Biotinidase Deficiency Clinical Presentation

  • Author: Ronald G Davis, MD, MPH, FAAP; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Mar 27, 2012
 

History

  • Partial biotinidase deficiency (10-30% of mean normal activity) is associated with an increased risk of developing the same symptoms that affect children with profound deficiency. However, the appearance of symptoms seems to be associated with metabolic stressors (eg, illness, fever, fasting), and children may not be symptomatic until such time.
    • This propensity to metabolic deterioration during stress may be a useful clue in the diagnosis of partial deficiency, although it also is a feature of other inborn errors of metabolism. Symptoms are likewise responsive to biotin administration.
    • Sudden death is reported in association with presumed biotinidase deficiency, possibly due to seizures or brain stem dysfunction. Therefore, include biotinidase deficiency in the evaluation of sudden infant death syndrome, especially when other family members have possible clinical manifestations of biotinidase deficiency.
    • The spectrum of clinical signs and symptoms varies. Consider biotinidase deficiency at presentation of intractable seizures, acidosis, rash, unexplained hearing[10] or visual loss, spastic paraparesis, or failure to thrive.
  • Seizures
    • In a recent retrospective study, 38% of patients with biotinidase deficiency presented with seizures, often in combination with other features of the disorder. Approximately 55% of these patients had seizures at some time during the period of review. Seizures most frequently were generalized, tonic-clonic or clonic, although myoclonic and infantile spasms were noted in a significant percentage.
    • Seizures and other manifestations typically are not responsive to conventional therapies but are rapidly responsive to pharmacological dosing of biotin.
  • Other neurological sequelae
    • Developmental delay
    • Ataxia
    • Neuropathy
    • Auditory nerve dysfunction
    • Spastic paraparesis: Biotinidase deficiency rarely presents as spastic paraparesis.
    • Severe injury: Although most symptoms respond well to administration of biotin, severe permanent neurological injury can result from untreated biotinidase deficiency.
    • Permanent ophthalmological and audiological injury: Permanent ophthalmological and audiological injury recalcitrant to biotin therapy is also reported.
  • Immunological deficiencies
    • Chronic and possibly lethal fungal infections characterize immunological deficiencies.
    • Cellular immunity abnormalities are possibly due to accumulation of toxic metabolites or biotin deficiency itself.
    • The immunological dysfunction is ameliorated with biotin treatment.
  • Breathing abnormalities
    • These are common and include apnea, hyperventilation, and laryngeal stridor.
    • Stridor and breathing pattern abnormalities are possibly due to dysfunction of medullary breathing centers affected by the metabolic disorder. This may lead to other bulbar symptoms, such as swallowing difficulties.
  • Metabolic abnormalities: Profound deficiency leads to metabolic ketoacidosis or organic acidosis.
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Physical

  • Eye: Perform a detailed ophthalmological examination to find evidence of optic atrophy.
  • Skin
    • Dermatological manifestations are particularly striking when they develop; these include alopecia and an eczematous, scaly perioral/facial rash. Distribution of the rash is described as periorificial, indicating a propensity to affect areas surrounding the body orifices. Rashes may be mistaken for eczema or zinc deficiency. For this reason, recalcitrance to conventional therapy for skin rashes should lead one to consider an inborn error of metabolism, including biotinidase deficiency.
    • Alopecia with loss of hair color also develops.
    • Intriguingly, these dermatological findings may be attributable to abnormal fatty acid synthesis and metabolism, possibly due to the secondary carboxylase dysfunction.
    • Although they may be severe, the rash and alopecia typically respond rapidly to biotin administration over days to months.
    • Chronic candidiasis may develop.
  • Neurodevelopmental effects
    • Hypotonia and developmental delay are manifestations in infancy.
    • Presentation in older children includes ataxia and developmental delay.
    • Optic atrophy and audiological deficits develop as isolated signs or in association with spastic paraparesis. As many as 20-30% of symptomatic patients have hearing loss.
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Causes

  • The gene that encodes biotinidase is localized at 3p25.
  • The most common mutation, 98-104del7ins3 (which is present in approximately one half of symptomatic children), has been identified.
  • A second, less common mutation, Arg538 R → C, has also been described.
  • Wolf continues to describe novel mutations, with 150 reported thus far.[11] At that time, this group reiterated the difficulty in correlating genotypes with phenotypes, indicating that age at presentation and disease course primarily depend on residual enzyme functioning.
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Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

Specialty Editor Board

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

Disclosure: Nothing to disclose.

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, New York

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

Disclosure: Genzyme Grant/research funds PI

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

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