Intermediate phenotypes

The human leukodystrophies are inherited disorders of central nervous system white matter. These disorders are characterized by a diffuse deficiency of myelin caused by a variety of genetic lesions and often manifest before 10 years of age (Table 38-1). Some are caused by mutations in the PLP gene and resemble the PLP animal mutants described in Chapter 4 [ 1,23]. As with the animal models, depending on the nature of the mutation, they vary from a severe form in connatal Pelizaeus-Merzbacher disease (PMD) through an intermediate phenotype in classical PMD to a mild phenotype in spastic paraplegia. It is noteworthy that some mutations of the PLP gene also cause a peripheral neuropathy [24], very probably related to the expression of low levels of PLP in peripheral nerve (see Ch. 4). 

Pavlu-Pereira H, Asfaw B, Poupetova H, Ledvinova J, Sikora J, Vanier MT, Sandhoff K, Zeman J, Novaotna Z, Chudoba D, Elleder M (2005) Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study. J Inherit Metab Dis 28 203-227... 

Reist C, et al. Inter-relationships of intermediate phenotypes for serotonin function, impulsivity, and a 5-HT2A candidate allele His452Tyr. Mol Psychiatry 2004 9(9) 871-878. 

Meyer-Lindenberg A, Weinberger DR. 2006. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7 818-827. 

Straub RE, Egan MF, Hashimoto R, Matsumoto M, Weickert CS, et al. 2003. The schizophrenia susceptibility gene dysbindin (DTNBP1, 6p22.3) Analysis of haplotypes, intermediate phenotypes and alternative transcripts. Biol Psychiatry 53(suppl.) 167S-168S. 

Cannon TD. 2005. The inheritance of intermediate phenotypes for schizophrenia. Curr Opin Psychiatry 18 135-140. 

Flossmann E, Schulz UG, Rothwell PM (2005). Potential confounding by intermediate phenotypes in studies of... 

Flossmann E, Rothwell, PM (2005). Family history of stroke in patients with TIA in relation to hypertension and other intermediate phenotypes. Stroke 36 830-835 Flossmann E, Rothwell PM (2006). Family history of stroke does not predict risk of stroke after transient ischemic attack. Stroke 37 544-546... 

Harris, H., and M. Whittaker. 1962. The serum cholinesterase variants. A study of twenty-two families selected via the "intermediate" phenotype. Ann. Hum. Genet. 26 59-72. 

Harris, H. and M. Whitaker. 1962. The serum chohnesterase variants. Study of twenty-two famihes selected via the "intermediate phenotype. Am. Hum. Genet. 26 59—72. (Cited in Hayes, 1982)... 

Newell et al. analyzed human CD8+ T cells through mass cytometry in order to characterize surface biomarkers, cytokines, and antigen specificity with modified peptide-MHC. They have built a panel of 17 cell surface markers of human CD8 + T cells. They have also added nine additional markers six intracellular cytokines, CD107, two cytotoxic granule components, and the perforin and granzyme B. The samples were recollected from six healthy individuals and were stimulated to demonstrate their functional abilities. The analysis was carried out through principal component analysis. This group found that common definitions of naive, central memory, effector memory, and terminal effector subsets correspond to phenotypic clusters in their analysis. Moreover, they have found intermediate phenotypes that connect the clusters to form a continuum, but also exceptional cells that lead the classic definition (44). 

Irwin and Hein (13) reported a family in which DN and FN values indicated that the father was of the usual phenotype, the mother the atypical phenotype, and the two sons the intermediate phenotype. However, one of the sons had about 25% more cholinesterase activity with benzoylcholine as substrate than did his father. Furthermore, the son s cholinesterase activity was greater than that of his father when tested with several other substrates. The pattern of values for this son indicated that his cholinesterase was qualitatively different from that of anyone else in his family. An unidentified gene that affects the amount of enzyme activity, as well as the qualitative properties of cholinesterase, might exist in this family. However, the findings may have been complicated by a physiologically high level of cholinesterase activity which is found in some children, and which decreases to normal adult values at puberty. 

Developmentally, the best characterized cell lineage within the neural crest is probably the sympathoadrenal lineage. There are three cell types in this lineage, the sympathetic neuron, the adrenal chromaffin cell and a third cell of an intermediate phenotype, the so called small, intensely fluorescent cell (SIF cell) (see Anderson, 1989 Patterson, 1990). Although progenitors of this lineage have not been isolated from neural crest cultures, they have have been isolated from embryonic adrenal medulla as well as from both embryonic and neonatal sympathetic ganglia. 

The specific-locus method consists essentially of mating treated and untreated wild-type mice, either male or female, to a strain homozygous for a number of recessive genes which have readily visible phenotypic effects. The offspring produced from the cross will be wild type unless a mutation has occurred at one of the loci represented by the recessive genes, when the recessive phenotype or perhaps a new or intermediate phenotype will be seen. The system thus provides a simple means of estimating the mutation frequencies to recessive visibles, including those with lethal effects. Dominant visibles would, of course, also be detected. 

---