Biotinidase Deficiency (BTD)
INTRODUCTION
Our body requires biotin, a water-soluble B-vitamin that is required for metabolism in the
body. 4 It acts as a cofactor for carboxylation reactions needed for gluconeogenesis, lipid
4
metabolism and amino acid catabolism. There are a variety of carboxylases that require biotin
4
in order to facilitate carboxylation reactions. It is vital that the necessary enzymes are present
to complete their role in these metabolic pathways.
CLASSIFICATION OF SYMPTOMS
Based on residual enzyme activity
PROFOUND DEFICIENCY
(10% of normal enzymatic activity)
Seizures
Hypotonia
Delayed development
Cutaneous manifestations
Optic atrophy
Hyperventilation
Hearing loss
WHAT IS BIOTINIDASE DEFICIENCY
Biotinidase is an important enzyme required for the formation of biotin through a series of
1
reactions known as biotin turnover and biotin recycling. Without this enzyme, there is a
reduction of free biotin available to act as cofactors leading to multiple carboxylase
2
deficiency, where the carboxylases are unable to function. Biotinidase also plays a vital
role in the central nervous system (CNS) where it is localized to red nucleus and cerebellar
2
purkinje cells. This makes the enzyme an important aspect to proper CNS function.
PARTIAL DEFICIENCY
(10-30% of normal activity)
Biotinidase deficiency is an autosomal recessive disease that results in reduced or absent
biotinidase activity. 2 The cause of the disease are mutations in the BTD gene which
prevents the recycling of biotin within the body leading to a series of symptoms.
Symptoms only during metabolic stress:
- skin rash
- hair loss
BIOCHEMICAL PROCESSES
BIOTIN
2,7
SOURCES:
Figure 2. Image representation of
biotinidase symptom of hair loss
cooked egg
Organ meats
Fish
Sweet potatoes
Broccoli
Incidence
3
1 in 60, 000
KEY POINTS
Figure 3. artistic representation of
skin rash
Figure 1. Describes the biotin cycle where free biotin obtained from the diet binds to various apocarboxylases (inactivated carboxylases), done by
holocarboxylase synthetase. The listed apocarboxylases involved are: propionyl-CoA carboxylase (PCC), beta-methylcrotonyl-CoA carboxylase
(MCC), pyruvate carboxylase (PC) & acetyl-CoA carboxylase (ACC). The action done by the holocarboxylase synthetase results in a holocarboxylase
which is broken down to form biocytin and cleaved by biotinidase to remove a lysine, ultimately recycling the biotin. Adapted from: Fig. 1.,
Devanapalli et al. 1
Our body received biotin from the diet and microbiota, and in doing so, this acts as a source of
free biotin. The free biotin is then attached onto apocarboxylases and this results in
holocarboxylases. These holocarboxylase are necessary for carboxylation reactions in important
metabolism pathways including amino acid metabolism, fatty acid synthesis and
gluconeogenesis. These enzymes are then broken down into biocytin which is then able to be
turned into biotin when lysine is removed.
To treat this condition, there is a requirement for an increase in free biotin levels due to the
individual’s inability to recycle the biotin. Without the recycling ability of biotin means that
there is a requirement for biotin levels to be adjusted through receiving it from the
environment. This can be supplemented either through consumption of foods with biotin, or
7
biotin supplements.
DIAGNOSIS
6
Abnormal Newborn screening:
This can be detected through the use of fluorescent
or colorimetric tests to determine biotinidase activity
Symptomatic individual:
Atypical findings associated with partial biotinidase
deficiency
Lab findings:
Metabolic ketaactic acidosis
TREATMENT
5,7
5-10 mg/day for those who have
<10% mean normal serum enzyme
activity
2.5-10 mg/day for those who have
Daily administration of oral biotin
(initiated early)
Prevent clinical symptoms given
presymptomatic diagnosis &
early treatment
Biotinidase is a vital part of our
ability to recycle biotin in our
body, which plays an integral
role in many metabolism
pathways of our body. With a
deficiency, this leads to the
inability to properly metabolize
lipids, amino acids and hinder
the process of
gluconeogenesis.
Early detection is key in
managing the development of
symptoms and prevention of
severe symptoms. Support
from family and community is
important as an individual
navigates their life with this
disease. Educational resources
are also available for further
information.
REFERENCES
1. Arslan M, Oksuz Y, Kizilboga B, et al. A patient diagnosed with Li-Campeau syndrome and biotinidase deficiency. J Pediatr
Acad. 2023;4(3):113+. doi:10.4274/jpea.2023.221.
2. Devanapalli B, Wong RSH, Lim N, et al. Biotinidase deficiency: A treatable neurometabolic disorder. Brain Dev Case Rep.
2024;2(2):100021. doi:10.1016/j.bdcasr.2024.100021
3. Kannan B, Navamani HK, Jayaseelan VP, Arumugam P. A Rare Biotinidase Deficiency in the Pediatrics Population: GenotypePhenotype Analysis. J Pediatr Genet. 2022;12(1):1-15. Published 2022 Nov 1. doi:10.1055/s-0042-1757887
4. Perry CA, Butterick TA. Biotin. Adv Nutr. 2024;15(7):100251. doi:10.1016/j.advnut.2024.100251
5. Radelfahr F, Riedhammer KM, Keidel LF, et al. Biotinidase deficiency: A treatable cause of hereditary spastic paraparesis.
Neurol Genet. 2020;6(6):e525. Published 2020 Oct 13. doi:10.1212/NXG.0000000000000525
6. Tankeu, A. T., Van Winckel, G., Elmers, J., Jaccard, E., Superti-Furga, A., Wolf, B., & Tran, C. (2023, April). Biotinidase deficiency:
What have we learned in forty years?. Molecular Genetics and Metabolism.
https://www.sciencedirect.com/science/article/pii/S1096719223001907
7. Wolf, B. (2000, March 24). Biotinidase deficiency. In M. P. Adam, J. Feldman, G. M. Mirzaa, et al. (Eds.), GeneReviews® [Internet].
University of Washington. Updated May 25, 2023. Available from https://www.ncbi.nlm.nih.gov/books/NBK1322/