similar to retinitis pigmentosa. However, the reduction in ERG amplitudes are generally mild and more significant reduction occurs in the EOG. Eye trauma during delivery or in childhood may lead to retinal pigmentation which usually affects one eye with essentially normal electrophysiology of the fellow eye. Bear tracks in large numbers can occur as isolated ocular findings bilaterally, with normal electrophysiology and vascular caliber. Diffuse bear tracks in conjunction with a family history of colonic polyps and cancer should trigger appropriate workup by a gastrointestinal specialist for Gardner syndrome.

Molecular testing is becoming increasingly available to help further classify the disease and confirm the diagnosis. Several commercial molecular diagnostic centers process blood samples for genomic DNA information, to identify mutations in any of the large array of genes (e.g. Asperchips) that are now associated with retinitis pigmentosa.

12.4.1.7  Treatment

Beyond refractive correction, most other medical interventions are of questionable value for this degenerative condition. A few patients with documented leakage in the macula by fluorescein angiography could benefit from low dose acetazolamide treatment in the range of 125–500 mg/day [27]. Cataract extraction may be of some benefit in a select group of patients with dense posterior subcapsular cataracts. Minimizing intense light exposure with tinted corning 550 glasses, which attenuate the transmission of ultraviolet and low-wavelength light to the retina, is particularly recommended after cataract surgery. These provide comfort in bright light and have the added benefit of reducing the potential for light-induced photoreceptor damage that has been observed in some animal models [28].

A randomized clinical trial by Berson et al. [29] first suggested a benefit from high dose vitamin A palmitate (15,000 IU/day) in retarding disease progress and prolonging the span of vision by an average of 8 years. This treatment, however, remains controversial due to the modest effect on electrophysiology without definitive functional correlate, and the potential for long term vitamin A toxicity in children [30, 31]. Bone disease is of particular concern in young patients, as are the other adverse consequences of increased intracranial pressure and liver toxicity.

Additional molecular and surgical therapies targeting various stage of the disease could soon become available given the marked pace of progress and intensive investigation in these areas [6, 32]. Geneand stem cell-based therapies have shown preclinical promise in preserving and restoring photoreceptor integrity and function in a variety of animal models with retinal degenerative disorders. Prosthetic retinal replacements fabricated of photoelectric chips or nanotechnologic matrices are already being tested in select patients and animal models. Germ and somatic cell gene replacement therapy has been successful in reversing retinal degeneration and other autosomal recessive conditions in the transgenic rd mouse. Allele-specific targeting strategies such as ribozymes are being developed to address the more challenging treatment of autosomal dominant variants. Retinal transplantation of stem cells as well as retinal pigment epithelial translocation are being used as surgical options to replace the denuded retinal pigment epithelium and damaged retina. Although these strategies have yet to yield clinically applicable therapies, the future will likely be brighter for these patients.

12.4.1.8  Complications and

Disease Associations

Several systemic disorders may manifest in conjunction with pigmentary retinopathy in the pediatric age group. The most common is Usher syndrome, a retinitis pigmentosa variant with associated neurosensory hearing loss. Other pigmentary retinopathies with concurrent deafness include congenital rubella, Refsum disease and Bardet–Biedl syndrome. Syndromic retinitis pigmentosa can also involve a variety of other organ systems [33].

Usher syndrome refers to retinitis pigmentosa in association with early onset or congenital deafness, and accounts for nearly 50% of the deaf and blind population. Prevalence has been estimated from 1 in 50,000 to 6 in 100,000 [34, 35]. Patients with childhood manifestations are generally categorized into Type 1 and Type 2 disease. Usher Syndrome Type 1 presents with early vision loss, severe speech disorder, and vestibular-audi- tory dysfunction that causes profound congenital deafness, impaired balance, and delayed walking. Type 2 patients have a milder, nonprogressive deafness and retinopathy that first manifests in the teenage years [36]. Even patients with more severe Type 2 variants

will generally tend to have good vision in their early childhood years. Usher syndrome Type 3 is later onset disease with retinitis pigmentosa and progressive hearing loss, and is generally not seen in the pediatric age group.

Pathogenesis of Usher syndrome is related to the common ontogeny of the retinal photoreceptor and inner ear sensory hair cells. Both cell types will demonstrate abnormal axonemes, the cytoskeletal structures found within cilia of these cells. Multiple Usher’s genes have been mapped and identified, including Ush2A, Myo7A, CDH23, Ush1C and Ush1D [37, 38].

Neuronal ceroid lipofuscinosis, or Batten disease, affects patients of Scandinavian origin with an incidence of 1 in 12,500 but is far rarer in other backgrounds [39, 40]. It is characterized by accumulation of ceroid lipopigment in lysozymes of various tissues. Clinical features include progressive neurologic failure, mental retardation, seizures, and vision loss secondary to retinal degeneration. Ocular symptoms occur early in the disease and include generalized vision loss, night blindness, and photophobia [41]. The rate of progression is extremely rapid when compared to other retinal degenerations, including severe forms of retinitis pigmentosa [40]. Fundus findings vary with severity of disease at time of presentation, but generally progress from central retinal involvement to peripheral pigmentary degeneration. Findings may include bull’s eye maculopathy, vessel attenuation, optic nerve pallor and diffuse pigmentary degeneration. Maculopathy is an earlier manifestation of disease. However, full-field electroretinograms will still demonstrate diffuse loss of both rod and cone function even in early stages, which can be an important diagnostic feature for patients with bull’s eye maculopathy caused by this RP variant [41].

At least nine types of neuronal ceroid lipofuscinosis have been identified, with conventional classification according to age of presentation. Recent discoveries of associated gene mutations have allowed reclassification of these subtypes according to gene locus involvement. The three classic pediatric types of this neurodegenerative disorder are CLN1 (infantile form, Haltia-Santavuori disease) [42], CLN2 (late infantile form, Jansky– Bielschowsky disease) [43] and CLN3 (juvenile form, Spielmeyer-Sjogren disease) [44]. All types cause vision loss in association with neurodegenerative changes in the pediatric age group, and are inherited in an autosomal recessive pattern. Seizures are associated with the CLN1 and CLN2 variants.

Neuronal ceroid lipofuscinosis may be diagnosed using either pathologic, biochemical, or molecular

genetic techniques. Buffy coat leukocyte smear can be helpful in diagnosing all forms by showing accumulation of autofluorescent, blue, PAS-positive granules in white blood cells. This finding, however, can be nonspecific and therefore unable to distinguish this disease from other storage disorders. A more conclusive means of diagnosis and classification involves electron microscopy. Characteristic granular inclusions in CLN1, curvilinear inclusions for CLN2 and fingerprint inclusions for CLN3 can further classify these variants. Genetic testing will also provide a definitive diagnosis. The genes for each of these conditions have been cloned with CLN1 (chromosome 1p32) gene product functioning as protein palmitoyl transferase, CLN2 (chromosome 11p15) as pepstatin insensitive lysosomal peptidase, and CLN3 (chromosome 16p12) with no known function.

Bardet–Biedl syndrome is an autosomal recessive condition that represents a constellation of systemic findings including pigmentary retinopathy, obesity, polydactyly, and variable neurologic deficits. Mental retardation, nephropathy and urogenital defects are also seen in some cases [45, 46]. The syndrome occurs with highest frequency (1 in 14,000) [47] in populations of Arabic origin from Kuwait. Retinopathy and obesity are invariable features of the syndrome and required for the diagnosis. Loss of vision in early childhood is the rule with this disease, and accompanies variable pigmentary changes, ranging from little to diffuse pigmentation of the macula. Recent molecular studies have mapped multiple disease loci reflecting the heterogeneity of the disease, although the functions of these loci have yet to be identified.

Refsum disease is an autosomal recessive, neurodegenerative condition caused by phytanic acid accumulation in various organs and tissues. It occurs in two distinct infantile and adult forms, both of which are associated with retinitis pigmentosa [48, 49]. Infantile Refsum disease is one of the peroxisome biogenesis disorders (PBD) which represent defective assembly and function of the peroxisome organelle that is responsible for fatty acid metabolism. The Gly843Asp allele of the PEX1 gene on Chromosome 7 has been identified as the predominant mutation, present in over 50% of affected patients [50]. Infants may present at birth with hypotony, craniofacial dysmorphia and profound deafness. Characteristic facial features include hypoplastic supraorbital ridges, epicanthal folds, midfacial hypoplasia, and large anterior fontanelles. Seizures, anosmia, liver disease, psychomotor retardation, and leukodystrophy may be present. Associated ocular