Dietary deficiency of Biotin

Biotin is so widely distributed in foods that it is doubtful
whether a true dietary defi ciency of the vitamin
has ever occurred in human adults capable of utilizing
it. Artificial biotin defi ciency states have been induced
in healthy volunteers by feeding low-biotin diets containing
a high proportion of raw egg white. An initial
dry scaly dermatitis was followed by non-specifi c
symptoms that included anorexia and extreme lassitude.
All of the symptoms responded to injections
of 150–300 μg of biotin per day.

A unique opportunity to study dietary biotin
defi ciency was presented to Baugh et al. (1968) by a
62-year-old female patient who had consumed six raw
eggs and 4 pints of skimmed milk daily for 18 months.
This diet had been recommended by a physician (illadvisedly,
as we now know) as a dietary supplement
to provide a high intake of essential amino acids to
aid liver regeneration following a diagnosis of liver
cirrhosis. During this dietary period, the patient took
vitamin supplements, which included biotin, and
she also received 100 μg of vitamin B12 by injection
monthly. Thus the stage was set, unintentionally, for
the development of biotin defi ciency due to the avidin
content of raw egg whites, uncomplicated by defi ciencies
of other vitamins or common nutrients. Clinical
manifestations included anorexia, nausea, vomiting,
glossitis, pallor, depression, lassitude, substernal pain,
scaly dermatitis and desquamation of the lips. All
symptoms cleared or improved markedly after 2 to
5 days of parenteral (by injection) vitamin therapy
providing 200 μg of biotin daily, while the patient
continued her pre-treatment diet. In contrast to other
case reports, the patient did not exhibit anaemia,
muscle pains, hypercholesterolaemia or electrocardiographic
abnormalities.
Seborrhoeic dermatitis of the scalp and a more
generalized dermatitis known as Leiner’s disease have
been reported in breast-fed infants when the mother
is malnourished. These symptoms are relieved when
biotin is administered to the mother.

Inherited defects of biotin metabolism

There are two known congenital disorders of biotin
metabolism: (1) holocarboxylase synthetase (HCS)
defi ciency and (2) biotinidase defi ciency. Both disorders
are inherited as an autosomal recessive trait
and both lead to defi ciency of the four biotin-dependent
carboxylases, a condition known as multiple
carboxylase defi ciency (MCD). Because of the vital
role of these enzymes in protein, carbohydrate and
lipid metabolism, their defi ciency leads to severe lifethreatening
disease.
The two forms of MCD usually become symptomatic
in early infancy or childhood. The incidence of
biotinidase defi ciency is about one in 60 000 and that
of HCS defi ciency seems to be even lower. The underlying
cause of HCS defi ciency is decreased affi nity
of HCS for biotin resulting in reduced formation of
holocarboxylases with physiological concentrations
of biotin. In biotinidase defi ciency, MCD results from
progressive development of biotin defi ciency due to
inability to liberate biotin from the biocytin or short
biotinyl peptides that remain after metabolic degradation
of biotin-containing carboxylases. The recycling
of biotin salvaged from degraded enzymes is essential
to maintain an adequate supply of the vitamin. A lack
of biotinidase results in excessive urinary excretion of
biocytin and this raises the requirement for biotin to
above normal intakes.
The two forms of MCD differ biochemically in that
the HCS-defi cient patients have normal plasma biotin
concentrations but decreased carboxylase activities,
whereas patients with biotinidase defi ciency have
subnormal plasma biotin concentrations and normal
carboxylase activities. MCD arising from either inherited
defect causes a block in the biotin-dependent
metabolic pathways with characteristic accumulation
and urinary excretion of organic acids such as lactate,
3-hydroxyisovalerate, 3-methylcrotonylglycine and
methylcitrate.

The clinical presentation and age of onset of MCD
are extremely variable. HCS defi ciency may present
in the fi rst days of life, while biotinidase defi ciency
usually becomes manifest between the second and
fi fth months of age, depending on the amount of free
biotin in the diet. However, onset of HCS defi ciency
is delayed (2–21 months) in some cases and therefore
classifying the two disorders as neonatal- or earlyonset
and infantile- or late-onset MCD should be discouraged.
Clinical symptoms common to both disorders
include neurological abnormalities (hypotonia,
seizures, ataxia) and cutaneous changes (skin rash,
alopecia). In healthy persons receiving an adequate
diet, biotinidase activity in the brain is relatively very
low (Suchy et al., 1985) and so the brain relies largely
on biotin that is transferred across the blood–brain
barrier. This feature of the brain could explain the
rapid onset of neurological symptoms observed in
biotinidase deficiency.