findings are extensive vision loss, nystagmus, cataracts and severe retinopathy [51]. Fundus examination may demonstrate white flecks in the periphery and central pigment clumping, in addition to the classic fundus findings of RP. The ERG is generally extinguished and may be electronegative. Infantile Refsum disease may easily be confused with Usher syndrome or LCA in the neonatal period; progressive neurologic deterioration helps distinguish this syndrome. The disease is often fatal in the second decade of life [51].

Adult Refsum disease is caused by a defect in the PAHX gene encoding phytanoyl-CoA hydroxylase, an enzyme necessary for phytanic acid metabolism in peroxisomes [52]. Symptoms present in the second decade of life and include retinitis pigmentosa, cerebellar ataxia, peripheral polyneuropathy, ichthyosis, liver disease, nephropathy, or cardiac arrhythmias [53]. Serum phytanic acid is usually more elevated in the adult than infantile disease [51]. Dietary restriction of phytanic acid may reduce disease progression, particularly for peripheral neuropathy. Therapeutic plasma exchange is also effective for acute attacks and maintenance treatment [53].

Retinitis pigmentosa can also be associated with an autosomal recessive form of childhood nephropathy, familial juvenile nephrophthisis (Senior-Loken syndrome). These patients’ exhibit cystic medullary changes of the kidney leading to renal failure, and can benefit from steroid therapy. The benefit of steroids in retarding the course of retinopathy remains undetermined.

12.4.2  Congenital Leber Amaurosis

LCA is the counterpart of adult-onset retinitis pigmentosa and represents a number of genetically distinct disorders manifesting with blindness during infancy. The entity was first described by Leber in 1869 as a retinitis pigmentosa associated with congenital blindness, nystagmus, poor pupillary reactivity, and autosomal inheritance. Following the development of the ERG, an extinguished or near absent ERG with relatively normal fundus findings was added to this characterization.

12.4.2.1  Genetics

The most commonly encountered mode of inheritance is the autosomal recessive pattern. Like other inherited retinopathies, the genetic basis is heterogeneous and overlaps with a variety of other retinal dystrophies. Fourteen genes and over 400 mutations have been identified, approximating 70% of causative mutations for LCA. The most common mutations include CEP290 (15%), GUCY2D (12%), CRB1 (10%) and RPE65 (6%) [62]. An estimated 30% of mutations causing LCA have yet to be identified.

12.4.2.2  Pathophysiology

The pathogenesis of photoreceptor loss and dysfunction is highly variable and dependent on the affected gene locus. Mutations have been shown to disrupt normal

phototransduction (GUCY2D, AIPL1), photoreceptor development and structure (CRX, CRB1), the retinoid cycle (RDH12, LRAT, RPE65), and transport across the photoreceptor cilium (TULP1, RPGRIP1, CEP290, Lebercilin) [62].

Although the precise functions of most affected gene products are yet unknown, the GUCY2D gene is known to encode a membrane guanylate cyclase, a crucial enzyme required for regeneration of cGMP during phototransduction. The absence of guanylate cyclase activity in the phototransduction cascade will then trigger secondary apoptotic events in the photoreceptor. Alternatively, the CRX gene has been shown to encode a transcription factor required for photoreceptor differentiation and normal generation of outer segments. The resultant photoreceptors are therefore unable to process light signals and are defective from birth. Other gene mutations will have parallel effects, and several of the gene products associated with LCA are still being investigated.

12.4.2.3  Incidence/Prevalence

LCA accounts for 5% of all retinal degeneration worldwide [63].

12.4.2.4  Natural History and Prognosis

The disease is generally detected in infancy, presumably present since birth in most cases. Initial behavioral manifestations include poor visual attentiveness, excessive eye rubbing, and general inability to see in both dark and light environments. Some patients will demonstrate the oculodigital sign of Franceschetti, which consists of poking and pressing of the eye, and is believed to activate a perception of light from the intact visual cortex for the affected child [64]. The eye examination shows marked inability to fixate on or follow objects, together with roving nystagmus. The external and anterior segment examination findings include enophthalmos, cataracts, and variable degrees of keratoconus.

Simple, uncomplicated forms [65] may show isolated impairment of retinal function, whereas complicated cases have additional ocular and systemic manifestations. The fundus exam can be nearly normal in the simple forms, with only subtle retinal pigment

epithelial changes and mild vascular attenuation seen in later childhood. Complicated variants will demonstrate additional retinal abnormalities including macular coloboma, retinal flecks and white dots, and salt and pepper pigmentation. The latter is associated with RPE65 mutations [66–68] blocking regeneration of light activated rhodopsin in retinal pigment epithelium, hence making the patient essentially light adapted at all times. The macular coloboma has been shown to not be a true coloboma, but a histologic destruction of the macular region [62]. Additional systemic associations can involve virtually all organ systems.

In general, patients with the simple form can have variable prognosis. Some will demonstrate a stationary disorder which they can adapt to over a course of a lifetime, while others have a gradual decline in vision leading to complete blindness. Mutations involving RPE65 have been associated with the stationary variant and have a better prognosis than RET-GC mutations. RPE65 has also been shown to have the associated symptom of photophobia, and RET-GC with nyctalopia [69]. Visual prognosis and disease symptoms are therefore likely related to the gene locus involved.

12.4.2.5  Diagnostic Testing

The key to diagnosis of LCA is the absence of scotopic and photopic signals in the ERG of an infant with relatively subtle fundus changes.

12.4.2.6  Treatment

Gene therapy trials are currently underway to investigate treatment options for LCA patients. Promising results for gene therapy in canines with RPE65 mutations prompted investigations in human patients with this same mutation. Pioneering studies are being conducted with subretinal injections of the RPE65 gene with an adenovirus vector in selected young adult patients. Early results demonstrate a subjective improvement in visual acuity, as well as statistically significant improvement in dark-adapted full-field sensitivity testing [70]. One year follow-up reports show no change from the remarkable improvement in visual sensitivity that was noticed initially by treated patients [110]. These encouraging results are supporting the hope for future treatment options in LCA patients.

12.4.2.7  Complications and

Disease Associations

A variety of systemic conditions can present in association with the complicated form of LCA. Neurologic deficits are most frequent but abnormalities involving the liver, kidney, heart and the skeletal system are also found. Mental retardation has been classically associated, although the prevalence may be caused by psychomotor retardation from sensory deprivation, and not a true defect of the central nervous system [71].

12.4.3  Congenital Stationary

Night Blindness

CSNB is a heterogeneous group of congenital conditions characterized by retinal dysfunction without an accompanying compromise in retinal structural integrity. The fundus can have a normal or abnormal appearance depending on the specific diagnosis. Retention of relatively normal peripheral vision and fields are an important distinguishing feature of these disorders as compared to more progressive conditions such as retinitis pigmentosa and LCA variants.

12.4.3.1  Genetics

The autosomal dominant, autosomal recessive and X-linked recessive inheritance patterns have all been encountered with CSNB [72]. Several families, including the original Nougaret family [73] from France, carry mutations in the phototransduction gene encoding transducin [74]. Two genes of related X-linked forms of CSNB have been cloned, CACNA1F [75] and NYX [76], and carry multiple mutations responsible for the majority of cases of X-linked CSNB. Patients with abnormal fundi, including Oguchi disease and fundus albipunctatus with delayed recovery and regeneration of photoreceptors, lack function of crucial enzymes including rhodopsin kinase [77, 78], arrestin in photoreceptors [79] and RDH5 in pigment epithelium [80, 81].

12.4.3.2  Pathophysiology

This disease represents a dysfunction of the retina at the light capture or transmission level in the retina and

generally does not result in a great deal of morphologic disturbance. Defects in molecules that facilitate photoreceptor function underlie the pathogenesis of CSNB. Typical examples of such mutations occur in transducin alpha, rhodopsin, and PDE6, all of which participate in conversion of light to an electrical signal. Absence of any of these functional mediators in the process interferes with the vision in the dark without leading to a loss of integrity of the photoreceptors.

12.4.3.3  Incidence

The precise incidence is generally not known although they appear to be extremely rare.

12.4.3.4  Natural History and Prognosis

Patients are generally born with these conditions which may at times be confused with LCA. Infants may have difficulty locating the bottle in the dark, but can fix and follow without nystagmus. Difficulty with navigation in the dark is noted by the parents in later life. Some can adapt to darkness but require extraordinarily prolonged periods in order to do so. A family history is present for X-linked recessive and dominant forms. Myopia is especially prominent with the X-linked form. The vision is generally normal in classic forms with no deficit in the visual fields. Patients have a normal fundus exam except in cases of fundus albipunctatus and Oguchi disease. Fundus albipunctatus is distinguished from other forms of CSNB by characteristic scattered white dots throughout the midperipheral retina. Oguchi disease exhibits the Mizuo phenomenon, or a golden sheen of the light-adapted fundus, which can also be encountered in some macular dystrophies.

12.4.3.5  Diagnostic Testing

Electrophysiology in conjunction with dark-adaptome- try and visual field testing are cornerstones of proper evaluation of these disease entities, given the primary compromise in functional rather than structural aspects of the visual pathway. Vitamin A levels may be helpful to rule out vitamin A deficiency in patients at risk for malnutrition from iatrogenic or alimentary tract

diseases. Patients with stationary night blindness retain relatively normal Goldman visual fields.

Two major categories of electrophysiologic response with some subcategories may be expected [82, 83]. In the first category, delayed dark adaptation accompanies retention of normal scotopic threshold as in fundus albipunctatus and Oguchi disease. Both groups of patients recover the a-wave with prolonged dark adaptation, ideally after several hours in the dark. Oguchi patients, however, remain extremely sensitive to even minute dim flashes of light and poorly recover the dark adapted state after even a single flash of dim blue light [15].

In the second physiologic category, scotopic electrophysiologic response remains deficient regardless of duration of dark exposure. Generally these patients have normal fundi with a variety of inheritance patterns. This group of patients can further be subclassified into group I (lacking scotopic ERG signal), and group II (with electronegative ERG and relative b-wave deficit) [83]. Group I disease is generally caused by mutations in the photoreceptor proteins involved in phototransduction [84] whereas group II disorders involve a transmission defect in a group of patients that lack scotopic ERG signal completely, consistent with the absence of rod function.

12.4.3.6  Treatment

Since visual fields are generally not greatly compromised and most tasks in modern society are performed under well lit environments, patients may adapt readily to a relatively tolerable visual deficit and function without difficulty.

12.4.3.7  Achromatopsia

Achromatopsia is an inherited disorder of color blindness that presents with decreased vision, photophobia, and nystagmus. It exists in complete and incomplete forms, with similar clinical phenotypes. Complete achromatopsia, or rod monochromatism, is an autosomal recessively inherited condition that presents in infancy with severely decreased vision and sensory nystagmus. A paradoxical pupillary response is often noted, demonstrated by constriction of pupils when ambient light is dimmed. Visual acuity is usually worse than 20/200, and a brisk paradoxical pupillary response

may correlate with lower visual acuities [85]. Fundus examination classically reveals a normal appearance of optic nerve and retina, although macular pigment irregularities, vascular attenuation, and optic nerve pallor have been reported [86]. Despite the conventional perception of complete achromatopsia as a stationary disorder, visual acuity may deteriorate into adulthood in up to 12% of affected patients [86, 87].

Diagnosis may be made in infancy by clinical features and confirmed by electroretinogram findings. Even in early stages of disease, ERG will show a normal dark-adapted scotopic response, with absence of light-adapted photopic response [88]. Optical coherence tomography findings include reductions in total macular volume and decreased thickness of the central retina [89]. Genetic testing is available for the three known mutations for complete achromatopsia, CNGB3 (chromosome 2q11), CNGA3 (chromosome 8q21), and GNAT2 (chromosome 1p13), all of which encode proteins integral to the cone phototransduction cascade. CNGA3 and CNGB3 encode for the a- and b-subunits, respectively, of the cyclic nucleotide-gated ion channel type 3, which is located on cone outer membrane segments. GNAT2 encodes the a-subunit of cone transducin, which aids in hydrolyzation of cyclic guanosine monophosphate (cGMP), thereby reducing its intracellular concentration and leading to closure of the outer membrane channel [87, 90].

Incomplete achromatopsia refers to either incomplete rod monochromatism or, more commonly, blue cone monochromatism. Blue cone monochromatism is an X-linked disorder characterized by the absence of red and green cone sensitivity. Clinical features are similar to complete achromatopsia, although affected patients are predominantly male and have better visual acuities, in the range of 20/60–20/200. ERG findings demonstrate normal scotopic response with a severely attenuated, but present photopic response. The X-linked mutations for incomplete achromatopsia are caused by the red and green opsin gene array on Xq28. Mutations here have been shown to either inactivate the red and green pigment genes, or create a new gene product that carries an inactivation point mutation [91].

No definitive treatment exists for the achromatopsias. Therapeutic interventions are focused on low vision aids and relieving photophobia with tinted spectacles or contact lenses. Red contact lenses have shown particular benefit in relieving photophobia in achromatopsia patients [92].