A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency

Abstract

Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.

Neonatal screening for biotinidase deficiency: A 30-year single center experience

“…These excellent outcomes are in stark contrast with those of patients with late diagnosis of biotinidase deficiency, suffering from irreversible neurological damages if treated late and being even at risk of death if left untreated [16] . If newborn screening is not performed, indeed, the clinical diagnosis of biotinidase deficiency is invariably arduous, as biotinidase deficiency can mimic atopic dermatitis and a wide range of neurological conditions, including neuromyelitis optica, optic atrophy, and myelopathies [17] , [18] , [19] , [20] , [21] , [22] , [23] . Despite these clinical evidences and the cost-effectiveness of newborn screening for biotinidase deficiency [24] , however, the application of this preventive procedure is still not uniform in Europe (differently from the U.S.).…”

Biotin in metabolism, gene expression, and human disease

“…Some patients develop neurological disorders, which may include mental retardation, hearing loss, optic nerve atrophy, myelopathy, and Leigh syndrome. 4,48,49 The onset of symptoms varies from 2 weeks to 2 years of age but some patients have developed the disease much later in life. 50 All clinical and biochemical manifestations of biotinidase deficiency, excluding the neurological damage, can be ameliorated or reversed with pharmacological doses of biotin (5-20 mg/day).…”

“…The clinical and biochemical presentation of biotinidase deficiency includes alopecia, developmental delay, organic aciduria, seizures, skin rash, mild hyperammonemia, and breathing problems. Some patients develop neurological disorders, which may include mental retardation, hearing loss, optic nerve atrophy, myelopathy, and Leigh syndrome . The onset of symptoms varies from 2 weeks to 2 years of age but some patients have developed the disease much later in life .…”

“…Given the relevance of biotin function in the brain, it is not surprising that it has been linked to neurological disorders. Over the last 30 years, different biotin‐responsive neurological disorders have been identified including biotin‐responsive limb weakness, adult onset biotin‐responsive encephalopathy, biotin‐responsive Leigh syndrome, familial infantile bilateral striatal necrosis, and biotin‐responsive myelopathy . Some of these reports were later identified as cases of late‐onset biotinidase deficiency with unusual clinical profiles or were associated with raw‐egg consumption .…”

Biotinidase deficiency

“…Reports of late-onset patients are rare. 1 , 3 , 4 Hereditary spastic paraplegia (HSP) is defined as progressive lower limb spasticity and paresis. The presence of additional features such as neuropathy, ataxia, optic atrophy, and mental retardation is summarized as complex HSP.…”