Clinical consequences of heterozygosity for autosomal‐recessive diseases*,**

Abstract

Heterozygotes of autosomal‐recessive diseases can often be recognized by special heterozygote tests, since enzyme activities are normally reduced in comparison with the normal homozygote state. In Drosophila, the majority of recessive lethal mutations shows a reduction of fitness in heterozygotes, whereas in a strong minority fitness of heterozygotes is increased. This review will be devoted to a consideration of the extent to which heterozygotes for a wide variety of nominally recessive diseases are subject either to an increased liability for common diseases or slight shifts of behavioral characteristics. The available evidence has been collected and will be discussed in three steps: 1. Most studies are available for phenylketonuria. For this group of diseases, a slight reduction of average ‐ especially verbal ‐ I.Q. in heterozygotes has been reported together with signs of a slightly increased cerebral irritability, a possible slight increase of risk for mental disease, and an increase of blood phenylalanine levels in stress situations. The PKU example is used to discuss methodological problems involved in such studies. 2. Other conditions for which relevant deviations in heterozygotes are possible or even likely include among others lipid storage diseases, microcephaly, myoclonus epilepsy, Wilson's disease, galaktokinase deficiency, homocystinuria, recessive myotonia and ataxia‐teleangiectasia (increased cancer risk). 3. Since heterozygotes for autosomal recessive diseases are common, it is possible that an appreciable fraction of “multifactorial” genetic liabilities for common, “constitutional” or mental disease might simply be due to heterozygosity for genes whose homozygous affects are already well known. By the same token, much of the “normal” genetic variability influencing cognitive performance (I.Q.) ‐ especially in the lower range ‐ and personality characteristics could also be caused by recessive genes in the heterozygous state.

A genetic‐diagnostic survey in an institutionalized population of 158 mentally retarded patients. The Viaene experience

“…This could be considered as a partial heterozygote manifestation of autosomal recessive disorder. This controversial subject has been discussed at length by Vogel (1984).…”

Can heterozygotes of autosomal recessive disorders have clinical manifestations?

“…Heterozygosity in AR disorders can produce subclinical manifestations or milder phenotype . Two of our cases had late‐onset clinical manifestations and milder phenotype.…”

“…Clinicians then face a diagnostic conundrum of having a phenotype of an autosomal recessive (AR) disorder with heterozygous mutation(s) of likely clinical relevance, which cannot explain the condition. Literature suggests that heterozygosity can indeed influence individual susceptibility to disease, producing clinical or subclinical manifestations as seen in AR inherited conditions, such as Wilson disease, Gaucher disease, and Parkinson's disease caused by PTEN‐induced putative kinase 1 ( PINK1 ) gene mutations . Using 3 cases of AR movement disorders (Table ), having heterozygous mutations and a compatible phenotype, this letter highlights the issues and discusses the clinical implications.…”

“…Nucleosome positioning at the transcription start site plays an important role in gene expression . Interaction between genetic and environmental factors can potentially modify a phenotype . Modifier genes, which may be minimally penetrant in healthy individuals, can have their effect unmasked in patients with altered homeostasis …”

Wilson’s Disease in Brain Magnetic Resonance Spectroscopy

“…The number of heterozygotes -having only one faulty copy of the gene -is high, around 1-2% of the human population (Johnson, 2001). Heterozygote carriers should not have symptoms of hepatic, neurological dysfunctions, but in other recessive disorders such as phenyloketonuria, some deviations in brain function in the literature were reported (Vogel, 1984). Because 1 H-MRS is able to detect brain abnormalities that are invisible in clinical assessment and MRI a study using this method to investigate the probability of brain www.intechopen.com changes in Hzc was performed (Tarnacka et.al, 2009b).…”