Biotinidase Deficiency Clinical Presentation
- Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD more...
Partial biotinidase deficiency (10%-30% mean normal serum biotinidase activity) is associated with an increased risk of developing clinical symptoms that are similar to those seen in children who have a profound deficiency. However, symptom presentation appears to be correlated with metabolic stressors (eg, illness, fever, fasting), and these children may not be symptomatic or only mildly symptomatic until then.
Metabolic deterioration during stress can be a useful clue in diagnosing a partial deficiency, although this type of clinical decline does occur with other inborn errors of metabolism. If there is concern, laboratory studies that specifically measure biotinidase activity should be obtained. In addition, diagnostic clarification is further made with symptom response to biotin treatment.
Sudden death is reported in association with presumed biotinidase deficiency, possibly due to seizures and/or brain stem dysfunction. Therefore, the diagnosis of biotinidase deficiency should be considered when evaluating an infant who died from sudden infant death syndrome (SIDS), especially if there are family members who have possible clinical signs of partial biotinidase deficiency or are known to be heterozygous for a BTD gene mutation.
Clinical signs and symptoms of biotinidase deficiency vary. Consider biotinidase deficiency in patients who present with symptoms such as intractable seizures, hypotonia, spastic paraparesis, acidosis, unexplained visual loss or visual field loss, unexplained sensorineural hearing loss, alopecia, persistent rash, or failure to thrive.
In a retrospective study published in 1993, 38% of patients with biotinidase deficiency presented with seizures, often in combination with other clinical features indicative of biotinidase deficiency. Approximately 55% of these patients had seizures at some point during the clinical review period. Seizures were described as generalized, tonic-clonic, clonic or myoclonic. Infantile spasms were also reported.
Among patients with biotinidase deficiency, seizures or other neurologic manifestations (typically unresponsive to conventional therapies) quickly respond to pharmacologic doses of biotin. Most neurologic symptoms respond well to treatment with biotin; however, severe permanent neurologic sequelae can result from untreated biotinidase deficiency.
Other neurologic sequelae may include the following:
Auditory nerve dysfunction (sensorineural hearing loss)
Optic nerve atrophy and scotomata
Spastic paraparesis (an uncommon presentation)
Respiratory difficulties are common. Apnea, hyperventilation, and laryngeal stridor are observed. Stridor and breathing pattern abnormalities possibly result from dysfunction of medullary breathing centers affected by metabolic imbalance. Progression to other bulbar symptoms, such as swallowing difficulties, can occur.
Clinical manifestations, such as loss of hair color (achromotrichia), loss of hair (alopecia), and an eczematous, scaly perioral/facial rash, can be quite striking. The rash distribution is described as periorificial and can be mistaken for eczema, seborrheic dermatitis, or the dermatoses of zinc deficiency.
Abnormalities in cellular immunity can result from biotin deficiency. Chronic, potentially lethal fungal infections and recurrent viral infections characterize immunologic dysfunction. Immunologic dysfunction is ameliorated with proper biotin treatment.
Profound biotinidase deficiency can cause metabolic ketoacidosis or organic acidosis.
Conjunctivitis and/or sudden vision loss may be presenting signs. Comprehensive ophthalmologic examination by a trained ophthalmologist may reveal optic atrophy and scotomata (alteration in visual fields).
Hair and skin
Clinical findings such as achromotrichia, alopecia, and an eczematous scaly perioral/facial rash can be striking. The rash distribution is described as periorificial, indicating a propensity for the rash to affect areas surrounding body orifices. Rashes may be mistaken for eczema, seborrheic dermatitis, or the dermatoses observed in zinc deficiency. Recalcitrance to conventional treatments for these dermatoses should lead the medical provider to diagnostically consider an inborn error of metabolism, including biotinidase deficiency. Initiation of biotin treatment leads to clinical improvement of alopecia and the periorificial rash within days to months.
Causative explanations for the dermatologic findings may be abnormal fatty acid synthesis and metabolism, possibly secondary to carboxylase dysfunction. Chronic candidiasis may also develop (as part of immunologic dysfunction).
Infants may present with hypotonia and delay in developmental milestones. Older children may present with developmental delay and ataxia.
Twenty to 30% of symptomatic patients have sensorineural hearing loss. Of these patients, 76% of untreated children with profound biotinidase deficiency have sensorineural hearing loss that will not resolve or improve, but instead remains static, despite initiation of biotin treatment.
Visual loss with progressive optic neuropathy can develop in isolation or in association with spastic paraparesis. Treatment with biotin therapy has demonstrated resolution of ocular findings and improvement of spastic paraparesis.[23, 24]
Biotinidase deficiency is a genetic disorder that results from an autosomal-recessive Mendelian inheritance pattern. Both biological parents must contribute the biotinidase gene mutation for this deficiency to occur in offspring, as two altered gene copies are required. Biotinidase deficiency heterozygous carriers can be identified via mutation assay.
The gene that encodes biotinidase, called BTD, is cytogenetically located on the short arm (p) of chromosome 3, band 25.1 (3p25.1). The most common BTD mutation, 98_104del7ins3, is present in about 50% of symptomatic children. A less common BTD mutation, Arg538 R→C, has also been described. The BTD mutation known to cause partial deficiency is p.D444H.
As of 2012, Wolf has described 150 novel mutations of BTD. His research cites the difficulty of correlating genotypes with phenotypes, indicating that age at onset of clinical signs and the patient's disease path primarily depend on the amount of functioning biotinidase present.
Prenatal testing via BTD gene analysis can identify the causative mutation(s), identify carriers of a mutated gene, and diagnose biotinidase deficiency via mutation assay.
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