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