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Biotinidase Deficiency Clinical Presentation

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
 
Updated: May 06, 2016
 

History

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),[19] 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.[20]

Neurologic sequelae

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.[21]

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:

  • Developmental delay
  • Ataxia
  • Neuropathy
  • Auditory nerve dysfunction (sensorineural hearing loss)
  • Optic nerve atrophy and scotomata
  • Spastic paraparesis (an uncommon presentation)

Respiratory abnormalities

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.

Hair/Dermatoses

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.

Immunologic dysfunction

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.

Metabolic abnormalities

Profound biotinidase deficiency can cause metabolic ketoacidosis or organic acidosis.

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Physical

Eye

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).

Neurodevelopmental abnormalities

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.[22]

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]  

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Causes

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.[13]

As of 2012, Wolf has described 150 novel mutations of BTD.[25] 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.[1]

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Contributor Information and Disclosures
Author

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Acknowledgements

Ronald G Davis, MD, MPH, FAAP Assistant Clinical Professor, Child Neurology, Florida State University; Owner and Medical Director of Pediatric Neurology, PA and Pediatric Neurology Epilepsy Center of Central Florida; Medical Director of Epileptology, Arnold Palmer Hospital for Women and Children in Orlando, Florida; Medical Director, Central Florida Muscular Dystrophy Association Clinic

Ronald G Davis, MD, MPH, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose. Marc P DiFazio, MD Associate Professor, Department of Neurology, Uniformed Services University of the Health Sciences; Director, Pediatric Subspecialty Services, Shady Grove Adventist Hospital for Children

Marc P DiFazio, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Cerebral Palsy and Developmental Medicine, American Academy of Neurology, Child Neurology Society, and Movement Disorders Society

Disclosure: Nothing to disclose.

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