Biotinidase deficiency: clinical presentation, treatment
and screening
Ferenc PappUniversity of Szeged, Department of Pediatrics
Biotinidase deficiency
Inherited disorder of biotin metabolism
The body cannot recycle endogenous
biotin and develop a secondary biotin
deficiency
Biotin Water-soluble essential B-complex vitamin (vitamin H) Cofactor for all 4 carboxylase enzymes:
pyruvate caboxylase (gluconeogenesis)
acetyl-CoA carboxylase (fatty acid synthesis)
propionyl-CoA carboxylase (Ile, Val, Met, Thr catabolism)
methylcrotonyl-CoA carboxylase (Leu catabolism)
Dietary biotin is bound to proteins Free biotin is generated in the intestine by digestive
enzymes, by bacteria and by biotinidase
Free biotin
Holocarboxylases
Holocarboxylase synthase
Biocytin
Lysine
Proteolytic degradation
Proteolytic enzymesBacteria
Biotinidase
Biotinidase
Biotin cycle
Apocarboxylases
Protein catabolism
Fatty acid synthesis
Gluconeogenesis
Dietary biotinprotein-bound
MULTIPLE CARBOXYLASE DEFICIENCY
JUVENILE/LATE FORM
Apocarboxylases
MULTIPLE CARBOXYLASE DEFICIENCY
INFANTILE/EARLY FORM
Biotin
PyruvateAcetyl-CoAPropionyl-CoAMethylcrotonyl-CoA
Biotinidase deficiency
Two types:
Profound < 10% of mean normal enzymatic activity
Partial 10-30% reduced activity
Epidemiology
Incidence of profound and partial deficiency is 1:60.000 in most countries
Brazil 1:9.000 Relatively common in Hungaryestimated combined incidence is 1:23.00058 children had decreased biotinidase activity from
1.336.145 newborns (1989-2001, László et al., 2002)clinical, biochemical and genetic characterization of 20
pts (11 profound, 7 partial, 2 heterozygous)
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
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
Clinical presentation There is considerable variability of clinical features as
well as age of onset of symptoms in enzyme-deficient children
Symptoms may appear from several months to several years of age but may develop as early as 1 week of age (term late form does not apply to all cases!)
First clinical symptoms appear between 3-6 months of age in most of the cases
Symptoms can be seen mostly, but not only in profound form and in pts without treatment
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
Cutaneous findings
Dry skin
Seborrheic dermatitis
Ekzema
Rashes
Fine and brittle hair
Hair loss or total alopecia
Fungal skin infections
Neurological symptoms
Hypotonia Ataxia Lethargy Myoclonic seizures Developmental delay Mental retardation Hearing loss Visual problems
Clinical data of 37 symptomatic pts with profound biotinidase deficiency were analysed (Pomponio et al., USA, Ped Res, 1997)
Symptoms No. of pts (total 37)
%
Rash 25 67
Hypotonia 25 67
Seizures 23 62
Hearing deficits 23 62
Lethargy 22 59
Alopecia 22 59
Ataxia 18 48
Visual problems 14 38
Mental retardation 11 30
Gastrointestinal 8 21
Fungal skin infection 5 13
Age of onset: 1 to 180 months (mean 11.8)
Symptoms improved or resolved after therapy and the children have remained asymptomatic while taking biotin
In some pts the residual neurologic damage has continued
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
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
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
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)
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
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
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