Biotinidase Deficiency

Background

Biotin is part of the vitamin B complex that functions as a cofactor for four carboxylase enzymes in man. When biotin is covalently linked to a key lysine residue in the carboxylases, the enzymes are activated. When the carboxylase enzymes are degraded, biotinyl-lysine is produced. Biotinidase subsequently hydrolyzes biotinyl-lysine to release free biotin, allowing it to be recycled and made available for activating newly synthesized carboxylase enzymes. In the absence of normal Biotinidase activity, the patient develops functional biotin deficiency and its clinical symptoms. Biotinidase deficiency is also known as late-onset multiple carboxylase deficiency, which distinguishes it from an earlier onset form caused by holocarboxylase synthetase deficiency.

Clinical

Newborns with Biotinidase Deficiency appear normal at birth. Biotin deficiency develops over time with clinical symptoms beginning at a few weeks to several years of age. If untreated, patients will develop metabolic ketoacidosis and organic aciduria. Symptoms include ataxia, hypotonia, developmental delay, conjunctivitis, skin rash and alopecia, seizures, hearing loss, breathing problems and optic atrophy. There is variable expression of these symptoms probably related to dietary biotin intake and the degree of residual Biotinidase enzyme activity. Partial Biotinidase Deficiency appears as a milder disease with most patients exhibiting chiefly the cutaneous symptoms, partiularly when the patient is under metabolic stress.

Testing

Newborn screening of Biotinidase activity from dried blood spots can identify affected patients shortly after birth. Both complete and partial deficiencies can be detected. The diagnosis is confirmed by measuring Biotinidase activity in serum or analyzing DNA to detect the most common genotypes. In clinically symptomatic cases, urine analysis by gas chromatograph/mass spectrometry will identify elevation of ß-hydroxyisovalerate, lactate, ß-methylcrotonylglycine, ß-hydroxypropionate and methyl citrate. These build up due to the inactivity of the four biotin requiring enzymes.

Treatment

Biotinidase deficiency is treated with oral biotin supplementation, which prevents development of the clinical symptoms.

Because the diagnosis and therapy of metabolic disorders is complex, the pediatrician is advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Inheritance

This disorder most often follows an autosomal recessive inheritance pattern. With recessive disorders affected patients usually have two copies of a disease gene (or mutation) in order to show symptoms. People with only one copy of the disease gene (called carriers) generally do not show signs or symptoms of the condition but can pass the disease gene to their children. When both parents are carriers of the disease gene for a particular disorder, there is a 25% chance with each pregnancy that they will have a child affected with the disorder.

As with all genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

Reference

Wolf, B. Disorders of Biotin Metabolism. In, The Metabolic and Molecular Basis of Inherited Disease. 8th Edition, 2001. Scriver, Beaudet, et al. McGraw-Hill. Chapter 156, pg. 3935 - 3962.

Wolf, B., Grier, R.E., Allen, R.J., et al. Phenotypic variation in biotinidase deficiency. J Pediatrics 103:233, 1983.

Burton, B., Roach, E.S., Wolf, B. and Weissbecker, K.A. Sudden death associated with Biotinidase Deficiency. Pediatrics 79:482, 1987.

Lara, E.B., Sansaricq, C., Wolf, B., and Snyderman, S.E. Biotinidase Deficiency in black children. J Pediatrics 116:750, 1990.

Web Sites
SaveBabies.org
Site established and maintained by parents of newborns affected with a rare genetic defect, with information for parents and professionals and links to other informative sites.

National Newborn Screening and Genetics Resource Center
Provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

Disclaimers
The analyses conducted by PerkinElmer Genetics produce results that can be used by qualified physicians in the diagnosis of disorders described herein. Evidence of these conditions will be detected in the vast majority of affected individuals; however, due to genetic variability, age of the patient at the time of specimen collection, quality of the specimen, health status of the patient, and other variables, such conditions may not be detected in all affected patients. PerkinElmer Genetics makes no warranty whatsoever, express or implied, including any warranty as to accuracy, completeness or timeliness, concerning the information contained herein, and you should not assume that such information is complete or the most up-to-date information available. PerkinElmer Genetics shall not be liable for any loss, claim or damages caused in whole or in part by our provision of, or your use of, any of the information contained herein. As a general statement, this information was drawn from published literature and is not drawn from our patient population or screening experience. The information contained herein is not intended to be a substitute for professional medical advice and should not be used for the diagnosis or treatment of any medical condition. A licensed physician should be consulted for diagnosis and treatment of any and all medical conditions.

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