Biotinidase Deficiency

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Continuing Education Activity

Biotin acts as a coenzyme for four carboxylation enzymes in the body: 3-methylcrotonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC), and propionyl-CoA carboxylase (PCC). Biotinidase is an enzyme present abundantly in the serum, kidneys, and liver. Biotinidase deficiency can be partial (10 to 30% of enzyme activity) or profound (less than 30% of enzyme activity), significantly impacting the treatment approach. Partial cases can have little or no symptoms. However, profound cases can lead to coma or death if treatment is not initiated rapidly. This activity reviews the evaluation and treatment of biotinidase deficiency and highlights the interprofessional team's role in managing and improving care for patients with this condition.

Objectives:

  • Identify the etiology of biotinidase deficiency.
  • Review the approach used in the evaluation of a patient with biotinidase deficiency.
  • Outline the management options available for biotinidase deficiency.
  • Describe interprofessional team strategies for improving care coordination and communication to improve outcomes in patients with biotinidase deficiency.

Introduction

Vitamins are vital components of every individual’s day-to-day chemical reactions and molecular processes. They are cofactors for reactions, antioxidants, hormones, and even vision. Vitamin deficiencies can be acquired by a lack of adequate environmental supplies or due to abnormal vitamin processing within intracellular pathways. Biotin is an essential vitamin obtained through the diet and efficiently recycled for further use. When this recycling mechanism does not work due to enzyme deficiency, patients experience significant morbidity and mortality. This condition, known as biotinidase deficiency, is inherited in an autosomal recessive fashion.

Biotin acts as a coenzyme for four carboxylation enzymes in the body: 3-methylcrotonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC), and propionyl-CoA carboxylase (PCC). Biotinidase deficiency can be partial (10 to 30% of enzyme activity) or profound (less than 10% of enzyme activity), which significantly impacts the treatment approach. Partial cases can have little or no symptoms. However, profound cases can lead to coma or death if treatment is not initiated rapidly. Biotinidase deficiency has varying clinical manifestations, affecting ophthalmologic, neurologic, dermatologic, and immunologic systems.[1][2] Early recognition is critical as expeditious treatment could prevent or minimize clinical insult.[3]

Treatment is very straightforward as patients need consistent and high doses of biotin administered. This simple treatment can reverse many symptoms of the disease if initiated promptly. Therefore, early diagnosis and treatment can prevent developmental delay and disability and improve quality of life.[4][5][6] This is a key reason that this disorder is part of many newborn screenings.

The role of biotin in treating carboxylase deficiencies was first studied around 40 years ago. In 1971, patients with beta-methylcrotonylglycinuria, a carboxylase deficiency, clinically responded to biotin supplementation.[7] Ten years later, Wolf et al. further observed a neonatal type of multiple carboxylase deficiency because of biotin deficiency.[8][9]

Etiology

Biotinidase deficiency is inherited via an autosomal recessive pattern via two pathogenic variants in the BTD gene, located at chromosome 3p25.1.[4] BTD encodes for the biotinidase protein and enzyme, which recycles biotin, allowing the cofactor to become available to carboxylases.[10] Biotinidase converts biocytin into free biotin by removing a lysine group, thereby replenishing the biotin pool for further reactions. In the deficiency of biotin, carboxylase enzymes (MCC, ACC, PCC, PC) cannot correctly catalyze reactions, leading to the accumulation of substrates, which causes significant toxicity and disease signs and symptoms.

Epidemiology

Biotinidase deficiency is a rare disorder with an incidence ranging from 1 per 40,000 to 1 per 60,000 births worldwide. In 2006, the incidence of profound cases was 1:80,000, and the incidence of partial cases was from 1 per 31,000 to 1 per 40,000 in the US. The estimated carrier frequency is 1 in 123 individuals. The rates vary from country to country.[4][11][12]

In populations with more consanguinity, the incidence of biotinidase deficiency tends to be higher. This is observed in countries such as Turkey and the Kingdom of Saudi Arabia. Cowan et al. observed a higher incidence in Hispanic babies born in the western United States.[13] In contrast, a lower incidence has been reported in the African-American population. Today, newborn screening for biotinidase deficiency is routinely carried out in all US states and over 25 nations worldwide.[14][15]

Profound biotinidase deficiency typically manifests in the first six months of life, although there can be variation in the age of onset.[16][17] Symptoms can present from the first week of life to the age of 10 years, with the mean age being 3.5 months.

Pathophysiology

Biotin is a water-soluble B-complex vitamin. It is found in several food sources, such as milk, raw egg yolk, organ meats (liver, kidney), Swiss chard, leafy green vegetables, and brewer’s yeast. In addition, endogenous biotin is produced by colonic flora in the large intestine.

Apocarboxylase transforms into holocarboxylase through a catalytic reaction involving the attachment of biotin via the holocarboxylase synthetase enzyme. When holocarboxylase breaks down during proteolytic reactions, it releases biotinyl-peptides and biocytin. Biotinidase then recycles biotin from biotinyl-peptides and biocytin, making it available for carboxylases by increasing the free biotin pool. Biotinidase deficiency thus makes biotin unavailable for the four carboxylases, leading to blocks within the four pathways involving these key enzymes:

  1. Inefficient pyruvate carboxylase results in a buildup of lactic acid and alanine
  2. Propionate, 3-OH propionate, and methyl citrate become increased in the body due to deficient propionyl-CoA carboxylase
  3. 3-methylcrotonylglycine and 3-hydroxyisovalerate accumulate as a result of inefficient 3-methylcrotonyl-CoA carboxylase
  4. Acetyl-CoA carboxylase deficiency leads to the accumulation of acetyl-CoA

Accumulation of these substrates leads to variable neurological and dermatological manifestations of the disease.[11][12]

Histopathology

The degree of pathologic central nervous system findings in patients with biotinidase deficiency varies based on the severity of the clinical condition before death. Features are similar to those found in Wernicke encephalopathy or Leigh syndrome, although the pathologic brain lesions appear more widespread. Myelin seems to be significantly affected as opposed to neurons or axonal processes. Necrotic lesions have been observed in the pons, hypothalamus, medulla, and hippocampus. Microscopically, affected areas show microcavitation, gliosis, and capillary proliferation. In addition, extensive cerebral edema may be seen in many major white matter tracts.

History and Physical

Biotinidase deficiency falls into two categories: profound and partial. Individuals with less than 10% enzymatic activity than normal have a profound disease. Those with 10 to 30% enzymatic activity are classified and treated as partial biotinidase deficiency; this distinction is crucial for prognosis and treatment.

Patients with profound biotinidase deficiency present in early infancy with variable neurological and cutaneous manifestations. The neurological manifestations include:

  1. Seizures[18]
  2. Hypotonia
  3. Ataxia[19]
  4. Visual impairment leading to optic atrophy
  5. Sensorineural hearing loss
  6. Developmental delay
  7. Spastic paresis
  8. Lethargy/coma
  9. Death[12]

Cutaneous manifestations include:

  1. Skin rash
  2. Alopecia
  3. Conjunctivitis
  4. Seborrheic dermatitis

Other manifestations include:

  1. Viral and fungal recurrent infections (due to immunological dysfunction)[11]
  2. Apnea, tachypnea, or stridor
  3. Metabolic derangement – ketolactic acidosis, organic aciduria, and hyperammonemia

It is imperative to realize that all these symptoms are reversible with early detection and treatment with biotin. However, changes in vision, hearing loss, and developmental delay, if they occur, are irreversible.[20] Metabolic decompensation, coma, and death can result if patients are left untreated.[11]

Partial biotinidase deficiency can present from infancy to adulthood. The symptoms range from minor cutaneous reactions such as rash and alopecia to major neurological such as seizures, hypotonia, and developmental delay. Typically patients only have symptoms during periods of stress, such as illness. Furthermore, some individuals never have symptoms of the disease.[11]

Evaluation

The diagnosis of biotinidase deficiency is made by newborn screening or testing patients with disease symptoms. Enzyme activity is measurable in serum/plasma. When enzyme levels are abnormal, genetic testing can be performed to evaluate for BTD mutations.[21]

Laboratory tests may show high levels of lactic acid and ammonia within the blood or urine. Other tests to be done when biotinidase deficiency is suspected in a patient include arterial blood gas, serum amino acids, serum chemistries, etc. Urine tests may consist of urinary ketones and urinary organic acids.

Brain MRI imaging usually shows cerebral edema, bilateral compensatory ventriculomegaly, and delayed myelination in those who are untreated and in acute crisis.[22][23] Magnetic resonance spectroscopy (MRS) helps assess functional brain metabolism. It is not a widely available tool, but this may help characterize the nature of brain pathology in vivo. A positron emission tomography (PET) scan demonstrates changes in cerebral metabolic activity before and after biotin administration. Computerized tomography (CT) scanning may reveal bilateral basal ganglia calcifications that could be skipped on an MRI scan.

Biotinidase deficiency should be ruled out in recurrent fungal, viral, and skin infections.[4][24] Electroencephalography (EEG) findings range from diffuse polyspike discharges to rhythmic diffuse spike and wave discharges, and they tend to normalize completely after biotin treatment. An ophthalmologist may perform a dilated fundoscopic examination to look for scotomata and optic nerve atrophy. Visual evoked potentials (VEPs) and visual field testing help delineate the extent of optic nerve injury in affected patients.

Treatment / Management

The treatment for biotinidase deficiency is lifelong but relatively straightforward. The recommended treatment is biotin replacement with a starting dose of 5 to 20 mg daily. However, it takes a few hours to days for seizures and movement disorders to improve and some weeks for skin manifestations to improve. Sometimes, this dose will not be adequate, and the clinical signs may persist. Increasing the dose up to 40 mg/day is recommended in such scenarios.

Children with developmental delays may regain lost milestones or reach new milestones depending on the timing of treatment initiation and the extent of damage already experienced due to a delayed diagnosis.[6] Treatment will also prevent further damage in patients with irreversible neurological damage.[25]

In addition to oral biotin therapy, children with residual neurologic deficits may need medical interventions for spasticity, developmental delay, and bulbar dysfunction. Dystonia and spasticity may be treated with intrathecal baclofen and neurotoxins.[26]

Differential Diagnosis

Biotinidase deficiency can mimic the following:

  1. Isolated carboxylase deficiency
  2. Dietary biotin deficiency
  3. Holocarboxylase synthetase deficiency
  4. Meningitis (seizures and rash)
  5. Primary immunodeficiency (fungal and bacterial infections)
  6. Sensorineural deafness
  7. Acrodermatitis enteropathica
  8. Autism (developmental delay and inattentiveness)
  9. Myelopathies
  10. Neuromyelitis optica
  11. Optic atrophy[27]
  12. Seborrheic dermatitis[28]
  13. Infantile spasms

Prognosis

Biotinidase deficiency has a good prognosis with early intervention and continuance of care.[29] The prognosis for asymptomatic cases is good if they receive treatment before the symptoms appear. For symptomatic patients, pharmacological biotin therapy improves most clinical features but cannot reverse neurologic damage that has already occurred.[30]

Complications

If biotinidase deficiency is not detected early in infancy and is left untreated, it can lead to the following complications:

  1. Optic atrophy
  2. Acquired retinal dysplasia
  3. Sensorineural deafness[31]
  4. Developmental disability
  5. Paresis
  6. Metabolic derangement
  7. Hyperammonemia
  8. Organic aciduria
  9. Recurrent infections
  10. Coma
  11. Death

Consultations

All of the following departments can work as a team to reach an early diagnosis and give prompt treatment for biotinidase deficiency:

  • Metabolic team/medical genetics
  • Neonatology
  • Nutrition
  • Pediatrics
  • Radiology
  • Neurology
  • Physiotherapy

In the pediatric population, a pediatric neurologist, geneticist, and metabolic disorder specialist could collaborate in evaluating and managing a patient with biotinidase deficiency.[32]

Deterrence and Patient Education

It is important to emphasize to families that biotinidase deficiency requires lifelong and consistent treatment, given that it is a primary defect within the body’s ability to recycle biotin. Furthermore, complications are preventable by early diagnosis and management, but some complications are irreversible. Finally, given that this disorder is inherited in an autosomal recessive fashion, families should receive counseling that the risk of having another child with biotinidase deficiency is 25% with each pregnancy with the same two partners.

Enhancing Healthcare Team Outcomes

Early diagnosis made by geneticists and neonatologists can prevent irreversible damage and complications in the child. In addition, biochemical metabolite studies can confirm the diagnosis of biotinidase deficiency, and these measures are conducted on the newborn screen within the United States.

With the guidance of a medical geneticist, treatment should be implemented immediately and communicated to the primary care provider or a pediatrician so that they are aware of the disorder and treatment plan. Radiologists may detect early brain changes in the child to help guide diagnosis when missed and differentiate it from the similar brain and spinal cord diseases. When neurologic damage occurs, physiotherapists can provide therapies to help treat hypotonia and developmental disability.

Given the significant complications that can occur and the significantly improved outcomes with effective treatment, it is vital to understand that departments can work as a team to improve the clinical outcome and quality of life of an affected child.


Article Details

Article Author

Hira Saleem

Article Editor:

Brittany Simpson

Updated:

11/27/2022 5:51:28 PM

PubMed Link:

Biotinidase Deficiency

References

[1]

Chedrawi AK,Ali A,Al Hassnan ZN,Faiyaz-Ul-Haque M,Wolf B, Profound biotinidase deficiency in a child with predominantly spinal cord disease. Journal of child neurology. 2008 Sep;     [PubMed PMID: 18645204]

[2]

Yang Y,Yang JY,Chen XJ, Biotinidase deficiency characterized by skin and hair findings. Clinics in dermatology. 2020 Jul - Aug;     [PubMed PMID: 32972606]

[3]

Dahiphale R,Jain S,Agrawal M, Biotinidase deficiency. Indian pediatrics. 2008 Sep;     [PubMed PMID: 18820388]

[4]

Wolf B, Biotinidase Deficiency 1993;     [PubMed PMID: 20301497]

[5]

Ghazal S,Ali A,Bin Arif T,Memon F,Malik L, Biotinidase Deficiency With Suspected Sotos Syndrome: A Rare Entity. Cureus. 2020 May 7;     [PubMed PMID: 32523854]

[6]

Sondhi V,Sharma S, Vitamin-Responsive Movement Disorders in Children. Annals of Indian Academy of Neurology. 2020 May-Jun;     [PubMed PMID: 32606520]

[7]

Gompertz D,Draffan GH,Watts JL,Hull D, Biotin-responsive beta-methylcrotonylglycinuria. Lancet (London, England). 1971 Jul 3;     [PubMed PMID: 4103667]

[8]

Wolf B,Heard GS,Weissbecker KA,McVoy JR,Grier RE,Leshner RT, Biotinidase deficiency: initial clinical features and rapid diagnosis. Annals of neurology. 1985 Nov;     [PubMed PMID: 4073853]

[9]

Tsao CY,Kien CL, Complete biotinidase deficiency presenting as reversible progressive ataxia and sensorineural deafness. Journal of child neurology. 2002 Feb;     [PubMed PMID: 11952077]

[10]

Kasapkara ÇS,Akar M,Özbek MN,Tüzün H,Aldudak B,Baran RT,Tanyalçın T, Mutations in BTD gene causing biotinidase deficiency: a regional report. Journal of pediatric endocrinology     [PubMed PMID: 25423671]

[11]

Canda E,Kalkan Uçar S,Çoker M, Biotinidase Deficiency: Prevalence, Impact And Management Strategies. Pediatric health, medicine and therapeutics. 2020;     [PubMed PMID: 32440248]

[12]

Pindolia K,Chen J,Cardwell C,Cui X,Chopp M,Wolf B, Neurological deficits in mice with profound biotinidase deficiency are associated with demylination and axonal degeneration. Neurobiology of disease. 2012 Sep;     [PubMed PMID: 22579707]

[13]

Cowan TM,Kazerouni NN,Dharajiya N,Lorey F,Roberson M,Hodgkinson C,Schrijver I, Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Molecular genetics and metabolism. 2012 Aug;     [PubMed PMID: 22698809]

[14]

Hsu RH,Chien YH,Hwu WL,Chang IF,Ho HC,Chou SP,Huang TM,Lee NC, Genotypic and phenotypic correlations of biotinidase deficiency in the Chinese population. Orphanet journal of rare diseases. 2019 Jan 7;     [PubMed PMID: 30616616]

[15]

Hong X,Kumar AB,Ronald Scott C,Gelb MH, Multiplex tandem mass spectrometry assay for newborn screening of X-linked adrenoleukodystrophy, biotinidase deficiency, and galactosemia with flexibility to assay other enzyme assays and biomarkers. Molecular genetics and metabolism. 2018 Jun;     [PubMed PMID: 29680633]

[16]

Venkataraman V,Balaji P,Panigrahi D,Jamal R, Biotinidase deficiency in childhood. Neurology India. 2013 Jul-Aug;     [PubMed PMID: 24005734]

[17]

Thodi G,Schulpis KH,Molou E,Georgiou V,Loukas YL,Dotsikas Y,Papadopoulos K,Biti S, High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene. 2013 Jul 25;     [PubMed PMID: 23644139]

[18]

Patra S,Senthilnathan G,Bhari N, Acrodermatitis enteropathica-like skin eruption with neonatal seizures in a child with biotinidase deficiency. Clinical and experimental dermatology. 2020 Mar;     [PubMed PMID: 31323123]

[19]

Wolf B, Biotinidase deficiency should be considered in individuals exhibiting myelopathy with or without and vision loss. Molecular genetics and metabolism. 2015 Nov;     [PubMed PMID: 26358973]

[20]

Senanayake DN,Jasinge EA,Pindolia K,Wanigasinghe J,Monaghan K,Suchy SF,Wei S,Jaysena S,Wolf B, First contiguous gene deletion causing biotinidase deficiency: The enzyme deficiency in three Sri Lankan children. Molecular genetics and metabolism reports. 2015 Mar;     [PubMed PMID: 28649532]

[21]

Asgari A,Rouhi Dehnabeh S,Zargari M,Khani S,Mozafari H,Varasteh A,Keyfi F,Barzegari M,Hasanzaeh R,Khatami S, Clinical, Biochemical and Genetic Analysis of Biotinidase Deficiency in Iranian Population. Archives of Iranian medicine. 2016 Nov;     [PubMed PMID: 27845546]

[22]

Singh P,Gurnani R,Rawat A,Parihar A, Brain MRI findings in an infant with congenital biotinidase deficiency. BMJ case reports. 2021 Oct 8;     [PubMed PMID: 34625444]

[23]

Ranjan RS,Taneja S,Singh A,Gupta V, Congenital biotinidase deficiency - MRI findings in two cases. The Indian journal of radiology     [PubMed PMID: 31000952]

[24]

Kiykim E,Kiykim A,Cansever MS,Zeybek CA, Biotinidase deficiency mimicking primary immune deficiencies. BMJ case reports. 2015 May 8;     [PubMed PMID: 25956498]

[25]

Ferreira P,Chan A,Wolf B, Irreversibility of Symptoms with Biotin Therapy in an Adult with Profound Biotinidase Deficiency. JIMD reports. 2017;     [PubMed PMID: 28220409]

[26]

Armstrong RW,Steinbok P,Cochrane DD,Kube SD,Fife SE,Farrell K, Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin. Journal of neurosurgery. 1997 Sep;     [PubMed PMID: 9285607]

[27]

Porta F,Pagliardini V,Celestino I,Pavanello E,Pagliardini S,Guardamagna O,Ponzone A,Spada M, Neonatal screening for biotinidase deficiency: A 30-year single center experience. Molecular genetics and metabolism reports. 2017 Dec;     [PubMed PMID: 28971021]

[28]

Rajendiran A,Sampath S, Biotinidase deficiency--clinching the diagnosis rapidly can make all the difference! BMJ case reports. 2011 Sep 28;     [PubMed PMID: 22679321]

[29]

Wolf B, Biotinidase deficiency:     [PubMed PMID: 22241090]

[30]

Szymańska E,Średzińska M,Ługowska A,Pajdowska M,Rokicki D,Tylki-Szymańska A, Outcomes of oral biotin treatment in patients with biotinidase deficiency - Twenty years follow-up. Molecular genetics and metabolism reports. 2015 Dec;     [PubMed PMID: 28649539]

[31]

Taitz LS,Leonard JV,Bartlett K, Long-term auditory and visual complications of biotinidase deficiency. Early human development. 1985 Sep;     [PubMed PMID: 4054050]

[32]

Procter M,Wolf B,Crockett DK,Mao R, The Biotinidase Gene Variants Registry: A Paradigm Public Database. G3 (Bethesda, Md.). 2013 Apr 9;     [PubMed PMID: 23550138]