A Rare Biotinidase Deficiency in the Pediatrics Population: Genotype-Phenotype Analysis

Abstract

Biotinidase (BTD) deficiency is a rare autosomal recessive metabolic disorder caused by insufficient biotin metabolism, where it cannot recycle the vitamin biotin. When this deficiency is not treated with supplements, it can lead to severe neurological conditions. Approximately 1 in 60,000 newborns are affected by BTD deficiency. The BTD deficiency causes late-onset biotin-responsive multiple carboxylase deficiency, which leads to acidosis or lactic acidosis, hypoglycemia, and abnormal catabolism. BTD deficiency is of two types based on the amount of BTD Enzyme present in the serum. A wide range of pathogenic mutations in the BTD gene are reported worldwide. Mutations in the BTD gene lead to profound and partial BTD deficiency. Profound BTD deficiency results in a severe pathogenic condition. A high frequency of newborns are affected with the partial deficiency worldwide. They are mostly asymptomatic, but symptoms may appear during stressful conditions such as fasting or viral infections. Several pathogenic mutations are significantly associated with neurological, ophthalmological, and skin problems along with several other clinical features. This review discusses the BTD gene mutation in multiple populations detected with phenotypic features. The molecular-based biomarker screening is necessary for the disease during pregnancy, as it could be helpful for the early identification of BTD deficiency, providing a better treatment strategy. Moreover, implementing newborn screening for the BTD deficiency helps patients prevent several diseases.

Keywords: BTD gene mutation; biotinidase deficiency; multiple carboxylase deficiency; neurological problems.

Fig. 1

Mutation in the BTD gene affects the biotinidase enzymes that lead to insufficient biotin metabolism and causes BTD deficiency, which is classified into two types, such as profound BTD deficiency and partial BTD deficiency, based on the biotinidase level in the serum. Profound BTD deficiency means less than 10% of normal serum activity. This type of child cannot recycle their endogenous biotin by cleaving it from biocytin, which also consequently causes multiple carboxylase deficiency (MCD). Partial BTD deficiency means 10 to 30% of biotinidase in the normal serum activity, they are mostly asymptomatic, but symptoms may appear during stressful conditions such as fasting or viral infections. BTD, biotinidase.

Fig. 2

Untreated BTD children have several neurological symptoms and clinical signs, which includes seizures, ataxia, hypotonia, hearing loss, vision problems, skin rash, alopecia, conjunctivitis, ketolactic acidosis, organic aciduria, and developmental delay. Unfortunately, some symptoms are irreversible. BTD, biotinidase.