Fumarase deficiency

Lore & Background

Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH) gene, which encodes the enzyme that converts fumarate to malate in the mitochondria. The condition is one of the few known deficiencies of the Krebs cycle, the main enzymatic pathway of cellular aerobic respiration. It is an autosomal recessive disorder, usually requiring the mutant allele from both parents; affected children have often been born to first-cousin parents.

Until around 1990, only 13 cases were known worldwide. A subsequent cluster of 20 cases was documented in the twin towns of Colorado City, Arizona, and Hildale, Utah—formerly known as the Short Creek Community. This community of about 10,000 members of the Fundamentalist Church of Jesus Christ of Latter Day Saints (FLDS) has a history of successive endogamy, or marriage within the community. The syndrome has been linked to cousin marriage and reproductive isolation, with a high degree of consanguinity among community members.

Reader's Guide

Fumarase deficiency is significant as a rare inborn error of metabolism that illustrates the consequences of genetic isolation and founder effects. The cluster of 20 cases in the Short Creek Community, where successive endogamy concentrated the mutant FH allele, provides a clear example of how reproductive isolation can lead to a high prevalence of a rare autosomal recessive disorder. The condition's nickname, 'Polygamist's Down's', reflects its association with consanguinity in that community, though the underlying cause is the founder effect from the community's cofounders. With only about 100 documented cases worldwide, fumarase deficiency remains an extremely rare disorder, but its study has contributed to understanding of Krebs cycle deficiencies and the genetic basis of hereditary leiomyomatosis and renal cell cancer, which is caused by other mutant alleles of the same FH gene. The disorder underscores the importance of genetic counseling in isolated populations.

Did You Know?

• Only 13 cases were known worldwide until around 1990, after which a cluster of 20 cases was documented in the Short Creek Community in Arizona and Utah.
• The condition has been linked to cousin marriage and reproductive isolation in a genetically isolated community, where a high degree of consanguinity is present.
• Other mutant alleles of the same FH gene cause multiple cutaneous and uterine leiomyomata and hereditary leiomyomatosis and renal cell cancer.