Biotinidase deficiency (BTD) is inherited via an autosomal recessive pattern via two pathogenic variants in the BTD gene, located at chromosome 3p25.1. BTD encodes for the biotinidase protein and enzyme, which recycles biotin, allowing the cofactor to become available to carboxylases.[rx] BTD affects the way the body processes a vitamin called biotin (sometimes called vitamin H). Biotin deficiency affects the activity of biotin-dependent carboxylases. These carboxylases facilitate various metabolic reactions such as gluconeogenesis, fatty acid synthesis, and amino acid metabolism. Biotin is an important vitamin that helps the body break down protein, fats, and carbohydrates. Biotinidase is an enzyme that helps recycle biotin to be reused by the body. Biotinidase deficiency happens when this enzyme isn’t working properly. BTD is caused by genetic changes (mutations) in the BTD gene.
Biotin (B7 or vitamin H) is a water-soluble vitamin, which has received publicity for promoting the growth of hair and nails. Biotin also acts as a coenzyme for multiple carboxylases in humans, and it changes the irreversible carboxylation of acetyl-CoA to malonyl-CoA.[rx] These enzymes are vital in numerous metabolic processes. Recently, the new roles of biotin have been acknowledged, in particular, the roles in cell signaling and epigenetic regulation.[rx] Biotin’s mechanism of action occurs by attaching to specific lysine residues.[rx] Biotinidase deficiency is uncommon but has been documented. Frank deficiency of biotinidase may present as conjunctivitis, ataxia, seizure, skin infections, and developmental delay in children.[rx] Biotin may have benefits in those suffering from pathologic brittle hair syndrome or uncombable hair syndrome.[rx][rx] 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).
If untreated, BTD can cause health problems such as:
- Seizures
- Muscle weakness (hypotonia)
- Problems with controlling body movements (ataxia)
- Developmental delay
- Problems with vision and hearing
BTD can have other features as well, including skin differences like rashes (eczema) and hair loss (alopecia). BTD can be treated by giving people with the condition extra biotin for their body to use. If treated early, people with BTD can avoid all symptoms of the condition and lead a normal, healthy life.
Biotinidase deficiency is sometimes categorized into groups depending on how much of the biotinidase enzyme is working. These two categories are profound BTD and partial BTD. People with profound BTD tend to have more severe symptoms earlier in life than people with partial BTD. Both forms of BTD can be treated with biotin supplements. Early diagnosis and treatment of BTD can prevent symptoms from happening. Nearly all infants with either profound or partial BTD can be detected in the US by newborn screening. However, not every country has added BTD to its newborn screening program.
Symptoms
Infants with BTD may be born without signs of the condition. Symptoms of BTD usually appear after the first few weeks or months of life. Treating BTD with biotin supplements before symptoms show up can prevent them from happening. Below is a list of symptoms that infants and children with profound untreated BTD may have. It is important to know that not every person with BTD will show all of these symptoms.
Many of the symptoms of BTD are neurological, which means they affect the brain and nervous system.
About 70% of infants with BTD will experience seizures if they are not treated. This is often the first symptom of the condition. Seizures in infants may look different than seizures in adults. Some signs of seizures in infants include:
- Staring spells
- Jerking arm or leg movements
- Stiffening of the body
- Flickering of the eyelids
Because the seizures are caused by the body being unable to recycle biotin, they may not stop with seizure medications (anticonvulsants). However, the seizures do respond to biotin therapy and often should stop within minutes to hours of receiving biotin treatment.
Some infants with BTD may have weak muscles and low muscle tone. This is called hypotonia. Infants with hypotonia may look abnormally “floppy.” Hypotonia can affect feeding and motor skills such sitting up without assistance.
Affected infants and children may experience delays in reaching developmental milestones, including holding one’s head up or pulling up to stand.
Infants with BTD may also have problems with vision or hearing. These issues can be prevented if biotin therapy is started early.
Some other common features of BTD include eye infections, like pink eye (conjunctivitis), hair loss (alopecia), and a certain type of skin rash called eczema.
Infants with BTD may have specific molecules in their urine, such as lactic acid (lactic aciduria) or low but noticeable amounts of ammonia.
Some infants may have other symptoms like:
- Trouble controlling their body’s movements (ataxia)
- Breathing problems
- Drowsiness (lethargy)
- Enlarged liver (hepatomegaly)
- Enlarged spleen (splenomegaly)
- Speech problems.
Without treatment with biotin, infants with BTD can develop coma and may even die.
Children and adults with partial biotinidase who don’t receive biotin supplements may show mild symptoms of the condition during times of stress, like times of illness.
Causes
Biotinidase deficiency is a genetic disorder caused by changes (mutations) in the BTD gene. The BTD gene instructs the body in creating the enzyme biotinidase that helps the body recycle an important vitamin called biotin (vitamin H). When the body is not able to recycle biotin, health concerns like the symptoms above can happen. 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.
We all have two copies of every gene. We inherit one copy from out mother and one copy from our father. Genetic diseases are determined by the combination of genes received from our father and mother. Biotinidase deficiency is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same non-working gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
There are many causes of biotin deficiency. It can occur in rare inborn errors of metabolism, namely holocarboxylase synthetase deficiency or biotinidase deficiency.[rx][rx] Biotinidase deficiency is an autosomal recessive disorder. It can present as severe biotin deficiency with both neurological and dermatological features. It affects endogenous recycling and failure in releasing biotin from dietary protein. This affects the activity of 5 carboxylases that depends on biotin.[rx][rx] Gastrointestinal tract bacterial imbalances resulting from broad-spectrum antibiotics or inflammatory bowel disease can affect biotin synthesis in the intestine and thus lead to biotin deficiency.
Biotin deficiency can also occur in patients on parenteral nutrition without added biotin.[rx][rx][rx] Therefore, recommended daily dose of biotin must be added to total parental nutrition (TPN), particularly if TPN therapy is likely to be given for more than a week. Currently, all hospital pharmacies add biotin to TPN preparations.[rx][rx]
Low Biotin levels can occur in patients on antiepileptics such as carbamazepine, phenytoin, and phenobarbital. Possible underlying mechanisms include impaired biotin uptake across the intestinal mucosa, exaggerated biotin catabolism, and inhibition of renal reabsorption. Therefore, patients who are likely to be on anticonvulsants for long periods should receive biotin supplementation.[rx][rx]
Prolonged use of oral antibiotics may also lead to biotin deficiency. The most likely underlying mechanism is the inhibition of intestinal flora, leading to reduced biotin production. Another possible explanation is the bacterial infections. সহজ বাংলা: ব্যাকটেরিয়ার সংক্রমণের ওষুধ।" data-rx-term="antibiotic" data-rx-definition="An antibiotic is a medicine used to treat bacterial infections. সহজ বাংলা: ব্যাকটেরিয়ার সংক্রমণের ওষুধ।">antibiotic-driven overgrowth of biotin-consuming bacteria.[rx]
Likewise, low biotin levels can occur in patients on isotretinoin for acne treatment, elderly individuals, people with alcohol use disorder, and smokers (particularly women).[rx] Some studies have found biotin deficiency in a large percentage of pregnant and lactating women. Some experts argue that there can be teratogenic effects of decreased biotin levels, and a higher intake of biotin should be advised to pregnant women.[rx]
Reports exist of biotin deficiency in severely malnourished children in developing countries and through the intake of modified milk without biotin supplementation. Biotin deficiency has been observed in infants consuming hypoallergenic formulas.[rx]
Consuming large amounts of raw egg whites can lead to acquired biotin deficiency. Raw egg contains the glycoprotein avidin. Avidin binds to biotin in the gastrointestinal tract and prevents biotin absorption, also known as “egg white injury.”[rx][rx][rx][rx]
Diagnosis
Biotinidase deficiency can be diagnosed in newborns through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has the disease. Often, a repeat test must be done to confirm the diagnosis. A clinical diagnosis is possible after birth by testing for biotinidase activity in the blood. Usually, this is performed when signs and symptoms of BTD become clearer. In some infants, a genetic test may be ordered to identify the specific gene changes (mutation) that are causing BTD. Prenatal testing of sample fluid from the womb for biotinidase activity is available as early as 12 weeks of pregnancy (this includes chorionic villi sampling and amniocentesis).
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:
- Seizures
- Hypotonia
- Ataxia
- Visual impairment leading to optic atrophy
- Sensorineural hearing loss
- Developmental delay
- Spastic paresis
- Lethargy/coma
- Death[rx]
Cutaneous manifestations include:
- Skin rash
- Alopecia
- Conjunctivitis
- Seborrheic dermatitis
Other manifestations include:
- Apnea, tachypnea or stridor
- 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.[rx] Metabolic decompensation, coma, and death can result if patients are left untreated.[rx]
Biotinidase enzyme activity in serum. The working group of the American College of Medical Genetics Laboratory Quality Assurance Committee has established technical standards and guidelines for the diagnosis of biotinidase deficiency [Cowan et al 2010].
- Profound biotinidase deficiency: <10% mean normal serum biotinidase activity
- Partial biotinidase deficiency: 10%-30% of mean normal serum biotinidase activity
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.[rx]
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.[rx]
Laboratory tests may show high levels of lactic acid and ammonia in 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.[rx] Biotinidase deficiency should be ruled out in cases of recurrent fungal, viral, and skin infections.[rx][rx]
Biotinidase deficiency confirmation is done by DNA analysis, either allele-targeted methods or full-gene sequencing. Currently, all newborn screening programs in the U.S. and more than 30 other countries carry out screening for biotinidase deficiency.[rx][rx][rx][rx]
Various MRI changes have been reported in individuals with biotinidase deficiency.[rx][rx] Desai et al. noted MRI findings in four patients and observed:
- Encephalopathy
- Low cerebral volume
- Ventriculomegaly
- Widened extracerebral cerebrospinal fluid spaces
Treatment
Biotinidase deficiency is treated with oral biotin (vitamin H; coenzyme R, part of the vitamin B complex) supplements. Treatment should begin as soon as the diagnosis is made. With biotin treatment, symptoms of the disorder may disappear. However, a person with biotinidase deficiency may have to take biotin for his/her entire lifetime.
The treatment for biotinidase deficiency is lifelong but relatively straightforward. 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.
Oral biotin supplements have high bioavailability. Usually, a dose of 5 mg/day is given regardless of the etiology of biotin deficiency.[rx] The Food and Nutrition Board of the National Research Council recommends a range of 5 mcg/day in newborn infants to 35 mcg/day in lactating women.
Practitioners should be aware that biotin requirements may increase during anticonvulsant therapy.[rx] In biotinidase deficiency, patient therapy typically consists of lifelong doses of biotin. Biotin doses in the range of 5 to 20 mg can treat and prevent clinical signs and biotinidase deficiency symptoms.[rx][rx]
In the cases of holocarboxylase synthetase deficiency detected antenatally, antenatal biotin treatment has been found to be very useful.[rx]
Genetic counseling is recommended for families of a child with biotinidase deficiency. Genetic counselors are healthcare providers that help families understand genetic conditions and make genetic testing decisions.
References
