Biotinidase deficiency

from Wikipedia, the free encyclopedia
Classification according to ICD-10
E53.8 Deficiency of other specified vitamins of the vitamin B complex
ICD-10 online (WHO version 2019)

Biotinidase or late onset multiple carboxylase (engl. Biotinidase deficiency or late-onset multiple carboxylase deficiency ) is a rare metabolic disorder , the autosomal recessive inherited and causes the body the vitamin biotin can not sufficiently recycle. The biotinidase deficiency belongs to the multiple carboxylase deficiency .

The cause is a defect in the biotinidase enzyme . The effects of the biotinidase deficiency range from symptoms of the skin and malfunctions of the immune system to severe metabolic derailments to brain damage , coma and death.

A very effective therapy exists in the form of lifelong treatment with biotin. A test for biotinidase deficiency is part of newborn screening in many countries . A distinction is made between severe biotinidase deficiency with residual enzyme activity of less than 10% and partial biotinidase deficiency with enzyme activity of 10 to 30%.

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

distribution

Averaged worldwide, biotinidase deficiency occurs with a frequency of 1: 60,000, with severe and partial deficiencies being found with similar frequency. In purely mathematical terms, one in 123 people carries a corresponding defective gene . However, the numbers vary from country to country. The screening reports of the German Society for Newborn Screening for the years 2004 to 2006 show that the frequency of a biotinidase deficiency in the Federal Republic of Germany is in the range of 1: 20,000 to 1: 25,000.

Cause and development of the disease

genetics

The biotinidase gene is located on chromosome 3 in the p25 area. There are more than 60 known mutations that cause an enzyme defect . Severe biotinidase deficiency with less than 10% enzyme activity occurs when both alleles encode a completely or almost completely defective enzyme. A partial biotinidase deficiency with 10–30% enzyme activity occurs when one gene variant produces a serious defect while the other only produces a partial defect with considerable residual activity. In addition, there are other classifications in the literature.

metabolism

The citric acid cycle and the anaplerotic reactions of pyruvate carboxylase (PC) and propionyl-CoA carboxylase (PCC) as well as their connection with gluconeogenesis, respiratory chain (Oxphos) and ATP production

The enzyme biotinidase has the task of breaking down biocytin , an intermediate product of biotin metabolism, and thus recovering the biotin it contains for the organism. If this happens inefficiently, biocytin is lost through the kidneys . Due to the above-average loss, the body's biotin reserves are gradually being depleted, despite otherwise adequate nutrition . This impairs the function of the four biotin-dependent carboxylases , which perform basic tasks in the carbohydrate , protein and lipid metabolism:

As a result, on the one hand, the citric acid cycle is impaired and thus the energy supply of the cells ; on the other hand, metabolic intermediates accumulate in the mitochondria in harmful concentrations, which then pass into the cytosol and finally into the body fluids . If the abnormal breakdown products, often grouped under the term organic acids , can be detected in the urine , one speaks of organoaciduria .

Symptoms and pathology

The symptoms are similar to those of a biotin deficiency. The disease particularly affects organs with a high metabolic intensity or cell division rate , such as the brain , muscles and the immune system . The production of skin fat and prostaglandin can be disturbed. Movement disorders ( ataxia , spastic paresis , hypotension ), epilepsy-like seizures, encephalopathy , loss of hearing , damage to the eye ( restricted field of vision , retinal degeneration), weakness, loss of appetite, organoaciduria, lactic acidosis , ketoacidosis , abnormalities of the immune system, increased susceptibility to Conjunctivitis , dermatitis, and hair loss (alopecia).

Because the biotinidase defect affects four important enzymes (three mitochondrial and one cytosolic), the symptoms are very broad and can differ significantly from patient to patient. None of the above symptoms should occur in every patient. Different tissue types can also be affected to different degrees by the resulting carboxylase deficiency. The first symptoms usually appear between three and six months of age. The disease can also begin earlier or much later. The manifestation of the clinical picture can take place gradually, suddenly or in bursts with symptom-free or less symptomatic phases. In some cases, metabolic stress, for example due to common infections, is mentioned as a trigger.

In addition to the symptom combination of seizures, skin manifestations and, often only in an advanced stage, organoaciduria and metabolic acidosis, other forms of disease are also possible. The following examples show how differently the disease can develop:

  • In patients with partial biotinidase deficiency, only atopic or seborrheic dermatitis often occurs .
  • 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. A deficiency in immunoglobulin A (IgA) was found in the first patient, and a low number of T lymphocytes in the second . The third child also suffered from dermatitis infected with candida , conjunctivitis, hair loss and flare-ups of ataxia, but was not examined immunologically but metabolically. Lactic acidosis and organoaciduria occurred in stages.
  • One patient showed primarily neurological symptoms and died at the age of 21.5 months. However, he lacked organoaciduria, hair loss and rash. Post mortem , it turned out that the carboxylase activity in the body tissues was very different with 42% in the kidney, 29% in the liver , 10% in the lymphocytes and 3% in the brain.
  • In another case, a patient remained normal and symptom-free until the age of ten. Then he lost some of his vision during a flu-like infection . In the following five years the visual field impairment increased, neurological problems of the limbs and physical weakness came on top. No hair or skin problems were apparent, organic aciduria was only rudimentary. After the biotinidase deficiency was diagnosed at the age of 15 and biotin was administered, the neurological damage slowly receded and the eyesight was largely regenerated.

The clinical picture of biotinidase deficiency can manifest itself in completely different degrees of severity, which only partially depend on the measured residual activity of the enzyme. Although the disease takes a very severe course early in many cases, there are also adults in whom the biotinidase deficiency was only discovered by chance and who only show slight effects of the genetic defect. There are even known asymptomatic adults with less than 10% biotinidase activity who remained asymptomatic without additional biotin intake, and who only became aware of them because their children were noticed during the newborn screening. Nonetheless, even in individuals who appear asymptomatic, the activity of the biotin-dependent carboxylases is markedly reduced. The relationship between genotype and phenotype is still largely unexplained.

Diagnostics and differential diagnostics

Depending on the combination of symptoms in a particular patient, diagnosis is often difficult and lengthy. Since the biotinidase deficiency presents itself in very different manifestations, with the fact that comparable symptoms also occur in many other diseases, laboratory tests are indispensable.

Biochemical evidence

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

Direct diagnosis

Biotinidase deficiency can be detected by a blood test in which the enzyme activity of the biotinidase is determined directly. Such methods are also used for newborn screening. A colorimetric method with N - (+) - biotinyl-4-aminobenzoic acid is often used. A genetic test can confirm the diagnosis.

Differential diagnosis

Outward symptoms and biochemical conditions similar to the biotinidase deficiency can be caused by:

  1. Primary biotin deficiency , due to diet or due to damaged intestinal flora , biotin deficiency in dialysis patients as well as in patients who take long-term anticonvulsants .
  2. other forms of multiple carboxylase deficiency , such as the holocarboxylase synthetase deficiency or defects in biotin transport proteins , which probably include the biotin-responsive basal ganglia disease . Much higher doses of biotin are required for treatment.
  3. an isolated deficiency of the single carboxylases. There a diet tailored to the respective enzyme defect is the indicated therapy; biotin is only effective in exceptional cases.
  4. other diseases of the mitochondria ( mitochondriopathy , engl. mitochondrial disease ).

Treatment and prospect of recovery

Since it is a genetic defect, the disease is not actually curable, but there is a successful treatment method. It consists in the lifelong gift of biotin. Usually 5 to 20 mg per day is sufficient, but a case has also been described in which a child needed 40 mg biotin daily to be symptom-free. The high dose of free biotin bypasses the defective recycling enzyme. Side effects are not known.

If the therapy is started on time and carried out consistently, the prognosis is very good. The symptoms of the skin and the metabolism completely regress during the treatment, which also applies to many neurological disorders and developmental deficits. However, if the symptoms persist for a long time, irreversible neurological damage such as hearing impairment, visual impairment and intellectual disability can remain. Children who are diagnosed through neonatal screening and treated promptly develop normally.

Newborn screening

In Germany, according to the directive that came into force on April 1, 2005, a photometric biotinidase test is an integral part of newborn screening and a service provided by statutory health insurance companies . Before that, there was only a recommendation for the test, which was introduced at various times in the federal states . Further care of positively tested newborns is best done in a specialized metabolism center, the corresponding contact details are kept by the screening laboratories.

history

It has been known since the early 1970s that some metabolic diseases in which the function of the carboxylases is impaired can be treated with biotin. It soon turned out that in the case of patients responding to biotin, the function of several. Carboxylases is disturbed. At the beginning of the 1980s, a malfunction of the recycling enzyme biotinidase was discovered to be the cause of some of these biotin-dependent disorders . More than a further decade later, from the mid-1990s, the amino acid sequence of the human biotinidase enzyme was determined, the associated gene was sequenced and the first mutations were characterized, the number of which soon skyrocketed. During this time, the main research interest shifted to the question of how the severity of the disease can be deduced from the type of genetic defect and whether, in addition to the well-known recycling function, biotinidase may also have a transferase activity that influences the clinical picture .

Soon after the discovery of the biotinidase defect as the cause of the disease called multiple carboxylase deficiency, which was called the late onset of multiple carboxylase deficiency in 1982/83, a first test method for biotinidase activity suitable for mass examinations was presented in 1984 . In the years that followed, pilot programs were launched in various countries, which often resulted in the biotinidase activity being included in the newborn screening program. In 2006 around 25 countries carried out the biotinidase test, but not always across the board, as was the case in the USA , where in 2006 the test was a standard part of newborn screening in only half of the states .

Individual evidence

  1. ↑ a b c E. R. Baumgartner, T. Suormala: Multiple carboxylase deficiency: inherited and acquired disorders of biotin metabolism. In: Int. J. Vitam. Nutr. Res. Volume 67, No. 5, 1997, pp. 377-384 PMID 9350481 .
  2. ↑ a b c d e f g h i C. I. Kaye and the Committee on Genetics: Newborn screening fact sheets. In: Pediatrics. Volume 118, No. 3, September 2006, pp. E934 – e963, doi: 10.1542 / peds.2006-1783 (full text PDF, 413 kB).
  3. ↑ B. Wolf: Worldwide survey of neonatal screening for biotinidase deficiency. In: J. Inherit. Metab. Dis. Volume 14, No. 6, 1991, pp. 923-927, PMID 1779651 .
  4. ↑ a b Links to the screening reports ( Memento of the original from April 12, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. in 2004, 2005 and 2006 at the German Society for Newborn Screening. @1@ 2Template: Webachiv / IABot / www.screening-dgns.de
  5. ↑ a b c J. Hymes, CM Stanley, B. Wolf: Mutations in BTD causing biotinidase deficiency. In: Hum. Mutat. Volume 18, No. 5, November 2001, pp. 375-381, doi: 10.1002 / humu.1208 .
  6. ↑ JM Berg, JL Tymoczko, L. Stryer: Biochemistry. 6th edition. Spektrum Akademischer Verlag, Elsevier, Munich 2007, ISBN 978-3-8274-1800-5 , pp. 515f, 551, 697f, 711-713, 746.
  7. ↑ A. Fischer et al.: Biotin-responsive immunoregulatory dysfunction in multiple carboxylase deficiency. In: J. Clin. Immunol. Vol. 2, No. 1, January 1982, pp. 35-38, PMID 6212592 .
  8. ↑ ML Williams: Biotin-responsive multiple carboxylase deficiency and immunodeficiency. In: Curr. Problem dermatol. Volume 18, 1989, pp. 89-92, PMID 2663376 .
  9. ^ HJ Wastell, K. Bartlett, G. Dale, A. Shein: Biotinidase deficiency: a survey of 10 cases. In: Arch. Dis. Child. Vol. 63, No. 10, October 1988, pp. 1244-1249, PMID 3196050 (full text).
  10. ↑ a b J. R. McVoy et al: Partial biotinidase deficiency: clinical and biochemical features. In: J. Pediatr. Volume 116, No. 1, January 1990, pp. 78-83, PMID 2295967 .
  11. ^ A b c V. T. Ramaekers et al: A biotinidase Km variant causing late onset bilateral optic neuropathy. In: Arch. Dis. Child. Volume 67, No. 1, January 1992, pp. 115-119, PMID 1739323 (full text).
  12. ↑ MJ Cowan et al .: Multiple biotin-dependent carboxylase deficiencies associated with defects in T-cell and B-cell immunity. In: The Lancet . Vol. 2, No. 8134, July 1979, pp. 115-118, PMID 88554 .
  13. ↑ ER Baumgartner et al: Biotinidase deficiency: a cause of subacute necrotizing encephalomyelopathy (Leigh syndrome). Report of a case with lethal outcome. In: Pediatr Res . Vol. 26, No. 3, September 1989, pp. 260-266, PMID 2587127 .
  14. ↑ T. Baykal et al .: Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. In: J. Inherit. Metab. Dis. Volume 28, No. 6, 2005, pp. 903-912, PMID 16435182 .
  15. ↑ a b G. S. Heard, JR Secor McVoy, B. Wolf: A screening method for biotinidase deficiency in newborns. In: Clin. Chem. Vol. 30, No. 1, January 1984, pp. 125-127, PMID 6690118 .
  16. ↑ DM Mock, NI Mock, RP Nelson, KA Lombard: Disturbances in biotin metabolism in children undergoing long-term anticonvulsant therapy. In: J. Pediatr. Gastroenterol. Nutr. Volume 26, No. 3, March 1998, pp. 245-250, PMID 9523856 .
  17. ↑ R. Mardach et al: Biotin dependency due to a defect in biotin transport. In: J. Clin. Invest. Volume 109, No. 12, June 2002, pp. 1617-1623, PMID 12070309 (full text).
  18. ↑ MR Baumgartner et al .: Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy. In: Am. J. Hum. Genet. Volume 75, No. 5, November 2004, S 790-800, PMID 15359379 (full text).
  19. ↑ PC Navarro, A. Guerra, JG Alvarez, FJ Ortiz: Cutaneous and neurologic manifestations of biotinidase deficiency. In: International Journal of Dermatology Volume 39, No. 5, 2000, pp. 363-365, doi: 10.1046 / j.1365-4362.2000.00841.x .
  20. ↑ a b P. Weber, S. Scholl, ER Baumgartner: Outcome in patients with profound biotinidase deficiency: relevance of newborn screening. In: Dev Med Child Neurol . Volume 46, No. 7, 2004, pp. 481-484, PMID 15230462 .
  21. ↑ Current and previous guidelines for newborn screening ( Memento of the original from April 12, 2009 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. at the German Society for Newborn Screening. @1@ 2Template: Webachiv / IABot / www.screening-dgns.de
  22. ↑ D. Gompertz, K. Bartlett, D. Blair, CM Stern: Child with a defect in leucine metabolism associated with beta-hydroxyisovaleric aciduria and beta-methylcrotonylglycinuria. In: Arch. Dis. Child. Volume 48, No. 12, December 1973, pp. 975-977, PMID 4765660 (full text).
  23. ↑ B. Wolf, RE Grier, RJ Allen, SI Goodman, CL Kien: Biotinidase deficiency: the enzymatic defect in late-onset multiple carboxylase deficiency. In: Clin. Chim. Acta. Volume 131, No. 3, July 1983, pp. 273-281, PMID 6883721 .
  24. ↑ B. Wolf: Biotinidase: its role in biotinidase deficiency and biotin metabolism. In: J. Nutr. Biochem. Volume 16, No. 7, July 2005, pp. 441-445, PMID 15992688 .

Web links