Reversible deafness caused by biotinidase deficiency

Reversible Deafness Caused by Biotinidase Deficiency Rachel Straussberg, MD*, Esther Saiag, MD†, Liora Harel, MD*, Stanley H. Korman, MBBS§, and Jacob Amir, MD* We present a child with complete biotinidase deficiency who developed bilateral sensorineural deafness without a response to a maximal stimulus of 90 dB in brainstem acoustic-evoked response. After treatment with 20 mg biotin daily, a repeated brainstem acousticevoked response demonstrated an improved hearing threshold of 65 dB, and the child began to talk. The case is a rare example of reversible hearing loss caused by to biotinidase deficiency and highlights the need for immediate replacement therapy once the diagnosis is established. © 2000 by Elsevier Science Inc. All rights reserved. Straussberg R, Saiag E, Harel L, Attias J, Korman S, Amir J. Reversible deafness caused by biotinidase deficiency. Pediatr Neurol 2000;23:269-270.

Introduction Biotin is a cofactor required by the enzymes acetylcoenzyme A carboxylase, pyruvate carboxylase, propionylcoenzyme A carboxylase, and 3-methylcrotonyl-coenzyme A carboxylase. It is covalently attached to these apocarboxylases, where it functions at the active site as a carbon dioxide carrier in the carboxylation reactions. The turnover of the carboxylases yields biotinyllysine (biocytin), from which biotin is regenerated by the action of a specific amidolyase, biotinidase [1]. This enzyme is also required for the release of dietary protein bound biotin [2]. Biotinyl-transferase activity is another function of the enzyme [3,4].

The clinical features of biotinidase deficiency include seizures, hypotonia, ataxia, breathing problems, skin rash, alopecia, hearing loss, optic atrophy, and developmental delay [5]. The hearing loss is usually irreversible [6]. We present a patient in whom hearing impairment caused by biotinidase deficiency improved significantly after a few months of biotin treatment.

Case Report A 3-month-old infant was admitted because of myoclonic and generalized tonic-clonic seizures. He was born at term to a Palestinian couple who were first-degree cousins. The pregnancy had been uneventful. Delivery was performed by vacuum extraction. His Apgar score was normal. No perinatal or neonatal problems were evident. An older brother was healthy. On neurologic examination, the infant appeared lethargic. His eyes had a glazed expression. He failed to fixate his gaze and to follow objects. There was severe truncal and axial hypotonia with significant head lag, failure to sustain weight on a vertical position, and failure to lean on his elbows while lying prone. On physical examination, a mild seborrheic rash on the scalp was evident. Diffuse rhonchi and prolonged expiration were heard over the lungs. Mild conjunctivitis was present. No dysmorphic features were evident. Blood counts, electrolytes, renal and liver tests, blood gases, and ammonia were all within the normal range. The blood lactate level was 23 mg/dL (normal up to 18). The cerebrospinal fluid glucose and protein levels were normal but lactate was elevated at 44.4 mg/dL (normal up to 18). Assays for very long chain fatty acids, blood, urine, and cerebrospinal fluid amino acids were normal. Urinary organic acids manifested excessive excretion of 3-OH-isovalerate and 3-methylcrotonylglycine. Excretion of methylcitrate was mild. Examination of blood acylcarnitines revealed an elevation of 3-methylcrotonylcarnitine to 2.2 nmol/mL (normal up to 0.08). The blood biotinidase level was 0 nmol/min/mL (normal range ⫽ 4-15). The visual-evoked potential study revealed a clear cortical response, with normal high amplitude and latency within the upper normal range. The brainstem acoustic-evoked response performed at 4 months of age revealed no response from the acoustic nerve and brainstem to a maximal stimulus of 90 dB, applied separately to each ear. These findings suggested profound sensorineural deafness. Treatment with biotin 20 mg daily was initiated. Within days, he manifested a marked improvement. He became alert and vibrant, began to smile and laugh aloud, and was able to fixate his gaze and follow. The seizures stopped with the initiation of biotin administration. At 6 months of age, his tone had improved and no head lag was evident. When lying prone, he attempted to rise up. At 8 months old, he continued to improve. He began crawling, vocalizing, and laughing. At 10 months of age, he began saying two words. At 1 year of age (i.e., 8 months after the initial brainstem acousticevoked response) while receiving biotin therapy, a repeated brainstem acoustic-evoked response study demonstrated a marked improvement in

From the *Department Pediatrics; †Metabolic-Genetic Unit; and ‡ Electrophysiologic Unit; Schneider Children’s Medical Center of Israel; Sackler School of Medicine; Tel Aviv University; Petah Tiqva; and §Department of Clinical Biochemistry; Hadassah Medical Center; Hebrew University; Jerusalem, Israel.

Communications should be addressed to: Dr. Straussberg; Department Pediatrics C; Schneider Children’s Medical Center of Israel; Petah Tiqva, Israel. Received February 14, 2000; accepted May 1, 2000.

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Straussberg et al: Biotinidase Deficiency and Reversible Deafness 269

the function of the acoustic nerve and brainstem. The hearing threshold of the right and left ear was 65 dB and 70 dB, respectively. In the range of lower frequencies, his hearing was even better at 50-60 dB. At 1 year, 6 months, he was able to speak a few words.

Discussion Since the first description by Wolf in 1983 [7], sporadic reports of severe biotinidase deficiency have been published. It has been stressed that the presentation of biotinidase deficiency may vary [1]. The clinical course is characterized by either acute or insidious onset. The initial symptoms can appear in the very early neonatal period [8] or even during adolescence [9]. The usual age at onset is 3 months to 5 months, 2 weeks. The most common clinical features of biotinidase deficiency are hypotonia, seizures, ataxia, respiratory problems, skin rash, alopecia, developmental delay, hearing loss, optic atrophy, conjunctivitis, and fungal infections. Biochemical findings include lactic acidosis, organic aciduria, and hyperammonemia [7]. The physician should be alert during the early months after birth; a high index of suspicion is needed, because metabolic acidosis may not be a constant finding and the excretion of urinary organic acid may not be obvious. When the abnormalities occur late in childhood or during adolescence, they are characterized by motor limb weakness, spastic paresis, and eye problems such as loss of visual acuity and scotoma [9]. Hearing loss was diagnosed in 40% of 31 patients in the series by Wolf et al. [10] before the initiation of biotin treatment and was usually high-frequency sensorineural deafness. Wastell et al. [1] reported on the auditory complications caused by biotin deficiency in five of 10 patients. In one patient, sensorineural deafness, which was initially absent, developed while the child was receiving biotin treatment. In most reports, once sensorineural deafness was encountered, it remained a constant feature, and the children remained deaf [1,8,10,11]. To the best of our knowledge, only two cases concerning the reversal of sensorineural deafness after biotin treatment have been reported. In a report by Nothjunge et al. [12] in 1989, a 13-month-old patient developed hypotonia, deafness, and skin rash because of biotinidase deficiency. After 6 months of treatment with biotin 10 mg daily the deafness significantly improved. Another child who had moderate hearing loss, not as severe as in our child, improved to normal hearing after treatment with biotin (B. Wolf, personal communication). Currently, we do not know the exact mechanism by which biotinidase deficiency is responsible for deafness. The possibility that impairment of the biotin recycling pathway may be responsible for early biotin deprivation in the central nervous system has been suggested [13]. Early recognition of this condition and proper treatment may occasionally reverse the hearing loss (B. Wolf, personal communication).

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Because both the cutaneous signs and organic aciduria may be absent in the initial phase of the disease and the clinical features of the disorder are preventable by biotin therapy initiated before the appearance of the signs, it is imperative to perform a therapeutical trial with biotin in infants with severe and persistent seizures and developmental delay [14]. A neonatal screening method using dry blood-soaked filter papers, currently used in many states in the United States and other countries is another option for early detection of this treatable disorder [15]. In summary, we present an infant with complete biotinidase deficiency in whom early and high-dose biotin treatment resulted in the reversal of deficits, including sensorineural hearing loss.

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