Biotinidase deficiency:
clinical presentation, treatment
and screening
Ferenc Papp
University 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
Dietary biotin
protein-bound
Proteolytic enzymes
Bacteria
Biotinidase
MULTIPLE CARBOXYLASE
DEFICIENCY
JUVENILE/LATE FORM
Lysine
MULTIPLE CARBOXYLASE
DEFICIENCY
INFANTILE/EARLY FORM
Free biotin
Holocarboxylase
synthase
Biotinidase
Biocytin
Apocarboxylases
Biotin
cycle
Proteolytic
degradation
Apocarboxylases
Pyruvate
Acetyl-CoA
Propionyl-CoA
Methylcrotonyl-CoA
Biotin
Holocarboxylases
Protein
catabolism
Fatty acid
synthesis
Gluconeogenesis
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 Hungary
estimated combined incidence is 1:23.000
58 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)
 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
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
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-, 3hydroxyisovaleric 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