Biotinidase deficiency

Biotinidase or late -onset multiple carboxylase deficiency (English biotinidase deficiency or multiple carboxylase deficiency late-onset ) is a rare metabolic disorder that is inherited in an autosomal recessive, and the result is that the body can not adequately recycle the vitamin biotin. Cause is a defect in the enzyme biotinidase. The effects of Biotinidasemangels ranging from symptoms of the skin and immune system dysfunction of severe metabolic disturbances to brain damage, coma and death. A very effective therapy exists in the form of life-long treatment with biotin. A test for biotinidase deficiency in many countries is part of newborn screening. A distinction is made with an enzyme biotinidase heavy residual activity of less than 10 %, and partial biotinidase with an enzyme activity of 10 to 30%.

Biotinidase deficiency is one of the so -called rare diseases (English orphan disease ).

• 4.1 Biochemical evidence
• 4.2 Direct diagnosis
• 4.3 Differential Diagnosis

Dissemination

Averaged Worldwide, biotinidase deficiency occurs with a frequency of 1:60,000, with severe and partial deficiency are similar to commonly found. Purely mathematically carries one of 123 people a corresponding defective gene. The figures vary from country to country. The screening reports of the German Society for Newborn Screening for the years 2004 to 2006 shows that in the Federal Republic of Germany is the frequency of Biotinidasemangels in the order of 1:20,000 to 1:25,000.

Cause and pathogenesis

Genetics

The biotinidase gene is located on chromosome 3 in the region p25. There are more than 60 mutations known to cause an enzyme defect. Heavy biotinidase deficiency with less than 10 % of enzyme activity occurs when both alleles encode a completely or almost completely defective enzyme. For partial biotinidase deficiency with 10-30 % enzyme activity occurs when a gene variant a serious defect, the other has one partial defect produced with significant residual activity. In addition, can be found in the literature but also other organizations.

Metabolism

The enzyme biotinidase has to split the task biocytin, an intermediate in the biotin metabolism, and so regain the biotin contained therein for the organism. Serves the inefficient, biocytin is lost through the kidneys. Due to the above-average loss, the biotin inventories deplete the body despite otherwise adequate diet gradually. Thus, the function of the four biotin- dependent carboxylases is affected that fulfill basic tasks in carbohydrate, protein and lipid metabolism:

• Pyruvate carboxylase (provision of oxaloacetate for Krebs cycle and gluconeogenesis )
• Propionyl -CoA carboxylase (necessary for the metabolism of amino acids and fatty acids with odd-numbered or branched chains )
• Methylcrotonoyl -CoA carboxylase (necessary for the metabolism of the amino acid leucine)
• Acetyl- CoA carboxylase (necessary for lipogenesis )

As a result, the citric acid cycle is a hand affected and thus the energy supply of the cells, on the other hand, accumulate in the mitochondrial metabolic intermediates in harmful concentration, which then pass into the cytosol and finally into the body fluids. Are the abnormal breakdown products, often summarized under the term organic acids in the urine, it is called Organoazidurie.

The biotinidase belongs to the sphere of multiple Carboxylasemangels.

Symptoms and pathology

The symptoms resemble those of a biotin deficiency. The disease affects especially on organs with high metabolic intensity or rate of cell division, such as the brain, muscles and immune system. The production of sebum and prostaglandin may be disturbed. It comes to movement disorders (ataxia, spastic paresis, hypotension ), epilepsy -like seizures, encephalopathy, hearing loss, damage to the eye ( visual field, retinal degeneration), weakness, loss of appetite, Organoazidurie, lactic acidosis, ketoacidosis, abnormalities of the immune system, increased susceptibility to infections, conjunctivitis, dermatitis and hair loss (alopecia).

The fact that the biotinidase defect four important enzymes affected draws ( three mitochondrial and a cytosolic ), the symptoms are very broad and may differ materially from patient to patient. None of the above symptoms must occur in every patient. Even different types of tissue may be different greatly affected by the resulting carboxylase. The first symptoms usually occur between the ages of three to six months. The disease can also start earlier or much later. The severity of the disease can be insidious, suddenly or intermittently performed with asymptomatic or symptom- poor phases. In some cases, metabolic stress, called for example by banal infections as a trigger.

In addition to the frequently described in the literature symptom combination of seizures, skin lesions and often at an advanced stage, Organoazidurie and metabolic acidosis and other progressive forms are possible. The following examples show how different the disease can mint:

• In patients with partial biotinidase deficiency often occurs only atopic or seborrhoeic dermatitis.
• In the case of three siblings, two died of progressive deterioration of the central nervous system and uncontrollable infections, accompanied by rash and hair loss. The first patient, a lack of immunoglobulin A ( IgA) was found in the second a decreased number of T - lymphocytes. The third child also suffered from infected with Candida dermatitis, conjunctivitis, hair loss and episodes of ataxia, but was not immunologically, but metabolically studied. There was a episodic occurrence of lactic acidosis and Organoazidurie.
• One patient showed mainly neurological symptoms and died at the age of 21.5 months. However, lacked with him Organoazidurie, hair loss and skin rash. Post-mortem it was found that the carboxylase activity in the tissues was very different at 42% in kidney, 29% in liver, 10% in the lymphocytes and 3% in the brain.
• In another case, a patient stayed until the age of ten, unobtrusive and symptom free. Then he lost during a flu infection a part of his vision. In the following five years, reinforced the visual field defects, neurological problems and physical weakness of the limbs were added. There were no hair or skin problems obvious, Organoazidurie was only rudimentary. Once diagnosed with biotinidase deficiency at the age of 15 years and biotin was administered, the neurological damage regressed slowly, vision regenerated to a great extent.

The clinical picture of Biotinidasemangels can manifest itself in a totally different degrees of severity, which is only partially dependent on the measured residual activity of the enzyme. Although the disease early on taking a very difficult course, in many cases, there are also adults, in which the biotinidase deficiency was discovered only by chance and show only slight effects of the genetic defect. There are even life without extra biotin intake asymptomatic heart adults known with less than 10% biotinidase activity to which one was the only reason why attention because their children attracted attention in the newborn screening. Nevertheless, the activity of the biotin- dependent carboxylases is significantly reduced even in asymptomatic individuals appearing. The relationship between genotype and phenotype is still largely unclear.

Diagnosis and differential diagnosis

Depending on the combination of the symptoms of the respective patients, the diagnosis is often difficult and tedious. Since the biotinidase presents itself with very diverse manifestations, with the added that similar symptoms occur in many other diseases, laboratory tests are indispensable.

Biochemical evidence

A decreased activity of biotin- dependent carboxylases and the presence of so-called organic acids in the blood, urine, or cerebrospinal fluid are secondary or tertiary effects that could indicate a biotinidase. It should be noted that a Organoazidurie occurs only in about 80 % of patients with biotinidase deficiency, even if already present serious symptoms. On the other hand, such a finding also be caused by other defects of the biotin or biotin- independent metabolism acidurias.

Direct diagnosis

Biotinidase deficiency can be detected by a blood test, in which the enzyme activity of biotinidase is determined directly. Also for the newborn screening are those methods used. Often a colorimetric method using N - ( )- biotinyl -4 -amino benzoic acid is used. A genetic test can secure the diagnosis.

Differential Diagnosis

In external symptoms and biochemical respects the biotinidase similar symptoms can be caused by:

Treatment and cure views

Since it is a genetic defect, the disease is not curable in the strict sense, but there is a successful method of treatment. It consists in the lifelong gift of biotin. Usually 5 to 20 mg per day is sufficient, but there is also a case is described in which a child 40 mg biotin daily required to be free of symptoms. Due to the high dose of free biotin bypasses the defective one recycling enzyme. Side effects are not known.

If treatment is started in time and consistently carried out, the prognosis is very good. The symptoms of skin and metabolism are formed under the treatment completely back what is true of many neurological disorders and delayed development. Longer periods of symptoms but irreversible neurological damage such as hearing impairment, visual impairment and mental retardation may remain. Children who are diagnosed through neonatal screening and treated immediately, develop normally.

Newborn Screening

According to which came into force on 1 April 2005 Directive in Germany is a photometric biotinidase testing an integral part of the newborn screening and a performance of the statutory health insurance. Before, only a recommendation for the test, which was introduced at different times in the provinces. The more care tested positive newborns is best done in a specialized metabolic center, corresponding contact information will be kept by the screening laboratories.

History

The fact that some metabolic diseases in which the function of carboxylases is impaired, can be treated with biotin, has been known since the early 1970s. It soon turned out that in the biotin -responsive patients, the function of several carboxylases is always disturbed. Early 1980s could then be revealed as the cause of a part of these biotin- dependent disorders malfunction of the recycling enzyme biotinidase. More than another decade later, from the mid-1990s, succeeded in determining the amino acid sequence of the human biotinidase enzyme, the sequencing of the corresponding gene and the characterization of the first mutations, which were up by leaps and bounds soon. During this time, the main interest of the research shifted to the question of how can be concluded that the severity of the disease process from the nature of the genetic defect and whether biotinidase may also owns a the disease affecting transferase activity in addition to the well-known recycling function.

Soon after the discovery of biotinidase defect mentioned as the cause of the then late -onset multiple carboxylase deficiency disease 1982/83, a first grade for screening test method the biotinidase activity was introduced in 1984. In the following years were running in various countries in pilot programs that often had the effect that the test of biotinidase activity was included in the newborn screening program. In 2006, about 25 countries have led the biotinidase test, but not always, everywhere, such as in the U.S., where in 2006 was only in half of the states in the test standard part of the newborn screening.