OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: PKLR

PK deficiency
PK1
Pyruvate kinase deficiency of erythrocytes
PKLR
PKR
PKD

Hemolytic anemia
Pyruvate kinase
Nonspherocytic hemolytic anemia
Splenomegaly
Jaundice
Hyperbilirubinemia

Pyruvate Kinase Deficiency

Clinical Characteristics

General description (for patients):

Pyruvate kinase deficiency is due to an inherited deficiency in an enzyme which affects the survival of red blood cells.  In its absence, the lifespan of red blood cells is shortened and they break down too rapidly, resulting in anemia.  Symptoms of this condition include pale skin (pallor), jaundice, a yellowing of the white of the eyes (icterus), fatigue, and recurrent gallstones.  In severe, untreated cases, death may occur as early as the neonatal period. Others may require no treatment. Blood transfusions can temporarily correct the anemia, and removal of the spleen slows the breakdown of the red blood cells.

Medical description: 

PK deficiency is the most common cause of inherited nonspherocytic hemolytic anemia.  A variety of mutations in the PK gene may lead to instability as a result of decreased activity of pyruvate kinase, an essential glycolytic enzyme.   Unable to manufacture normal amounts of ATP, the cells become energy deficient and unable to maintain the activity of the basolateral Na+/K+ ATPase during maturation.   RBCs lose large amounts of potassium and water and often assume a reticulated shape susceptible to enhanced sequestering by the reticuloendothelial system.   The lysed red blood cells lead to jaundice, splenomegaly, and a hemolytic anemia.  Newborns and infants suffer life-threatening hemolytic crises and hyperbilirubinemia while older individuals are at risk for infections and may have asplenia and hemachromatosis.  Cholecystitis and cholelithiasis are sometimes also seen.  Jaundice is present at birth and may gradually fade, replaced by the pallor of anemia.  Splenomegaly can occur within 6 months and splenectomy prevents further anemia.

Genetics:

This is an autosomal recessive disorder caused by mutations of the PKLR gene located on chromosome 1 (1q21).  The PKLR gene encodes four isozymes, M1, M2, L, and R with more than 150 unique mutations identified so far. The original Amish cases were found in Mifflin County, Pennsylvania and twenty years later, additional Amish cases were reported from Geauga County, Ohio.  All could be traced to a single ancestral couple who lived in Mifflin County. The Amish point mutation, 1436G>A, occurs in the R isozyme mRNA.

Treatment:

Most affected individuals do not require treatment but severe untreated disease in infants can be lethal in the first year of life.  Blood transfusions may be needed in severe anemia.  The destruction of the RBCs can be reduced by splenectomy which can significantly reduce the severity of the anemia.  Cholelithiasis sometimes requires surgery. Most of the symptoms are limited to early life and at times of physiologic stress or infection.

Prognosis:  

The prognosis of PKD is highly variable depending on the genotype.  Early diagnosis and intervention with treatment of the anemia can be lifesaving in severe cases.  Individuals with a mild form of PKD may have few or no symptoms.

Ancillary treatments and support:

Splenectomy may be beneficial in cases with severe anemia.

Specialists and specialty centers: 

Hematologist, Pediatrician.

References:

Muir, W.A., Beutler, E., and Wasson, C.:  Erythrocyte pyruvate kinase deficiencty in the Ohio Amish: origin and characterization of the mutant enzyme.  Am. J. Hum. Genet. 36: 634-639, 1984.  PubMed ID: 6731438

Zanella, A.,  Fermo,E., Bianchi, P., and Valentini, G.:  Red cell pyruvate kinase deficiency: molecular and clinical aspects. Brit. J. Haemat. 130: 11–25, 2005.  PubMed ID: 15982340

Zanella, A., Bianchi, P., Fermo, E.:  Pyruvate kinase deficiency.  Haematologica  92: 721-723, 2007.  PubMed ID: 17550841

Bowman, H.S., and Procopio, F.:  Hereditary non-spherocytic hemolytic anemia of the pyruvate-kinase deficient type. Ann. Intern. Med. 58: 567-591, 1963.  PubMed ID: 14014643

Bowman, H.S., McKusick, V.A., and Dronamraju, K.R.:  Pyruvate kinase deficient hemolytic anemia in an Amish isolate. Am. J. Hum. Genet. 17: 1-8, 1965.  PubMed ID: 14255553

Kanno, H., Ballas, S.K., Miwa, s., Fujii, H., and Bowman, H.S.:  Molecular abnormality of erythrocyte pyruvate kinase deficiency in the Amish.  Blood 83: 2311-2316, 1994.  PubMed ID: 8161798

Rider, N.L., Strauss, K.A., Brown, K., Finkenstedt, A., Puffenberger, E.G., Hendrickson, C.L., Robinson, D.L., Muenke, N., Tseelepsis, C., Saunders, L., Zoller, H., and Morton, D.H.:  Erythrocyte pyruvate kinase deficiency in an old order Amish cohort: Longitudinal risk and disease management.  Am. J. Hematol. 86: 827-834, 2011  PubMed ID: 21815188.

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