Biotinidase deficiency

Alternate names

Biotin deficiency; BTD deficiency; Late-onset biotin-responsive multiple carboxylase deficiency; Late-onset multiple carboxylase deficiency

Definition

Biotinidase deficiency is an inherited disorder in which the body is unable to recycle the vitamin biotin.

Onset

The disorder may become apparent in the first few months of life, or later in childhood.

Epidemiology

Profound or partial biotinidase deficiency occurs in approximately 1 in 60,000 newborns

Cause

Mutations in the BTD gene cause biotinidase deficiency. The BTD gene provides instructions for making an enzyme called biotinidase. This enzyme recycles biotin, a B vitamin found in foods such as liver, egg yolks, and milk. Biotinidase removes biotin that is bound to proteins in food, leaving the vitamin in its free (unbound) state. Free biotin is needed by enzymes called biotin-dependent carboxylases to break down fats, proteins, and carbohydrates. Because several of these enzymes are impaired in biotinidase deficiency, the condition is considered a form of multiple carboxylase deficiency.

Mutations in the BTD gene reduce or eliminate the activity of biotinidase. 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.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the BTD gene in each cell have mutations. The parents of an individual with biotinidase deficiency each carry one copy of the mutated gene, but they typically do not have any health problems associated with the condition.

Signs and symptoms

Profound biotinidase deficiency, the more severe form of the condition, can cause seizures, weak muscle tone (hypotonia), breathing problems, hearing and vision loss, problems with movement and balance (ataxia), skin rashes, hair loss (alopecia), and a fungal infection called candidiasis. Affected children also have delayed development. Lifelong treatment can prevent these complications from occurring or improve them if they have already developed.

Partial biotinidase deficiency is a milder form of this condition. Without treatment, affected children may experience hypotonia, skin rashes, and hair loss, but these problems may appear only during illness, infection, or other times of stress.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Generalized myoclonic seizure
• Metabolic ketoacidosis
• Muscular hypotonia(Low or weak muscle tone)

30%-79% of people have these symptoms

• Alopecia(Hair loss)
• Ataxia
• Desquamation of skin soon after birth
• Global developmental delay
• Hearing impairment(Deafness)
• Keratoconjunctivitis
• Optic atrophy
• Perioral eczema(Eczema around the mouth)

5%-29% of people have these symptoms

• Abnormal cerebellum morphology(Abnormality of the cerebellum)
• Apnea
• Coma
• Growth delay(Delayed growth)
• Hypertonia
• Hyperventilation(Rapid breathing)
• Iris hypopigmentation(Light eye color)
• Laryngeal stridor
• Lethargy
• Muscle weakness(Muscular weakness)
• Myopia(Close sighted)
• Recurrent fungal infections
• Visual field defect(Partial loss of field of vision)

Diagnosis

Biotinidase deficiency should be suspected in infants with positive newborn screening results, untreated individuals with clinical findings, and persons with suggestive preliminary laboratory findings.

Virtually 100% of infants with either profound biotinidase deficiency or partial biotinidase deficiency can be detected in the US by newborn screening.

Clinical Findings

Children or adults with untreated profound biotinidase deficiency usually exhibit one or more of the following nonspecific features (which are also observed in many other inherited metabolic disorders):

• Seizures
• Hypotonia
• Respiratory problems including hyperventilation, laryngeal stridor, and apnea
• Developmental delay
• Hearing loss
• Vision problems, such as optic atrophy

Features more specific to profound biotinidase deficiency include the following:

• Eczematous skin rash
• Alopecia
• Conjunctivitis
• Candidiasis
• Ataxia

Older children and adolescents may exhibit limb weakness, paresis, and scotomata. Some have exhibited findings suggestive of a myelopathy and have been initially incorrectly diagnosed and treated as having another disorder before biotinidase deficiency is correctly diagnosed.

Children or adults with untreated partial biotinidase deficiency may exhibit any of the above signs and symptoms, but the manifestations are mild and occur only when the person is stressed, such as with a prolonged infection.

Preliminary Laboratory Findings

The following findings are suggestive of biotinidase deficiency:

• Metabolic ketolactic acidosis
• Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency; however, 3-hydroxyisovalerate may be the only metabolite present). Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic.
• Hyperammonemia

Molecular genetic testing is performed by single-gene testing.

Treatment

• All symptomatic children with profound biotinidase deficiency improve when treated with 5-10 mg of oral biotin per day. All individuals with profound biotinidase deficiency, even those who have some residual enzymatic activity, should have lifelong treatment with biotin.
• Children with vision problems may benefit from vision aids; those with hearing loss will usually benefit from hearing aids or cochlear implants, and those with developmental deficits from appropriate interventions.

 This article incorporates public domain material from the United States National Library of Medicine document "Genetics Home Reference".

NIH genetic and rare disease info

• NIH info on Biotinidase deficiency

Biotinidase deficiency is a rare disease.

Biotinidase deficiency Resources
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