BIOTINIDASE DEFICIENCY AND MUTATIONS IN PAKISTANI

POPULATION

BY

DR. FARYAL HUSNAIN (CHP-2017-2282)

RESIDENT, CHEMICAL PATHOLOGY,

THE AGA KHAN UNIVERSITY HOSPITAL,

KARACHI

SUPERVISOR

DR. AYSHA HABIB KHAN (CHP-99-2613)

ASSOSIATE PROFESSOR,

CHEMICAL PATHOLOGY

THE AGA KHAN UNIVERSITY HOSPITAL,

KARACHI
INTRODUCTION: Biotinidase deficiency (OMIM #253260)
is a rare autosomal recessive disorder of biotin metabolism.
The biotinidase gene (BTD: OMIM 609019) is located on
chromosome 3q25. The encoded enzyme, biotinidase, is
required to separate the essential vitamin biotin from either the
ingested protein-bound form or biotin-dependent enzymes in
the body.

 Biotin (vitamin H or B8) is important for fatty-acid synthesis,

amino-acid catabolism and gluconeogenesis. Its function is to
act as a co-factor for the carboxylase enzymes involved in
these three processes.

 Biotinidase deficiency can cause insufficient biotin to be made

available for the maintenance of these processes; this can lead
to acidosis or lactic acidosis, abnormal catabolism and/or
hypoglycaemia. These metabolic abnormalities can in turn lead
to neurological symptoms such as seizures, hearing loss,
developmental delay and/or cutaneous symptoms such as rash
and alopecia.

Different mutations in BTD may result in varying levels of

biotinidase activity. Patients with the lowest enzyme activities
usually present with the severest symptoms. Once cerebral
damage, developmental delay and/or hearing loss have
occurred in patients with biotinidase deficiency; they are
usually irreversible.

To prevent these symptoms, timely initiation of treatment with

oral free biotin is essential, which explains why various
countries have included biotinidase deficiency in their neonatal
screening programmes.

Only patients with a profound biotinidase deficiency appear to

be at risk of developing severe and irreversible symptoms, and
should therefore be the main target of screening. Although
screening has also been advocated for partial deficiency, few
individuals with a partial deficiency have been known to
develop symptoms. Not only were the symptoms in these
cases, such as skin-lesions and hair loss, generally mild and
easily treated with biotin,they usually presented after an a
Profound biotinidase deficiency results when the activity of
biotinidase is reduced to less than 10 percent of normal. Partial
biotinidase deficiency occurs when biotinidase activity is
reduced to between 10 percent and 30 percent of normal.
Without enough of this enzyme, biotin cannot be recycled. The
resulting shortage of free biotin impairs the activity of biotin-
dependent carboxylases, leading to a buildup of potentially
toxic compounds in the body. If the condition is not treated
promptly, this buildup damages various cells and tissues,
causing the signs and symptoms described above.

Profound or partial biotinidase deficiency occurs in

approximately 1 in 60,000 newborns

This condition has profound effects on the neurological

system,various neurocutaneous manifestations and metabolic
derangements.We report a case of 3-year-old male child who
presented in ER withsevere respiratory distress for 1 day in a
tertiary care set up. He had been referred from multiple
peripheral centres. His associated complaints included severe
rash, restlessnessand progressivemental deterioration for 2
years. He was managed on symptomatically initially, later a
diagnosis of Biotinidase deficiency was made, he responded
well on supplemental biotin.Our intention to document this
case was for sake of its uniqueness with very common
symptoms, varied presentation and rarity of the disease which
makes it a diagnostic dilemma.

3INTRODUCTIONBiotinidase deficiency is an autosomal

recessive metabolic disorder which ,various neurocutaneous
manifestations and metabolic is characterized by the lack
of cleavage of biotin a vitamin (water-soluble vitamin B7
formerly known as vitamin H or coenzyme R) and
important enzyme co factor in several carboxylation
reactions.Usually parents of patients of this inborn error of
metabolism are carriers and siblings of the affected patients
have the altered gene.1 This diseasehas been reported very
rarely with the incidence found to be1 per 60,089 and 1
per 112,271 of live births, respectively.1This condition has
the profound effects on the neurological system
derangements, whichresponds well tobiotin enzyme
supplements and also prevent severe consequences and
disabilities due to the deficiency.1,2Frequently neonates
present to the clinics demonstrate metabolic ketolactic
acidosis, organic aciduria, and mild hyperammonemia,
condition is asymptomatic until the child develops metabolic
ketolactic acidosisorganic aciduria.2Biotinidase deficiency can
be diagnosed in the newborn through the prenatal molecular
analysis for mutation, it has been recommended that child
with the positive family history must undergo the genetic
analysis to diagnose the carrier state.3Biotinidase deficiency
most of the time presents at the age of 2–3 years but few
cases though have been reported in the neonatal age group,
therefore Biotinidase deficiency must be screened in new-borns
with the suspected symptoms as well as those with the
positive family history.

OBJECTIVE
The objective of our study will be to determine the
frequency of biotinidase deficiency in our poepluation
and the associated mutationsThe objective of this study
was to determine the frequency of biotinidase
deficiency,to identify the spectrum of biotinidase (BTD)
gene mutations in our patients and to determine the
clinical and laboratory findings of our patients.
RATIONALE Such a study has not been conducted in
Pakistan and we have no data so it would be a landmark
study and would benefit people with the disease.
RELEVANCE Inborn errors of metabolism are rare
diseases individually but quite common as a group and it
is imperative that we as pathologists research on these
diseases,especially in our part of the world.
SUBJECTS AND METHODS:
STUDY DESIGN: case control, descriptive
STUDY SETTING: An interdisciplinary study will be
conducted at the Section of Chemical Pathology,
Department of Pathology & Lab Medicine, Aga Khan
University. All biochemical analysis will be done at
Section of Chemical Pathology
STUDY DURATION: One year after the approval of
ERC.
SAMPLE SIZE: Prevalence of Biotinidase enzyme
deficiency is 1 in 60,000 newborns,so we used this to
calculate our sample size which is:
SAMPLING TECHNIQUE: Purposive, non-Probability
SAMPLE SELECTION CRITERIA:
Inclusion criteria: Subjects diagnosed as having
biotinidase deficiency(partial or profound) will be
included in our study
Exclusion Criteria:
DATA COLLECTION PROCEDURE: Subjects will
be recruited from BGL via ILMS, identified by an
endocrinologist and informed consent will be taken after
explaining procedure. Subject’s demographic details
along with their TSH levels AND OTHER AVAILABLE
biochemical parameter, as T3, T4, Ft3 and thyroid
imaging will be filled in Performa, at the time of sample
collection. Ethical review committees’ approval will be
sought.
DATA ANALYSIS: Data will be entered into SPSS
version 19.0 and analysed.
Frequencies of A986S and R990G polymorphisms will be
generated. Means and standard deviations of TSH,
fT4,T3, and TRAb and will be generated if appropriate;
otherwise median with inter-quartile range will be
reported.
REFRENCES:
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