Biotinidase deficiency: clinical presentation, treatment and screening

1. Biotinidase deficiency: clinical presentation, treatment and screening Ferenc Papp University of Szeged, Department of Pediatrics

2. Biotinidase deficiency • Inherited disorder of biotin metabolism • The body cannot recycle endogenous biotin and develop a secondary biotin deficiency

3. Biotin • Water-solubleessentialB-complex vitamin (vitamin H) • Cofactorforall 4 carboxylaseenzymes: pyruvatecaboxylase (gluconeogenesis) acetyl-CoAcarboxylase (fattyacidsynthesis) propionyl-CoAcarboxylase (Ile, Val, Met, Thrcatabolism) methylcrotonyl-CoAcarboxylase (Leucatabolism) • Dietarybiotin is boundtoproteins • Free biotin is generatedintheintestinebydigestiveenzymes, bybacteria and bybiotinidase

4. Dietary biotin protein-bound Proteolytic enzymes Bacteria Biotinidase Multiplecarboxylasedeficiency Infantile/earlyform Multiplecarboxylasedeficiency Juvenile/lateform Free biotin Holocarboxylase synthase Lysine Biotinidase Biotin cycle Apocarboxylases Biocytin Pyruvate Acetyl-CoA Propionyl-CoA Methylcrotonyl-CoA Apocarboxylases Proteolytic degradation Biotin Holocarboxylases Protein catabolism Fatty acid synthesis Gluconeogenesis

5. Biotinidase deficiency Twotypes: • Profound < 10% of meannormalenzymaticactivity • Partial 10-30% reducedactivity

6. Epidemiology • Incidence of profound and partial deficiency is 1:60.000 in most countries • Brazil 1:9.000 • Relatively common in Hungary estimated combined incidence is 1:23.000 58 children had decreased biotinidase activity from1.336.145 newborns (1989-2001, László et al., 2002) clinical, biochemical and genetic characterization of 20 pts (11 profound, 7 partial, 2 heterozygous)

7. Genetic background • Autosomal recessive inheritance • BTD gene 3p25, 4 exons • > 140 disease-causing mutations • Spectrum and frequency of mutations are considerably variable in different ethnic groups • 5 mutations are very common in Caucasians: p.D444H, p.Q456H, p.R538C, p.A171T:D444H, c.98:d7i3

8. Genetic background • p.D444H mutation causes 50% reduction in enzyme activity and is almost always associated with partial deficiency • In partial form p.D444H is combined with a severe mutation  10 to 30% enzyme activity • Patients with complete deficiency have two severe mutations  less than 10% enzyme activity

9. Clinical presentation • There is considerable variability of clinical features as well as age of onset of symptoms in enzyme-deficient children • Symptomsmayappearfromseveralmonthstoseveralyears of agebutmaydevelopasearlyas 1 week of age (termlateformdoesnotapplytoallcases!) • Firstclinical symptomsappearbetween 3-6 months of agein most of thecases • Symptomscan be seenmostly, butnotonlyinprofoundform and inptswithouttreatment

10. Clinical presentaion • Skin manifestations • Neurological symptoms • Hearing loss, eye problems • Immunodeficiency (fungal and bacterial infections) • Gastrointestinal problems (nausea, vomiting, anorexia) • Metabolic decompensation with acidosis and organic aciduria

11. Cutaneous findings • Dry skin • Seborrheic dermatitis • Ekzema • Rashes • Fine and brittle hair • Hair loss or total alopecia • Fungal skin infections

12. Neurological symptoms • Hypotonia • Ataxia • Lethargy • Myoclonic seizures • Developmental delay • Mental retardation • Hearing loss • Visual problems

13. Clinical data of 37 symptomatic pts with profound biotinidase deficiency were analysed (Pomponio et al., USA, Ped Res, 1997) • Age of onset: 1 to 180 months (mean 11.8) • Symptoms improved or resolved aftertherapy and the children have remained asymptomatic while taking biotin • In some pts the residual neurologic damage has continued

14. Laboratory findings • Metabolic acidosis, ketosis, hyperammonaemia • Elevated C3 and C5OH detected by MS/MS • Pathological organic acid profile in the urine (propionic acid, methylcitrate, 3-methylcrotonic-, 3-hydroxyisovaleric acid, 3-methylcrotonylglycine) These lab findings can be observed mostly in untreated pts or in metabolic decompensation

15. Diagnosis • Based on detection of decreased biotinidase activity in the blood and/or in the serum compared to a normal control by using colorimetric test • DNA testing is also available, but this is not necessary for confirmation of biotinidase deficiency

16. Treatment • Pharmacologic dose of biotin resolves many of the clinical features in symptomatic pts and prevents the development of symptoms in asymptomatic pts • Recommended daily dose is 5-20 mg orally • Lifelong treatment is needed (carriers do not need therapy) • Hearing loss, eye problems and developmental delay do not resolve completely with biotin therapy • Early diagnosis and treatment are needed before permanent neurologic damage occurs

17. Screening • A colorimetric method for diagnosing of biotinidase deficiency was developed by Knappe (1963) • It was adopted for newborn screening by Heard (1984) • In Hungary screening was introduced in 1989 • Biotinidase deficiency has been screened in 47 of 51 states of the USA and in 6 European countries (Sweden, Germany, Switzerland, Austria, Lichtenstein and Hungary) at 2007 • Screening has been started in 4 more European countries with pilot studies at the same time (Spain, Belgium, Italy, Turkey)

18. Screening method • A quantitative colorimetric method is used • Enzyme activity is measured directly in the DBS • Result is not influenced by days of life, gestational age or breast feeding • Only transfusion of a newborn can interfere with biotinidase screening, in that case screening needs to be repeated at the age of 2 weeks and 60 days

19. Summary • Inherited disorder of biotin recycling • Two severity forms: profound and partial • If left untreated affected individuals develop severe clinical abnormalities • In symptomatic pts mostly neurologic and cutaneous complications can be observed • It can be treated effectively with biotin supplementation

20. Summary • Permanent neurologic symptoms do not resolve with therapy • Early diagnosis is very important, so that therapy can be initiated before clinical symptoms appear • Clinical consequencies of biotinidase deficiency can be minimized effectively by newborn screening