In 1979, Pearson et al (1) reported the case of a young infant who presented with refractory anemia, marked vacuolization of bone marrow cells, pancreatic insufficiency, and marked lactic acidosis. Since then, additional, although rare, cases have been studied, and the DNA defect determined. A defined, multi-system syndrome with a variable clinical presentation has emerged as "Pearson's Syndrome."
Children with Pearson's syndrome characteristically present in early infancy with pallor, failure to thrive, pancytopenia, diarrhea, and markedly increased serum and/or cerebrospinal fluid lactate. Additional manifestations often include progressive external ophthalmoplegia, proximal myopathy with weakness, and neurologic disturbances (seizures, ataxia, stroke-like episodes) (3,4). The extent of multiple organ involvement is quite variable. Most infants die before age 3, often due to unremitting metabolic acidosis, infection, or liver failure. Those few individuals who can be medically supported through infancy may experience a full recovery of marrow and pancreatic function. However, these individuals eventually undergo a phenotypic transformation from Pearson's syndrome to Kearns-Sayre syndrome (discussed below), with the development of ptosis, incoordination, mental retardation, and episodic coma. Cardiac conduction abnormalities and hearing loss can also develop (4,5).
The combination of marked metabolic acidosis, complex organic aciduria (i.e., large amounts of lactic, 3-hydroxy-butyric, beta-hydroxy-butyric, fumaric, malic, succinic, and, often, 3-methyl-glutaconic acids), together with cytoplasmic vacuolization of bone marrow cells, is highly suggestive of Pearson's syndrome and consistent with a common underlying defect within the mitochondrial respiratory chain (6). In 1991, Rotig et al (7) reported a single large (4978 bp) deletion within mitochondrial DNA (mtDNA) of five unrelated patients. This large deletion constitutes > 30% of the entire mitochondrial genome and includes genes coding for subunits of cytochrome c oxidase and NADH-dehydrogenase. (Human mtDNA encodes 36 genes: 22 tRNA, 2 rRNA, and 13 polypeptide coding genes--all components of the respiratory chain. See Image 09.) Less common large deletions within the same vicinity have been reported (8). Generally, these large deletions are flanked by short direct nucleotide repeats (7). To date, the deletion in this case has not been fully mapped, but appears quite extensive. Mitochondrial DNA is, theoretically, only transmitted to offspring through the mother via the large cytoplasmic component of the oocyte. Nearly all cases of Pearson's syndrome arise from de novo deletions; mitochondria have extremely poor DNA repair mechanisms, and mutations accumulate very rapidly. There is a reported case of multiple, different mtDNA deletions present in two brothers with Pearson's syndrome, as well as in their asymptomatic mother (9). No mtDNA mutations were detected in the mother of the present patient.
How, then, does a single large deletion present with such a varied clinical picture, in terms of the extent of organ involvement and "phenotypic switch" to a different syndrome (i.e., Kearns-Sayre syndrome, see above)? The answer lies in the important concept of 'heteroplasmy.' Heteroplasmy is the coexistence, within the same cell, of both wild-type and mutated mtDNA. It is believed that the segregation of mtDNA is random among cells. Therefore, it is possible that the phenotypic expression of a mutation may vary both in time (when it appears during development) and in space (what cells and tissues contain the mutated mtDNA) (10). Different tissues may be affected clinically if the number of mutant mtDNA molecules exceeds a particular threshold for that tissue. For example, brain, muscle (skeletal and cardiac), and eye have very high oxidative energy requirements; therefore, these tissues may have a lower threshold for mitochondrial dysfunction. Additionally, tissues with rapid turnover (i.e., mucosa, bone marrow cells) may eventually 'select out' mutant mtDNA if that mutation offers a reproductive disadvantage; theoretically, the pool of wild-type mtDNA could be totally restored. However, brain and muscle cells do not divide after fetal development; mtDNA mutations are essentially 'permanent' in these tissues.
While intellectually challenging to the clinician and researcher, a diagnosis of Pearson's syndrome results in an extremely grave prognosis for the patient. Unfortunately, at this point, treatment can only be directed toward symptomatic relief. Clinical trials involving dichloroacetate (DCA) administration are ongoing for patients with lactic acidosis of varying etiologies, and it is hoped that the experimental use of DCA in Pearson's syndrome may provide additional relief of symptoms (Carolyn Bay, MD, personal communication).
The spectrum of mitochondria-based disorders is extremely complex, and even a simplified overview is beyond the scope of the present discussion. Interested individuals, however, are directed to an excellent, thorough discussion of human mtDNA and related pathology (11).
Contributed by Karen Deal, MD PhD, David Finegold, MD, Lydia Contis, MD, Lorna Cropcho, CLA (ASCP), MT (HEW), and Mohamed Virji, MD PhD.