Biotinidase Deficiency

Etiology

Biotinidase deficiency is inherited via an autosomal recessive pattern via two pathogenic variants in the BTD gene, located at chromosome 3p25.1.[4] BTD encodes for the biotinidase protein and enzyme, which recycles biotin, allowing the cofactor to become available to carboxylases.[10] 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 correctly catalyze reactions, leading to the accumulation of substrates, which causes significant toxicity and disease signs and symptoms.

Epidemiology

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.[4][11][12]

In populations with more consanguinity, the incidence of biotinidase deficiency tends to be higher. This is observed in countries such as Turkey and the Kingdom of Saudi Arabia. Cowan et al. observed a higher incidence in Hispanic babies born in the western United States.[13] In contrast, a lower incidence has been reported in the African-American population. Today, newborn screening for biotinidase deficiency is routinely carried out in all US states and over 25 nations worldwide.[14][15]

Profound biotinidase deficiency typically manifests in the first six months of life, although there can be variation in the age of onset.[16][17] Symptoms can present from the first week of life to the age of 10 years, with the mean age being 3.5 months.

Pathophysiology

Biotin is a water-soluble B-complex vitamin. It is found in several food sources, such as milk, raw egg yolk, organ meats (liver, kidney), Swiss chard, leafy green vegetables, and brewer’s yeast. In addition, endogenous biotin is produced by colonic flora in the large intestine.

Apocarboxylase transforms into holocarboxylase through a catalytic reaction involving the attachment of biotin via the holocarboxylase synthetase enzyme. When holocarboxylase breaks down during proteolytic reactions, it releases 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:

1. Inefficient pyruvate carboxylase results in a buildup of lactic acid and alanine
2. Propionate, 3-OH propionate, and methyl citrate become increased in the body due to deficient propionyl-CoA carboxylase
3. 3-methylcrotonylglycine and 3-hydroxyisovalerate accumulate as a result of inefficient 3-methylcrotonyl-CoA carboxylase
4. Acetyl-CoA carboxylase deficiency leads to the accumulation of acetyl-CoA

Accumulation of these substrates leads to variable neurological and dermatological manifestations of the disease.[11][12]

Histopathology

The degree of pathologic central nervous system findings in patients with biotinidase deficiency varies based on the severity of the clinical condition before death. Features are similar to those found in Wernicke encephalopathy or Leigh syndrome, although the pathologic brain lesions appear more widespread. Myelin seems to be significantly affected as opposed to neurons or axonal processes. Necrotic lesions have been observed in the pons, hypothalamus, medulla, and hippocampus. Microscopically, affected areas show micro-cavitation, gliosis, and capillary proliferation. In addition, extensive cerebral edema may be seen in many major white matter tracts.

History and Physical

Biotinidase deficiency falls into two categories: profound and partial. Individuals with less than 10% enzymatic activity than normal have a profound disease. Those with 10 to 30% enzymatic activity are classified and treated as partial biotinidase deficiency; this distinction is crucial 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[18]
2. Hypotonia
3. Ataxia[19]
4. Visual impairment leading to optic atrophy
5. Sensorineural hearing loss
6. Developmental delay
7. Spastic paresis
8. Lethargy/coma
9. Death[12]

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)[11]
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.[20] Metabolic decompensation, coma, and death can result if patients are left untreated.[11]

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.[11]

Evaluation

The diagnosis of biotinidase deficiency is made by newborn screening or testing patients with disease symptoms. Enzyme activity is measurable in serum/plasma. When enzyme levels are abnormal, genetic testing can be performed to evaluate for BTD mutations.[21]

Laboratory tests may show high levels of lactic acid and ammonia within the blood or urine. Other tests to be done when biotinidase deficiency is suspected in a patient include arterial blood gas, serum amino acids, serum chemistries, etc. Urine tests may consist of urinary ketones and urinary organic acids.

Brain MRI imaging usually shows cerebral edema, bilateral compensatory ventriculomegaly, and delayed myelination in those who are untreated and in acute crisis.[22][23] Magnetic resonance spectroscopy (MRS) helps assess functional brain metabolism. It is not a widely available tool, but it may help characterize brain pathology's nature in vivo. A positron emission tomography (PET) scan demonstrates changes in cerebral metabolic activity before and after biotin administration. Computerized tomography (CT) scanning may reveal bilateral basal ganglia calcifications that could be skipped on an MRI scan.

Biotinidase deficiency should be ruled out in recurrent fungal, viral, and skin infections.[4][24] Electroencephalography (EEG) findings range from diffuse polyspike discharges to rhythmic diffuse spike and wave discharges, and they tend to normalize completely after biotin treatment. An ophthalmologist may perform a dilated fundoscopic examination to look for scotomata and optic nerve atrophy. Visual evoked potentials (VEPs) and visual field testing help delineate the extent of optic nerve injury in affected patients.

Treatment / Management

The treatment for biotinidase deficiency is lifelong but relatively straightforward. The recommended treatment is biotin replacement with a starting dose of 5 to 20 mg daily. However, it takes a few hours to days for seizures and movement disorders to improve and some weeks for skin manifestations to improve. Sometimes, this dose will not be adequate, and the clinical signs may persist. Increasing the dose to 40 mg/day is recommended in such scenarios.

Children with developmental delays may regain lost milestones or reach new milestones depending on the timing of treatment initiation and the extent of damage already experienced due to a delayed diagnosis.[6] Treatment will also prevent further damage in patients with irreversible neurological damage.[25]

In addition to oral biotin therapy, children with residual neurologic deficits may need medical interventions for spasticity, developmental delay, and bulbar dysfunction. Dystonia and spasticity may be treated with intrathecal baclofen and neurotoxins.[26](A1)

Differential Diagnosis

Biotinidase deficiency can mimic the following:

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. Acrodermatitis enteropathica
8. Autism (developmental delay and inattentiveness)
9. Myelopathies
10. Neuromyelitis optica
11. Optic atrophy[27]
12. Seborrheic dermatitis[28]
13. Infantile spasms

Prognosis

Biotinidase deficiency has a good prognosis with early intervention and continuance of care.[29] The prognosis for asymptomatic cases is good if they receive treatment before the symptoms appear. For symptomatic patients, pharmacological biotin therapy improves most clinical features but cannot reverse neurologic damage that has already occurred.[30]

Complications

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[31]
4. Developmental disability
5. Paresis
6. Metabolic derangement
7. Hyperammonemia
8. Organic aciduria
9. Recurrent infections
10. Coma
11. Death