What is Biotinidase Deficiency?
Vitamins are essential parts of our daily lives. They help us carry out important bodily functions such as energy production, cell health, and even eyesight. Sometimes, a person might lack certain vitamins due to limited food sources or the body’s inability to properly absorb and use these vitamins. Biotin is a vitamin we get from our diets and it’s used over and over again by our bodies. But in some people, due to a lack of certain enzymes, the recycling of biotin does not function well. This can lead to serious health problems or even death. This condition is called biotinidase deficiency and it is usually inherited from parents.
Biotin is used by four main body enzymes to help metabolize different compounds. Depending on how severe biotinidase deficiency is, it can vary from moderate to severe, affecting the treatment strategy significantly. People with a partial (10 to 30%) deficiency often have little or no symptoms. However, those with a profound deficiency (less than 10%) can experience severe complications such as coma or even death if treatment is not started immediately. This deficiency can affect eye health, nerve function, skin health, and the immune system. It’s vital to identify the deficiency early, because quick treatment can prevent or reduce the severity of symptoms.
Fortunately, treatment is quite simple. Patients just need to consistently take high doses of biotin. If started promptly, this straightforward treatment can reverse many symptoms of the disease. Hence, early diagnosis and treatment can help avoid problems with development or disabilities, improving a person’s quality of life. This is why this disorder is included in many newborn screenings to catch it as soon as possible.
The effective use of biotin to treat such deficiencies was first discovered around 40 years ago. In 1971, researchers found that patients with a certain enzyme deficiency responded well to biotin. Ten years later, they observed similar benefits in newborns with multiple enzyme deficiencies due to a lack of biotin.
What Causes Biotinidase Deficiency?
Biotinidase deficiency is a condition that people inherit from their parents. It happens when two copies of a faulty gene are passed on. This faulty gene, known as BTD, is situated on chromosome 3p25.1. The BTD gene is in charge of creating a protein and enzyme called biotinidase, which is responsible for reusing the nutrient biotin. Biotin is a key component for certain body processes.
Normally, biotinidase turns biocytin, another substance in the body, into free biotin. It does this by getting rid of a group of molecules made of lysine. This ‘recycling’ process helps to maintain a good supply of biotin, which is then available for further biochemical reactions in the body.
When a person has biotinidase deficiency, they lack biotin in their body. This means that other parts of the body which need biotin, like a group of enzymes known as carboxylases (MCC, ACC, PCC, PC), can’t function properly. These enzymes need biotin to enable them to trigger chemical reactions in the body. If they aren’t working correctly, other substances start to build up in the body, leading to sickness and signs of illness.
Risk Factors and Frequency for Biotinidase Deficiency
Biotinidase deficiency is a rare disorder that affects between 1 in 40,000 to 1 in 60,000 babies worldwide. In 2006, severe cases were observed in 1 out of 80,000 babies, and less serious cases were found in 1 out of 31,000 to 1 out of 40,000 babies in the U.S. It is estimated that 1 in 123 individuals carry the gene for this disorder. However, the rate varies between different countries.
In populations where marriages between relatives are common, such as Turkey and Saudi Arabia, the occurrence of biotinidase deficiency can be higher. Conversely, it has been reported to be less frequent among the African-American population. In the U.S and in more than 25 countries globally, newborns are now routinely screened for this deficiency.
Severe biotinidase deficiency typically becomes apparent within the first six months of a child’s life, but the symptoms can start to show anywhere from the first week to up to 10 years of age. On average, symptoms usually appear when a child is around 3.5 months old.
Signs and Symptoms of Biotinidase Deficiency
Biotinidase deficiency is a condition defined by how much biotinidase enzyme someone has. There are two types: profound and partial. Profound biotinidase deficiency means the individual has less than 10% of the normal activity of the enzyme while partial deficiency is classified as 10 to 30% of the normal enzyme activity. Understanding the type of deficiency is important as it affects the prognosis and treatment.
People with profound biotinidase deficiency usually show symptoms in early infancy. They can have different neurological and cutaneous (skin) symptoms. Neurological symptoms include seizures, weakened muscles (hypotonia), lack of coordination (ataxia), visual impairment leading to optic atrophy, impaired hearing, delayed development, spastic paresis, lethargy, coma, and even death.
- Seizures
- Muscle weakness
- Lack of coordination
- Visual impairment leading to optic atrophy
- Hearing loss
- Developmental delay
- Spastic paresis
- Lethargy/coma
- Death
Cutaneous symptoms include:
- Skin rash
- Hair loss (alopecia)
- Conjunctivitis
- Seborrheic dermatitis
There may also be other symptoms like:
- Recurrent viral and fungal infections
- Apnea, rapid breathing, or stridor (whistling sound while breathing)
- Metabolic issues like ketolactic acidosis, organic aciduria, and high ammonia levels
The good news is that if detected early, all of these symptoms can be reversed with biotin treatment. However, changes in vision, hearing loss, and developmental delay might be permanent. If not treated, this condition can lead to coma and death.
People with partial biotinidase deficiency can show symptoms from infancy to adulthood. These range from minor skin reactions like rashes and hair loss to major neurological symptoms like seizures, muscle weakness, and developmental delay. Usually, symptoms only appear during times of stress, like illness, and some people never show symptoms at all.
Testing for Biotinidase Deficiency
Biotinidase deficiency is usually detected through newborn screening or tests conducted on those showing signs of the disease. This deficiency can be identified through measuring enzyme activity in the blood. If a patient has abnormal enzyme levels, further tests can be done to check for mutations in the BTD gene.
Doctors might also conduct laboratory tests to observe levels of lactic acid and ammonia in a patient’s blood or urine. Urine tests can be used to detect urinary ketones and urinary organic acids. Other tests, like blood gas tests and serum chemistry, can also be done if biotinidase deficiency is suspected.
Imaging of the brain, particularly through MRI, often reveals signs of the deficiency in untreated patients going through an intense crisis. This might include swelling of the brain, increased ventricular size, and delayed myelination. Another form of imaging, Magnetic Resonance Spectroscopy (MRS), helps to assess brain metabolism. Although not widely available, it can provide valuable insight into the nature of brain pathology in real time.
A Positron Emission Tomography (PET) scan can show changes in brain metabolism before and after the administration of biotin. A CT scan, another type of imaging, might spot bilateral basal ganglia calcifications, a type of brain abnormality, that might be missed on an MRI.
If a patient is experiencing recurrent fungal, viral, or skin infections, it is essential to rule out biotinidase deficiency. The doctor may also employ EEG, a test to measure electrical activity in the brain, to look for specific patterns which can change after biotin treatment. An eye specialist might conduct a dilated fundus examination, a test of the retina, to check for specific visual field defects and damage to the optic nerve. They might also employ visual evoked potentials (VEPs), a test to measure electrical signals in the brain caused by sight, and visual field testing to evaluate the extent of optic nerve injury.
Treatment Options for Biotinidase Deficiency
The treatment for biotinidase deficiency, a rare genetic disorder, involves taking biotin supplements throughout one’s lifetime. Biotin, also known as vitamin B7, is a vital nutrient that helps the body convert food into energy. Starting the biotin treatment can range from a daily dose of 5 to 20 milligrams. After starting this treatment, seizures and movement disorders may begin to improve within a few hours to a few days, while skin symptoms might take a few weeks to get better.
However, the initial dosage might not always be enough for some patients. If the symptoms persist, the daily dosage of biotin might be increased to up to 40 milligrams.
The timing of when treatment begins and how much damage the deficiency has already caused can influence a child’s development. Starting the treatment early can prevent further damage and potentially help children with developmental delays to catch up on lost milestones or reach new ones.
For children already having neurological problems due to biotinidase deficiency, additional medical treatments might be needed alongside the oral biotin supplements. For example, certain interventions can help manage spasticity (stiff or rigid muscles), developmental delay, and bulbar dysfunction (problems with swallowing, speaking or breathing). Medications such as baclofen and neurotoxins may help address issues like dystonia (involuntary muscle contractions) and spasticity.
What else can Biotinidase Deficiency be?
Biotinidase deficiency can sometimes appear similar to various other conditions. These include:
- Isolated carboxylase deficiency
- Dietary biotin deficiency
- Holocarboxylase synthetase deficiency
- Meningitis, characterized by seizures and rash
- Primary immunodeficiency, often indicated by fungal and bacterial infections
- Sensorineural deafness
- Acrodermatitis enteropathica
- Autism, often marked by developmental delay and inattentiveness
- Myelopathies
- Neuromyelitis optica
- Optic atrophy
- Seborrheic dermatitis
- Infantile spasms
What to expect with Biotinidase Deficiency
Biotinidase deficiency can be effectively managed with early identification and continued care. For those who don’t show any symptoms yet, the outlook is promising if they start treatment before any signs of the condition show up. For those patients who are already showing symptoms, taking biotin, a type of medication, can improve most of their symptoms. However, it cannot undo any damage to the nervous system that has already happened.
Possible Complications When Diagnosed with Biotinidase Deficiency
If a baby’s biotinidase deficiency is not found and treated early, they could face a number of complications. These include:
- Optic atrophy – damage to the optic nerve
- Acquired retinal dysplasia – abnormal development of the retina
- Sensorineural deafness – loss of hearing due to problems in the inner ear
- Developmental disability – problems with mental and physical growth
- Paresis – weakness of the muscles
- Metabolic derangement – disruption of the body’s chemical reactions
- Hyperammonemia – too much ammonia in the blood
- Organic aciduria – high levels of certain acids in the urine
- Recurrent infections – getting sick often
- Coma – a prolonged state of unconsciousness
- Death – the most serious outcome
Preventing Biotinidase Deficiency
It’s vital to let families know that biotinidase deficiency, a condition where the body can’t properly reuse biotin, needs to be managed consistently and throughout the person’s lifetime. Early diagnosis and treatment can prevent many of the complications associated with this condition. However, keep in mind that some complications cannot be reversed once they’ve occurred. This condition is inherited, meaning it is passed down from parents to their children. If both parents carry the gene for this condition, there is a 25% chance that any child they have might also have biotinidase deficiency. Therefore, genetic counseling could be a helpful tool for these families to understand the risks associated with future pregnancies.