History
Presentation depends on the etiology and severity of the deficiency.
Biotinidase deficiency is the most common etiology; in most developed countries including the US, newborn screening includes tests for biotinidase deficiency and the condition, therefore, is identified in a majority of individuals even before symptoms develop.
Impaired growth, skin, and hair changes and neurological problems are common in individuals with profound biotinidase deficiency (< 10% normal serum biotinidase activity) who are diagnosed late or are untreated. Individuals with partial biotinidase deficiency (10-30% of normal serum biotinidase activity) usually become symptomatic only during periods of stress, such as an infection.
Most individuals with untreated profound biotinidase deficiency develop symptoms in early infancy (mean age 3.5 months); however some may develop it as early as one week of life, and others may remain asymptomatic until adolescence. Some individuals present with a single finding and others present with multiple findings.
The first symptoms are usually associated with the skin and hair [29] and may include:
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Dry skin
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conjunctivitis
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Seborrheic dermatitis
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Fungal infections, especially candidiasis.
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scaly, red rash, around eyes, nose, mouth, and perineum
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Fine and brittle hair
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brittle nails
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Hair loss or total alopecia
If undiagnosed and left untreated neurologic symptoms begin to develop. [13, 30, 31, 32, 33, 34, 35, 36] The most common neurologic findings include the following:
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hypotonia, motor, weakness, and lethargy
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ataxia and developmental delay
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Mild depression, which may progress to profound lassitude and, eventually, to somnolence and coma
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Changes in mental status
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Generalized muscular pains (myalgias)
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hallucinations
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Hyperesthesias and paresthesias
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seizures (commonly myoclonic, grand mal and focal seizures as well as infantile spasms)
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progressive spastic paresis and myelopathy
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Optic atrophy
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Sensorineural hearing loss may develop in 75% of untreated infants with profound biotinidase deficiency. [24]
Intestinal tract symptoms also develop and most commonly include the following:
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Nausea, occasionally severe
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Vomiting
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Anorexia
Respiratory symptoms include stridor, apnea and hyperventilation.
Metabolic problems include organic aciduria, ketolactic acidosis, and mild hyperammonemia. [37] In severe cases, especially with profound untreated biotinidase deficiency, coma and death may ensue.
Holocarboxylase synthetase deficiency may present as early as during fetal life with intrauterine growth retardation and abnormal CNS findings. [38]
Physical
Physical manifestations usually involve the skin and hair, central and peripheral nervous systems, and intestinal tract.
Skin and hair
The first signs that develop in biotin deficiency are associated with the skin and hair. Dry skin is a consistent finding and is often associated with seborrheic dermatitis, which can be severe. The skin lesions provide an ideal environment for fungal infections that may be resistant to treatment until the biotin-deficient state is reversed. An erythematous periorofacial macular rash is a common finding and may be confused with the rash seen with zinc deficiency. The hair quickly becomes fine and brittle, and total alopecia often develops. [29]
Hearing
Individuals with untreated biotinidase deficiency develop sensorineural hearing loss. [31] [24] The hearing loss varies in severity from mild to profound.
Central and peripheral nervous systems
The neurologic signs are multiple [30, 31] and nonspecific. With untreated, profound biotinidase deficiency seizures [34] and hypotonia are common. [24] Progressive spastic paresis, myelopathy, encephalopathy, ataxia, and developmental delay may also occur. Occasionally, changes in mental status are observed. They include mild depression, which may progress to profound lassitude, and, eventually, somnolence. Generalized muscular pains (myalgias), hyperesthesias, and paresthesias are common findings that occasionally become disabling. Profound biotinidase deficiency in a 3-year-old boy with progressive spastic paraparesis and ascending weakness but not the typical neurological symptoms was noted by Chedrawi et al. [32] Biotinidase deficiency with hypertonia was noted by Rathi and Rathi. [33]
Intestinal tract
Nausea, occasionally severe, is an occasional finding, as is anorexia. These problems are rarely severe enough to significantly interfere with the adequate oral intake of food.
Physical Examination
Once biotin deficiency has been confirmed, physical exam should be focused on evaluating the extent and severity of the disease and should include a detailed neurological exam, developmental assessment (if appropriate), visual and hearing assessment.
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Biotin is a bicyclic (more precisely, heterocyclic) compound composed of an ureido ring (A) fused with a tetrahydrothiophene ring (B). A valeric acid substituent is attached to one of the carbon atoms of the tetrahydrothiophene ring.
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Carboxybiotin carboxylase is the activated form of a carboxylase that conducts the actual carboxylation of a substrate. The CO2 residue attached to the nitrogen atom diagonally across from the valeric acid substituent is transferred to the substrate to be carboxylated, and the original carboxylase is liberated intact.
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Depiction of the flow of biotin in the biotin cycle.
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Biocytin is the product of the complete proteolysis of biotin-containing proteins and peptides. The enzyme biotinidase cleaves biocytin into free biotin and the amino acid lysine. The free biotin is then available for intestinal absorption or intracellular coupling to an apocarboxylase to form a holocarboxylase.
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The biotin molecule is bound to the protein by a peptide bond to an e-amino group of an apocarboxylase to form a holocarboxylase.
