to mutations in
the OA1 gene(approved gene symbol GPR143)
18. Autosomal recessive inheritance
With autosomal recessive
inheritance, an individual
must receive faulty copies
of a gene from the mother
and father to develop
albinism.
Most often, the parents of
an individual with an
autosomal recessive
condition each carry one
copy of the mutated gene,
but they do not show signs
and symptoms of the
condition.
19. X-linked inheritance
X-linked recessive conditions mainly
affect males.
Because females carry two X
chromosomes, if one gene damaged, the
other can often make up the shortfall.
Females can still carry and pass on the
gene.
Men, however, have one X and one Y
chromosome. This means that any albino
mutations in their singular X chromosome
will generate the condition.
If the mother has an X-linked mutation,
each daughter will have a 1 in 2 chance
of becoming a carrier and each son will
have a 1 in 2 chance of developing
albinism
21. Diagnosis
Genetic testing is the most reliable and the only way to diagnose albinism.
Tested with a sample of blood (e.g. CVS), hair or skin. However, in families
with a history of albinism, this is not always necessary.
The process of diagnosing albinism most often involves:
Medical history and physical exam
Tests of the skin and brain's response to light
discussion about skin and hair pigmentation changes
examination of the eyes by an expert (ophthalmologist)
comparing the individual's coloration with that of family members
Other diseases can also cause changes in pigmentation, but they will not cause
changes in vision. If pigment changes and vision changes are both present,
albinism is very likely to be the cause.
22. Treatment
Because the disease is genetic, there is no cure. Treatment focuses on
minimizing the symptoms and watching for changes.
Getting the right care for eye problems is essential.
Strategies that may help include:
* Prescription glasses, dark glasses to protect the eyes from the sun
* Wear protective clothing and use of sunscreen SPF 15 or higher for
protection.
* Surgery on the optical muscles can sometimes minimize the "shaking“ in
Nystagmus.
• Procedures to minimize Strabismus can make it less noticeable, but
surgery will not improve vision.
23. Cont.
* Using a large computer screen or high-contrast print material
* Regular skin checks for early detection of skin cancer should be
offered.
* Regular eye exams
* Installing software that converts text to speech
* Using a brightly colored ball when playing games
Albinism does not worsen with age. A child with albinism can flourish
and achieve the same education and employment as a person
without the condition.
An effective therapy is unavailable for albinism at present. However,
to fight OCA in the future, gene therapy can be used.
25. Gene Therapy
Gene therapy has shown important improvements in animal models. This
technique can increase melanin production in the OCA. For this purpose, gene
correction techniques are already available. These comprise techniques to
edit erroneous segments in the genes such as TYR gene.
This technique can include Gene delivery vectors and Gene editing tools.
Gene delivery vectors therapy are retrovirus, adenovirus and AAV, Sendai virus,
and herpes simplex virus type 1 (HSV-1). It is very beneficial for treating
Albinism disorder, For example using AAV technique for curing OCA1 and
OA1.
In addition, to fight albinism, genome editing techniques can be used. These
techniques can comprise (MNs, ZFNs system, TALENs system and
CRISPR/Cas9 system). For example ,CRISPR/Cas9 system can correct
albinism phenotype in rats. Either TALENs or CRISPR/Cas9 system in
combination with iPSCs can be useful to fight albinism.
Research results in animal models have shown remarkable advances.
26. Gene Therapy
To treat certain inherited disorders such as OCA.
GAT technique can be used. Nelwan, Strachan
and Reap showed that GAT aim is clinically
reversible disorders. It also helps to get no exact
for expression levels of the introduced gene and a
clinical outcome at low expression levels .
In this technique, moderate demonstration levels of
an injected gene may result in a significant
difference. In animal models, research results have
shown important advances to treat OCA disorder.
Ikawa et al. introduced a potential primary attempt
toward the progress of in vivo gene therapy
approaches for Hermansky-Pudlak. The authors
showed that lentiviral-mediated gene transfer
corrected HPS1 gene expression and role in human
epidermal melanocytes. HPS1 is one of the
syndromic oculocutaneous albinisms
27. Gene Delivery Vehicles
This method can edit incorrect segments in the albinism genes, for example. For
this purpose, viral vectors such as lentiviruses and AAV can deliver these incorrect
segments for treatment of OCA. These vectors can also deliver gene editing tools
such as MNs, ZFNs system, TALENs and CRISPR/Cas9 to repair albinism genes. in
the hemophilia A case, the CRISPR/Cas9 system in combination with iPSCs is
possible. Nelwan showed that this combination may be useful to overcome
albinism disorder.
They examined the effectiveness of TALENs in making mutations in genes in
Xenopus tropicalis. The authors targeted the tyr gene in their investigation.
They used TALENs in combination with (iPSCs) in their study. Thus, to reverse the
incorrect segments in the tyr gene, It is possible. It seems TALENs system may be
useful to treat albinism in human.
the CRISPR/Cas9 system uses sgRNA to produce site-specific gene editing in
aim cells with great frequency. It operates sgRNA to find the matching string in the
DNA and later construct DSBs. (NHEJ)fixes DSBs. NHEJ generates indel mutations,
guiding to knock-out the role of gene.
28. The purpose of this study:
Subretinal injection of AAV vectors encoding OA1 in
adult Oal-/- mice resulted in amelioration of several-
wave amplitude when the promoters drove the
transgenic expression. AAV-mediated human Tyr gene
delivery to the Tyrc-2j retina resulted in de-novo
melanin synthesis. These data will be crucial to fully
characterize the albino visual phenotype and to assess
the impact of AAV-mediated gene transfer
1- characterize retinal function in Tyrc-2j mice and the
visual pathways in both models
2- determine the therapeutic time window to rescue
the congenital and functional anomalies present in the
albino models
3- optimize gene transfer in Oal-/- retina. In order to
optimize Oal retinal gene transfer they have generated
AAV 2/1 vectors harboring the human OA1 gene under
the expression control of the CMV ubiquitous
promoter, or under the human RPE65 or OA1
promoters to restrict the expression into the retinal
pigment epithelium (RPE).
29. References
DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in
Molecular Diagnostics . In PMC US National Library of MedicineNational Institutes of Health (Hum Mutat.
2013. Apr 30; 34(6): 827–835.
Newman, Tim. "Everything you need to know about albinism." Medical News Today. MediLexicon, Intl.,Jul.18.
2018.
elethon Institute of Genetics and Medicine, TIGEM, Naples, Italy;Department of Pediatrics, “Federico II”
University, Naples, Italy. AAV-Mediated Gene Therapy of Albinism Volume 15, Supplement 1, May 2007, Page
S286
Martin L. Nelwan1. Treat Oculocutaneous Albinism with Gene Therapy 16(3): 1-12, 2017; Article
no.JABB.38504 SS: 2394-1081
Amelioration of both Functional and Morphological Abnormalities in the Retina of a Mouse Model of Ocular
Albinism Following AAV-Mediated Gene Transfer volume 12, Issue 4, October 2005, Pages 652-658
Brilliant MH. The mouse pink-eyed dilution locus: a model for aspects of Prader-Willi syndrome, Angelman
syndrome, and a form of hypomelanosis of Ito. Mamm Genome. 1992;3:187–91
Increasing the complexity: new genes and new types of albinism 21 September 2013
AAV-mediated Tyrosinase Gene Transfer Restores Melanogenesis and Retinal Function in a Model of Oculo-
cutaneous Albinism Type I (OCA1)
Editor's Notes
Occurs when genetic defects make the body unable to produce melanin
The most common cause of albinism is an interruption in the functioning of the enzyme tyrosinase.
The skin will likely burn easily in the sun. It does not usually tan.
Melanin protects the skin and eyes against the harmful consequences of environmental light radiation, so
Vision problems related to albinism tend to be worst in newborns but improve rapidly over the first 6 months of life. However, problems with eye health are likely to persist.
OCA1 and OCA2 are the most frequent types and account for approximately 40% and 50%, respectively, of OCA worldwide
OCA3 and OCA4 are far less frequent, OCA4 is rare among Caucasians as well as Africans. It is the majority common in Japanese.
OCA5 has seemed in a Pakistani family. OCA6 has arisen in a Chinese family and a man from eastern India. Finally, OCA7 has seemed in a consanguineous Faroese family, and Lithuanian patients in Denmark
OCA1 is the greatest common subtype discovered in Caucasian. It influences 1 in 40,000 people worldwide. It is extremely rare in African-American. The carrier frequency of OCA1 is 1 in 100 people
Alterations in the MC1R gene can change the appearance of people with OCA 2. This gene helps regulate melanin production and is responsible for some normal variation in pigmentation.
OCA3 or ROCA (Rufous OCA), is extremely rare in Caucasians and Asiatic people
Moreover, there are syndromic forms of albinism, which are characterized by more severe phenotypes affecting a range of additional cell type
If female child is said to have ocular albinism, their parents should be suspicious. while possible if the mother is a carrier of ocular albinism and father has ocular albinism, it is extremely rare case.
RPE= retinal pigment epithelium
one or more defective genes
which means both copies of a 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 they do not show signs and symptoms of the condition.
Diagnosis is based on clinical findings of hypopigmentation of the skin and hair in addition to the characteristic ocular symptoms
The level of success in reducing symptoms varies between individuals
Persons with OCA have normal lifespan, development, intelligence and fertility.
*(last sentence) The article published by 1Telethon Institute of Genetics and Medicine, TIGEM, Naples, Italy;2Department of Pediatrics, “Federico II” University, Naples, Italy.in Volume 15, Supplement 1, May 2007, Page S286
*Martin L. Nelwan-Department of Animal Science – Other, Nelwan Institution for Human Resource Development Jl. A.Yani No.24, Palu, Indonesia.
Article in a Journal of advances in biology and biotechnology, Dec.29th.2017
Induced Pluripotent Stem Cells
gene augmentation therapy
MNs as a gene editing tool have not been widely used. Both ZFNs and TALENs have the same techniques. These two techniques use different DNA binding arrays.
Currently performing gene transfer to the fetal and newborn Oa1 -/- and Tyrc-2j retina to determine the therapeutic time window for rescue of both developmental and progressive post-natal landmarks of the disease