Autosomal recessive forms of inherited metabolic diseases, in contrast to dominant ones, occur only in the homozygous state (both alleles are abnormal). They are usually characterized by an onset soon after birth. The basic abnormality in the recessively inherited diseases discussed in this chapter is more often an enzyme deficiency than an abnormality of some other protein.
In disorders of X-linked genes, in which the mutant gene affects mainly one sex, the female will suffer the same fate as the male if one X chromosome has been inactivated, as happens in most cells during embryonic development (the Lyon phenomenon). However, even if the abnormal X chromosome is not widely expressed, the female carrier may still exhibit minor abnormalities. In the latter case, sex-linked inheritance becomes difficult to distinguish from dominant inheritance. Also, sex linkage is deceptive when a disease is lethal to one sex. In contrast to autosomal recessive mutations, the abnormality has more often been one of a basic protein than an enzyme deficiency.
Multifactorial genetic diseases may also be familial. They may present as constitutional disorders with gene abnormalities located on several chromosomes (polygenic, or “complex genetics”) or may arise from single nucleotide polymorphisms or copy number variations. Here, the relative contributions of genetic and environmental influences are highly variable. The occurrence of many disorders that display high degrees of familial incidence, such as schizophrenia and Gilles de la Tourette syndrome, but do not strictly conform to classic genetic principles has been attributed to this type of complex genetics.
The separation of metabolic-genetic from degenerative diseases (accorded a separate chapter) may disquiet the reader, for there are many overlaps between the two groups. The current division is tenable only until such time as all the degenerative diseases will have been shown to have a comprehensible pathogenesis.
The Genetics of Mitochondrial Disease
An entirely different type of genetic transmission relating to the DNA that lies in the mitochondria has been elucidated. Mitochondria contain their own extrachromosomal DNA, distinct from nuclear DNA. Mitochondrial DNA (“the other human genome”) is a double-stranded, circular molecule that encodes the protein subunits required mainly for translation of the proteins located on the mitochondrial inner membrane. Of the 37 mitochondrial genes, small in number by comparison with nuclear DNA, 13 partake in the cellular processes of oxidative phosphorylation and the production of adenosine triphosphate (ATP). A few genes in the cell’s nucleus also code for a considerable number of oxidative enzymes of the mitochondria, but their inheritance follows a mendelian pattern; consequently, a mitochondrial disorder may fail to display maternal inheritance that is characteristic of mitochondrial mutations as described below.
Each mitochondrion contains up to 10 ringed DNA molecules, and each cell, of course, contains numerous mitochondria. In the cell, mitochondria with mutant genes may exist next to normal mitochondria (heteroplasmy), a state that permits an otherwise lethal mutation to persist (Johns). The presence of either completely normal or completely mutant mitochondrial DNA is termed homoplasmy. The essential feature of mitochondrial genes and the mutations to which they are subject is that they are inherited almost exclusively through maternal lineage. This is explained by the transmission of virtually all mitochondria from the ovum at the time of conception. Moreover, mitochondrial DNA does not recombine, thus permitting the accumulation of mutations through maternal lines. Also, the replication and distribution of mitochondrial DNA during cell division do not follow the nuclear mitotic cycle. Instead, there are contributions during cell division from the genes of various mitochondria to the progeny of dividing cells. The combination of a heteroplasmic state and the capricious dispersion of mitochondria to daughter cells (replicative segregation) explains the variable expression of mitochondrial mutations in different tissues and in different regions of the nervous system.