Biotinidase Deficiency

Biotinidase deficiency is a treatable inherited disorder where the body cannot recycle biotin, a vital vitamin needed for breaking down food into energy. Early diagnosis and simple daily treatment with biotin supplements can prevent serious health problems and allow children to develop normally.

Table of contents

• What Is Biotinidase Deficiency?
• Other Names for This Condition
• How Common Is This Condition?
• Two Forms of the Condition
• What Causes Biotinidase Deficiency?
• Signs and Symptoms
• Diagnosis and Testing
• Treatment and Management
• How Is It Inherited?

What Is Biotinidase Deficiency?

Biotinidase deficiency is an inherited disorder in which the body cannot recycle biotin, a B vitamin (also known as vitamin B7 or vitamin H) that is essential for health^[1]. Biotin helps the body break down proteins, fats, and carbohydrates from food and convert them into energy that the body needs to function^[8].

The body needs an enzyme called biotinidase to recycle biotin after it has been used. This enzyme removes biotin from proteins in food and makes it available for reuse^[1]. When biotinidase is missing or not working properly, the body cannot recycle enough biotin. Without sufficient biotin, several important enzymes that depend on it cannot work properly, leading to problems with breaking down nutrients and getting rid of waste products^[5].

The condition is considered a form of multiple carboxylase deficiency because it affects several enzymes that need biotin to function^[1]. These enzymes play essential roles in producing energy and removing waste from the body. Without proper treatment, toxic waste products can build up and cause damage to various cells and tissues^[1].

Other Names for This Condition

Late-Onset Multiple Carboxylase Deficiency, BTD deficiency, BIOT, Carboxylase deficiency multiple late-onset, Late-onset biotin-responsive multiple carboxylase deficiency, Biotinidase, Multiple carboxylase deficiency late-onset, Delayed-onset biotinidase deficiency, Infantile multiple carboxylase deficiency, Juvenile multiple carboxylase deficiency

How Common Is This Condition?

Profound or partial biotinidase deficiency occurs in approximately 1 in 60,000 newborns^[1]. In the United States, it is estimated that fewer than 70 babies are born with some form of this condition each year^[8].

Two Forms of the Condition

There are two types of biotinidase deficiency: profound (severe) and partial (mild). The type depends on how much biotinidase enzyme activity remains in the body^[8].

Profound biotinidase deficiency is the more severe form. It occurs when the activity of biotinidase is reduced to less than 10 percent of normal levels^[1]. Without treatment, symptoms typically appear within the first few months of life, although they can also become apparent later in childhood^[1]. Children with profound deficiency usually develop symptoms between ages one week and ten years^[2].

Partial biotinidase deficiency is a milder form of the condition. It occurs when biotinidase activity is reduced to between 10 percent and 30 percent of normal levels^[1]. Children with partial deficiency may have few or no symptoms under normal circumstances. However, symptoms may appear only during times of stress, such as when they have an illness or infection^[2].

What Causes Biotinidase Deficiency?

Biotinidase deficiency is caused by mutations in the BTD gene^[1]. This gene provides instructions for making the biotinidase enzyme. Mutations in the BTD gene reduce or completely eliminate the activity of biotinidase, which prevents the body from recycling biotin effectively^[1].

Biotin is found in foods such as liver, egg yolks, and milk^[1]. It is also produced by bacteria in the large intestine^[5]. The biotinidase enzyme normally removes biotin from proteins, leaving the vitamin in its free state. Free biotin is then needed by four important enzymes in the body called biotin-dependent carboxylases. These enzymes are involved in breaking down fats, proteins, and carbohydrates^[1].

When biotinidase is deficient, 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^[1]. If the condition is not treated promptly, this buildup damages various cells and tissues, causing the signs and symptoms of the disorder.

Signs and Symptoms

Children with biotinidase deficiency who are diagnosed early through newborn screening and treated with biotin before symptoms appear have normal development^[2]. However, if the condition is not recognized and treated, symptoms can develop and cause serious health problems.

In profound biotinidase deficiency, untreated children typically develop symptoms that include seizures, weak muscle tone (called hypotonia), and breathing problems^[1]. They may also experience hearing and vision loss, problems with movement and balance (called ataxia), skin rashes, hair loss (called alopecia), and a fungal infection called candidiasis^[1]. Affected children often have delayed development^[2].

Children with partial biotinidase deficiency may experience milder symptoms. Without treatment, they may have hypotonia, skin rashes, and hair loss, but these problems often appear only during illness, infection, or other times of stress^[1].

Untreated adolescents and adults with biotinidase deficiency usually exhibit problems with the spinal cord (called myelopathy) and optic nerve damage (called optic neuropathy). These individuals are often initially misdiagnosed with multiple sclerosis^[2]. Most of these individuals experience improvement in their symptoms with biotin supplementation.

Some symptoms can be reversed with treatment if diagnosed early. Feeding issues, skin manifestations, and respiratory issues usually resolve with biotin therapy^[2]. However, other problems such as optic atrophy, hearing loss, and developmental delay may improve but are usually not completely reversible if they occur before treatment begins^[2].

Diagnosis and Testing

Biotinidase deficiency is included in newborn screening programs in many locations^[8]. Newborn screening uses a small amount of blood collected from the baby’s heel to measure the activity of the biotinidase enzyme^[8]. Babies who do not have enough biotinidase enzyme activity may have biotinidase deficiency and need further testing.

The diagnosis of biotinidase deficiency can be established in two ways. The first method is detecting deficient biotinidase enzyme activity in serum or plasma samples^[2]. The second method involves genetic testing to identify mutations in both copies of the BTD gene, which is used when enzyme testing results are unclear^[2].

If a baby’s newborn screening result is out of range, follow-up testing should be completed as soon as possible. This may include blood and urine tests, as well as genetic testing using a blood sample^[8]. An out-of-range screening result does not mean the baby definitely has the condition, but it does mean more testing is needed. False-positive results can occur, especially in babies born prematurely or when screening samples are exposed to high heat or humidity^[8].

Treatment and Management

Treatment for biotinidase deficiency is straightforward and highly effective. All individuals with profound or partial biotinidase deficiency should be treated with oral biotin supplements in free form, not the protein-bound form found in regular multivitamins^[2][7]. Biotin therapy is lifelong, especially for those with profound deficiency^[2].

The typical starting dose is 5 to 10 milligrams of free biotin per day for those with less than 10 percent of normal enzyme activity^[2]. For those with 10 to 30 percent of normal enzyme activity, the dose is 2.5 to 10 milligrams per day^[2]. Some patients may require higher daily doses, up to 40 milligrams per day, if they do not respond well to lower doses^[7].

Lifelong treatment can prevent complications from occurring or improve them if they have already developed^[1]. If treatment is started early before symptoms appear, children can have normal development^[2]. For symptomatic individuals, biotin therapy can rapidly resolve metabolic problems within hours to days^[2].

Additional supportive care may be needed for individuals who developed symptoms before treatment began. This includes hydration and bicarbonate for those with metabolic problems, developmental therapies and educational resources for those with developmental delay, specialized eye care for those with optic problems, and hearing aids or cochlear implants for those with severe hearing loss^[2].

Children with residual neurological problems may require medical interventions for developmental delay, muscle stiffness (called spasticity), and difficulties with swallowing or speaking^[7]. Ongoing physical therapy may be needed to prevent long-term orthopedic problems in children with residual neurological injury.

How Is It Inherited?

Biotinidase deficiency is inherited in an autosomal recessive pattern^[1]. This means both copies of the BTD gene in each cell must have mutations for a person to be affected by the condition.

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^[1]. When both parents are carriers, each of their children has a 25 percent chance of inheriting both mutated genes and having the condition.