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 Table of Contents  
CASE SERIES
Year : 2022  |  Volume : 2  |  Issue : 1  |  Page : 12-16

Biotin supplementation in children with symptomatic profound biotinidase deficiency and their pregnant mothers


1 Department of Pediatrics, Division of Genetics, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India
2 Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India
3 Department of Gynaecology and Obstetrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India

Date of Submission15-Jan-2022
Date of Decision01-Feb-2022
Date of Acceptance04-Feb-2022
Date of Web Publication25-Feb-2022

Correspondence Address:
Dr. Sharmila B Mukherjee
Department of Pediatrics, Kalawati Saran Children's Hospital, Bangla Sahib Marg., New Delhi - 110 001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_12_22

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  Abstract 

Background: Biotin is the coenzyme of multiple carboxylases involved in gluconeogenesis, fatty acid synthesis, and amino acid catabolism. Biotinidase (BTD) deficiency is an autosomal recessive disorder affecting the biotin cycle. It disrupts endogenous biotin recycling and results in multiple carboxylase deficiency depending upon the level of enzyme activity. Children with profound deficiency often present in infancy with neurocutaneous manifestations. Management of symptomatic children or screen-positive newborns is lifelong oral supplementation with biotin. There may be partial or complete resolution of symptoms in the former. Clinical Description: We describe two unrelated families diagnosed as profound BTD deficiency, with three affected children in each family. The first family had two symptomatic surviving children, a 2-year-old boy with seizures, developmental delay, and hearing loss, and a 1.5-month-old boy with seizures. Diagnosis was established while ascertaining etiology for seizures refractory to multiple anticonvulsant therapy. The second family was referred for postconceptional counseling following two infantile deaths with similar phenotype, early-onset seizures, encephalopathy, and acute metabolic decompensation. Management: The affected children in the first family showed a dramatic response in seizure controls with oral biotin though the other symptoms such as developmental delay and hearing loss remained unaffected. Mother was advised regarding prenatal diagnosis in the next pregnancy but was unwilling. In the second family, stored genetic material from the earlier affected infant revealed a pathogenic homozygous indel in the BTD gene, which was confirmed in utero in the subsequent pregnancy. Both women were started on oral biotin on the lines of antenatal management of holocarboxylase synthetase deficiency. After birth, therapy was continued on the confirmation of profound BTD deficiency in both babies. They have remained asymptomatic on follow-up; the first baby till a year and the second till 3 months. Conclusion: There is a considerable phenotypic variability in profound BTD deficiency. Early detection and prompt treatment with biotin may result in complete resolution of some symptoms and ameliorate others. Antenatal biotin supplementation in families at high risk or with prenatal diagnosis of BTD deficiency may have a favorable outcome in affected progeny.

Keywords: Alopecia, encephalopathy, hearing loss, multiple carboxylase deficiency, seizures


How to cite this article:
Mishra R, Gupta MB, Mukherjee SB, Lomash A, Gupta S, Kapoor S. Biotin supplementation in children with symptomatic profound biotinidase deficiency and their pregnant mothers. Indian Pediatr Case Rep 2022;2:12-6

How to cite this URL:
Mishra R, Gupta MB, Mukherjee SB, Lomash A, Gupta S, Kapoor S. Biotin supplementation in children with symptomatic profound biotinidase deficiency and their pregnant mothers. Indian Pediatr Case Rep [serial online] 2022 [cited 2022 May 27];2:12-6. Available from: http://www.ipcares.org/text.asp?2022/2/1/12/338475

Biotin is a water-soluble vitamin that exists as a free form or protein bound biotinylated peptide. It is the coenzyme of multiple carboxylases involved in gluconeogenesis, fatty acid synthesis, and amino acid catabolism [Figure 1].[1] Inactive apoenzymes get converted to active holoenzymes after linkage with free biotin through reactions involving the holocarboxylase synthetase (HLCS) family of enzymes.[1] Biotinidase (BTD) is an enzyme that maintains the biotin pool by recycling bound and releasing protein bound biotin. BTD deficiency is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in the BTD gene, which depletes the biotin pool, and results in multiple carboxylase deficiencies. Globally, the incidence is 1 per 40,000–60,000 births.[2] BTD deficiency was the most common (6.5%) inborn error of metabolism (IEM) in an Indian study of screen-positive neonates.[3]
Figure 1: The biotin cycle (Adapted from Mathias R et al.)

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Classification of BTD deficiency is based on the level of mean serum activity; profound (<10% activity) and partial (10%–30% activity). There is a significant variability in clinical presentation that may not commensurate with level of activity.[1] Although the mean age of presentation of profound BTD deficiency is 3.5 months, the age at which symptoms can appear varies from as early as 1 week to as late as 10 years.[4] The clinical manifestations are usually neurocutaneous including ataxia, developmental delay, hypotonia, seizures, conjunctivitis, skin rashes, and alopecia.[4] Other manifestations include hearing loss (75%) and visual problems (50%).[4] Acute episodes of metabolic decompensation resulting in encephalopathy or death have rarely been reported.[5] Partial deficiency results in milder symptoms that are precipitated by stressful conditions such as infections.[4],[5] All screen- positive newborns and symptomatic individuals should be managed with lifelong oral biotin.[1] Positive outcomes have been reported after daily biotin supplementation (10 mg) during pregnancy, in women at risk of, or with antenatally diagnosed HLCS deficiency, a disorder that also involves the biotin cycle. Although scientifically the same principle should apply in BTD deficiency, we were unable to find the reports of or studies on antenatal supplementation.

This case series highlights several interesting facets that emerged from the management of two families with profound BTD deficiency in terms of clinical presentation and the positive outcomes of antenatal and postnatal biotin supplementation.


  Clinical Descriptions Top


Family 1

A 1.5-month-old boy was brought by his parents with complaints of multiple seizures for a week. Each episode involved stiffening and jerky movement of all his limbs and transient loss of consciousness lasting for a few seconds, and occurring 5–10 times a day. The baby was active and breastfeeding well in between each seizure. There was no history of fever, vomiting, loose stools, skin lesions, lethargy, trauma, or prior vaccination. The antenatal period was uneventful, with normal perception of quickening and fetal movements. The baby was born at term by normal delivery with birth weight 3.5 kg, normal APGAR scores and was discharged within a day.

He was the fourth issue of a third-degree consanguineous marriage [Figure 2]a. The parents were asymptomatic. The first child was a typically developing 3.5-year-old boy. The second issue was a boy born at term, with normal antenatal and perinatal periods, who developed seizures at the age of 2 months. The infant succumbed after 2 weeks without the cause of seizures being ascertained. The third child was a 2-year-old boy with developmental delay, hearing impairment, and generalized tonic–clonic seizures, which started when he was a year old. His seizures were persisting despite the use of phenytoin and sodium valproate [Table 1].
Figure 2: Three generation pedigree of family 2 (a) and family 2 (b)

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Table 1: Clinical details of affected members with profound biotinidase deficiency

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Vital parameters and anthropometry of the proband were normal. The cranium, spine, skin, and hair were normal. The infant was not dysmorphic and had no neurocutaneous markers. The only salient neurodevelopmental finding was mild generalized hypotonia. Remaining systemic examination was normal. The evaluation of the first child was normal, whereas the third was symptomatic [Table 1].

Preliminary first-line biochemical investigations excluded hypoglycemia and hypocalcemia. The biomarkers for sepsis were negative. The cranial ultrasonogram was normal, but electroencephalogram showed multifocal sharp waves. Automated brain stem response revealed profound bilateral sensorineural hearing impairment (SNHI). BTD deficiency was strongly considered in the family in view of various clinical manifestations, seizures, SNHI, and developmental delay. Enzyme assay confirmed profound deficiency in both symptomatic children with normal BTD levels in the parents and unaffected sibling. After genetic counseling, the affected individuals were started on 20 mg of daily oral biotin. Follow-up after a year of therapy showed significant improvement as depicted in [Table 1].

The mother conceived again after 1.5 years. Although the parents were concerned regarding the outcome, they were unwilling for prenatal diagnosis. After a genetic consultation at 6-week gestation, they decided to start oral biotin supplementation (20 mg daily). Compliance was good and the pregnancy proceeded normally. A baby boy weighing 3 kg was born at term. He was started on crushed oral biotin mixed with breast milk from day 1. Enzyme assay identified profound BTD deficiency. The infant is under follow-up and remains asymptomatic at 1 year [Table 1].

Family 2

A fourth gravida 6 weeks pregnant woman presented to the genetic clinic for postconceptional counseling in view of two infantile deaths, one of which was due to profound BTD deficiency [Figure 2]b. The first pregnancy was an 8 weeks spontaneous abortion. The second pregnancy resulted in a girl delivered by cesarean section (indication being breech presentation), weighing 2500 g, and discharged on exclusive breast feeds after 4 days. She developed multiple seizures (generalized tonic–clonic seizures and flexor spasms) at 2.5 months, followed by poor feeding and lethargy within 3 days. There was no history of fever, loose motions, vomiting, or trauma. Photographs were unavailable but review of medical documents revealed the absence of social smile, hypertonicity, and exclusion of hypoglycemia, hypocalcemia, and hyper/hyponatremia. Seizures persisted despite the administration of phenobarbitone, levetiracetam, and sodium valproate. Parenteral antibiotics were started empirically. Carnitine and sodium benzoate were added suspecting an IEM. She was placed on ventilatory support within 3 days. Cranial noncontrast computed tomography revealed bilateral hyperintensities in the periventricular, frontal, and cerebellar white matter. Significant metabolic abnormalities were identified including lactic acidosis (lactate 6.0 mmol/L and pH 7.3), increased plasma ammonia (227 μg/dl), increased urinary excretion of 3-hydroxy isovaleric and 3-hydroxypropionic acids on gas chromatography–mass spectrometry (GCMS), and elevated plasma hydroxy valeryl carnitine on tandem mass spectroscopy (TMS). This metabolic profile suggested multiple carboxylase deficiency, and BTD assay revealed profound deficiency. Despite counseling, the family did not consent for genetic studies or deoxyribonucleic acid (DNA) storage. The child died after 3 days.

The third conception was a boy born at term weighing 2900 g, with no significant antenatal or perinatal history. The parents noted that he had sparse scalp hair, but normal skin (similar to the previous issue). At 3.5 months, the infant developed multiple seizures for which he was admitted in a private hospital. Clinical details were procured from history and the review of past records. It was learnt that seizures continued despite being administered phenobarbitone, valproate, levetiracetam, and clonazepam. The next day, he became unresponsive and was given ventilatory support, but he expired within 5 days. The baseline hemogram and first-line biochemistry reports were normal, and sepsis screen was negative. Plasma acylcarnitine analysis exhibited elevated nonspecific metabolites that were attributed to the critical premortem state. BTD levels were unavailable. DNA was stored for future evaluation.

Taking all clinical details into consideration [Table 1], the plan for the fourth pregnancy included genetic counseling, the need for processing the stored DNA, options for prenatal diagnosis, and administering antenatal biotin (10 mg twice a day). Clinical exome study performed on the stored DNA of the previous issue identified a pathogenic homozygous insertion and deletion (indel) in exon 4 of the BTD gene (c. 98_104delinsTCC; p. Cys33PhefsTer36). This has been reported earlier in BTD deficiency[6] and is known to cause frameshift termination 36 amino acids downstream of codon 33. After chorionic villus sampling, Sanger sequencing identified the same mutation. The couple was appraised of the likelihood of an affected fetus. Maternal risks of surgical termination of pregnancy in view of previous cesareans were discussed. An educated decision to continue the pregnancy with biotin supplementation was taken by the parents. The pregnancy proceeded uneventfully. A girl weighing 3300 g was born at term and oral biotin (5 mg) was started on the 1st day and continued after profound BTD deficiency was established on subsequent enzyme assay. The baby is under follow-up and is asymptomatic, thriving well, has normal hair and skin, bilateral pass on hearing screening by otoacoustic emission and has age-appropriate neurodevelopmental examination at 3 months.


  Discussion Top


Biotin, also known as Vitamin B7 or Vitamin H, acts as the coenzyme of multiple carboxylases, cytosolic acetyl-CoA carboxylase (ACC) 1, outer mitochondrial membrane ACC 2, 3-methylcrotonyl-CoA carboxylase, pyruvate carboxylase, and propionyl-CoA carboxylase.[2] Since it can be administered in the free form, oral biotin can directly enter the biotin cycle and replenish the pool. Thus, any dosage greater than the recommended daily allowance (RDA), i.e., 5–10 mg/day, may resolve the multiple carboxylase dysfunction that arises from BTD deficiency.[2] The normal RDA of biotin in women (pregnant or nonpregnant) is 30 μg/day. During pregnancy, there may be increased requirement to meet growing metabolic demands, especially in a BTD deficient fetus. It is well known that the biotin content of breast milk is low (1.7–2.8 μg/L) and may not satisfy the RDA of infants under 6 months of age (5 μg/day).

Biotin supplementation results in rapid resolution of seizures and biochemical abnormalities, whereas cutaneous abnormalities and alopecia takes weeks to months to improve.[4] Some symptoms such as developmental delay, hearing loss, and optic atrophy are irreversible after becoming clinically apparent, even after initiating biotin.[4] This was evident in family 1: seizures abated in the third and fourth sons after postnatal biotin was started; developmental delay and hearing impairment remained unaltered in the third son, whereas development proceeded typically with unaffected hearing in the fourth son; and the fifth son remained asymptomatic with combined antenatal and postnatal biotin.

The clinical phenotypes of all affected children were similar in both families: Seizures, hearing loss, the absence of skin/hair changes, and no metabolic derangement in family 1, and; sparse hair but normal skin, intractable seizures followed by acute encephalopathy, death, and metabolic derangement in family 2. However, some intrafamilial variability was also noted. Whether this was due to the oral biotin or hitherto unknown epigenetic or environmental factors affecting the biotin cycle, remains unresolved.[7]

The common metabolic derangements in untreated BTD deficiency are lactic acidosis, organic aciduria, and mild hyperammonemia.[4] Urine and plasma may reveal elevated metabolites indicative of multiple carboxylase deficiency. Routine GCMS and TMS are not recommended, as many children with profound deficiency may exhibit metabolic profiles that are normal, intermittently abnormal, or falsely negative.[8] Diagnosis is primarily by measuring BTD activity in plasma/serum by colorimetric assay. Confirmation by DNA analysis is indicated only when enzyme assay results are ambiguous,[4] and postmortem or prenatal diagnosis is required, as in the second family.

The mutation that was identified in this family has a worldwide distribution among racially and ethnically diverse population.[6] Genotype–phenotype correlations are not well defined in profound BTD deficiency. Null variants are reportedly at higher risk of hearing loss than missense variants.[9] It is noteworthy that the affected infant had normal hearing despite the null variant. One possible explanation could be the antenatal biotin that the mother was receiving from the 6th week of gestation onward. There was no indication for ascertaining genotype in the other family, despite the presence of hearing loss in symptomatic members.

Most researchers have used biotin (10 mg per day) in pregnancies at risk of HLCS deficiency.[10] We used an empirical dose of 20 mg per day in both these families affected with BTD deficiency due to nonavailability of supportive literature. Neither of the women reported any adverse effects ascribed to biotin such as skin rashes or gastrointestinal symptoms. After birth, both babies have remained asymptomatic with typical neurodevelopment, despite profound BTD deficiency.

Thus, BTD deficiency is a readily treatable disorder with oral biotin that is a safe, easily available, and economical drug. It can be given to symptomatic individuals, screen-positive neonates, and mothers at high risk of or antenatally diagnosed with BTD deficiency. We hope this case report triggers more widespread use and generates research aimed at ascertaining the optimal prenatal dosage.



Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Baumgartner MR, Suormala T. Biotin responsive disorders. In: Saudubray JM, Baumgartner MR, Walter J, editors. Inborn Metabolic Diseases. 6th ed. Verlag Berlin Heidelberg: Springer; 2016. p. 375-83.  Back to cited text no. 1
    
2.
Wolf B. Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab 2010;100:6-13.  Back to cited text no. 2
    
3.
Lodh M, Kerketta A. Inborn errors of metabolism in a tertiary care hospital of eastern India. Indian Pediatr 2013;50:1155-6.  Back to cited text no. 3
    
4.
Wolf B. Biotinidase deficiency: “if you have to have an inherited metabolic disease, this is the one to have”. Genet Med 2012;14:565-75.  Back to cited text no. 4
    
5.
Wolf B. Biotinidase Deficiency/Synonym Late Onset Multiple Carboxylase Deficiency. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1322/. [Last accessed on 2022 Jan 01].  Back to cited text no. 5
    
6.
Pomponio RJ, Reynolds TR, Cole H, et al. Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency. Nat Genet 1995;11:96-8.  Back to cited text no. 6
    
7.
Wolf B. The further adventures of newborn screening for biotinidase deficiency: where it is at and what we still need to know. Int. J Neonatal Screen 2016;2:9.  Back to cited text no. 7
    
8.
Strovel ET, Cowan TM, Scott AI, et al. Laboratory diagnosis of biotinidase deficiency, 2017 update: A technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med 2017;19:10. [doi: 10.1038/gim. 2017.84].  Back to cited text no. 8
    
9.
Sivri HS, Genç GA, Tokatli A, et al. Hearing loss in biotinidase deficiency: Genotype-phenotype correlation. J Pediatr 2007;150:439-42.  Back to cited text no. 9
    
10.
Thuy LP, Belmont J, Nyhan WL. Prenatal diagnosis and treatment of holocarboxylase synthetase deficiency. Prenat Diagn 1999;19:108-12.  Back to cited text no. 10
    


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