Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Incomplete (Consensus scoring is Complete)
• Curation Status (Adult): Released
• Status (Pediatric): Incomplete (Consensus scoring is Complete)
• GENE/GENE PANEL: BTD
• Condition: Biotinidase Deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• BTD ⇔ 0009665 (biotinidase deficiency): Limited Actionability

Actionability Rationale

Most experts agreed with the assertion computed according to the rubric. Actionability was asserted as definitive in a pediatric setting by the pediatric AWG with treatment continuing into adulthood. There are limited data regarding disease course and penetrance in unselected adult patients as well as the efficacy of biotin therapy in asymptomatic, previously undiagnosed adults.

Final Consensus Scores

Gene Condition Pairs: BTD ⇔ 0009665 (OMIM:253260)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from biotin deficiency / Referral to a metabolic specialist for evaluation and biotin supplementation	1	0D	2C	3	6DC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Worldwide screening of biotinidase deficiency (BTD) has estimated an incidence of 1/80,000 to 1/137,401 for profound BTD and 1/31,000 to 1/109,921 for partial BTD, with a combined incidence of 1/47,486 to 1/61,067. Incidence may vary by population. [1, 2, 3, 4]

Clinical Features

Children with untreated profound BTD usually exhibit neurologic abnormalities (seizures, hypotonia, ataxia, developmental delay), cutaneous abnormalities (alopecia, eczematous skin rash, and/or candidiasis), eye findings (optic atrophy, conjunctivitis), sensorineural hearing loss, and respiratory problems. Many symptomatic children exhibit a variety of central nervous system (CNS) abnormalities on brain magnetic resonance imaging (MRI) or computerized tomography (CT). Older children and adolescents with profound BTD may present with limb weakness, spastic paresis, and eye problems, such as optic neuropathy, loss of visual acuity, and scotoma rather than the more characteristic symptoms observed in younger untreated children with profound BTD. Children or adults with untreated partial BTD may exhibit any of the above signs and symptoms, but the manifestations are mild and occur only when the person is stressed, such as prolonged infection. Laboratory findings suggestive of BTD are metabolic ketolactic acidosis, organic aciduria, and hyperammonemia. [1, 2, 3, 4, 5]

Natural History

Virtually 100% of infants with either profound or partial BTD can be detected in the US by newborn screening. Individuals who are diagnosed before they develop symptoms should remain asymptomatic if biotin therapy is instituted early and continuously lifelong. In untreated individuals with profound BTD, symptoms usually appear between 1 week of age and adolescence, with most exhibiting symptoms between 3-6 months. Neurologic abnormalities are frequently the first features to occur. Affected individuals may have features ranging from multiple, mild episodes of seizures and ataxia, to severe metabolic compromise, which can result in coma or death. Several asymptomatic, untreated adults with profound BTD have been reported. The explanation as to why they have remained asymptomatic is unknown. Individuals with partial BTD are largely asymptomatic but may develop symptoms during periods of stress (e.g., illness, infection, fever, or fasting). Symptomatic individuals improve with biotin therapy, with the exception of vision problems, hearing loss, and developmental delay which are usually irreversible. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening:
https://www.acmg.net/PDFLibrary/Biotinidase-Deficiency-ACT-Sheet.pdf [6]

To establish the extent of disease and needs in an individual diagnosed with BTD, the following evaluations are recommended (Tier 4):
•History of seizures, balance problems, feeding problems, breathing problems, loss of hair, fungal infections, skin rash, and conjunctivitis
•Physical examination for hypotonia, ataxia, eye findings, eczematous skin rash, alopecia, conjunctivitis, breathing abnormalities, thrush, and candidiasis
•Evaluation for sensorineural hearing loss
•Evaluation for psychomotor deficits
•Ophthalmologic examination
•Identification of cellular immunologic abnormalities
•Consultation with a metabolic specialist or clinical geneticist (Tier 4) [1]

Biotin is an effective treatment of BTD. All individuals with profound BTD, even those with some residual biotinidase enzyme activity, should have lifelong treatment with biotin. Biotin supplementation appears to prevent the development of symptoms in presymptomatic children with profound BTD. Furthermore, all symptomatic children with profound BTD who have been treated with pharmacological doses of biotin (5-20 mg daily) have shown clinical improvement. However, sensorineural hearing loss usually does not resolve or improve with biotin treatment. A retrospective review of 22 individuals with profound BTD identified by newborn screening supports the long-term benefit of treatment and management. Individuals with profound BTD ranged from 1 to 20 years of age, with a mean age of 8.3 years. All but one of the individuals were started on 10 to 15 mg of biotin at 1 week to 3 weeks of age. At the time of their last clinic visit, none of the individuals exhibited hypotonia, seizures, developmental delay, optic atrophy, or hearing problems. Seven individuals had cutaneous issues that included rashes, eczema, and contact dermatitis. Five individuals had some vision issues, which included astigmatism or requiring glasses or contacts. The authors concluded that these clinical problems were mild and unlikely attributable to BTD. Another study described self-reported outcomes of 44 older adolescents and adults with profound BTD identified by newborn screening. The mean age was 23.1 years, with a range of 16 to 32 years. In general, most individuals were initially treated with 10 mg of biotin daily, starting before 6 weeks of age. One individual who developed symptoms at 2 weeks of age, before biotin was started, developed bilateral sensorineural hearing loss requiring lifelong use of hearing aids. Three individuals had unilateral hearing loss (2 conductive and 1 possibly sensorineural) not requiring hearing aids. Two individuals had a single seizure as children. None reported major vision problems. Several of the individuals had episodes of rashes or eczema that did not resolve by increasing the dose of biotin. All individuals had successfully completed high school, and 31/44 (70%) were attending college or graduate school. Compliance in using biotin was excellent. Several individuals developed a variety of symptoms when they discontinued biotin for days or weeks, which readily resolved when biotin was resumed. (Tier 3) [1, 2]

The biochemical abnormalities and seizures rapidly resolve after biotin therapy, followed by improvement of cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between onset and initiation of treatment. Some treated children have rapidly achieved developmental milestone, whereas others have continued to show developmental delay. CNS abnormalities on brain MRI or CT may improve or become normal after biotin treatment. Children with BTD who have failed to comply with their biotin therapy, developed symptoms within several weeks to months. These children illustrate the importance of early diagnosis and initiation of lifelong treatment. Asymptomatic individuals with BTD can be treated with biotin. These individuals should be followed regularly by a metabolic disease specialist. (Tier 4) [1, 2, 3, 4]

There is no consensus within the field regarding treatment of individuals with partial BTD. Partial BTD is usually treated with 1-10 mg of biotin per day lifelong. (Tier 4) A retrospective study reviewing clinical histories of 120 individuals with partial BTD identified by newborn screening supports the long-term benefit of treatment and management of partial BTD. Individuals with partial BTD ranged from 2 weeks old to 29 years; the mean age was 5.8 years. The median dose of biotin used to treat the individuals with partial BTD was 5 mg per day. At the time of their last clinic visit, 20 of the individuals reported cutaneous symptoms, one had a history of seizures, five had hearing problems, and 11 reported developmental delays. The authors concluded that these clinical problems were unlikely attributable to BTD (Tier 3) [1, 2, 3]

Surveillance

All individuals with BTD should undergo:
•Ophthalmologic examination and auditory testing: annually for profound BTD and every 2 years for partial BTD.
•Regularly scheduled appointments with primary care physicians or as needed.
•Evaluation by a clinical geneticist or metabolic specialist: annually for profound BTD and every 2 years for partial BTD.
•Neurological evaluations: periodically. (Tier 4) [1, 4]

Circumstances to Avoid

Raw eggs should be avoided because they contain avidin, an egg-white protein that binds biotin, thus decreasing its bioavailability. (Tier 4) [1, 4]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive [1, 2, 3, 4, 5]

Prevalence of Genetic Variants

Pathogenic variants in BTD are detected in ~99% of individuals with BTD. Thus, pathogenic variants associated with BTD are expected to have a similar prevalence as BTD, roughly 1/61,000. (Tier 3) [1]

The carrier frequency in the general population is approximately 1/120. (Tier 3) [1]

Penetrance

Almost 100% of children identified with two alleles of profound BTD become symptomatic or are at high risk of becoming symptomatic if not treated. (Tier 4) [1, 3]

Several reports describe untreated adults with profound BTD who have never had symptoms. In addition, several enzyme-deficient sibs of symptomatic children have never exhibited symptoms. (Tier 3) [1, 2, 5]

Among untreated, symptomatic children with profound BTD:
•Approximately 76% have sensorineural hearing loss.
•More than 70% exhibit seizures, hypotonia, skin rash, or alopecia.
•Approximately 50% have ataxia, developmental delay, conjunctivitis, and visual problems, including optic atrophy.
•Four of 31 children (13%) died while in metabolic coma (Tier 3) [1, 2, 5]

Individuals with partial BTD are largely asymptomatic but may develop symptoms during periods of stress. (Tier 4) [2, 4]

Relative Risk

Information on relative risk was not identified.

Expressivity

The initial clinical presentation and ultimate expression of profound BTD are quite variable, even within the same family. (Tier 3) [2]

Some children with BTD manifest only a single finding, whereas others exhibit multiple neurologic and cutaneous findings. (Tier 4) [1]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified were medical exams, blood screenings, and lifelong biotin therapy, which are low intensity and minimally invasive. Biotin is usually dispensed as a tablet or a capsule. To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. Biotin has no known toxicity. There are no known adverse side effects from pharmacologic doses of biotin. Non-compliance with prescribed treatment is problematic. [1, 3, 4]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

All newborn screening programs in the US and many other countries worldwide include BTD in their panel of screened conditions. Virtually 100% of infants with either profound or partial BTD can be detected in the US by newborn screening. However, occasionally a child who has not been screened or has been mistakenly thought to have normal biotinidase activity on newborn screening will present with clinical symptoms (Tier 4) [1, 2]

In many cases, clinicians, geneticists, and metabolic specialists fail to identify BTD before occurrence of irreversible symptoms and lesions, such as developmental delay, hearing loss and optic atrophy, which complications all imply lifelong medical care. Individuals with BTD may exhibit clinical features that are misdiagnosed as other disorders before they are correctly identified. (Tier 3) [1, 3]

Multiple adults with optic neuropathy and/or peripheral neuropathy, that is often mistakenly diagnosed as multiple sclerosis, have been shown to have profound BTD. (Tier 4) [4]

Several asymptomatic, untreated adults with profound BTD have been reported. (Tier 3) [1]

Date of Search: 04.04.2016 (updated 05.31.2022)

Reference List

1. B Wolf. Biotinidase Deficiency. 2000 Mar 24 [Updated 2016 Jun 09]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1322

2. Strovel ET, Cowan TM, Scott AI, Wolf B. 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(1530-0366).

3. Kury S, Ramaekers V, Bezieau S, Wolf B. Clinical utility gene card for: biotinidase deficiency. Eur J Hum Genet. (2012) 20(5).

4. Biotinidase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=79241

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. BIOTINIDASE DEFICIENCY. MIM: 253260: 2020 Aug 06. World Wide Web URL: http://omim.org.

6. ACMG. Newborn Screening ACT Sheet: Biotinidase Deficiency. (2021) Website: https://www.ncbi.nlm.nih.gov/books/NBK55827/bin/Biotinidase.pdf