Molecular pathology

In all but one of the cases that have been adequately investigated, PMPS was due to deletions within mtDNA. The size of the deletion is variable; in one study, 43% of the patients had an identical 4.9-kb deletion which has also been found in patients with other mitochondrial diseases (such as KSS and progressive external ophthalmoplegia; Figure 12.3). In some cases, deletion dimers and/or deletion multimers were observed. There is no obvious correlation between the size or location of the deletion and the clinical severity of the disease; rather, what probably largely determines the clinical pheno-type is the proportion of mutated mtDNA in a particular tissue. For example, patients with PMPS have mutated mtDNA in all tissues examined, whereas in patients with classical KSS the mutated mtDNA is restricted to muscle and is not found in blood cells. Since the mothers of PMPS patients are invariably unaffected, it can be expected that the deletion has taken place de novo, and this has been documented in a number of cases.

A difficult practical problem is that of genetic counseling for couples who have had the misfortune of having a child with PMPS. The risk of recurrence depends on whether the deletion is present in most, or only in some, of the mother's gonadal cells. At the moment there is no established method for determining this. At an experimental level, it could be achieved by inducing multiple ovulation and using the polymerase chain reaction (PCR) to test individual oocytes for the deletion previously detected in an affected sib. The same could be done in very early embryos after in vitro fertilization (pre-implantation prenatal diagnosis). Because of the high copy number of mtDNA, testing for mtDNA mutations is much easier than testing for mutations in nuclear genes.

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