Albinism, Oculocutaneous, Type Ia

A number sign (#) is used with this entry because oculocutaneous albinism type IA (OCA1A) is caused by homozygous or compound heterozygous mutation in the tyrosinase gene (TYR; 606933) on chromosome 11q14.

Description

Oculocutaneous albinism is a genetically heterogeneous congenital disorder characterized by decreased or absent pigmentation in the hair, skin, and eyes. The term 'albinism' includes specific ocular changes that are the results of reduced amounts of melanin in the developing eye; these abnormalities in the eye and optic system are specific and necessary for the diagnosis. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus (King et al., 2001).

Although OCA caused by mutations in the TYR gene was classically known as 'tyrosinase-negative' OCA, Tripathi et al. (1992) noted that some patients with 'tyrosinase-positive' OCA may indeed have TYR mutations resulting in residual enzyme activity. These patients can be classified as having OCA1B.

Genetic Heterogeneity of Oculocutaneous Albinism

OCA1, caused by mutations in the TYR gene, is divided clinically into 2 types: type IA, OCA1A, characterized by complete lack of tyrosinase activity due to production of an inactive enzyme, and type IB (OCA1B; 606952), characterized by reduced activity of tyrosinase. OCA2 (203200), OCA3 (203290), and OCA4 (606574) are somewhat milder forms of the disorder, caused by mutations in the OCA2 (611409), TYRP1 (115501), and MATP (SLC45A2; 606202) genes, respectively. OCA5 (615312) has been mapped to chromosome 4q24. OCA6 (see 113750) is caused by mutation in the SLC24A5 gene (609802). OCA7 (615179) is caused by mutation in the C10ORF11 gene (614537).

See also ocular albinism (OA1; 300500), which is restricted phenotypically to ocular involvement only.

Clinical Features

Taylor (1978) pointed out that in the albino the ganglion cell layer does not thin out in the foveolar pit but shows a layer 6 to 8 cells thick where there should be none. He commented that 'this must degrade the retinal image....There is therefore ample reason for the uncorrectable defective central fixation, and...the ocular nystagmus, in this case of the optical variety.' In 60% of his patients he noted an abnormal head posture, which minimized the nystagmus with slight improvement in visual acuity, at least for reading. All types of conditions with oculocutaneous or ocular hypopigmentation in man and animals with nystagmus tested to date have shown either electrophysiologic or anatomic evidence of a decussation defect in the optic tracts. Patients without nystagmus do not (Witkop et al., 1982).

Evidence that anomalous decussation exists also in the auditory system was presented by Creel et al. (1980). The amount of pigment in the inner ear correlates directly with the amount in the iris; otic pigment is lacking in albinos. In homozygotes an abnormal proportion of fibers from the ganglion cells of the temporal retina decussate to the contralateral cerebral hemisphere; this can be demonstrated by monocular visual evoked potential (VEP) asymmetry (Apkarian et al., 1983).

Van Dorp (1987) suggested that patients with autosomal recessive albinism may have normal pigmentation. In a family with several albinos, they found a cousin, the offspring of a consanguineous mating, who was normally pigmented but had absence of macromelanosomes on skin biopsy as well as ocular and electrophysiologic signs of albinism. Van Dorp (1987) also concluded that patients with X-linked ocular albinism (300500, 300600) may be generally underpigmented and that patients with the Hermansky-Pudlak syndrome (203300) may have a dark complexion.

Summers et al. (1991) observed striking discordance in ocular expression of albinism in 2 brothers. Both had foveal hypoplasia and misrouting of the optic fibers at the chiasm, as judged by VEP: one had strabismus and nystagmus with maximum correction of vision to 20/100, whereas the other had vision with myopic correction to 20/20 in both eyes and no nystagmus or strabismus.

Using MRI, Schmitz et al. (2003) found that the size and configuration of the optic chiasm in humans with albinism are distinctly different from the chiasms of normal control subjects. These chiasmal changes reflect the atypical crossing of the optic fibers, irrespective of the causative gene mutation. Eight patients had tyrosinase gene-related oculocutaneous albinism, 4 patients had pink-eyed dilution gene-related OCA2 (203200), 1 had ocular albinism (OA1; 300500); the albinism-causing mutation had not been identified in 4 other patients.

Summers and King (1994) described minimal pigment oculocutaneous albinism, a tyrosinase-related form of the disorder. They reported the findings in 9 patients followed for up to 11 years. Patients were born with white scalp hair and skin, and nystagmus developed. Visual acuity was reduced, but in 1 patient vision improved with maturity. The irides were blue. In 7 of the 9 patients, including the 1 patient with improved visual acuity, iris pigment developed as demonstrated by transillumination with slit-lamp biomicroscopy.

Meyer et al. (2002) found that optical coherence tomography (OCT) could be used to document foveal hypoplasia in patients with oculocutaneous albinism. In a patient with OCA, the OCT did not detect a foveal pit; instead, widespread thickening of the retina occurred throughout the entire fovea with no difference from the surrounding macula. Foveal thickness was 300 micrometers in the patient versus 150 micrometers in a normal subject. Recchia et al. (2002) also found that OCT allowed detailed examination of the macular anatomy in patients with foveal hypoplasia. Their patient's OCT data showed preservation of multiple inner retinal layers where there should have been none, indicating that the fovea was thicker than normal. The authors proposed that a more accurate term would be 'foveal dysgenesis,' and suggested that OCT might prove helpful in the evaluation of patients with unexplained visual loss.

Albinism is associated with a variety of ophthalmologic signs, including iris transillumination, nystagmus, strabismus, high refractive errors, foveal dysgenesis, chorioretinal hypopigmentation, and the 'albinotic' optic disc. Brodsky and Fray (2004) reported that a positive angle kappa is also associated with albinism in patients with congenital nystagmus. The authors suggested that this association might be related to the anomalous decussation of the optic axons that characterizes the albinotic visual system.

Biochemical Features

Amelanic melanocytes are present in the skin of albinos. These contain granules similar to the premelanosomes of normal melanocytes. In the test developed by King and Witkop (1977), which determines free (unbound) tyrosine, heterozygotes have shown little or no tyrosinase (606933) activity. Witkop et al. (1989) postulated that what tyrosinase is synthesized in the heterozygote is immediately bound to the melanosome matrix.

Inheritance

Pipkin and Pipkin (1942) claimed dominant inheritance for total albinism without other features in one family, but a quasidominant pedigree pattern of the usual recessive forms seems likely.

McLeod and Lowry (1976) observed seemingly dominant inheritance in 2 generations of 1 family but concluded that partial penetrance of the albinism II gene in heterozygotes was responsible.

In an extensive review of modifier genes in mice and humans, Nadeau (2001) pointed out that albinism due to deficiency of the tyrosinase protein is one of the few examples of a phenotype in which the expression is constant regardless of genetic background. The reason for its lack of modification is thought to result from the structure of the melanin synthesis pathway, the position of tyrosinase in this pathway, and the nature of the molecular lesion. Tyrosinase catalyzes 3 steps in this linear pathway that is thought to consist of only 4 steps. In the absence of tyrosinase, there are no metabolites that can act as targets for modification. Although deficiency of tyrosinase results in a constant phenotype, mutations that affect the preceding biochemical step, which converts phenylalanine to tyrosine (see PAH; 612349), result in substantial phenotypic variability.

Mapping

Using RFLPs identified within the human tyrosinase gene, Spritz et al. (1989) did linkage analysis in albinism families and demonstrated absolute linkage.

Giebel et al. (1990, 1991) demonstrated genetic linkage between classic tyrosinase-negative oculocutaneous albinism (type IA) and the tyrosinase gene RFLP (lod = 6.17 at theta = 0). Barton et al. (1988) mapped the TYR locus to 11q14-q21.

Molecular Genetics

In a child with tyrosinase-negative oculocutaneous albinism, Tomita et al. (1989) identified a homozygous 1-bp insertion in the TYR gene (606933.0001).

In a patient with classic tyrosinase-negative OCA, Spritz et al. (1989) found a thr-to-lys substitution that abolished 1 of 6 putative N-linked glycosylation sites that are completely conserved between humans and mice; see 606933.0003. Spritz et al. (1989) found no cases of tyrosinase gene deletions or other rearrangements, even in DNAs from patients with both tyrosinase-deficient oculocutaneous albinism and mental retardation. The families studied exhibited several different pigmentation phenotypes suggesting that tyrosinase-deficient OCA results from heteroallelism for different small defects of the tyrosinase gene.

Tripathi et al. (1992) stated that more than 60 independent albinism-producing alleles had been described at the TYR locus. They reviewed 29 of these and commented on 2 additional novel missense substitutions in a 'note added in proof.' They commented that type I OCA in Caucasians clearly results from a great variety of different uncommon alleles. About 90% of OCA in Caucasians was accounted for by the 29 mutations they described. More than 80% of the then-known missense substitutions clustered within 2 relatively small regions of the tyrosinase polypeptide, suggesting that these may represent functionally critical sites within the enzyme.

Oetting and King (1993) tabulated 36 mutations identified in type I OCA: 24 missense, 4 nonsense, and 8 frameshift mutations. The affected individuals in these cases were compound heterozygotes. They also listed 6 polymorphic sites useful in haplotype analysis: 2 in the promoter region, 2 in the coding region associated with alternative amino acids in the tyrosinase protein, and 2 RFLPs in the first intron.

Diagnosis

King and Olds (1985) examined hairbulb tyrosinase activity in 72 individuals with albinism and 64 obligate heterozygotes. Several different types were distinguished based on biochemical features. Type IA was tyrosinase-negative and type IB had low or no measurable activity; heterozygotes in both groups could be detected with this assay. Type II was tyrosinase-positive with moderate-to-high activity; heterozygotes could not be detected with this assay. The authors cited a third type, previously referred to as 'minimal pigment' type, with low tyrosinase activity; this form is now considered to be a variant of OCA1B (King et al., 2001).

Prenatal Diagnosis

Commenting on the availability of prenatal diagnosis in albinism, Taylor (1987) argued that elective abortion of albino fetuses is difficult to defend because of the satisfactory adjustment and even success in some areas of activity of albino individuals. Persistent ocular albinism and nystagmus permit accurate diagnosis in the adult.

Shimizu et al. (1994) made the prenatal diagnosis of tyrosinase-negative OCA by an electron-microscopic DOPA reaction test of fetal skin at 20 weeks' gestation. A previous child born with albinism was 9 years old at the time; the pregnancy in which the diagnosis had been made was terminated at 21 weeks.

Population Genetics

Froggatt (1960) estimated a phenotype frequency of albinism I to be 1 in 10,000 in Northern Ireland. First-cousin marriages occurred in 4.5% of the parents. An excess of males was almost exclusively in the probands and the sex ratio of secondary cases was about 1; therefore, bias of ascertainment probably accounted for the excess of males. The mutation rate was estimated to be between 3.3 and 7 x 10(-5) per gene per generation. Abnormal iris translucency, occurring in 70% of the parents and children of albinos, was interpreted as a heterozygous manifestation.

In British Columbia, McLeod and Lowry (1976) found the incidence of type I albinism to be 1 in 67,800 live births and of type II albinism (203200) to be 1 in 35,700 live births.

Jay et al. (1982) tabulated the frequency of different types of albinism in England: tyrosine-negative OCA, 54; tyrosinase-positive OCA, 50; yellow mutant OCA, 7; Hermansky-Pudlak syndrome, 2; X-linked ocular albinism hemizygotes, 21, and heterozygotes, 15; autosomal recessive ocular albinism, 16. In surveying congenital anomaly syndromes in a Spanish gypsy population, Martinez-Frias and Bermejo (1992) found an impressive frequency of albinism. In one of the pedigrees, there were 2 examples of pseudodominant inheritance, i.e., apparent parent-to-child transmission.

King et al. (2003) evaluated proposed clinical criteria for OCA1 by performing mutation analysis on 120 probands who met these proposed criteria. They defined 2 types: OCA1A, in which there is life-long absence of melanin pigment after birth; and OCA1B, in which there is development of minimal to moderate amounts of cutaneous and ocular pigment. They concluded that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 (203200) may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.

Gronskov et al. (2009) identified 218 individuals with albinism born in Denmark between 1961 and 2005, of whom 55% were categorized as having OCA and 45% as having ocular albinism only (autosomal recessive ocular albinism; AROA). However, the authors noted that in Nordic populations, the categorization of patients as having OCA or AROA is often arbitrary due to the abundance of fair skin and hair in the general population, and stated that the overdiagnosis of AROA in OCA cases could not be excluded. A minimum birth prevalence for albinism of 1 in 14,000 was calculated.

Wei et al. (2013) stated that oculocutaneous albinism has a worldwide prevalence of approximately 1 in 17,000.

Genotype/Phenotype Correlations

Gronskov et al. (2009) analyzed 4 known OCA genes, TYR, OCA2, TYRP1, and MATP, in 62 patients with autosomal recessive albinism; they identified 2 mutations in 1 OCA gene in 44% of the patients. Mutations in TYR were found in 16 patients (26%), whereas mutations in OCA2 and MATP were present in 9 (15%) and 2 (3%) patients, respectively; no mutations were found in the TYRP1 gene. Of the remaining patients, 18 (29%) were heterozygous for a mutation in either TYR or OCA2, and no mutations were found in 17 patients (27%). Although there was a tendency toward a more severe phenotype in patients with TYR mutations, Gronskov et al. (2009) observed considerable overlap of skin color, hair color, and Fitzpatrick tanning pattern within the TYR and OCA2 subgroups. Ocular parameters were uninformative with respect to mutational background, except for a clear preponderance of severe photophobia among patients with TYR mutations.

Simeonov et al. (2013) reviewed the clinical and molecular characteristics of OCA and reported 22 novel mutations in OCA patients, including 14 in TYR, 5 in OCA2, 1 in TYRP1, and 2 in SLC45A2. In addition, they provided a comprehensive list of almost 600 previously reported OCA mutations, along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions. Simeonov et al. (2013) demonstrated the utility of multiple detection methods to identify mutations missed by Sanger sequencing.

Animal Model

Working with albino melanomas and tyrosinase inhibitor in animals, Chian and Wilgram (1967) found that the inhibitor is effective against soluble tyrosinase but not against tyrosinase aggregated into melanosomes. In one type of albino mutation, tyrosinase apparently could not aggregate because of genetic alteration in its protein carrier and therefore was vulnerable to the effects of the inhibitor. These workers suggested that a similar situation may obtain in some type of albinism of man.

In a wide variety of animals, the albinism gene is known to have a pleiotropic effect on the visual pathways (Guillery, 1974). Some of the optic nerve fibers do not decussate as in the normal. This structural abnormality, the mechanism of which is unknown, can be associated with crossed eyes in albino animals. Carroll et al. (1980) presented evidence that the human albino has the same anatomic peculiarity of the visual pathways, resulting in misrouting of the retinogeniculate projections, that has been found in albinos of other species.

Leventhal et al. (1985) studied cats who were obligatory heterozygotes for a c-locus tyrosinase-negative allele (Cc) and had no relationship to 'deaf white cats' (W). In these normally pigmented animals abnormalities of the retinogeniculocortical pathways were found to be similar to those in homozygous albinos. By unilateral injection of horseradish peroxidase (HRP) into the dorsal lateral geniculate nucleus, they could map the retrogradely labeled retinal ganglion cells. Compared to homozygous normal controls, heterozygotes showed labeling of an abnormally large number of cells, especially large alpha cells, in the contralateral temporal retina. The authors pointed out that 1 to 2% of the human population may be heterozygous for albinism and that the above described abnormality may have an adverse effect on binocular depth perception. The locus ceruleus and substantia nigra are normally pigmented in albinos. They owe their pigmentation to neuromelanin, which is synthesized by tyrosine hydroxylase rather than tyrosinase (Witkop et al., 1989).

Snyder (1980) pointed out that in Mus musculus, Rattus norvegicus, and Peromyscus maniculatus, glucosephosphate isomerase (Gpi-1), albinism (c), and beta-type globin (Hbb) are linked. In the first 2 species, pink-eyed dilution (p) is also known to be in this same cluster. (Indeed, the pink-eye--albinism linkage in the mouse was the first to be demonstrated in any mammal, by Haldane et al., 1915.) See Lyon et al. (1992) and Gardner et al. (1992) for genetic and molecular analyses of the pink-eyed dilution gene in the mouse. Gardner et al. (1992) demonstrated that the human homolog of the mouse p mutation is a gene located on 15q11.2-q12, a region associated with Prader-Willi syndrome (176270) and Angelman syndrome (105830); see 203200. It is not linked to the human homolog of any of the 3 above-mentioned genes that are located on mouse chromosome 7 in linkage with 'pink-eye.'

O'Brien et al. (1986) found that the albino locus in the domestic cat is linked to the beta-globin locus at a distance of approximately 8 cM. Evolutionary conservation of syntenic homology of feline chromosome D1 and human chromosome 11 is extensive. High resolution G-trypsin-banded preparations of the 2 chromosomes showed similarities. (A tyrosinase-related gene, which contains only exons 4 and 5, is located on 11p; see 191270.)

'Dark-eyed albino' is a recessive mutation at the mouse albino 'c' locus, which encodes tyrosinase. Similar to type IB OCA in humans, overall production of pigment is greatly reduced in dark-eyed albino mice and obvious only in the eyes.

Using a human tyrosinase cDNA clone, Barton et al. (1988) and Kwon et al. (1989) isolated mouse tyrosinase genomic clones and used them to map the mouse tyrosinase locus to a site at or near the albino locus on mouse chromosome 7. Mouse tyrosinase mRNA was found to measure approximately 2.4 kb. A mutation in tyrosinase responsible for the albino mouse appears to be a change of cysteine-85 to serine (Kwon et al., 1988), resulting from a change of guanine 390 to cytosine. Jackson and Bennett (1990) studied revertant cells and found that loss of the mutant allele was responsible.

History

In describing albinism in the Caribe Cuna Indians, Keeler (1953) commented on the abundant straight white down consisting of hairs up to 2.5 cm long that develops on the body and extremities. It is not clear that this indicated genetic distinctness; it may somehow be related to the exposure of the subjects--partial hirsutism.

Famous albinos include Noah of flood fame and the Rev. Dr. Spooner. Evidence that Noah was an albino was presented by Sorsby (1958). Spooner was a brilliant classicist at Oxford whose amusing tendency to errors of speech came to be known as spoonerisms. Although probably elaborated on by students, the aberration appears to have been marked. As a classicist, Spooner must have read extensively. The aberration of speech was probably related to his nystagmus which caused a jumbling of information from the printed page. His intelligence was such that his mind comprehended despite the jumbling, but a jumbling of sorts occurred with oral output (Edwards, 1980). (Spooner was warden of New College, Oxford University, where his brightly colored portrait hangs (Gibson, 1980).) It would be of interest to know whether spoonerism (as a process and phenomenon) is more frequent in albinos or others with nystagmus. An 'albino society' has been formed in England.

Of interest in connection with the possible linkage of beta-globin and albinism (suggested by homology to the mouse) were the reports of a family with both albinism and sicklemia (Massie and Hartmann, 1957) and of a Sicilian boy with albinism and an unusual combination of hemoglobinopathies (Schiliro et al., 1983).