Enzyme defects

Autosomal recessive diseases often result from defects in enzymatic proteins. Most of the so-called inborn errors of metabolism that result from enzyme defects are autosomal recessive traits, although a few are X-linked recessive disorders (eg, Lesch-Nyhan syndrome).

Table 6-1 Known Enzyme Disorders and Corresponding Ocular Signs

In some other disorders with genetic blocks in metabolism, the phenotypic consequences are related to the lack of a normal product distal to the block. One example is albinism, in which the metabolic block involves a step between the amino acid tyrosine and the formation of melanin. In still other inborn errors of metabolism, the phenotypic expression results from excessive production of a product through a normally alternative and minor metabolic pathway.

Carrier heterozygotes

The heterozygous carrier of a mutant gene may show minimal evidence of the gene defect in recessive conditions. However, dysfunction may be evident at a biochemical level. Thus, carrier heterozygotes have been detected by a variety of methods:

• identification of abnormal metabolites by electrophoresis (eg, galactokinase deficiency)

• hair bulb assay (eg, oculocutaneous albinism and Fabry disease)

• monitoring of enzyme activity in leukocytes (eg, galactose-1-phosphate uridyltransferase in galactosemia)

• skin culture for analysis of enzyme activity in fibroblasts (eg, ornithine aminotransferase deficiency in gyrate atrophy of the retina and choroid)

• assay of serum and tears (eg, hexosaminidase A in Tay-Sachs disease)

In contrast to the transmission of dominant traits, most reproduction resulting in transmission of recessive disorders involves phenotypically normal heterozygous parents. Among 4 offspring produced by parents carrying the same gene for an autosomal recessive disease, on average, 1 will be affected (homozygote), 2 will be carriers (heterozygotes), and 1 will be genetically and phenotypically unaffected. Thus, clinically unaffected heterozygous parents will produce offspring with a ratio of 1 clinically affected to 3 clinically normal. There is no predilection for either sex. In 2-child families, the patient with a recessive disease is frequently the only affected family member. For instance, approximately 40%–50% of patients with retinitis pigmentosa (RP) have no family history of the disorder. However, their age at onset, rate of progression, and other phenotypic characteristics are similar to those with defined recessive inheritance patterns.

This concept has specific implications for genetic counseling. All offspring of an affected individual will be carriers; they are unlikely to be affected with the disorder unless their clinically unaffected parent is also by chance a carrier of the gene. The normal-appearing sibling of a child with a recessive disorder has a statistical risk of 2 chances in 3 of being a genetic carrier. As the genes for recessive diseases are identified, these individuals and their offspring will benefit from predictive DNA testing.

Consanguinity

The mating of close relatives can increase the probability that their children will inherit a homozygous genotype for recessive traits, particularly relatively rare ones. For example, the probability that the same allele is present in first cousins is 1 in 8. In the offspring of a first-cousin sexual union, 1 of every 16 genes is commonly present in a homozygous state. It follows that each offspring from a first-cousin union has a 1 in 16 chance of manifesting an autosomal recessive trait within a given family. Approximately 1% of all sexual unions may be consanguineous. A vigorous search for consanguinity between the parents should be made in any case of a rare recessive disease.

In contrast, the expression of common recessive genes is less influenced by inbreeding because most homozygous offspring are the progeny of unrelated parents. This pattern is usually the case with such frequent disorders as sickle cell disease and cystic fibrosis. The characteristics of autosomal recessive inheritance are summarized in Table 6-2.

Pseudodominance

Occasionally, an affected homozygote mates with a heterozygote. Of their offspring, 50% will be carriers and 50% will be affected homozygotes. Because this segregation pattern mimics that of dominant inheritance, it is called pseudodominance. Such matings are usually rare and are unlikely to affect more than 2 vertical generations.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.