Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) Syndrome

Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, also known as ornithine translocase deficiency, is an inherited disorder that causes accumulation of toxic levels of ammonia in the blood. The severity and age of onset of the HHH syndrome varies widely among individuals, with onset in infancy having the most severe outcome. For most affected individuals, symptoms begin anywhere from around three years of age on into adulthood. Symptoms include episodes of low energy, vomiting, seizures, problems with coordination, confusion, or blurred vision. If these episodes occur frequently and are left untreated, individuals with HHH syndrome can develop learning disabilities, developmental delay, and stiffness caused by abnormal tensing of the muscles. People with HHH syndrome cannot tolerate high-protein foods, such as meat. Symptoms of HHH syndrome can be triggered by high-protein meals or stress caused by illness or periods without food. Healthy growth and development is possible by starting infants on a strict diet with supplements and medications, along with life-long medical surveillance. HHH syndrome is caused by pathogenic variants in the SLC25A15 gene.

HHH syndrome is inherited in an autosomal recessive manner. This type of inheritance requires the presence of two copies of a pathogenic variant in the gene for a person to have the genetic disease. Both parents must be carriers of a pathogenic variant in the gene in order to be at risk to have an affected child. The child must inherit a pathogenic variant from each carrier parent in order to be affected. There is a 1 in 4 chance that a baby will inherit two mutated copies of the gene and be affected when both parents are carriers.

There are generally no signs or symptoms associated with being a carrier for HHH syndrome. However, the risk to have a child affected with HHH syndrome is increased. Testing of reproductive partners is recommended for carriers of HHH syndrome.

HHH syndrome is a very rare disorder. Fewer than 100 affected individuals have been reported worldwide. Although the frequency of HHH syndrome in the general population is not known, it occurs most often in individuals of French Canadian ancestry.

Genetics Home Reference: Ornithine translocase deficiency (http://ghr.nlm.nih.gov/)

OMIM [Hyperornithinemia-Hyperammonemia-Homocitrullinuria syndrome: 238970] (http://www.ncbi.nlm.nih.gov/omim)
Hyperornithinemia-Hyperammonemia-Homocitrullinuria Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1116/)

• Full gene sequencing