A Case Report of Riboflavin Treatment and Cochlear Implants in a 4-Year-Old Girl with Progressive Hearing Loss and Delayed Speech Development: Brown-Vialetto-Van Laere Syndrome

Background

Brown-Vialetto-Van Laere syndrome, also called riboflavin transporter deficiency (BVVL or RTD), is a very rare (<1/1 000 000) progressive neurodegenerative syndrome with polyneuropathic symptoms. The origin of the disease is a mutation of the genes SLC52A2 and SLC52A3, inherited and autosomally recessive, encoding the riboflavin transporters RFVT2 and RFVT3, respectively, resulting in impaired intestinal riboflavin transport and reduced riboflavin concentrations in the body [1,2]. The symptoms consist of progressive sensorineural hearing loss with auditory neuropathy features, pontobulbar palsy (dysphagia, dysarthria), muscular weakness, sensory ataxia of the limbs and trunk, vision loss, and respiratory failure [1–5]. Diagnosis of BVVL is based on genetic testing for mutated SLC52A2 and SLC52A3 genes, but treatment with riboflavin can be started based on suspicion and clinical observations [1,2]. The primary treatment for BVVL syndrome is supplementation with high doses of riboflavin (vitamin B2) [1,6].

Riboflavin (vitamin B2) is a water-soluble organic chemical compound composed of ribitol and flavin that is absorbed by active transport in the upper small intestine. Inside cells, riboflavin is converted into its bioactive coenzymes: flavin mono-nucleotide (FMN) and flavin adenine dinucleotide (FAD). These are cofactors involved in oxidative phosphorylation and are an essential component in the metabolism of carbohydrates, proteins, and fats [3,7–10].

Brown-Vialetto-Van Laere syndrome is caused by an autosomal recessive mutation in the SLC52A2 and SLC52A3 genes, which encode the riboflavin transporters RFVT2 and RFVT3 respectively [1,3,11]. The RFVT3 transporters are located in the small intestine and are responsible for the absorption of vitamin B2 from the gastrointestinal tract and resorption in the kidneys, whereas the RFTV2 transporters are responsible for the distribution of vitamin B2 to tissues and are more highly expressed in the nervous system [1,3,7,12]. A mutant form of the RFVT3 transporter results in reduced plasma levels of riboflavin, and its coenzyme forms FMN and FAD due to impaired uptake. Reduced B2 transport leads to impaired mitochondrial activity and ultrastructural abnormalities [8–10,13].

The motor nerve dysfunction in BVVL caused by RFVT2 deficiency is due to abnormal myelin permeability. Thin or leaky myelin results in increased permeability of the myelin sheath, as riboflavin is an important cofactor in myelin synthesis [7,10]. Such impaired permeability would explain the postsynaptic nature of the auditory neuropathy underlying the hearing loss in BVVL syndrome [4,13,14].

To date, more than 100 cases of Brown-Vialetto-Van Laere syndrome have been described [1,15]. The vast majority of cases are males, and because of the higher disease burden, males with the syndrome die earlier than females. Onset of the disease ranges from infancy to the third decade of life [4,16].

The symptom most closely associated with BVVL syndrome is pontobulbar palsy with features of dysarthria and dysphagia, involving of the lower cranial nerves (VII, VIII, IX, X, XI, and XII, and less commonly upper II to VI) and motor neurons, the latter causing muscle weakness and sensory ataxia of the limbs and trunk [1,3,4,16]. As the disease progresses, it can lead to irreversible diaphragmatic dysfunction with symptoms of respiratory failure. The first symptoms of BVVL are sometimes preceded by viral infection, surgery, or trauma [2,16].

Before 2010, when the cause of the syndrome was unknown, diagnosis was based on clinical observations [1,2]. The current basis for diagnosis is genetic testing for mutated SLC52A2 and SLC52A3 genes.

The aim of this study was to present a case of Brown-Vialetto-Van Laere syndrome and to describe the method of treating the deep sensorineural hearing loss associated with this syndrome using cochlear implants.

To date, 9 cases of patients diagnosed with BVVL syndrome who were candidates for cochlear implantation have been described in the literature. The mean age at diagnosis was 6 years 8 months (SD=5), the age at which hearing loss was detected ranged from 18 months to 14.5 years (M=7 years 9 months, SD=4.66), and in 6 patients auditory neuropathy was confirmed with no response in an auditory evoked response test with otoemission. Seven patients in this group had used hearing aids, while speech discrimination benefit was limited despite riboflavin therapy. Consequently, 8 patients received cochlear implants, 1 of them bilateral [7,15,17–20].

Based on data from the available literature, Table 1 lists the patients for whom a decision was made to proceed with a cochlear implantation. The table includes a comparison of the effects of implantation.

This report is of a 4-year-old Polish girl with progressive hearing loss and delayed speech development and a diagnosis of Brown-Vialetto-Van Laere syndrome treated with riboflavin (vitamin B2) and cochlear implants.

Case Report

A four-year old girl with a diagnosis of Brown-Vialetto-Van Laere syndrome type 2 presented to the Institute of Physiology and Pathology of Hearing – World Hearing Center in Kajetany (Poland) due to progressive hearing loss and poor speech.

The history indicated normal pregnancy and delivery. Hearing screening at birth was normal. Initially, psychomotor and speech development was normal.

At the age of 2 years 10 months, the parents noticed the child’s first symptoms: clumsiness of movement, stumbling, increased tiredness, and pain in the right knee. Over time, the ailments increased: the child did not want to stand on her feet, fell over, and eventually stopped walking on her own. When sitting, she could hardly keep her balance. There was suspicion of hearing loss and deterioration of vision, there was a swallowing disorder and coughing when drinking, and she had deterioration in speech.

Due to symptoms of unclear etiology and the progressive nature of the disease, the patient was repeatedly hospitalized in the Department of Pediatrics and Neurology and the Department of Pediatric Infectious Disease.

Neurological examination revealed features of ataxia in the upper extremities, dysmetria, a shaky gait with a stagger to the right on a wide base, trunk ataxia, right-sided functional scoliosis, and lower-limb ataxia with predominance of the right side. Deep reflexes from the upper extremities were present but weak, reflexes from the lower extremities were absent, and abdominal skin reflexes were present but weak.

In addition, the parents noticed problems with visual acuity: myopia, and later horizontal nystagmus. Ophthalmologic examination revealed normal pupil responses to light, and no anterior or posterior eye abnormalities. An evoked visual potentials test could not be performed.

After an electromyography neuromuscular conduction study, there was a suspicion of generalized damage to the sensory fibers of the peripheral nerves, primarily of an axonal nature.

Magnetic resonance imaging (MRI) of the head and cervical and thoracic spine showed no abnormalities apart from a 5-mm pineal cyst (a stable lesion with no progression on subsequent examination), while lumbosacral MRI showed thickening of the spinal nerve roots with normal signal. The image was primarily consistent with post-inflammatory lesions of the meningeal sac in the L-S segment with ‘holding’ in adhesions of the spinal nerve roots.

A lumbar puncture was also performed, which revealed no cerebrospinal fluid lesions.

Laboratory tests showed elevated levels of phosphocreatine kinase and aspartate aminotransferase, and slightly elevated urea, sodium, and potassium. PCR analysis searching for viral central nervous system infection was negative. However, assays for metabolic defects by tandem mass spectrometry showed a lowered free carnitine concentration of 5.6 µmol/L (normal range, 7.3–86).

During a cardiology examination, echocardiography showed left ventricular enlargement with normal systolic function. The electrocardiogram showed a negative P-wave of 2 mm in the V1 lead (which did not meet the criteria for left atrial hypertrophy). In contrast, the patient did not show features of dyspnea, with O2 saturation of 98–99%.

A differential diagnosis included genetic and autoimmune causes, encephalomyelitis, Guillain-Barre syndrome, viral infection, neuroblastoma tumor, CLN2 disorders, and Newman-Pick type C disease.

In view of the clinical picture and test results, it was decided to institute treatment with pulses of glucocorticosteroids. After the problems worsened, immunoglobulin preparations were administered by infusion, with some improvement observed in muscle strength, fine and gross motor skills, and speech. Continuous physical rehabilitation was recommended.

The first genetic test for SCA cerebellar ataxia type 1, 2, or 3 was negative. In the karyotype study performed at MedGen Genetic Clinic, whole-exome sequencing was performed, and variants detected in genes correlated with the patient’s symptoms were analyzed (the test was performed at the age of 3 years 7 months). In the analyzed panel of genes, changes within the SLC52A2 gene in each allele were detected, with 2 pathogenic changes: a mutation localized within p.Cys159Trp(c.477C>G) and a p.Gly306Arg (c.916G>C) - heterozygous genotype. The results of the genetic test finally provided a diagnosis of Brown-Vialetto-Van Laere syndrome at the age of 3 years 9 months, allowing treatment to begin.

The positive genetic diagnosis for this patient was also able to confirm Brown-Vialetto-Van Laere syndrome in the patient’s younger sister, who was at an earlier stage of the disease. The younger girl exhibited a somewhat atactic gait, a balance disorder, kyphoscoliosis, sensory disturbance, dysarthria, and bilateral hearing loss requiring classic hearing aids. Since beginning vitamin B2 supplementation, the hearing loss has not progressed. In the family history, the other siblings – a younger brother and older children from a previous relationship of the mother – remain healthy. The parents are not related. The exact genetic status of other family members is not known.

After BVVL syndrome was confirmed, riboflavin (vitamin B2) supplementation in large doses was immediately introduced. The disease has not progressed since treatment began. Physical rehabilitation and early developmental support classes have continued.

The patient’s hearing loss was first suspected at the age of 3 years 3 months. The child asked many questions and required repeated commands. The first result of an auditory evoked potentials test at the age of 3 years 3 months was normal. Recordings from stimulation of the right and left ears showed normal values of latencies and intervals. Another ABR examination 9 months later showed bilateral unresponsiveness for 0.5 kHz and click (2–4 kHz). During this period, the patient did not wear hearing aids.

An otolaryngological examination revealed normal eardrums bilaterally, but reduced motor skills in the larynx. The child did not communicate verbally, but shouted and used gestures, body movements, and eye contact. She did not respond to sudden environmental sounds.

Another ABR test was performed, which showed no response bilaterally for 0.5, 1, 2, and 4 kHz. In impedance audiometry, there were As-type tympanograms in the right ear and A-type in the left, and absent stapedius muscle reflexes both ipsilaterally and contralaterally bilaterally. An otoacoustic emission study recorded bilateral responses at all frequencies tested. Bilateral profound sensorineural hearing loss with features of auditory neuropathy was found. The patient was qualified for cochlear implantation, initially in the right ear and then in the left ear.

At the age of 4 years 4 months, the team at the Institute of Hearing Physiology and Pathology – World Hearing Center inserted a Med-El Synchrony cochlear implant according to the PDT procedure in the patient’s right ear, followed 7 months later with another in the left. The procedures were performed using Skarżyński’s minimally invasive 6-step procedure [21–24]. Standard electrodes were inserted through the round window and encountered little resistance. No complications were reported.

The patient remains under the care of the Institute of Physiology and Pathology of Hearing World Hearing Center and is undergoing rehabilitation after cochlear implantation. Audiograms measured 5 months after implantation in the right ear and 4 months in the left ear are shown in Figures 1 and 2. Tests were performed using behavioral observation audiometry and visual reinforcement audiometry since the patient’s cooperation is limited and responses are difficult to assess. Five months after the implantation to the right ear, the mean postoperative free-field thresholds determined by behavioral observation audiometry (average frequency for 0.25, 0.5, 1, 4, and 6 kHz) with the speech processor on in the right ear (left ear open) were 74 dB. Four months after the implantation in the left ear, the mean postoperative free-field thresholds determined by behavioral observation audiometry and visual reinforcement audiometry (average frequency for 0.25, 0.5, 1, 2, 4, and 6 kHz) with the speech processor on in the left ear (right ear open) were 63 dB. Intensive auditory training, detection-level listening exercises, and sound differentiation trials have been recommended.

The parents have noted steady progress in their child’s auditory development.

Discussion

In case of the development of atypical progressive polyneuropathy-like neurological symptoms of unknown etiology in a young patient, genetic testing is indicated to detect mutations in the SLC52A2 and SLC52A3 genes, confirm Brown-Vialetto-Van Laere syndrome, and start riboflavin treatment as soon as possible.

The number of cases of this syndrome in Poland is not known, as there is no publicly available registry of cases of Brown-Vialetto-Van Laere syndrome. Only whole-exome genetic testing in the patient described allowed the detection of the SLC52A2 mutation, the correct diagnosis, and targeted treatment that stopped the progression of the disease. In the study group, the SLC52A2 mutation was detected in 6 patients and the SLC52A3 mutation in 3.

The mainstay of treatment is supplementation with high doses of riboflavin (7 to 70 mg/kg daily) [7]. Vitamin B2 therapy not only halts the progression of the disease but also saves the patient’s life – no patient has died during the follow-up period of riboflavin treatment. Before B2 therapy, the disease was considered potentially fatal [7]. Oral riboflavin supplementation should be started with 10 mg/kg/day in 3 doses for 1 month, gradually increasing the dosage by 10 mg/kg/day every month to a target dose of 50 mg/kg daily in 3 doses [10].

In some cases, a dose of 70 mg/kg/day is needed to achieve a clinical response, keeping in mind that an overdose of vita-min B2 is not possible with normal renal function, as the excess is excreted in the urine [1,3,6,25].

One of the first symptoms of BVVL syndrome is sensorineural hearing loss, gradually or suddenly progressing to profound auditory neuropathy, as shown in Table 1 [11,22,26–29]. Auditory neuropathy can be both pre- and postsynaptic in nature [4]. Fazio-Londe syndrome, which has an identical basis to BVVL, differs from the described syndrome only in the absence of auditory symptoms, probably due to the earlier development of the condition and a worse prognosis, which, untreated, typically led to death [2,5]. The time of onset of deafness to subsequent symptoms averages 5 years in males and 11 years in females [16].

Of the 62 BVVL syndrome type 2 patients reported to date, sensorineural hearing loss has been found in 84% of them. After ataxia, hearing loss is the second most common symptom of the syndrome [7]. Treatment of hearing loss in BVVL syndrome depends on the degree of impairment and the stage of the underlying disease. The literature shows an improvement in the clinical picture and hearing level after riboflavin therapy. For example, Foley and colleagues successfully treated a patient with a dose of 10 mg/kg/day, which was increased to 50 mg/kg/day over 12 weeks with evaluation after 3 months [3]. There was a marked improvement in audiometric tests, from 80 dB at 8 kHz before riboflavin therapy to 40–55 dB at 8 kHz afterwards [3]. Recently, Carey and colleagues reported hearing improvement in 3 cases after long-term (3–6 months) treatment with riboflavin (1–1.5 g/d), use of hearing aids, and speech therapy [27].

Mutlu et al [28] described the case of a 6-year-old boy with features of auditory neuropathy, in whom rapid 20-month supplementation with very high doses of riboflavin (750–900 mg/d) resulted in an improvement in hearing threshold. Before therapy, thresholds in play audiometry showed a profound degree of hearing loss and no benefit from hearing aids; after therapy the speech recognition threshold rose to 30 dB SPL measured by free-field audiometry in a quiet room. With hearing aids, a speech discrimination score of 84% was achieved.

Unfortunately, the effects of therapy are not good in all cases. Supplementation often improves the neurological condition of the patient, but the accompanying hearing loss does not regress and hearing aids do not provide much benefit in speech understanding, as shown in Table 1 [22,26,27–29]. In such cases, cochlear implants are the treatment of choice, and the post-device effects are comparable to auditory neuropathy from other etiologies [4,14,31–33].

The neuropathological basis of hearing loss has been demonstrated by changes, among others, in the auditory pathway (neuronal degeneration in the cochlear nucleus of the brainstem and astrocytic gliosis in the inferior thalamus). These pathologies have been detected in postmortem examinations of the brains of patients with BVVL [7,34,35].

Preliminary functional magnetic resonance imaging studies using intermittent toneburst stimulation at 2 kHz in a patient described by Salmina et al suggest that the central auditory pathways remain intact and provide a positive argument for cochlear implantation to restore hearing [33].

The patient’s case is compared in Table 1 with case reports of BVVL patients qualified for cochlear implantation available in the literature. In 4 cases, the hearing loss preceded the onset of the other symptoms of the disease; in our patient, the hearing loss joined the motor symptoms after 5 months and was gradually progressive. An interesting case is described by Gedik at al [17], in whom a sudden deterioration in speech understanding was noted in the patient’s first speech audiometry and tonal audiometry study, without a deterioration in hearing thresholds. Bilateral profound sensorineural hearing loss was noted in all cases, with auditory neuropathy in 6 cases [7,15,17–20].

Hearing aids were tried in all patients, but unfortunately the benefit was limited, or the hearing aids provided no benefit in speech understanding despite supplementation with high doses of riboflavin. Our patient did not wear hearing aids permanently, (1 hearing aid fitting was performed, without observing the benefit of hearing aids). Eight out of 9 patients decided to have a cochlear implant, and 1 patient decided not to. Our patient’s first cochlear implant was implanted about 1 year after the diagnosis of hearing loss, while the average time from the diagnosis of hearing loss to cochlear implantation in the study group was about 11 years [7,15,17–20].

The post-implantation effects in our patient were evaluated 4 and 5 months after implantation, whereas in the other patients this evaluation was performed at between 3 months and 5 years. Different methods were used: free-field audiometry, which showed effects at the level of mild to moderate hearing loss for frequencies of 2 and 4 kHz in 3 cases described by Anderson et all [18] and 1 case described by Sinnathuray et al [20], and verbal audiometry using the Bench-Kowal-Bamfort sentence test, which showed effects of 0%, 25%, and 94%, respectively, for the cases described by Menzes et al [19] and Sinnathuray et al [20]. Our patient’s post-implantation effects were assessed 4 and 5 months after implantation at the level of progression from profound to moderate hearing loss in the right ear and severe hearing loss in the left ear (averaged for frequencies from 0.25 to 6 kHz, assessed separately for each device). In a free-field test using behavioral observation audiometry (BOA) after 5 months after implantation, the average hearing level was 74 dB in the right ear (left ear open). In the left ear, the average hearing level was 63 dB (right ear open) 4 months after implantation using behavioral observation audiometry (BOA) and visual reinforcement audiometry (VRA). The effects of the device after cochlear implantation in the described patient are comparable to the results in patients with auditory neuropathy [14].

It is difficult to compare of the effects after cochlear implantation in the analyzed group because of the different ages of onset of hearing loss (pre-, peri-, post-lingual), the time elapsed between the onset of symptoms and the start of riboflavin therapy and its different dosage, the time of assessment of the effects after implantation, and the use of different methods of assessing the effects after implantation.

Conclusions

This report has highlighted the importance of genetic testing in infants who present with atypical symptoms or signs. Brown-Vialetto-Van Laere syndrome, despite its extreme rarity, should be taken into account during the differential diagnosis of young patients with progressive auditory neuropathic symptoms accompanied by ataxia and sternocleidomastoid palsy of unclear etiology. It is then advisable to extend the genetic diagnosis to BVVL syndrome.

If Brown-Vialetto-Van Laere syndrome is suspected, vitamin B2 supplementation should be started immediately, even in the absence of a genetic test result, in order to prevent the possible progression of the disease. Unfortunately, in the vast majority of cases, it is not possible to improve the hearing threshold despite the supply of riboflavin, so early therapy is extremely important to preserve the patient’s hearing.

In cases of severe or profound hearing loss in BVVL syndrome, especially when the patient does not experience improvement in speech understanding despite the use of hearing aids, the treatment of choice is cochlear implantation. The effects after implantation depend on the stage of the underlying disease, the time of onset of the hearing loss (pre- or postlingual), and its duration until cochlear implantation, and they are comparable to those seen in other postsynaptic auditory neuropathies.

In this case, the diagnosis of Brown-Vialetto-Van Laere syndrome led to timely correction of the genetic riboflavin (vita-min B2) deficiency and improved hearing following cochlear implantation.

Patients with this condition require multispecialist care—neurological, otolaryngological, and ophthalmological, as well as physiotherapeutic and neurological.