AUTHOR INFORMATION

Section 1 of 11

Authored by Marc P DiFazio, MD, Consulting Staff, Private Practice

Coauthored by Ronald G Davis, MD, MPH, FAAP, Assistant Professor, Department of Neurology, Division of Child and Adolescent Neurology, Children's Hospital of Boston and Harvard University Medical School

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

Edited by Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Marc P DiFazio, MD
Editor's Email:	Christian J Renner, MD

eMedicine Journal, March 29 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: Biotinidase is a ubiquitous mammalian cell enzyme occurring at high levels in the liver, serum, and kidney. The primary function is to cleave biotin from biocytin, preserving the pool of biotin for use as a cofactor for biotin dependent enzymes, namely the 4 human carboxylases.

Multiple carboxylase deficiency responsive to biotin administration was first described in 1971. Wolf and colleagues further characterized the infantile form of multiple carboxylase deficiency as biotinidase deficiency in the 1980s. The neonatal period is the usual period of presentation for multiple carboxylase deficiency, and the infantile form usually is due to biotinidase deficiency.

Disease caused by complete or partial absence of the enzyme is associated with a wide spectrum of clinical manifestations, including abnormalities of the neurological, dermatological, immunological, and ophthalmological systems. In spite of its rarity, early recognition is crucial because expeditious treatment may reverse all of its manifestations.

Pathophysiology: Biotin is an imidazole derivative found in many natural foods. Bacteria in the intestine synthesize large amounts of human biotin. It serves as a cofactor for human carboxylases, including pyruvate carboxylase, propionyl-coenzyme A (CoA) carboxylase, beta-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylase.

Biotin is covalently bound to these enzymes. Under normal conditions it undergoes proteolytic metabolism to biocytin or biotinyl peptides. Cleavage of these breakdown products results in restoration of free biotin for continued cofactor functioning. Biotinidase affects this cleavage and its absence or deficiency impairs this step causing a deficiency of free biotin and slowing the functioning of the biotin-dependent carboxylases. The carboxylases serve important roles in intermediary metabolism and impairment causes abnormalities in fatty acid synthesis, amino acid catabolism, and gluconeogenesis. These abnormalities may manifest in various clinical and laboratory findings, which are presented below.

Biotinidase deficiency typically accounts for the so-called late-onset multiple carboxylase deficiency. The early or neonatal onset of multiple carboxylase deficiency is more likely due to another biotin-responsive biochemical abnormality, holocarboxylase synthetase deficiency. This enzyme is responsible for covalently attaching biotin to the various apocarboxylases. The defect occurs in the Michaelis constant values of biotin, requiring greater amounts of free biotin to ensure binding.

Biotin dependency due to a novel inherited defect of biotin transport has recently been described. The underlying etiology of this defect remains unclear. Children with clinical and laboratory evidence of biotin deficiency who do not demonstrate a defect of biotinidase or holocarboxylase functioning may exhibit this presumably less common defect. This syndrome is also clinically responsive to biotin and may warrant empiric treatment of conditions that mimic biotinidase deficiency.

Frequency:

• In the US: The incidence of profound biotinidase deficiency is estimated at 1 per 137,401 population. The combined incidence of partial and profound deficiencies is 1 per 61,067 population. In Virginia in 1986, Heard and colleagues determined that neonatal screening was cost effective. Now screening for biotinidase deficiency is performed routinely in several states and around the world.

Age: Profound biotinidase deficiency ( <10% of normal serum enzyme activity) typically presents in the first 6 months of life, although presentation in the neonatal period or after the first decade occurs.

CLINICAL

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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 is varied. Consider biotinidase deficiency at presentation of intractable seizures, acidosis, rash, unexplained hearing 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
  
  
  
  • Biotinidase deficiency rarely presents as spastic paraparesis.
  
  
  
  • Although most symptoms respond well to administration of biotin, severe permanent neurological injury can result from untreated biotinidase deficiency.
  
  
  
  • Permanent ophthalmological and audiological injury recalcitrant to biotin therapy also is 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.
  
  
  

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.
  
  
  

Causes:

• The gene that encodes biotinidase is localized at 3p25.



• A common mutation, which is present in approximately one half of symptomatic children, has been identified.



• A second, less common mutation, Arg538 to Cys, also has been described.



• Wolf continues to describe novel mutations, with 17 reported in 2002. At that time, this group reiterated the difficulty in correlating genotypes with phenotypes, indicating that age at presentation and disease course depend primarily on residual enzyme functioning.

DIFFERENTIALS

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Other Problems to be Considered:

Consider sepsis, meningitis, or toxic exposure in a child who presents in extremis with intractable epilepsy or severe metabolic disruption.

If laboratory testing indicates hyperammonemia and/or acidosis, other inborn errors of metabolism are a possibility.

Neonatal-onset symptoms of biotinidase deficiency may be difficult to differentiate from holocarboxylase synthetase deficiency (see Pathophysiology) and also responds clinically to administration of biotin.

WORKUP

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Lab Studies:

• Upon presentation, obtain laboratory studies to determine if an inborn error of metabolism is present. These studies are detailed below.



• Illness or catabolic stress may cause metabolic disruption, and obtaining laboratory studies at that time may provide clues to the etiology of the disorder.



• Obtaining samples during the illness is important because these clues may disappear in the otherwise healthy child, especially in one with partial enzyme deficiency.



• Specific tests


• • Serum ammonia
  
  
  
  • Urine organic acids
  
  
  
  • Plasma amino acids
  
  
  
  • Urine ketones
  
  
  
  • Blood gas
  
  
  
  • Serum chemistries
  
  
  
  • Biotinidase, carnitine, and acylcarnitine profiles
  
  
  

Imaging Studies:

• MRI is the neuroimaging study of choice for the evaluation of a child with a possible inborn error of metabolism. Children with biotinidase deficiency may demonstrate cerebral edema, low attenuation of white matter signal, cerebral atrophy, and compensatory ventricular enlargement.



• Magnetic resonance spectroscopy also helps determine the functional metabolism of the brain. Some facilities have access to these techniques and using them may help to delineate the nature of the brain disorder in vivo.



• Positron emission tomography is used in an experimental setting to demonstrate the change in cerebral metabolic activity before and after biotin therapy.



• CT scan may demonstrate bilateral basal ganglia calcifications that may not be as readily demonstrated on MRI.

Other Tests:

• Ophthalmologic testing


• • An experienced ophthalmologist should perform a dilated funduscopic examination to evaluate for optic atrophy.
  
  
  
  • Visual field testing and visual evoked potentials may help to determine the degree of optic nerve injury in affected patients.
  
  
  
• Audiologic testing


• • Perform audiologic testing in all children, as hearing deficits in symptomatic children are common and can be persistent after treatment.
  
  
  
  • Brainstem auditory evoked potentials may help to delineate the abnormality in younger children or in developmentally delayed patients.
  
  
  
• Electroencephalography


• • EEG findings prior to treatment demonstrate poor organization of background and absence of typical sleep morphology.
  
  
  
  • Frequent focal spikes were observed in 1 child during the interictal period.
  
  
  
  • Ictal manifestations were well described in 1 report, demonstrating diffuse polyspike discharges at the onset of seizures (myoclonic) followed by the appearance of rhythmic diffuse spike and wave discharges during clinical manifestations of a generalized tonic-clonic seizure.
  
  
  
  • EEG findings are variable and may normalize completely after therapy.
  
  
  

TREATMENT

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Medical Care:

• Therapy for biotinidase deficiency is oral biotin, typically administered at an initial dose of 10 mg/d.



• Some patients require higher dosages. If the enzymatic defect is present but does not respond to lower dosages, consider a high-dose therapy (up to 40 mg/d).



• If children are left with residual neurological disease, they may require treatments for developmental delay, spasticity, and bulbar dysfunction in addition to biotin. Newer treatments for spasticity and dystonia associated with inborn errors of metabolism have been reported, including intrathecal baclofen and neurotoxins.

Consultations:

• An experienced child neurologist, metabolic specialist, or geneticist should assist in the workup and evaluation.



• A neurologist or a pediatrician skilled in the evaluation of a child who is neurologically impaired should perform follow-up examinations and procedures to document residual neurological injury.



• Children with residual neurologic injury that causes spasticity or dystonia should receive ongoing physical therapy to prevent long-term orthopedic deterioration.

MEDICATION

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Drug Category: Vitamins and cofactors -- Organic substances required by the body in small amounts for various metabolic processes. Used clinically for the prevention and treatment of specific deficiency states. Biotin is the DOC for biotinidase deficiency.

Drug Name	Biotin -- An essential coenzyme in fat metabolism and in other carboxylation reactions. Biotin deficiency may result in the urinary excretion of organic acids and changes in skin and hair. Functions as a coenzyme or a prosthetic group in all 4 of the body's carboxylases. Each of these carboxylases maintain critical roles in intermediary metabolism. In these enzymes, biotin serves as a carrier for CO2.
Adult Dose	10-40 mg/d PO
Pediatric Dose	6-40 mg/d PO
Contraindications	Documented hypersensitivity
Interactions	PO anticonvulsant medications may impair biotin absorption
Pregnancy	A - Safe in pregnancy
Precautions	None reported

FOLLOW-UP

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Complications:

• Failure to recognize and treat patients with biotinidase deficiency may lead to permanent neurological, ophthalmological, and audiological damage. Ultimately, death can occur. The importance of early recognition and treatment is emphasized by recent data that demonstrate that children identified based on newborn screening and treated before they exhibited clinical signs were healthy upon a subsequent examination. In the same study, children treated after the development of clinical signs of biotinidase deficiency were more likely to experience residual neurologic difficulties.



• Immunological disruption may result in fulminant fungal infections.

Prognosis:

• With treatment, patients have an excellent prognosis and potential for a normal lifestyle.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Due to the varied presentation in biotinidase deficiency and the potentially treatable nature, consider testing in children with unexplained seizures, encephalopathy, acidosis, optic atrophy, developmental delay, or paraparesis. Testing remains relatively inexpensive to perform.



• Because parents subsequently may have a similarly affected child, genetic counseling needs to be offered prior to pregnancy. Test all children for the deficiency.

TEST QUESTIONS

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CME Question 1: A 9-month-old and her parents present with persistent diaper rash as the chief symptom. Which other sign indicates biotinidase deficiency as a cause?

A: Failure to thrive on examination of growth curves due to persistent vomiting and gastroesophageal reflux
B: Sudden death of a 10-month-old sibling
C: Thinning hair
D: Increased resting respiratory rate
E: All of the above

The correct answer is E: Answers A, C, and D all may be characteristics of children with biotinidase deficiency. Answer B may provide a clue that a potentially lethal genetic disorder is present in other family members. Family history plays a pivotal role in deciding when to investigate further for inborn error of metabolism.

CME Question 2: Which of the following clinical scenarios suggests testing for biotinidase deficiency?

A: A 5-month-old girl with failure to thrive and new-onset infantile spasm
B: A 13-year-old adolescent with unexplained progressive optic atrophy and visual loss, now with gait disturbance
C: A 10-year-old child with ataxia, mild developmental delay, and a history of febrile seizures
D: A 3-year-old boy who was born at an overseas military facility has a history of seizures and developmental delay. Laboratory evaluation overseas included urine organic acid panel, plasma amino acid panel, and chemistries. All laboratory findings reportedly were within reference ranges. Results of neonatal metabolic screen are not available.
E: All of the above

The correct answer is E: Biotinidase deficiency may present with widely disparate manifestations, from the neonatal period through the second decade. Although initial manifestations outside the normal age of presentation (after the neonatal period in the first year) are rare, a high degree of suspicion should be maintained as treatment may arrest or ameliorate symptoms.

Pearl Question 1 (T/F): The biochemical function of biotinidase is to cleave biotin from the human carboxylases.

The correct answer is True: Biotinidase cleaves biotin from the biotin dependent carboxylases. Deficiency of free biotin results in enzymatic dysfunction and clinical symptoms.

Pearl Question 2 (T/F): Common neurological manifestations of biotinidase deficiency include seizures, ataxia, and auditory nerve dysfunction.

The correct answer is True: Seizures, developmental delay, ataxia, and, importantly, optic neuropathy and auditory nerve dysfunction all are important signs of biotinidase deficiency. Skin rash, paraparesis, and cortical atrophy also are observed with this biochemical defect.

Pearl Question 3 (T/F): Findings observed on neuroimaging in patients with biotinidase deficiency include basal ganglia calcifications.

The correct answer is True: The radiological findings also include cerebral atrophy, attenuation of white matter and symmetric hypointense lesions.

Pearl Question 4 (T/F): The appropriate dose of biotin for patients with biotinidase deficiency is 10 mg/d.

The correct answer is True: This is the appropriate initial dose and is sufficient for most patients; however, some patients may require higher doses, up to 40 mg/d.

BIBLIOGRAPHY

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