الفهرس 
Genetics and pathophysiology ofOnly 14 pages are availabe for public view
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Abstract
Retinitis pigmentosa (RP) is a group of inherited disorders characterized by
progressive peripheral vision loss and night vision difficulties (nyctalopia)
that can lead to central vision loss.
With advances in molecular research, it is now known that RP constitutes
many retinal dystrophies and retinal pigment epithelium (RPE) dystrophies
caused by molecular defects in more than 40 different genes for isolated RP
and more than 50 different genes for syndromic RP. Not only is the
genotype heterogeneous, but patients with the same mutation can
phenotypically have different disease manifestations.
RP can be passed on by all types of inheritance: approximately 20% of RP is
autosomal dominant (ADRP), 20% is autosomal recessive (ARRP), and 10%
is X linked (XLRP), while the remaining 50% is found in patients without
any known affected relatives. RP is most commonly found in isolation, but it
can be associated with systemic disease. The most common systemic
association is hearing loss (up to 30% of patients). Many of these patients
are diagnosed with Usher syndrome. Other systemic conditions also
demonstrate retinal changes identical to RP.
RP is typically thought of as a rod-cone dystrophy in which the genetic
defects cause cell death (apoptosis), predominantly in the rod
photoreceptors; less commonly, the genetic defects affect the RPE and cone
photoreceptors. RP has significant phenotypic variation, as there are many
different genes that lead to a diagnosis of RP, and patients with the same
genetic mutation can present with very different retinal findings.
Histopathologic changes in RP have been well documented, and, more
recently, specific histologic changes associated with certain gene mutations
are being reported. The final common pathway remains photoreceptor cell
death by apoptosis. The first histologic change found in the photoreceptors is
shortening of the rod outer segments. The outer segments progressively
shorten, followed by loss of the rod photoreceptor. This occurs most
significantly in the mid periphery of the retina. These regions of the retina
reflect the cell apoptosis by having decreased nuclei in the outer nuclear
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layer. In many cases, the degeneration tends to be worse in the inferior
retina, thereby suggesting a role for light exposure.
The final common pathway in RP is typically death of the rod
photoreceptors that leads to vision loss. As rods are most densely found in
the midperipheral retina, cell loss in this area tends to lead to peripheral
vision loss and night vision loss. How a gene mutation leads to slow
progressive rod photoreceptor death can occur by many paths, as illustrated
by the fact that so many different mutations can lead to a similar clinical
picture.
Cone photoreceptor death occurs in a similar manner to rod apoptosis with
shortening of the outer segments followed by cell loss. This can occur early
or late in the various forms of RP.
• Presenting symptoms of RP vary, but the classic symptoms include the
following:
• Nyctalopia: The earliest symptom in RP is most commonly night blindness
and is considered a hallmark of the disease.
• Patients may also report a prolonged period of time needed to adapt from
light to dark.
• Visual loss: Peripheral vision loss is often asymptomatic; however, some
patients notice this vision loss and report it as tunnel vision.
• The loss of vision is painless and slow to progress.
• Photopsia: Many patients with RP report seeing flashes of light (photopsia)
and describe them as small, shimmering, blinking lights similar to the
symptoms of an ophthalmic migraine. However, in contrast to the patient
with an ophthalmic migraine, the photopsia may be continuous rather than
episodic.
• A careful family history with pedigree and possible examination of family
members can be useful.
• Drug history is essential to rule out phenothiazine/thioridazine toxicity.
The application of molecular biology to clinical medicine is a relatively
recent development but has already had great impact upon our understanding
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of disease processes. It has improved our ability to care for RP patients by
allowing us to establish a diagnosis of ADRP, even when clinical suspicion
may be low, as well as to remove the fear of disease from unaffected
relatives. Refinement in the diagnosis of simplex cases, where no family
history is available, is now possible for many retinal dystrophies using
molecular genetic techniques to identify abnormal candidate genes. Early
success in treating retinal degenerations in animals give us hope that
advances in the molecular understanding of retinal degenerations can soon
be translated into more effective treatments for these diseases.
In advanced stages, when there are few or no functional photoreceptors,
strategies that may benefit include retinal transplantation, electronic retinal
implants or a newly described optogenetic technique using a light-activated
channel to genetically resensitize remnant cone-photoreceptor cells.