Biotinidase deficiency represents an autosomal recessive metabolic disease when biotin cannot be isolated from proteins containing in food during protein metabolism in a cell or digestion. The availability of such violations results in the insufficiency of biotin in the organism. Biotin is also called vitamin B7. It is a substantial nutrient water-soluble substance involved in the metabolism of proteins, carbohydrates, and fats. According to the researches, the prevalence of the disease is estimated as 1:45 000 – 1:61 000 newborns (Saudubray, Baumgartner, & Walter, 2016). The average age of the manifestations of biotinidase deficiency is about 3-6 months. Deficiency of biotin can be a reason for learning difficulties, as well as coordination and mental disorders. Timely diagnosis is extremely important because the early initiation of treatment with biotin in the neonatal period gives a possibility to prevent the formation of mental retardation and other difficult clinical manifestations.
The Name of the Enzyme and Genetics
The biotinidase gene is mapped in the p25 segment of the third chromosome. In DNA diagnostics, the mutations G98d7i3 and R538C are the most frequently detected in more than 50% mutant alleles (Nyhan, Hoffman, Barshop, & Al-Aqeel, 2012). Q456X is the most often mutation in deep insufficiency of biotinidase; D444H with partial deficiency (Nyhan et al., 2012). A biotin-deficient state with the development of carboxylase deficiency lies at the heart of the illness. The biotin molecule comprises of a heterocyclic ring with carboxyl groups attached to it. The exchange of biotin is held with the participation of the biotinidase enzyme.
After a discovery of biotin more than 100 years ago, researchers have not completely understood its functions and chemical characteristics until recently. These days, scientists know eight forms of this vitamin. However, only one of them appears in natural compounds and is biologically active. It is the dextrorotatory isomer of D-biotin (Hollak & Lachmann, 2016). The researchers recognize biotin as one of the most active vitamin-catalysts. The most important biological function of biotin reflects the fact that it serves as a part of the enzymes involved in the metabolism of glucose. It regulates the expression of genes, which are responsible for the metabolism of glucose and insulin. Biotin supports the metabolism of carbohydrates and amino acids and promotes the formation of fatty acids (Hollak & Lachmann, 2016). In addition, it is responsible for the normal functioning of the sweat and male gonads, digestive, nervous, and immune systems, hair, skin, and bone marrow (Hollak & Lachmann, 2016). Scientists have found that biotin has a lipotropic effect and serves as the growth factor. Along with this vitamin, such reactions as transport and activation of carbon dioxide proceed. Biotin helps sulfur participate in the synthesis of collagen and minimize symptoms of zinc deficiency.
Deficiency of biotin is a rare disorder, which causes the shortage of vitamin B7 or rather its water-soluble form. From the pathophysiological point of view, the shortage of the biotinidase enzyme entails the shortage of biotin. This deficiency causes more than 100 various genetic disorders (Hollak & Lachmann, 2016). A large number of states around the world have included the analysis on biotinidase deficiency in programs of newborn screening. Deficiency of this substance is highly rare in physically healthy people consuming diverse products (Hollak & Lachmann, 2016). Nonetheless, this state is also possible when a person takes broad-spectrum or anticonvulsants antibiotics. Highly low prevalence of biotin shortage consists in the combination of a number of factors. First, the daily requirement for biotin is about 2002 ?g / day, which is rather low (Saudubray et al., 2016). Moreover, practically all products have a sufficient amount of biotin. The third factor consists in the fact that vitamin B7 is synthesized by intestinal flora and, thus, the major part of it is absorbed into the blood (Saudubray, Baumgartner & Walter, 2016). Besides, the body reworks biotin repeatedly and processes the already produced vitamin one more time until the time when urine or feces remove it fully from the body (Saudubray et al., 2016). Despite these factors, biotin deficiency can still be present. The major causes of its shortage include nutrition with products containing the insufficient amount of vitamin B7, eating of raw egg whites, prolong oral antibiotic therapy, anticonvulsant therapy, and genetic mutation. These issues can cause deficiency of biotin.
The Overall Effect on Metabolism
The biotinidase enzyme participates in the exchange of biotin. It cleaves biocytin that is a product of the degradation of biotin-dependent carboxylases thus providing the restoring of unstable free biotin. It also disengages biotin from food and connectes to a protein (Saudubray et al., 2016). It makes it available for binding to apo-carboxylase and the formation of an active enzyme. The shortage of biotinidase leads to the deficit of intracellular biotin that can be partial or deep. The estimated frequency of these forms includes 1: 61,000 (Saudubray et al., 2016). The violation of the carboxylases function results in the storage of substrates of carboxylase-controlled enzyme reactions. These substrates along with their derivatives are toxic to the human body and result in the development of secondary hyperammonemia and metabolic acidosis (Saudubray et al., 2016). Ketoacidosis serves as an attribute of the prolonged insufficiency of biotin in the body and may not manifest itself at the beginning of the illness.
Researchers have proved that biotin regulates the expression of genes that are responsible for metabolism of glucose and insulin. It stimulates the work of genes accountable for the digestion of blood glucose through the production of insulin and through insulin receptors, hepatic and pancreatic glucokinase (Nyhan et al., 2012). On the contrary, biotin lowers the expression of hepatic phosphoenolpyruvate of carbooxycinase. It is an enzyme, which stimulates the production of glucose by the liver. In such a way, biotin regulates the activity of genes, which provide intermediate metabolism, especially fat and carbohydrate.
The heaviness of clinical manifestations depends on the level of the activity of biotinidase. Such manifestations as decreased vision and hearing, skin manifestations, neurological symptoms, and secondary infectious complications connected with the impaired immunity dominate in the clinical picture (Nyhan et al., 2012). Dry skin is regarded the initial external symptom of the disease. Afterwards, severe seborrheic dermatitis develops. Injuries of skin are a perfect environment for numerous fungal infections that can be resistant to treatment (Nyhan et al., 2012). There is erythematous macular rash and alopecia due to this state. Hair is brittle and thin. Another manifestation regards hearing. It is necessary to note that more than 50% of children with severe biotinidase deficiency have neurosensory hearing loss (Nyhan et al., 2012). It can be mild and deep.
In case of the deficit of biotinidase, the central nervous system is especially vulnerable. It reflects the fact that the activity of biotinidase is highly low in the brain and the constant and sufficient supply of biotin through the blood-brain barrier is necessary for the normal functioning of neurons (Rosenberg & Pascual, 2015). It is a reason of neurological illnesses that may be the only attribute of the disease during a particular period (Rosenberg & Pascual, 2015). There are changes in the spinal cord, subcortical structures, and cerebellum usually explained by the toxic effect. Neurological signs are nonspecific and diverse. They include mild depression that often progresses to deep apathy and, subsequently, constant drowsiness (Rosenberg & Pascual, 2015). There are also changes in the mental state, paresthesia, hyperesthesia, muscle pain, anxiety, and convulsions. Such manifestations as convulsions and muscle hypotension are very frequent. More than half of patients have seizures (Rosenberg & Pascual, 2015). They are represented by generalized tonic-clonic, infantile, and myoclonic spasms. Convulsions and muscular hypotension still exist during the conventional therapy. Nevertheless, they quickly stop with the appointment of biotin. Thus, manifestations in the nervous system are highly diverse.
The age of the debut is from one to six months. However, the disease can also develop in the first weeks of life or in adolescence. Regardless of the etiology of biotin deficiency, clinical manifestations are practically the same (Rosenberg & Pascual, 2015). Nonetheless, the pace of the development of the symptoms and sequence of their occurrence can vary significantly. In such a way, clinical manifestations are limited to hair, skin, central and peripheral nervous systems, and the gastrointestinal tract. It is also necessary to note that today there is no established mechanism accountable for the development of clinical manifestations.
The most important methods for diagnosing biotinidase shortage include molecular genetics and biochemical methods. Metabolic acidosis may cause the development of metabolic disorders. Its severity determines the heaviness of the patients state (Nyhan et al., 2012). Acidosis is accompanied by aciduria, ketosis, pyruvic acidemia, and lactic. To diagnose the illness, it is important to identify low serum biotinidase activity and specific organic aciduria. In the normal condition, the activity of serum biotinidase includes 4.4-12 nmol / min / ml (Nyhan et al., 2012). At the initial stages of the disease, it is impossible to detect violations with computed tomography and the electroencephalographic study. Later, the electroencephalographic study determines bilateral bioelectric modifications with typical peaks of the high-amplitude activity (Nyhan et al., 2012). For computed tomography, such manifestations as the brain grooves and the expansion of the ventricular system are typical. Furthermore, there are also diffuse transformations in the white matter with signs of cerebellar and cerebral atrophy. There are frequent disturbances in the lenticular and caudate nucleus like the hemorrhagic infarction (Nyhan et al., 2012). With the magnetic resonance imaging of the brain, it is possible to detect swelling of the white matter, myelination disorders, and atrophic changes in the cortex.
It is necessary to state about screening of newborns. Neonatal screening includes the mass examination of newborns being one of the most efficient methods of identification of the most widespread hereditary and congenital illnesses (Hollak & Lachmann, 2016). In accordance with the recommendations of the World Health Organization when choosing illnesses for mass screening of newborns, such factors as the prevalence and severity of diseases, the reliability and simplicity of their diagnostic methods, and the accessibility of efficient and affordable treatments are highly important (Hollak & Lachmann, 2016). Screening of newborns emerged in the developed states in the 1960s, when the examination for phenylketonuria started (Hollak & Lachmann, 2016). In addition, testing for other hereditary diseases has started in different programs worldwide. Nonetheless, a new era in the development of neonatal screening began with the appearance of tandem mass spectrometry. It is a technology, which helps to improve the quality of diagnosis greatly. It also allows expanding a list of detectable illnesses, which doctors can successfully treat. Earlier, not all diseases were possible to detect applying previous methods of screening programs. The World Health Organization recommends the inclusion of biotinidase deficiency in the mandatory newborn screening programs (Hollak & Lachmann, 2016). This screening allows applying early diagnosis and treatment of this pathology and helps to reduce child disability.
The Principle of Treatment
The major method of pathogenetic treatment includes oral administration of biotin in the dose of 6-40 mg per day (Hollak & Lachmann, 2016). Gradually, the dose increases. It is necessary to use this medicine for a long time. Besides, the doctors prescribe the therapy with biotin without waiting for the results of defining the activity of biotinidase in the blood serum. Individual intolerance can be the only contraindication to this therapy (Hollak & Lachmann, 2016). When the patient has convulsions, doctors prescribe anticonvulsants. However, it is necessary to mention that they are not efficient without the simultaneous application of biotin. Moreover, it necessary to remember that absorption of biotin decreases against the background of taking anticonvulsants. However, practically all patients with biotinidase deficiency receive anticonvulsants from the valproate group taking into consideration the high frequency of seizures and their polymorphic and serial nature. Doctors prescribe such a drug as Convulex to small children (Hollak & Lachmann, 2016). Produced in the form of syrup and drops for ingestion, it belongs to the valproate group. The early treatment with biotin in the neonatal period makes it possible to prevent the formation of mental retardation and severe clinical manifestations. The late treatment results in the vanishing of particular symptoms including alopecia and dermatitis (Hollak & Lachmann, 2016). However, it does not reverse fully neurologic disorders. Accordingly, it is extremely important to start the treatment of the disease as soon as possible.
Hereditary predisposition is one of the major reasons of biotin deficiency. Nevertheless, there are also other actions and conditions causing the decrease of biotin content to an extremely low level. Biotindase deficiency includes a great number of clinical manifestations. The most typical are skin and neurological disorders. This illness usually does not progress but if not treated, it can result in coma and death of the patient in the future. Because of the rather high prevalence of biotinidase deficiency, its curability, and inclusion in the screening program for newborns, a wide range of specialists should this study pathology.