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.

Biallelic loss-of-function variations in BTD cause profound biotinidase deficiency in an Indian patient

“…In patients with profound BD, the neurological system is often the most affected, with over 70% of children exhibiting seizures, hypotonia, skin rash, or alopecia. Partial BD typically results in milder symptoms, which are often exacerbated by stress, such as prolonged fasting or infection [14,23,24].…”

“…BD is genetic disorder, with the severity determined by the speci c mutations in the BTD gene. The complete absence of enzyme activity is usually due to deletions, insertions, or nonsense mutations, while missense mutations can have varied effects [14,24,25]. For instance, a study by Iqbal found the nonsense variant c.1275T > G in Austrian patients, leading to a premature stop codon and profound de ciency, although the affected infants did not exhibit symptoms initially [26].…”

“…Cole et al rst identi ed this gene in 1994 [13]. Mutations within the BTD gene are responsible for BD, with over 300 pathogenic variants reported worldwide [14]. A strong correlation often exists between speci c mutations and the phenotypic severity observed in patients.…”

Biotin Homeostasis and Human Disorders: Recent Findings and Perspectives

“…Diagnosis of BD can be life-saving and meets the major criteria for inclusion in newborn screening programs [ 29 ]. To this end, many countries worldwide, e.g., the USA, have included screening for BD in their national programs for newborn screening [ 35 ].…”

“…Enzyme activity assessment : Diagnosis of BD is mostly based on evaluating the enzyme activity in patient blood samples [ 30 ]. More specifically, biotinidase activity is determined following the hydrolysis of either natural or artificial substrates of the enzyme by means of various systems, including initially described radioassays [ 36 ], subsequent colorimetric or fluorometric assays [ 35 , 37 ], or more sophisticated assays, such as tandem mass spectrometry-based ones [ 38 ]. Patients with less than 10% mean normal serum enzyme activity are classified as having profound BD and those with 10–30% mean normal serum activity are classified as having partial BD [ 33 ].…”