An inborn error of metabolism is caused by a genetic inability to produce the full complement of a given functioning protein in its normal configuration. Although many of these disorders are rare, they often produce devastating ocular manifestations. Because of the severity and the high incidence of these ocular manifestations, the ophthalmologist is often involved in the care of these patients. In addition, the ophthalmologist is often asked to play an early role in order to detect subtle, early, and occasionally pathognomonic lesions to aid in the diagnosis of these rare disorders. This chapter will discuss those inborn errors of metabolism that may have an effect on both retinal function and appearance.

6.1  Disorders of Amino

Acid Metabolism

6.1.1  Albinism

Albinism comprises a heterogeneous group of clinical syndromes exhibiting hypomelanosis based on heritable metabolic defects of the melanin pigment system. All types of albinism are characterized by foveal hypoplasia, nystagmus, photophobia, and decreased visual acuity in addition to absent or decreased melanotic pigment in skin, hair, and eyes (oculocutaneous albinism (OCA)) or in the eye alone (ocular albinism (OA)). Individuals who are homozygous for the genetic

mutations responsible for OCA have an abnormal proportion of fibers from the ganglion cells of the temporal retina that decussate to the contralateral cerebral hemisphere; this can be demonstrated by monocular visual evoked potential asymmetry [1]. This may play a role in the high incidence of subnormal binocular vision and strabismus in albinos.

In affected persons with OA, the cutaneous pigmentary dilution is much less noticeable than is the ocular involvement. The skin pigmentation in these patients typically falls within the normal range. However, when these affected persons are compared with their nonaffected siblings, they typically have a lighter complexion. The ocular findings in OA are similar to those in OCA. However, in patients with OA, the pigmentary dilution of the eye may be subtle. In whites, there is usually iris transillumination. In blacks, the iris often does not transilluminate and the retina is usually moderately pigmented [2]. Regardless of the pigmentation of affected patients, all have foveal hypoplasia (Fig. 6.1).

The term albinoidism refers to hypomelanotic disorders in which the patients do not have nystagmus, decreased visual acuity, or foveal hypoplasia.

All forms of albinism, with the exception of OA, are inherited in an autosomal recessive fashion. OA is inherited as an X-linked disorder.

From a molecular basis, albinism can be divided into those forms that are caused by a defect specific to the melanosome and systemic molecular defects in which albinism in just one observed abnormality.

6.1.1.1  Disorders Specific to Melanosomes

mud­ -spattered appearance of the fundus with hyperpigmented streaks as well as iris transillumination defects [6]. OA is caused by a defect in the OA1 gene which encodes for a melanosomal membrane glycoprotein. Giant melanosomes are found in the melanocytes of affected individuals.

6.1.1.3  Systemic Disorders Associated

With Albinism

Four forms of OCA have been identified, each mapped to a different genetic locus. OCA1 represents tyrosinasenegative albinism and is caused by a defect in the TYR gene which produces tryosinase. OCA1 can be further subdivided into two types. In OCA1A, there is complete inactivity of tyrosinase. Affected patients show severe hypopigmentation that does not change with time. OCA1B is associated with some tyrosinase activity. Over time, patients may develop some skin pigmentation with possible freckle development. They may be able to tan.

Tyrosinase-positive OCA (OCA2) is the most prevalent type of albinism in the world [3]. The mutated protein is a transmembrane polypeptide (P protein) that is encoded by the Pgene that may play a role in transporting small molecules such as tyrosinase [4]. Affected individuals show some degree of pigmentation and have less profound clinical manifestations than those with OCA1.

In OCA3 a mutation occurs in the TYRP1 gene. This gene is responsible for producing tyrosinase-related protein-1 (TYPR-1) [5]. The function of TYPR-1 is not known but it appears to have a role in the regulation of tyrosinase activity. Patients with OCA3 have reddish hair and red–brown skin color. They may develop a faint tan with sun exposure.

OCA4 is caused by a defect in the gene that encodes for a membrane-associated transporter protein. People with OCA4 are phenotypically similar to those with OCA2.

6.1.1.2  Ocular Albinism

(Nettleship–Falls Albinism)

Patients with OA demonstrate similar ocular findings to those patients with OCA. However, the skin and hair of those patients with OA are normal. OA is an X-linked recessive disorder. Although males are principally involved, carrier females may demonstrate a

Hermansky–Pudlak Syndrome

Patients with OCA should be questioned about a history of bleeding because of the association of albinism with a hemorrhagic diathesis, the Hermansky–Pudlak syndrome [7]. Four subtypes have been identified. All four subtypes consist of a combination of OCA with lysosomal accumulation of ceroid lipofuscin and deficient platelet function. The hemostatic defect in the Hermansky– Pudlak syndrome is typically mild; the most common manifestations are gingival bleeding, epistaxis, and easy bruisability [8]. More serious bleeding episodes have followed surgical procedures, especially when aspirin was used to control postoperative discomfort [9]. Accumulation of ceroid lipofuscin leads to intestinal fibrosis and granulomatous colitis. The Hermansky– Pudlak syndrome is the most common form of albinism seen in Puerto Rico. A deficiency of platelet dense bodies, as observed by electron microscopy, is the most reliable method of diagnosing this syndrome [10].

Chediak–Higashi Syndrome

Patients with Chediak–Higashi Syndrome demonstrate characteristics of albinism with hypopigmentation of the eyes, hair and skin. In addition, they also have defects in their immune system characterized by dysfunction of natural killer cell activity and poor chemotaxis. Frequent bacterial infections may occur over time.

Diagnosis and Treatment

Diagnosis of albinism is generally made based upon clinical examination. If needed, DNA testing is available for some forms of albinism and electron microscopic evaluation of the skin of patients with suspected