What Is Biotinidase Deficiency?

Introduction

What is biotinidase deficiency, and why is it important to understand it?

Biotinidase is an important enzyme that helps the body utilize biotin effectively. Biotin, also known as vitamin B7 or vitamin H, is essential for various metabolic processes in the body.

Biotin, a B-complex and water-soluble vitamin, is present in various foods, including milk, raw egg yolk, organ meats like liver and kidney, leafy greens such as Swiss chard, and brewer's yeast. The body also produces its own biotin through colonic flora residing in the colon (large intestine). The small intestine is the primary place where the body absorbs biotin, with a smaller amount also being absorbed in the proximal colon. Biotin is absorbed more effectively when the body lacks enough biotin or has low biotin intake, compared to when biotin levels are sufficient or when higher doses of biotin are taken.⁴

In individuals with biotinidase deficiency, the biotin cannot be properly detached from biocytin (a combination of biotin and protein) as well as from proteins obtained from the diet. As a result, biotin is not effectively reused by the body, leading to a deficiency of this essential vitamin.¹

Biotin is crucial for processing food into energy; it is an essential nutrient and coenzyme that plays an important role in various metabolic processes; without it, various health issues arise. Understanding this condition is essential as it highlights the importance of early newborn screening, which promotes early interventions, thereby preventing complications and improving the quality of life of affected individuals. 

How does biotinidase deficiency affect the body's metabolic processes?

Biotinidase deficiency (BTD) is a genetic disorder inherited in an autosomal recessive manner, affecting both the nervous system and the skin.¹

When someone has biotinidase deficiency, the lack of adequate biotin affects important enzymes like carboxylases. Without biotin, these enzymes can't work properly, causing issues in four different pathways:³

• Affecting an enzyme called pyruvate carboxylase leads to the accumulation of lactic acid and alanine
• It affects propionyl-CoA carboxylase, thereby resulting in an increase in the levels of propionate, methyl citrate, etc.
• It can result in 3-methylcrotonyl-CoA carboxylase deficiency, and people with this deficiency are short on the enzyme required to break down proteins containing leucine 
• Acetyl-CoA carboxylase deficiency results in the accumulation of acetyl-CoA

All these buildups can lead to various problems affecting the brain and skin in people with biotinidase deficiency.

When does biotinidase deficiency manifest, and who does it affect?

BTD is an uncommon disorder with diverse manifestations. The profound BTD form starts manifesting early in the neonatal period, whereas the partial BTD form typically emerges around three months of age. Those assigned females at birth (AFAB) and those assigned males at birth (AMAB) are equally affected.

• Profound BTD affects 1 in 140,000 individuals
• Partial BTD affects 1 in 110,000 individuals
• Either form impacts 1 in 60,000 individuals

Interestingly, around 1 in 120 people carry a single BTD gene, a ratio that can vary in different populations – potentially higher in Hispanics and lower in African-American persons.

What causes biotinidase deficiency to arise?

Biotinidase deficiency emerges as a result of genetic alterations (mutations) within the BTD gene. This particular gene plays a pivotal role in guiding the production of biotinidase enzyme – a critical component facilitating the recycling of the essential vitamin, biotin. In instances where biotin recycling is impaired, a range of health complications might occur.²

What does biotinidase gene mutation mean?

Every individual inherits two copies of each gene – one from each parent. The interplay of these genes determines the presence of genetic disorders. Biotinidase deficiency adheres to an autosomal recessive inheritance pattern. This means that for this genetic disorder, an individual must inherit the non-functioning gene from both parents to manifest the condition. In scenarios where only one normal gene and one gene associated with the disease are inherited, the person becomes a carrier, often without displaying symptoms.²

The likelihood of two carrier parents passing on the non-functioning gene to have an affected child stands at 25% with each pregnancy. The probability of a child inheriting the carrier status from both parents is 50% per pregnancy. Conversely, there's a 25% chance of a child receiving normal genes from both parents, thus avoiding the genetic trait in question. This pattern holds true for both AMABs and AFABs, underscoring the genetic intricacies of biotinidase deficiency inheritance.² 

How is this genetic condition diagnosed? 

Biotinidase deficiency could be diagnosed through:

• Testing Enzymes: To check for potential issues during pregnancy, a test can measure the activity of the biotinidase enzyme in the amniotic fluid surrounding the baby. This fluid is collected using a procedure called amniocentesis, usually done around 15-18 weeks into pregnancy
• DNA Testing: Another way to test for possible problems during pregnancy is by studying the baby's DNA. The DNA can be obtained through amniocentesis (15-18 weeks into pregnancy) or chorionic villus sampling (10-12 weeks into pregnancy). However, it's important to know about the specific disease-causing parts of the genes before this kind of testing can be done
• Newborn Screening: In newborns, a condition like biotinidase deficiency can be identified early. This is done by checking the biotinidase activity using a few drops of blood on special paper, just like how other newborn tests are conducted
• Confirming the diagnosis: After a child is identified as being potentially biotinidase deficient through newborn screening, the next step involves verifying their diagnosis. To confirm the presence of the condition, the child's blood is tested to measure the activity of the biotinidase enzyme in their serum or plasma

What are the signs and symptoms of biotinidase deficiency?

Symptoms vary according to the type of BTD: 

In profound biotinidase deficiency, symptoms include: 

• Seizures
• Weak muscle tone (hypotonia)
• Breathing problems
• Delayed development

Untreated profound biotinidase deficiency may cause:

• Hearing loss
• Eye abnormalities and vision loss
• Movement and balance issues (ataxia)
• Skin rashes
• Hair loss (alopecia)
• Candidiasis (fungal infection)

Partial biotinidase deficiency is the milder form in which the symptoms may appear regularly or during illness/stress and includes:

• Weak muscle tone
• Skin rashes
• Hair loss

How is biotinidase deficiency managed?

Managing biotinidase deficiency involves lifelong efforts, but the approach is relatively uncomplicated.³

The recommended course of action revolves around biotin replacement, usually beginning with a daily dose of 5 to 20 mg. It's important to note that while improvements in seizures and movement disorders might take several hours to days, skin issues might require a few weeks to improve. Occasionally, this initial dose might fall short, leading to persistent clinical signs. In such cases, increasing the dose to 40 mg per day is advised.³

For children facing developmental delays, the timing of treatment initiation plays a role in their potential to regain lost milestones or achieve new ones. Treatment acts as a safeguard against further harm in cases involving irreversible neurological damage. Apart from oral biotin therapy, children with lingering neurologic issues might require further medical interventions.³

Challenges like spasticity, developmental delay, and bulbar dysfunction can be managed through a range of approaches. For instance, dystonia and spasticity might be addressed using intrathecal baclofen and neurotoxins.

The key lies in a comprehensive and tailored strategy to ensure the best possible quality of life for individuals with biotinidase deficiency. 

Who makes up the biotinidase deficiency management team?

The management team for biotinidase deficiency typically includes professionals from various medical fields who collaborate to ensure effective care and treatment for individuals with the condition. These experts include:³

• Metabolic specialists: Medical professionals with expertise in metabolism and genetic disorders
• Pediatricians: Doctors specializing in the care of infants, children, and adolescents
• Neonatologists: Medical professionals with expertise in the care of newborns, particularly important for early detection and intervention in cases identified shortly after birth 
• Nutritionists: Experts who provide guidance on dietary management and nutritional supplementation to support individuals with biotinidase deficiency
• Geneticists: Specialists in genetics who assist in understanding the genetic basis of the condition and provide counselling for families
• Neurologists: Medical professionals with expertise in neurological disorders, important for managing the neurological aspects of the condition
• Radiologists: Professionals who utilize imaging techniques to aid in diagnosis and monitoring
• Physiotherapists: Experts who assist with physical therapy and rehabilitation for individuals experiencing motor or movement challenges
• Supportive healthcare personnel: Nurses, social workers, and other healthcare providers who offer emotional support and assist with coordination of care

Together, this multidisciplinary team collaborate to ensure comprehensive and effective management for individuals with biotinidase deficiency.

What is the prognosis of biotinidase deficiency?

The outlook for individuals with biotinidase deficiency is optimistic with early intervention and consistent care.

For cases without symptoms, the prognosis remains favourable if treatment is administered before symptom onset. However, for those already experiencing symptoms, pharmacological biotin therapy can improve most clinical aspects, but it's important to note that it cannot undo neurological damage that has already taken place.³

Are there other terms used to identify Biotinidase deficiency?

BTD is identified by various other terms, such as:

• BTD deficiency
• Juvenile-onset multiple carboxylase deficiency
• Late-onset multiple carboxylase deficiency
• Multiple carboxylase deficiency

Summary 

Biotinidase deficiency presents as a rare genetic disorder, impacting the recycling and utilization of biotin, a B-complex and water-soluble vitamin present in various foods, including milk, raw egg yolk, organ meats like liver and kidney, leafy greens such as Swiss chard, and brewer's yeast. The body also produces its own biotin through colonic flora residing in the colon (large intestine). The small intestine is the primary place where the body absorbs biotin, with a smaller amount also being absorbed in the proximal colon. 

Biotin is absorbed more effectively when the body lacks enough biotin or has low biotin intake, compared to when biotin levels are sufficient or when higher doses of biotin are taken. The absence or deficiency of the biotinidase enzyme disrupts the body's ability to free biotin from proteins, leading to a range of potential health issues.

With varying symptom severity and forms, early detection through newborn screening programs has become instrumental in effective management. 

Timely biotin supplementation offers individuals with this condition the chance to lead relatively normal lives, emphasizing the importance of early diagnosis and intervention.