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Providing perspectives on recent research into vitamins and nutritionals


From Newborn Screening to Personalized Nutrition: The Example of Biotinidase Deficiency

By Julia Bird

Recently, Vallejo-Torres and co-workers looked at the costs and benefits of introducing biotinidase deficiency screening to the national newborn screening program in Spain. Biotinidase is an enzyme that the body makes to extract the vitamin biotin from food, and also to recycle biotin from its complex with carboxylase enzymes.  When the enzyme does not work as it should, biotin cannot be properly absorbed or recovered after use in the metabolism. Individuals with profound biotinidase deficiency have 10% of the normal enzyme activity, while partial biotinidase deficiency occurs with 10 to 30% of the normal enzyme activity. Around 1 in 60,000 people have biotinidase deficiency. The disease results in the classic symptoms of biotin deficiency such as seizures, poor muscle tone, and skin abnormalities such as a rash and frequent viral or fungal infections from immune dysfunction. In partial biotinidase deficiency, symptoms may only appear in times of stress, such as after a long illness.

What causes biotinidase deficiency? It is an inherited condition that arises when an individual receives two copies of genes that code for defective versions of the biotinidase enzyme, one from each parent (autosomal recessive). Newborns generally start to show signs of deficiency around 3 to 4 months of age, and if left untreated, infants can experience irreversible developmental delay including cognitive deficits, and loss of hearing or vision. Death is an uncommon yet possible outcome. Biotinidase deficiency is easily treated by lifelong supplementation with biotin: a large dose of 5 to 10 mg daily is recommended after biotinidase deficiency is diagnosed. However, it needs to be discovered early to prevent irreversible neurological symptoms. That’s why many countries include biotinidase deficiency in their battery of tests for newborns: Vallejo-Torres et al. found its inclusion to be cost-effective.

However, the idea that an individual must receive two copies of the gene is a simplistic view of how the condition is acquired. There are in fact over 175 different genetic variants currently found that are associated with reduced enzyme activity. The exact combination of the two genetic variants received (one from each parent) determines the extent of activity loss in the enzyme. Proctor and co-workers describe how the genetic variants can affect the disease. Combinations of the  four mutations c.98_104delinsTCC, p.Q456H, p.R538C and p.D444H;A171T result in profound biotinidase deficiency. However, mutation p.D444H is considered to be mild, and only results in partial biotinidase activity when combined with one of the four “profound deficiency” mutations. Each combination of genetic mutations would have a different effect on the final enzyme activity in individuals.

The genetically-derived disease of biotinidase deficiency has been described in the scientific literature as it results in a defined disease state. However, as can be seen from the information on the number of genetic mutations that are associated with the disease, there is a spectrum in biotinidase enzyme activity that is based on the exact gene mutations inherited from parents. Are there people out there with reduced biotinidase activity who lack overt symptoms but nevertheless could benefit from additional biotin? This is a possibility. As we move beyond the newborn heel prick test, and into the realm of personalized medicine and nutrigenomics, nutrition advice will move beyond general guidelines and into specific regimens for individuals based on their genetic background.   

Main citation:

Laura Vallejo-Torres, Iván Castilla, María L Couce, Celia Pérez-Cerdá, Elena Martín-Hernández, Mercé Pineda, Jaume Campistol, Arantzazu Arrospide, Stephen Morris, and Pedro Serrano-Aguilar. Cost-Effectiveness Analysis of a National Newborn Screening Program for Biotinidase Deficiency. Pediatrics peds.2014-3399; published ahead of print July 13, 2015, doi:10.1542/peds.2014-3399


Supporting citations:

Hymes J, Stanley CM, Wolf B. Mutations in BTD causing biotinidase deficiency. Hum Mutat. 2001 Nov;18(5):375-81.

Procter M, Wolf B, Crockett DK, Mao R. The Biotinidase Gene Variants Registry: A Paradigm Public Database. G3 (Bethesda). 2013 Mar 11. pii: g3.113.005835v1. doi: 10.1534/g3.113.005835. [Epub ahead of print]