INTRODUCTION TO INHERITED RETINAL DEGENRATIONS

Inherited retinal degenerations

Inherited retinl degenerations (IRDs) is a group of progressive heritable genetic disorder that
can be from birth through late middle age leading to blindness. Symptoms of the disease
include loss of night vision, visual field, color and central acuity. Sophisticated imaging
modalities and electrophysiology permit genotype phenotype correlations. The genetic of the
disease is increasingly understood and lead to the development of gene therapies programs
one of which is now licensed treatment.

it is vital for pediatricians to understand the risk of systemic associations and equally, the
development impact of blindness; supporting patient and families together with ophthalmology
is important. Linked retinoschisis also present the commonest macula dystrophies presenting in
childhood include Stargardt’s and Best disease. Stationary non-progressive cone and rod
dysfunction syndrome such as achromatopsia (ACH) or Congenital Stationary Night Blindness
(CSNB) also present in childhood.

There are number of childhood onset IRDs that have systemic features including but not limited
to Usher syndrome (sensorineural hearing loss); Alstrom (hearing loss. Cardiomyopathy,
obesity); Bardet Biedl (obesity, reduced renal function, polydactyly); Joubert (Cerebellar
hypoplasia); Senior-Loken (nephronophthisis), Cohen (microcephaly, hyotonia, intellectual
disability, characteristics facies) or Battens- neuronal ceroid Lipofuscinosis
(neurodegeneration). There are four syndrome which are associated with retinal
degeneration’s for which treatment exist: abetalipoproteinemia treated with vitamins A and E;
Gyrate atrophy with elevated plasma orthenine and treated with a low protein diet; ataxia with
vitamin E deficiency (AVED); Refsum disease treated with dietary reduction in phytanic acid

The genetic of retinal dystrophies and stationary dysfunctions syndrome are increasingly
understood and there are 271 gene known to be responsible. These encodes a wide variety of
proteins responsible for numerous cellular functions in both photoreceptor the pigment
epithelium and other retinal cells. The majority of these conditions have a simplex, or
autosomal recessive pattern, but all modes of inheritance are found (Henderson, 2019).

Types of IRDs

Ciliopathies

Although the concept of a ciliopathy is relatively contemporary, the observation that ciliary
dysfunction may result in both the retinal degeneration and abnormal sperm motility observed
in patients with Usher syndrome was made 2 decades ago (Hunter et al., 1986). Since then a
number of disorders have been classified as ciliopathies, including certain forms of retinitis
pigmentosa (RP), Usher syndrome, Bardet-Biedl syndrome (BBS), polycystic kidney disease,
nephronophthisis, Meckel syndrome, and Jeune syndrome, among others (Hildebrandt et al.,
2011).

Classically, cilia have been divided into primary or motile though this distinction has recently
been questioned.3 Transport between the cilium and cytoplasm occurs along the axoneme by
specialized motor proteins in a process termed as intraflagellar transport.4 Photoreceptors
possess a primary cilium, the connecting cilium, which connects the inner and outer segment
and, in addition to its structural role, is responsible for the transport of phototransduction
proteins and membrane lipids to the outer segment from the inner segment where they are
made.5 Nearly all cells within the human body possess cilia and it is this shared feature which
unites this group of disorders. (Courtney & Pennesi, 2012).

Usher Syndrome

Although it was first described by von Graefe in 1858, Usher syndrome is attributed to the
British ophthalmologist, Charles Usher, who first reported its inheritance pattern (Usher, 1914).
Defined as autosomal recessively inherited sensorineural deafness and RP with variable
vestibular involvement, Usher syndrome is the most common syndromic cause of RP, the most
common cause of syndromic deafness and blindness, and occurs with a prevalence of 1.8 to 6.2
per 100,000 (Weleber and Gregory., 2006).

Three clinical types are recognized; Type 1 (USH1) is most severe, with prelingual onset of
profound sensorineural deafness, childhood-onset retinopathy and vestibular symptoms, which
typically present as delayed motor development. Type 2 (USH2) is less severe, with congenital
partial deafness, pubertal or post pubertal onset of retinopathy and no vestibular symptoms.
Type 3 (USH3) consists of post pubertal onset progressive deafness, retinopathy and variable
vestibular involvement.

To date, 9 responsible genes have been identified (Millan et al., 2011). All but one of the
encoded proteins are known to participate in a larger protein network, the Usher
‘‘interactome’’ which is found in the photoreceptor connecting cilia and in the stereocilia of the
hair cells of the organ of corti and vestibular system (Adam et al., 2007). Although the gene
products span separate protein classes, a defect in any one component may result in
dysfunction of the larger complex and the clinical disease state.

Bardet-Biedl Syndrome

The triad of polydactyly, obesity and retinopathy was described by Bardet in 1920 (Bardet,
1920).

In 1922, Biedl included the two additional features of mental retardation and hypogenitalism in
what would be termed Bardet- Biedl syndrome (BBS) (Biedl, 1922).

Currently, BBS is an autosomal recessive dis- order consisting of 4 of 6 primary features: rod-
cone dystrophy, polydactyly, learning disability, hypogonadism, obesity, and renal anomalies; or
if only 3 primary characteristics are present, there may be 2 additional secondary features such
as strabismus/cataract/astigmatism, trophy, and hepatic fibrosis (Beales et al., 1999).

Laurence-Moon syndrome is generally considered part of the BBS spectrum though it includes
ataxia and lacks polydactyly among its features. There are currently 15 BBS genes that have
been identified, emphasizing the genetic heterogeneity underlying the various phenotypes
(Chen et al., 2011).
The BBS gene products span a variety of protein classes and similar to USH have been recently
shown to interact in a BBSome. The BBSome is an octomeric complex consisting of a novel
proteinand BBS proteins that is thought to function in trafficking membrane proteins to primary
cilia.16 BBS proteins have been localized to the photoreceptor and a variety of organ system
tissues, explaining the clinical syndrome (Blacque et al., 2006).

Nephronophthisis-associated Syndromes: Senior-Loken and Joubert Syndromes

Nephronophthisis is a cystic kidney disease characterized by atrophy and the development of

degenerative cysts at the corticomedullary junction. Senior-Loken syndrome is a rare autosomal
recessive disorder consisting of nephronophthisis and retinal degeneration, named for Senior
and Loken who separately described the association in 1961 (Senior, 1961).

The retinal degeneration may be early (present at birth or within the first 2 y) or late
(childhood) in onset. Mutations in the genes NPHP1-4 are typically associated with later onset
of retinal degeneration, whereas NPHP5 mutation is seen in early-onset SLS, and can overlap
with the diagnosis of Leber congenital amaurosis (Hildebrandt, 2007).

Joubert syndrome (JS) is defined by the presence of the molar tooth sign on neuroimaging
because of a malformation of the midbrain- hindbrain junction, which results in the clinical
features of mental retardation and ataxia. A number of organ system manifestations may
accompany the brain abnormality including nephronophthisis and retinal degeneration,
prompting a recent proposal to change the classification of the disorder into pure JS and JS with
ocular or renal or oculorenal or hepatic or orofaciodigital defect (Brancati et al., 2010).

Numerous genes have been associated with JS occurring with retinal degeneration, including 2
nephronophthisis genes, NPHP1 and NPHP6, as well as AHI1 (Parisi et al., 2006).

On the basis of the evidence that the gene products of the implicated NPHP loci localize to
primary cilia and basal bodies, it is believed that cystic kidney disease, including
nephronophthisis and its associated syndrome is related to ciliary dysfunction (Hildebrandt and
Otto., 2005).
Moreover, many of the proteins function in tandem with one another, suggesting a common
pathologic endpoint. Inversin (NPHP2), nephrocystin (NPHP1), and b-tubulin (a principle
component of microtubules) interact with one another and have been localized to the renal
tubule cell primary cilia and, at least for nephrocystin, the connecting cilia in photoreceptors as
well (Fliegauf et al., 2006).

The products of NPHP3-6 have also been shown to interact with nephrocystin and also localize
to the photoreceptor connecting cilia.26 NPHP5 and NPHP6 are thought to function in tandem
and mutations in these genes always produce retinal degeneration27; interestingly, either locus
may cause a retinal degeneration (Leber congenital amaurosis in clinical presentation) without
associated systemic features (Stone at al., 2011).

Many of the NPHP genes have been shown to colocalize or interact with genes underlying
certain forms of RP, including the RP GTPase regulator. Although NPHP5-mediated and NPHP6-
mediated disease typically results in severe retinal degeneration and poor vision, there is
optimism that the remaining central cone receptors may be amenable to future gene therapy
(Cideciyan et al., 2011).

Alstrom and Jeune Syndrome

Additional syndromes are emerging under the collection of ciliopathies. Alstrom syndrome
(ALMS) is a rare, autosomal recessive disorder related to mutations in the ALMS1 gene. It is
characterized by early onset, severe cone-rod dystrophy with nystagmus, deafness, obesity,
diabetes mellitus, dilated cardiomyopathy, and renal and hepatic dysfunction (Maeshall et al.,
2007).

The ALMS1 gene is expressed in a variety of cells and has been shown to localize to the
centrioles and ciliary base.32 Additionally, it may play a role in cilia formation (Li et al., 2007).

Jeune syndrome, also known as asphyxiat- ing thoracic dystrophy, is an adult Refsum disorder
consisting of a characteristic bony thoracic deformity as well as the frequent association of
hepatic, renal, and pancreatic defects; a pigmentary retinopathy is present in approximately
15% of cases (Keppler et al., 2011).
A portion of patients with Jeune syndrome have been found to have mutations in the IFT80
gene, which encodes a protein involved in intraflagellar transport (Beales et al., 2007).

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