Biotinidase Deficiency Induced Optic Neuropathy: A Case Report and Literature Review

ABSTRACT

We report a case of a 19-year-old Somali American woman who presented with 6 months of progressive bilateral vision changes and ocular discharge, with systemic symptoms including angular cheilitis and dermatitis. The patient was evaluated with comprehensive ophthalmic examination, optical coherence tomography, corticospinal magnetic resonance imaging, and fundus imaging. Comprehensive ophthalmic examination revealed bilateral optic neuropathy. Laboratory testing showed a biotinidase level of <0.1 (normal, 5.5–10 nmol/min/ml). The patient was treated with oral biotin supplementation with improvement in her visual function. Furthermore, a review of the literature of reported cases of biotinidase deficiency optic neuropathy published between June 1987 and February 2024 revealed 40 cases. This entity presents more commonly in males (63%) (n = 27), with an average age of 11.7 ± 12.0 years (n = 35). Patients experienced symptoms for an average of 4.3 ± 8.3 years before they were correctly diagnosed (n = 25). Individuals had an average BCVA of 20/300 in the right eye and 20/250 in the left eye (n = 15) at the time of presentation. Additionally, 38.9% of patients had color vision deficits (n = 18), and 100% of patients had visual field deficits (n = 19). All patients were treated with oral biotin supplementation (n = 25). This case and review of the literature underscore that biotinidase deficiency should be considered in patients with bilateral and progressive optic neuropathy among young adults. Early diagnosis is important as biotin supplementation may halt and/or reverse the disease process.

Introduction

Biotinidase deficiency is an autosomal recessive-inherited metabolic disorder in which the body cannot process biotin (vitamin B7) due to a deficiency in the enzyme biotinidase.¹ Biotinidase deficiency can be categorized as either profound biotinidase deficiency or partial biotinidase deficiency. The incidence of profound and partial biotinidase deficiencies is 1 in 137,400 and 1 in 110,000, respectively.² The combined incidence of both profound and partial deficiencies is approximately 1 in 61,000.²

A wide spectrum of clinical conditions are associated with biotinidase deficiency, including immunologic, dermatologic, neurologic, and ophthalmic manifestations.^3,4 Optic neuropathy, and a resemblance to neuromyelitis optica spectrum disorder, are the most common ophthalmic symptoms associated with biotinidase deficiency.³ Early detection and diagnosis of biotinidase deficiency is critical as treatment with biotin supplementation can lead to reversal or prevention of further symptoms. Herein, we report a case of biotinidase deficiency optic neuropathy in a young adult who presented with vision loss, and review the clinical characteristics and outcomes of 40 cases of biotinidase deficiency optic neuropathy reported in the literature.

Materials and methods

A retrospective chart review of the electronic medical record of a patient with biotinidase deficiency induced optic neuropathy seen in a single tertiary referral practice was conducted. In addition, a literature review of biotinidase deficiency induced optic neuropathy was conducted using the keywords ‘biotinidase deficiency’, ‘optic neuropathy’, ‘optic neuritis’, and ‘optic atrophy’ in PubMed and references from relevant articles. Written informed consent to publish the details from the affected individual has been obtained. Research for a single-case study is IRB exempt and, the review follows in accordance with the Declaration of Helsinki. All case reports that described patients having symptoms of biotinidase deficiency associated with optic neuropathy or neuromyelitis optica spectrum disorder between June 1987 and February 2024 were included. Continuous variables were analyzed using the mean and standard deviation. Categorical variables were presented as percentages. Individual visual acuities were converted to logMAR values for statistical analysis, and the equivalent Snellen values were reported.

Case report

A 19-year-old Somali American woman with a history of type 1 diabetes mellitus presented with 6 months of worsening bilateral ‘blurry’ and ‘hazy’ vision at distance and near. Additional ocular symptoms included bilateral ocular discharge with mild periocular skin erythema. She also reported headaches after extended reading and computer use. She noted difficulty with identifying the colors of stoplights while driving but denied flashes, floaters, or ocular pain. A review of systems was positive for the angular cheilitis and dermatitis on her hands. She denied any peripheral neurologic symptoms or signs of myelopathy, however, a full neurologic examination was not performed. Her only pertinent past ocular history included bilateral myopia with astigmatism. According to chart review and discussion, the patient first reported worsening vision during an annual visit with optometry 3 years prior to presentation to our clinic and also noted a decline in distance vision and increased difficulty driving without glasses 1 year prior. No specific events were identified as triggers for her symptoms at this presentation. Family history revealed the patient’s brother also had a history of myelopathy and vision difficulties, including slow progressive vision loss. He underwent genetic testing and was found to have evidence of a defect causing biotinidase deficiency. Additional family history was notable for a cousin who was also reportedly diagnosed with biotinidase deficiency. Our patient did not undergo genetic testing.

On ophthalmic examination, the patient had a best-corrected visual acuity (BCVA) of 20/50 in the right eye and 20/60 in the left eye with the Snellen chart. Tonometry showed the intraocular pressure in her right and left eye were 15 mmHg and 17 mmHg, respectively. The patient identified 10 out of 11 Ishihara colored plates bilaterally. Fundus examination demonstrated bilateral optic nerve pallor (Figure 1a,b). 30-2 automated perimetry (Octopus 900, Haag-Streit International, Koeniz, Switzerland) showed bilateral central scotomata (Figure 2). Retinal nerve fiber layer showed temporal thinning bilaterally (HRA OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) (Figure 3). Magnetic resonance imaging of the brain and orbit showed bilateral increased T2 signal and mild atrophy of the intraorbital optic nerves. There was no optic nerve enhancement or other abnormalities in the remainder of the brain. Laboratory results showed low-normal vitamin B12 (477 pg/mL; normal 232–1,245 pg/mL), B1 (112 nmol/L; normal 70–180 nmol/L), and folate levels (9.3 ng/mL; normal 4.6–34.8 ng/mL), a mild anemia, a mildly elevated alkaline phosphatase level and negative heavy metals testing. Infectious workup was negative for Treponema antibodies and QuantiFERON gold. Given her family history, the patient underwent testing for biotinidase deficiency. However, biotin (vitamin B7) levels were not assessed. Notably, she had a biotinidase level of <0.1 nmol/min/ml (normal 5.5–10 nmol/min/ml). The patient was diagnosed with bilateral optic neuropathy secondary to biotinidase deficiency. The patient declined a follow-up visit but reported that her vision had returned to normal following treatment with oral biotin.

Figure 1.

Fundus photographs of right eye (a) and left eye (b). Optic nerves show bilateral temporal pallor.

Figure 2.

Visual fields of the left eye (a) and right eye (b). Both eyes had depressed mean deviation with central scotoma on octopus visual field testing.

Figure 3.

Optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) images of the right eye (OD) and left eye (OS). OCT RNFL showed bilateral temporal thinning.

Discussion

Although optic neuropathy is an associated symptom of biotinidase deficiency, the incidence of biotinidase deficiency induced optic neuropathy has not been well defined. We found 40 cases reported in the literature.

Characteristics of biotinidase deficiency induced optic neuropathy

The onset of biotinidase deficiency induced optic neuropathy has been detected in all ages, ranging from neonates to adults worldwide (3 months to 49 years of age). Biotinidase deficiency induced optic neuropathy presents more commonly in males (63%) (n = 27) with an average age of 11.7 ± 12.0 years (n = 35) (Table 1). Patients experienced symptoms of biotinidase deficiency for an average of 4.3 ± 8.3 years before they were correctly diagnosed (n = 25) (Table 1). Remarkably, Ferreira et al.⁵ and Radelfahr et al.⁶ reported cases in which the patients were misdiagnosed for two and three decades, respectively, before receiving a diagnosis of biotinidase deficiency induced optic neuropathy. Individuals reported with biotinidase deficiency induced optic neuropathy had an average BCVA of 20/300 in the right eye and 20/250 in the left eye (n = 15) at the time of presentation. Only 38.9% of patients had color vision deficits (n = 18), and 100% of patients had visual field deficits (n = 19), most commonly central scotoma (n = 7) (Table 1). About 21.1% of patients had a full recovery of symptoms at the time of reporting (n = 19). Patients were treated for an average of 6.0 ± 4.9 months until recovery (n = 5) (Table 1). All patients were treated with oral biotin supplementation, with doses ranging between 10 and 300 mg per day (n = 25). The average final BCVA was 20/40 in the right eye and 20/50 in the left eye (n = 13) (Table 1).

Table 1.

Characteristics and clinical findings of patients reported with biotinidase deficiency induced optic neuropathy.^4–31

Characteristics
% Male (n = 27)	63
Average age (years) (mean ± SD) (n = 35)	11.7 ± 12.0
Average length of time experiencing symptoms before diagnosis (years) (n = 25)	4.3 ± 8.3
Overall % with full recovery (n = 19)	21.1%
Time to recovery (months) (mean ± SD) (n = 5)	6.0 ± 4.9
Case reports of patients from the following countries of origin or race were represented	Sub-Sahara Africa, France, Australia, United Arab Emirates, China, Haiti, Poland, Malaysia, Germany, Iraq, Syria, Somalia, United States
Clinical Findings
Visual field deficits (n = 19)	100%
Decreased color vision (n = 18)	38.9%
Scotoma (n = 7)	100%
% Peripheral neuropathy (n = 27)	59.3
Visual acuity at presentation in right eye (n = 15)	20/300
Final visual acuity in right eye (n = 13)	20/40
Visual acuity at presentation in left eye (n = 15)	20/250
Final visual acuity in left eye (n = 13)	20/50

n = number; SD = standard deviation.

Biotinidase deficiency detected by newborn screening

Biotinidase deficiency is an inherited disorder included in newborn screening in the United States and many other countries.³¹ The first newborn screening program that included biotinidase deficiency began in Virginia in 1984.³¹ This disorder is detected on the newborn screen through a proband that indicates multiple carboxylase deficiency based on detection of biotinidase enzyme activity deficiency in the plasma or identification of biallelic pathogenic variants in biotinidase deficiency in molecular genetic testing.³ Approximately 140 mutations have been reported for biotinidase deficiency, with the majority being homozygous or compound heterozygous.¹

However, partial biotinidase deficiency may not be detected on the newborn screen. The enzyme deficiency may appear in later childhood or even adulthood. Khan reported a case of juvenile progressive optic atrophy secondary to biotinidase deficiency in a 13-year-old female.⁷ While newborn screening for biotinidase deficiency had been performed at the hospital where this patient was born, her screening was reportedly normal.⁷

The individual with biotinidase deficiency induced optic neuropathy described in this case study was a Minnesota-born Somali American female. Sarafoglou et al. reported that newborn screening blood spots detected a high incidence of profound biotinidase deficiency in the Somali population in Minnesota.⁸ The incidence of combined partial and profound biotinidase deficiency detected by the Minnesota Newborn Screening Program between 2004 and 2008 was 1 in 8,540, and the incidence of profound biotinidase deficiency was 1 in 52,945⁸; however, the patient herein was born in 2003, prior to screening onset. Meanwhile, the reported worldwide incidence of combined and profound biotinidase deficiencies is 1 in 61,000 and 1 in 137,400, respectively,² suggesting that certain populations demonstrate higher rates of biotinidase deficiency detected in newborn screening.

Additionally, diagnostic tests for biotinidase deficiency involve detecting 3-hydroxyisovaleric acid and biotin in the urine, as well as assessing the activity of carboxylases in lymphocytes.³² Biotin-dependent carboxylases, such as propionyl-CoA carboxylase and 3-methylcrotonyl-CoA carboxylase, in lymphocytes are among the most reliable markers of biotin status. Conversely, serum biotin levels are less dependable for detecting marginal biotin deficiency, as studies indicate that serum biotin concentration often remains unchanged in patients with biotin deficiency receiving biotin-free total parenteral nutrition.³²

Pathophysiology of biotinidase deficiency

The deficiency of biotinidase leads to a lack of biotin availability for carboxylases that play key roles in several catalytic reactions.³² Biotinidase deficiency results in blockage of the following pathways, including accumulation of lactic acid and alanine due to inefficient pyruvate carboxylase; accumulation of 3-methylcrotonylglycine and 3-hydroxyisovalerate due to inefficient 3-methylcrotonyl-CoA carboxylase; accumulation of acetyl-CoA due to deficient acetyl-CoA carboxylase; and accumulation of propionate, 3-OH propionate, and methyl citrate due to deficient propionyl-CoA carboxylase.³²

Biotinidase deficiency can also have mechanistic effects on other vitamins, notably vitamin B12 and folic acid.^9,33 Biotin is a required precursor of methylmalonyl-CoA, a substrate required for the synthesis of vitamin B12.⁹ The deficiency of biotin can therefore lead to a functional B12 deficiency.⁹ Our patient with biotinidase deficiency had a low normal level of vitamin B12, B1, and folate, which may have been secondary to her low level of biotin.

It is also common for multiple related individuals or members of a family to have biotinidase deficiency due to its autosomal recessive inheritance. Although our patient did not undergo genetic testing to confirm the cause of her biotinidase deficiency, her brother showed a known genetic mutation. He experienced progressive vision loss and myelopathy. Similarly, Kellom et al. reported a case series of two brothers with biotinidase deficiency where only one of the brothers experienced optic atrophy and corresponding vision loss.¹⁰ This underscores the phenotypic variability of this disorder.

Biotinidase deficiency associated neuromyelitis optica spectrum disorder

There have been reports of biotinidase deficiency disorder mimicking neuromyelitis optica spectrum disorder (NMOSD).^{10–16,34,35} The clinical features of biotinidase deficiency can resemble symptoms typically seen with NMOSD. Neuroimaging between the disorders can also be similar and include features such as optic neuritis and involvement of the medulla, area postrema, and mamillary bodies on craniospinal magnetic resonance imaging (MRI).¹¹ As a result, many patients receive a misdiagnosis of NMOSD and have a persistence and development of new symptoms before being correctly diagnosed with biotinidase deficiency induced optic neuropathy. Differentiation between these two disorders is important as the treatment for each condition differs. NMOSD is typically treated with intravenous high-dose corticosteroids, such as methylprednisolone, to reduce inflammation of the nervous system, whereas treatment of biotinidase deficiency requires supplementation as described below.¹⁷

Treatment of biotinidase deficiency optic neuropathy

Biotinidase deficiency is one of the most treatable inherited disorders. The standard treatment for biotinidase deficiency, including cases associated with optic neuropathy, is supplementation with oral biotin. A review of patients reported with biotinidase deficiency induced optic neuropathy showed that all patients were immediately started on oral biotin supplementation once diagnosed. The dose of biotin ranged between 10 and 100 mg per day, with three outlying patients treated with 200 or 300 mg per day for a period to prevent progression of symptoms. About 21.1% of patients had a full recovery following treatment with biotin (n = 19) (Table 1), suggesting this disorder is readily treatable and reversible in some cases. Because biotin is a water-soluble vitamin that is metabolized by the liver and excreted by the kidneys, the excess accumulation of biotin in the body is rare.¹⁸ There have been no reported bodily injury secondary to the consumption of excess biotin, although adverse effects of excess biotin intake can include signs of hyperglycemia (increased urination, excessive thirst, insomnia), anaphylaxis, and eosinophilic pleuropericardial effusion.¹⁸ In the event of suspected biotin overdose or toxicity, poison control centers should be contacted.

Non-ophthalmic manifestations of biotinidase deficiency

It is important to note additional manifestations of biotinidase deficiency when performing a complete review of systems for these patients. Patients may present anywhere on the spectrum from a single presenting symptom to a multitude of neurologic or cutaneous findings.³ Neurologic manifestations may include seizures, hearing impairment, developmental delay, spinal cord involvement (i.e. hypotonia, spastic paresis, limb weakness, myelopathy).³ Cutaneous findings include skin rash, alopecia, or other dermatologic findings similar to our patient’s dermatitis and angular cheilitis. Biotinidase deficiency can also result in respiratory or gastrointestinal problems that typically resolve with treatment.³

In conclusion, this case study and review of the literature underscore that biotinidase deficiency induced optic neuropathy should be considered in patients with manifestations of bilateral optic neuropathy or NMOSD. Untreated biotinidase deficiency induced optic neuropathy may lead to progression or development of additional dermatological, immunological, neurological, and ophthalmological symptoms. Therefore, it is important to undergo a thorough review of systems for these patients to highlight any additional manifestations that may point toward this uncommon diagnosis. Early diagnosis is critical as biotin supplementation can prevent and reverse disease.

Disclosure statement

No potential conflict of interest was reported by the author(s).