Cochlear Implantation in Biotinidase Enzyme Deficiency

Abstract Metabolic syndromes associated with hearing loss are rare and are characterized by specific enzyme pathway deficiencies involving lysosomal storage, peroxi- somes, fatty acid enzymes, organic acids and amino acids. The deficiency of biotinidase, an enzyme involved in the metabolism of biotin, is one such rare cause of congenital hearing loss estimated at 1:60,000 newborns. The parents of a 5-year-old girl presented to the clinic with complaints that she was hard of hearing with no speech development. At age 2 she had been diagnosed with organic aciduria and hydronephrourethrosis and was operated for renal calculi. Clinical examination showed periorificial scaly skin lesions and eczematous otitis externa. An audiological evaluation showed bilateral profound SNHL. Imaging and routine investigations were unremarkable, except for a mild low anion gap metabolic acidosis. General anaesthesia involved avoidance of neuromuscular agents due to the risk of inducing hypotonia. Surgery consisted of cortical mas- toidectomy followed by the facial recess approach. A standard electrode array was inserted via the round window technique and complete atraumatic insertion was achieved. Intraoperative electrode impedance and NRT tracings were good. Hearing loss in biotinidase deficiency may be expected to be of progressive nature and regular evaluation of hearing and speech is required. Cochlear implantation is currently the best available solution for severe to profound hearing loss in this disorder although the enzymatic pathology affects the entire auditory pathway. Biotin sup- plementation is required lifelong for its management.

Introduction
The genetic causes of hearing loss can be divided into non- syndromic (70%) and syndromic (30%) [1]. Of the latter, hearing loss in metabolic syndromes characterized by specific enzyme deficiencies is rare. These include lyso- somal storage disorders, peroxisomal disorders, fatty acid enzyme disorders, organic acid and amino acid disorders. The parents of a 5-year-old girl presented to the clinic with complaints that she was hard of hearing with no speech development. She was the only child, born after two con- secutive miscarriages to second degree consanguineous parents, out of a full-term pregnancy via normal vaginal delivery with no intra-partum complications. The mother had been treated for gestational diabetes mellitus with metformin. Birth weight was 2.45 kg with an APGAR score of 6. The child had a history of NICU care for central hypotonia with neonatal seizures of the GTC variety which have been controlled with regular prophylaxis involving Phenytoin and Sodium Valproate. She was diagnosed with organic aciduria with hydronephrourethrosis and was operated for renal calculi at age 2 years. Although her milestones were noted to be delayed, she is capable of self- care at present.Her clinical examination was unremarkable, except for periorificial scaly erythematous lesions and eczematous otitis externa (Fig. 1). Audiometry showed bilateral pro- found SNHL on BERA with absent OAE. Tympanometry demonstrated type A curves bilaterally with the aided audiogram showing out of spectrum thresholds. An HRCT of the temporal bones showed bilaterally normal cochleovestibular anatomy with pneumatized mastoids (Fig. 2). MRI demonstrated bilaterally normal VII and VIII cranial nerve complexes and normal brain anatomy. Rou- tine preoperative investigations revealed normal renal function and serum electrolytes in the presence of a low anion gap metabolic acidosis on ABG. Her urine was negative for ketones and she was recently treated for aurinary tract infection. Serum biotinidase level was0.5nmol/min/ml (Normal [ 5 nmol/min/ml). Cardiac and ophthalmology consultations were unremarkable, but the dermatologist consult revealed acrodermatitis acidemia with alopecia. Speech evaluation showed a language dis- order secondary to hearing impairment. After an MDT consultation, she was cleared for surgery.Anaesthesia was induced with low dose propofol and fentanyl with avoidance of neuromuscular agents due to the risk of inducing hypotonia. Anaesthesia in such cases demands complete avoidance of hypoxia and acidosis while maintaining the patient’s hemodynamic status. Sur- gery involved development of an anteriorly based Palva flap. Cortical mastoidectomy was done followed by the facial recess approach via which the round window was identified and its bony overhang drilled to improve visu- alization. A standard electrode array introduced via the round window technique allowed for complete and atrau- matic insertion. Intraoperative electrode impedance and NRT tracings indicated correct placement. Anaesthesia emergence was smooth and uneventful resulting in the child getting discharged from hospital the next day.

Discussion
Biotin is a water-soluble vitamin, which in its free, unbound form is actively transported across intestines as biocytin (the protein bound form of biotin), and enters the free biotin pool. It is used as a coenzyme by carboxylases in catabolism of several branch chain amino acids, fatty acids and gluconeogenesis. Biotinidase is a cytosolicenzyme that liberates free biotin from biocytin during the normal proteolytic turnover of these carboxylases, making the vitamin available again in the free biotin pool [3]. Thus, this enzyme deficiency results in failure of recycling and consequent emptying of the biotin pool [4].Biotinidase deficiency is an inherited autosomal reces- sive disorder characterized by secondary consequences in amino acid, carbohydrate and fatty acids metabolism [5]. It has been classified as a multiple carboxylase deficiency with two forms: neonatal and late-onset. Biochemical features common to both include metabolic ketoacidosis, hyperammonemia and organic acidemia. Clinically the symptoms range from vomiting, lethargy and hypotonia in the neonatal form, to seizures, ataxia, skin rash, alopecia, vision and hearing disturbances in the late-onset form. The cutaneous and neurologic symptoms occur early in the disease with ketoacidosis and organic aciduria appearing only after protracted biotin deficiency [6]. The diagnosis is based on serum levels of enzymatic activity, with less than 10% of mean normal levels indicating profound enzyme deficiency while 10–30% of mean normal levels indicating partial biotinidase deficiency [7]. The mean normal serum biotinidase activity is 7 U/L with a range of 4.4 to 12.2 U/L [8].Clinical manifestations primarily involve four sys- tems—neurologic, cutaneous, vision and hearing. Seizures are seen in 70% of patients and often as the first sign [9].

There is no type of seizure or pattern on EEG associated with this disorder. Seizures tend to be intractable to routine anticonvulsant medications but sensitive to biotin therapy within minutes to hours of administration. It is recom- mended that a trial of biotin should be considered in any child with poorly controlled seizures [10]. The most common eye finding is optic neuropathy, with or without vision loss. Infections like conjunctivitis, blepharitis and corneal ulceration are also common. The infections respond to biotin treatment, while the optic neuropathy does not [11]. Skin manifestations include a periorificial dermatitis characterized by mild, scaly erythema and crusted erosions [12]. Alopecia is evident in the diffusely thin and fine scalp hair with marked hair fall [13]. Sec- ondary skin infections in these patients have been linked to defects in T cell and B-cell immunity [14], which was evident in this patient who had been treated for otitisexterna due to Proteus Mirabilis, an uncommon cause, and vulvar candidiasis [15].Sensorineural hearing loss is noted in 76% of children with biotinidase deficiency [16]. This has been demon- strated to be reversible if diet is supplemented with biotin within the 1st months of life, beyond which no response is seen [16, 17]. A study on biotin metabolism of the brain showed that biotinidase immunoreactive neurons were found in the dorsal and ventral cochlear nuclei, superior olivary complex and vestibular nucleus. Also noted was that although the enzyme is expressed in low levels throughout the brain, its activity is concentrated along the auditory pathway including the cochlear nuclei, cochlea and inner hair cells [18]. Various studies have addressed BERA findings in this group with responses that have been variable ranging from completely absent [19], or absent responses specific to higher frequencies [20], to delayed latencies [21], with prolongation of latencies worsening with time [8].The cornerstone of treatment is supplementation with Biotin up to 10 mg/day with an increase in dose considered in the presence of persistent symptoms. The hearing dis- ability can be expected to be progressive subject to dietary supplementation. Bilateral hearing aids are indicated for moderate to severe loss, while severe to profound loss is best managed with cochlear implants. Children might not report hearing loss, especially when progressive, and a high index of suspicion must be maintained in known cases of this enzyme deficiency. Audiometry (BERA and OAE) with speech and language evaluation should be done every 6 months in the early years of development. There is no data evaluating the long-term hearing outcomes in this enzyme deficiency. Evidence is also required regarding the long-term benefits of cochlear implantation, considering the underlying pathology of this disease.

Conclusion
Early diagnosis and treatment with biotin is essential for preserving normal central and peripheral hearing [8, 16, 22]. Hearing loss can be expected to be of pro- gressive nature and regular evaluation of hearing and speech is required. Cochlear implantation is currently the best available solution for severe to profound or worse hearing loss in this BAY-1816032 disorder although the enzymatic pathology affects the entire auditory pathway. Biotin sup- plementation is required lifelong for the management of this multisystem metabolic disorder.