Biotinidase Deficiency

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Continuing Education Activity

Biotin acts as a coenzyme for four carboxylation enzymes in the body: 3-methylcrontonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC) and propionyl-CoA carboxylase (PCC). Biotinidase deficiency can be partial(10 to 30% of enzyme activity) or profound(less than 30% of enzyme activity), which has significant impacts on the treatment approach. Partial cases can have little or no symptoms. However, profound cases can lead to coma or death if treatment is not initiated rapidly. This activity reviews the evaluation and treatment of biotinidase deficiency as well as highlights the role of the interprofessional team in managing and improving care for patients with this condition.


  • Identify the etiology of biotinidase deficiency.
  • Review the approach used in the evaluation of a patient with biotinidase deficiency.
  • List the management options available for biotinidase deficiency.
  • Discuss interprofessional team strategies for improving care coordination and communication to improve outcomes in biotinidase deficiency.


Vitamins are vital components to every individual’s day to day chemical reactions and molecular processes. They are used as cofactors for reactions, antioxidants, hormones, and even for vision. Vitamin deficiencies can be acquired by a lack of adequate environmental supplies or due to abnormal vitamin processing within intracellular pathways. Biotin is an essential vitamin that is obtained through the diet and also efficiently recycled for further use. When this recycling mechanism does not work due to enzyme deficiency, patients experience significant morbidity and mortality. This condition is known as biotinidase deficiency, which is inherited in an autosomal recessive fashion.

Biotin acts as a coenzyme for four carboxylation enzymes in the body: 3-methylcrontonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC) and propionyl-CoA carboxylase (PCC). Biotinidase deficiency can be partial(10 to 30% of enzyme activity) or profound(less than 30% of enzyme activity), which has significant impacts on the treatment approach. Partial cases can have little or no symptoms. However, profound cases can lead to coma or death if treatment is not initiated rapidly.

Treatment is very straightforward as patients need consistent and high doses of biotin administered. This simple treatment can reverse many symptoms of the disease if initiated promptly. Therefore, early diagnosis and treatment can prevent developmental delay, disability, and improve quality of life.[1][2][3] This fact is a key reason that this disorder is part of many newborn screenings.


Biotinidase deficiency is inherited via an autosomal recessive pattern via two pathogenic variants in the BTD gene, located at chromosome 3p25.1.[1] BTD encodes for the biotinidase protein and enzyme, which recycles biotin, allowing the cofactor to become available to carboxylases.[4] Biotinidase converts biocytin into free biotin by removing a lysine group, thereby replenishing the biotin pool for further reactions. In the deficiency of biotin, carboxylase enzymes (MCC, ACC, PCC, PC) cannot properly catalyze reactions, leading to the accumulation of substrates, which causes significant toxicity and disease signs and symptoms.


Biotinidase deficiency is a rare disorder with an incidence ranging from 1 per 40,000 to 1 per 60,000 births worldwide. In 2006, the incidence of profound cases was 1:80,000, and the incidence of partial cases was from 1 per 31,000 to 1 per 40,000 in the US. The estimated carrier frequency is 1 in 123 individuals. The rates vary from country to country.[1][5][6]


Apocarboxylases transform into holocarboxylases through a catalytic reaction involving the attachment of biotin via the holocarboxylase synthetase enzyme. When holocarboxylases break down during proteolytic reactions, they release biotinyl-peptides and biocytin. Biotinidase then recycles biotin from biotinyl peptides and biocytin, making it available for carboxylases by increasing the free biotin pool. Biotinidase deficiency thus makes biotin unavailable for the four carboxylases, leading to blocks within the four pathways involving these key enzymes. Inefficient pyruvate carboxylase (PC) results in a buildup of lactic acid and alanine. Similarly, propionate, 3-OH propionate, and methyl citrate become increased in the body due to deficient propionyl-CoA carboxylase (PCC). 3-methylcrotonylglycine and 3-hydroxyisolerate accumulate as a result of inefficient 3-methylcrotonyl-CoA carboxylase (MCC). Lastly, acetyl-CoA carboxylase (ACC) deficiency leads to the accumulation of acetyl-CoA. Aggregation of these substrates leads to variable neurological and dermatological manifestations of the disease.[5][6]

History and Physical

Biotinidase deficiency falls into two categories: profound and partial. Individuals with <10% enzymatic activity when compared to normal have profound disease. Those with 10 to 30% enzymatic activity are classified and treated as partial biotinidase deficiency; this is very important both for prognosis and treatment.

Patients with profound biotinidase deficiency present in early infancy with variable neurological and cutaneous manifestations. The neurological manifestations include:

  1. Seizures
  2. Hypotonia
  3. Ataxia
  4. Visual impairment leading to optic atrophy
  5. Sensorineural hearing loss
  6. Developmental delay
  7. Spastic paresis
  8. Lethargy/coma
  9. Death[6]

Cutaneous manifestations include:

  1. Skin rash
  2. Alopecia
  3. Conjunctivitis
  4. Seborrheic dermatitis

Other manifestations include:

  1. Viral and fungal recurrent infections(due to immunological dysfunction).[5]
  2. Apnea, tachypnea or stridor
  3. Metabolic derangement – ketolactic acidosis, organic aciduria, and hyperammonemia

It is imperative to realize that all these symptoms are reversible with early detection and treatment with biotin. However, changes in vision, hearing loss, and developmental delay, if they occur, are irreversible.[7] Metabolic decompensation, coma, and death can result if patients are left untreated.[5]

Partial biotinidase deficiency can present from infancy to adulthood. The symptoms range from minor cutaneous reactions such as rash and alopecia to major neurological such as seizures, hypotonia, and developmental delay. Typically patients only have symptoms during periods of stress such as illness. Furthermore, some individuals never have symptoms of the disease.[5]


The diagnosis of biotinidase deficiency is made by newborn screening or testing patients with symptoms of the disease. Enzyme activity is measurable in serum/plasma. When enzyme levels are abnormal, genetic testing can be performed to evaluate for BTD pathogenic mutations.[8] 

Laboratory tests may show high levels of lactic acid and ammonia within the blood or urine. Brain MRI imaging usually shows cerebral atrophy and edema along with bilateral compensatory ventriculomegaly and delayed myelination in those who are untreated and in acute crisis.[9] Biotinidase deficiency should be ruled out in cases of recurrent fungal, viral, and skin infections.[1][10] 

Treatment / Management

The treatment for biotinidase deficiency is lifelong but relatively straight forward. 5 to 20 mg of biotin per day is the pharmacologic dose for patients with biotinidase deficiency. It takes a few hours to days for seizures and movement disorders to improve and some weeks for skin manifestations to improve.

Children with developmental delays may regain lost milestones or reach new milestones depending on the timing of treatment initiation and extent of damage already experienced due to a delayed diagnosis.[3] Treatment will also prevent further damage in patients with irreversible neurological damage.[11]

Differential Diagnosis

Biotinidase deficiency can mimic:

  1. Isolated carboxylase deficiency
  2. Dietary biotin deficiency
  3. Holocarboxylase synthetase deficiency
  4. Meningitis (seizures and rash)
  5. Primary immunodeficiency (fungal and bacterial infections)
  6. Sensorineural deafness
  7. Acrodermatitic enteropathica
  8. Autism (developmental delay and inattentiveness)
  9. Myelopathies
  10. Neumyelitis optica
  11. Optic atrophy[12]
  12. Seborrheic dermatitis[13]
  13. Infantile spasms


Biotinidase deficiency has a good prognosis when intervention is implemented early in those with profound disease. The prognosis for asymptomatic cases is good if they receive treatment before the symptoms appear. For symptomatic cases, pharmacological biotin therapy improves most of the clinical features but cannot reverse neurologic damage that has already occurred.[14]


If biotinidase deficiency is not detected early in infancy and is left untreated, it can lead to the following complications:

  1. Optic atrophy
  2. Acquired retinal dysplasia
  3. Sensorineural deafness[15]
  4. Developmental disability
  5. Paresis
  6. Metabolic derangement
  7. Hyperammonemia
  8. Organic aciduria
  9. Recurrent infections
  10. Coma
  11. Death


All of the following departments can work as a team to reach an early diagnosis and give prompt treatment for biotinidase deficiency:

  • Metabolic team/medical genetics
  • Neonatology
  • Nutrition
  • Pediatrics
  • Radiology
  • Neurology
  • Physiotherapy

Deterrence and Patient Education

It is important to emphasize to families that biotinidase deficiency requires lifelong and consistent treatment, given that it is a primary defect within the body’s ability to recycle biotin. Furthermore, complications are preventable by early diagnosis and management, but some complications are irreversible. Given that this disorder is inherited in an autosomal recessive fashion, families should receive counseling that the risk of having another child with biotinidase deficiency is 25% with each pregnancy with the same two partners.

Enhancing Healthcare Team Outcomes

Early diagnosis made by geneticists and neonatologists can prevent irreversible damage and complications in the child. Biochemical metabolite studies can confirm the diagnosis of biotinidase deficiency, and these measures are conducted on the newborn screen within the United States.

With the guidance of a medical geneticist, treatment should be implemented immediately and communicated to the primary care provider, such as a pediatrician, so that they are aware of the disorder and treatment plan. Radiologists may detect early brain changes in the child to help guide diagnosis when missed as well as differentiate it from similar brain and spinal cord diseases. When neurologic damage occurs, physiotherapists can provide therapies to help treat hypotonia and developmental disability.

Given the significant complications that can occur and the significantly improved outcomes with effective treatment, it is vital to understand that departments can work as a team to improve the clinical outcome and quality of life of an affected child.

Article Details

Article Author

Hira Saleem

Article Editor:

Brittany Simpson


8/8/2022 9:02:55 PM

PubMed Link:

Biotinidase Deficiency



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