Reversal of Vision Loss in a 49-Year-Old Man With Progressive Optic Atrophy Due to Profound Biotinidase Deficiency

Biotinidase is the enzyme that recycles the vitamin, biotin, for use in the body (1). Biotinidase deficiency, an autosomal recessive disorder, is due to mutations in the biotinidase gene BTD and is a readily treatable inherited disorder of metabolism (1,2). Left untreated, individuals cannot recycle biotin, which subsequently causes secondary biotin deficiency and multiple carboxylase deficiencies resulting in metabolic abnormalities (3). In childhood, the untreated disorder usually exhibits various neurological and cutaneous symptoms including seizures, hypotonia, ataxia, respiratory problems, dermatitis, alopecia, sensorineural hearing loss, optic atrophy, and developmental delay (4). Occasionally, this leads to coma and death. The disorder can also present in adolescence or young adulthood (5–8). Older untreated individuals develop optic atrophy and/or peripheral neuropathy, with the oldest reported being a 36-year-old mother (5,9,10). Because these symptoms can be completely prevented and treated by biotin supplementation, biotinidase deficiency has been added to newborn screening programs throughout the United States and in many countries (2). However, most adults with the enzymatic deficiency are too old to have been screened as a newborn. We report a 49-year-old man exhibiting progressive optic atrophy, peripheral neuropathy, and systemic weakness and fatigue due to biotinidase deficiency. His profound biotinidase deficiency was identified by whole exome sequencing (WES) and confirmed by enzymatic testing in serum. His symptoms improved, and vision lost was partially restored with biotin therapy. METHODS A 49-year-old man was referred for genetic counseling for bilateral, progressive optic atrophy, which began at about 40 years of age. Initial symptoms included fluctuating vision and difficulty focusing while reading or driving and were attributed to dry eye and refractive error. By 46 years of age, bright lights would "wash out" his vision. He also began experiencing photophobia, tunnel vision, dyschromatopsia, and nyctalopia. Optic nerve damage was noted on examination at 47 years of age, prompting a tentative diagnosis of low-tension glaucoma given intraocular pressures of 11 and 10 mm Hg in the right and left eyes, respectively. Ishihara color testing was 0/11 plates bilaterally. Snellen visual acuity was 20/25-2 bilaterally, and Humphrey visual field 24-2 SITA standard testing showed severe restriction to the degree of legal blindness (Fig. 1A, B). The patient was then referred to neurology and neuro-ophthalmology where fundus photography of the optic nerves was performed (Fig. 2). There was marked cupping and pallor of both optic nerves with bilateral thinning to the edge of the disc temporally. Laboratory evaluations for nutritional optic neuropathy (vitamin B12 and folate) and infectious neuropathies (Lyme disease and syphilis) were negative. Electroretinogram and visual-evoked potentials were not pursued at that time.FIG. 1.: Humphrey visual field 24-2 SITA standard threshold test demonstrating visual field defects of both the (A) left eye and (B) right eye 15 months before treatment with biotin supplementation (reliable tests, both eyes, mean deviation −29.3 db right, −29.51 db left). Five months after starting biotin treatment, both (C) left eye and (D) right eye show significant improvement with inferior visual field most improved in both eyes (reliable tests in both eyes, mean deviation −17.02 db right, −17.43 db left).FIG. 2.: Fundus photography of right eye (A) and left eye (B). Optic nerves show pallor and temporal enlarged optic nerve cupping. Macula and retinal vasculature otherwise are unremarkable, in both eyes.An MRI of the head and orbits demonstrated symmetric T2/FLAIR signal propagation, thickening, and enhancement involving the intraorbital, intracanalicular segments of both optic nerves and optic chiasm. In addition, there was dilation of the optic nerve sheaths. This imaging was suggestive of perineuritis. A diagnosis of multiple sclerosis was considered, in part due to his lower extremity weakness. However, cerebrospinal fluid was normal/negative with normal oligoclonal bands and immunoglobulin G synthesis rates. At a neuro-ophthalmology follow-up visit 10 months later, he had a working diagnosis of progressive bilateral optic neuropathy. Visual acuity remained stable at Snellen visual acuity of 20/25 both eyes and normal intraocular pressures at 11 and 13 mm Hg of the right and left eyes, respectively. However, he complained of further visual field loss. Optical coherence tomography-retinal nerve fiber layer testing showed further thinning of the retina ganglion cell layer bilaterally. Consideration for OPA1 molecular testing was discussed, although not performed at the time due to denial of insurance coverage. He was then referred to medical genetics. Given the broad differential diagnosis for syndromic optic atrophy, he elected to undergo WES. WES was negative for common genetic causes of optic atrophy, but revealed 3 mutations in the BTD gene: The c.98_104delinsTCC variant results in the replacement of GCGGCTG nucleotides at positions c.98 through c.104 of the BTD gene with TCC nucleotides, causing a frameshift in the protein-reading frame, resulting in a nonfunctional protein. This variant is commonly reported in individuals with profound biotinidase deficiency and is classified as pathogenic (11). The c.[511G>A;1330G>C](p.[A171T;D444H]) combination allele consists of 2 variants. The c.1330G>C (p.D444H) missense variant results in the substitution of the aspartic acid codon at amino acid position 444 with a histidine codon 9. This variant, when not part of the complex allele, is a common cause of partial biotinidase deficiency (12). The c.511G>A (p.A171T) missense variant results in the substitution of the alanine codon at amino acid position 171 with a threonine codon. These combined variants when in cis result in very low enzyme activity (13). His serum biotinidase activity demonstrated minimal residual activity (0.3-nmol PABA/mL/min; normal: >5-nmol PABA/mL/min), confirming a diagnosis of profound biotinidase deficiency (2). The patient was immediately started on 10 mg of oral biotin supplementation daily. RESULTS Within 2 weeks of starting biotin supplementation, he reported subjective improvements in contrast and peripheral vision to the point that he was able to see a constellation of stars in the night sky. Before treatment, per the patient, he could see only one or 2, bright stars. He underwent re-evaluation at 2 months and again at 5 months after initiating treatment. Visual acuity remained at 20/25 by Snellen bilaterally at both visits, and intraocular pressures remained stable at 10, 11 mm Hg in the right eye and 12, 13 mm Hg in the left eye. At 2 months after treatment, he broke into tears after viewing an Amsler grid and realizing the improvement in central vision from his initial evaluation about 18 months earlier. At 5 months after treatment, visual field testing revealed continued recovery of peripheral vision (Fig. 1C, D). He asked to be assessed again for driving, and both Goldmann and HVF testing showed improvement to where his driver's license could be reinstated. The patient also reported subjective improvement in photophobia, dyschromatopsia, and nyctalopia, although Ishihara color testing was minimally improved (4/11 in the right eye and 3/11 in the left eye) compared with 0/11 in both eyes at baseline. Dilated fundus examination was very stable with continued optic nerve pallor and temporal cupping. Subjective improvements in other systemic symptoms were also noted. Previous pruritus resolved, potentially due to improvement in dry skin. Neuropathic extremity pain, previously attributed to degenerative disc disease, improved substantially. This allowed him to wean completely from pain medication, ambulate for much farther distances and perform home improvement projects without fatigue. Previously reported hearing loss, which may or may not have been due to his deficiency, has remained unchanged. CONCLUSIONS Biotinidase deficiency is a readily treatable inherited disorder of metabolism, which typically presents in childhood. This case reports the oldest known individual with biotinidase deficiency to present initially with symptoms—in this case, with symptomatic onset in late 20s. As in other later-onset cases of biotinidase deficiency, this individual presented with optic atrophy and peripheral neuropathy (7,10,14). Similar to other cases, multiple sclerosis was a leading diagnosis (15). Other individuals have also been diagnosed with vision abnormalities and myelopathies, such as neuromyeletis optica (7,10,14). In addition, our patient is the oldest to exhibit reversal of symptoms. This case demonstrates the treatability and reversibility of symptoms into adulthood. A previous report of a 36-year-old woman with the identical genotype as the patient from this report had no improvement in her symptoms, suggesting that the damage that occurred before diagnosis and treatment may be irreversible (16). Our case suggests there is a broad window of successful treatability; however, the sooner the diagnosis and treatment, the better the chance that the symptoms are reversible. Although the optic atrophy in children with biotinidase deficiency appears to be irreversible once it develops (3), the optic neuropathy in this case and in other enzyme-deficient adults is reversible to varying degrees. Therefore, the ophthalmological pathology in maturely developed eyes of adults may be more responsive to biotin therapy than in children. The mechanism for this sensitivity to biotin remains to be determined. However, as we have seen in adults, if too long a period occurs from the development of optic neuropathic symptoms to the time of diagnosis and therapy, these findings may be irreversible. Screening by determining serum biotinidase activity testing is a rapid, inexpensive, and effective diagnostic method. Identification and treatment have the potential to ameliorate or at least halt the ophthalmological and neurological issues associated with biotinidase deficiency. This individual highlights the importance of considering biotinidase deficiency in the differential diagnosis and testing for it in older individuals with progressive optic atrophy. Failure to make the diagnosis and initiate treatment in a timely manner may result in irreversible clinical symptoms. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. R. Kellom, B. Wolf, G. M. Rice, and K. E. Stepien; b. Acquisition of data: E. R. Kellom, G. M. Rice, and K. E. Stepien; c. Analysis and interpretation of data: E. R. Kellom, B. Wolf, G. M. Rice, and K. E. Stepien. Category 2: a. Drafting the manuscript: E. R. Kellom, B. Wolf, G. M. Rice, and K. E. Stepien; b. Revising it for intellectual content: E. R. Kellom, B. Wolf, G. M. Rice, and K. E. Stepien. Category 3: a. Final approval of the completed manuscript: E. R. Kellom, B. Wolf, G. M. Rice, and K. E. Stepien.