Research paperPerinatal thiamine deficiency causes cochlear innervation abnormalities in mice
Introduction
Auditory neuropathy is a type of sensorineural hearing loss resulting from disorders affecting inner hair cells (IHCs), cochlear sensory neurons or the synapses between them (for review, see Starr and Rance, 2015). It can be congenital (Bahmad et al., 2007, Santarelli et al., 2009, Pangrsic et al., 2010) or acquired (Beutner et al., 2007), and it is diagnosed based on the presence of otoacoustic emissions despite an absent or highly disorganized auditory brainstem response (Hood, 2015). A number of risk factors have been identified. For example a high incidence of auditory neuropathy is found in infants born prematurely (Xoinis et al., 2007). Recently, a study of infant temporal bones revealed that 30% of preterm babies who died in the NICU had selective inner hair cell (IHC) loss, while only 3% of full-term infants presented such a phenotype (Amatuzzi et al., 2011). This high prevalence for such a rare histopathology (Schuknecht, 1993) suggested that selective IHC loss might be a common cause of auditory neuropathy.
Our group recently reported a link between IHC loss and thiamine, a water-soluble vitamin (B1) required for intermediary metabolism. Patients with the syndromic disorder known as Thiamine-Responsive Megaloblastic Anemia (TRMA) have hearing loss in addition to the pathognomonic anemic symptoms (Fleming et al., 1999, Fleming et al., 2001). Genetic analysis revealed a mutation in one of the two transporters involved in trafficking thiamine across cell membranes: SLC19A2. Targeted deletion of SLC19A2 in mice causes auditory neuropathy and selective IHC loss when animals are challenged with a diet low in thiamine (Liberman et al., 2006).
Further evidence for a link between thiamine and auditory neuropathy was provided by a study of children who were bottle-fed from birth with an infant formula completely lacking in thiamine due to a manufacturing error. As infants, these children were hospitalized with a variety of neurological symptoms consistent with thiamine deficiency, collectively known as Wernicke's encephalopathy (Fattal-Valevski et al., 2005). Continued follow-up showed an extraordinarily high percentage of auditory neuropathy (Attias et al., 2012).
Combining all these observations, we wondered if the link between prematurity and auditory neuropathy might reflect an immaturity of thiamine transporters in preterm infants coupled with varying standards for thiamine supplementation during NICU stays (Friel et al., 2001). To gain insight into the effects of thiamine deprivation in the perinatal period, we deprived mice of dietary thiamine during pregnancy and/or nursing. We let the offspring mature to varying ages, measured cochlear function by ABRs and DPOAEs and evaluated the degeneration of hair cells and their afferent and efferent innervation. We found no evidence for selective IHC loss; however, many thiamine-deprived animals showed dramatic abnormalities in the cochlear afferent and efferent innervation, and associated cochlear functional abnormalities consistent with the diagnosis of auditory neuropathy.
Section snippets
Animals, procedure and statistical analysis
CBA/CaJ mice were used in all experiments. To control thiamine intake, a thiamine-free chow was obtained from TestDiet® (TestDiet.com) in powdered form. The formulation was identical, in all other respects, to that established for use in mice by the American Institute of Nutrition. The desired thiamine concentration was adjusted by addition of powdered thiamine diluted in water. The mixture was provided as a moist gruel.
Mice were assigned to one of three groups: 1) Control animals, which were
Results
Normal mouse chow contains 22 mg/kg thiamine. In this study, mice were fed with a chow containing either 1) 22 mg/kg thiamine, 2) 0.2 mg/kg thiamine or 3) 0 mg/kg thiamine. As schematized in Fig. 1, thiamine deprivation was implemented either prenatally or postnatally for durations ranging from 2 to 6 wks. There were no pregnancies when mice were fed 0 mg/kg thiamine for more than 3 wks. Under a low-thiamine diet (0.2 mg/kg), pregnancies went to term only when thiamine restriction lasted less
Cochlear synaptopathy and cochlear development
Here, we investigated the effects of thiamine deficiency on the mouse cochlea during embryonic and postnatal development. We were inspired by a clinical report describing a high rate of auditory neuropathy in newborns fed with a commercial infant formula totally lacking in thiamine (Fattal-Valevski et al., 2005, Attias et al., 2012), also known vitamin B1, a key co-factor in intermediary metabolism. The diagnosis of auditory neuropathy in humans is based on the presence of otoacoustic emissions
Acknowledgments
Research supported by grants from the NIDCD: R21 DC 012599 and P30 DC 05209.
References (46)
- et al.
Non-alcoholic acute Wernicke's encephalopathy: role of MRI in non typical cases
Eur. J. Radiol.
(2012) - et al.
Characterization of a murine high-affinity thiamine transporter, Slc19a2
Mol. Genet. Metab.
(2001) Auditory neuropathy/Dys-synchrony disorder: diagnosis and management
Otolaryngol. Clin. North Am.
(2015)- et al.
Synaptic profiles during neurite extension, refinement and retraction in the developing cochlea
Neural Dev.
(2012) - et al.
Synaptopathy in the noise-exposed and aging cochlea: primary neural degeneration in acquired sensorineural hearing loss
Hear. Res.
(2015) - et al.
RIBEYE, a component of synaptic ribbons: a protein's journey through evolution provides insight into synaptic ribbon function
Neuron
(2000) - et al.
Auditory neuropathy
Handb. Clin. Neurol.
(2015) - et al.
No longer falling on deaf ears: mechanisms of degeneration and regeneration of cochlear ribbon synapses
Hear. Res.
(2015) - et al.
Selective inner hair cell loss in prematurity: a temporal bone study of infants from a neonatal intensive care unit
J. Assoc. Res. Otolaryngol.
(2011) - et al.
Auditory system dysfunction due to infantile thiamine deficiency: long-term auditory sequelae
Audiol. Neurootol.
(2012)
Otopathology in Mohr-Tranebjaerg syndrome
Laryngoscope
Enzymic evaluation of thiamin, riboflavin and pyridoxine status of parturient women and their newborn infants
Br. J. Nutr.
From placode to polarization: new tunes in inner ear development
Development
Risk factors for auditory neuropathy/auditory synaptopathy
ORL J. Otorhinolaryngol. Relat. Spec.
Dopaminergic innervation of the mouse inner ear: evidence for a separate cytochemical group of cochlear efferent fibers
J. Comp. Neurol.
MR of reversible thalamic lesions in Wernicke syndrome
AJNR Am. J. Neuroradiol.
Imaging of the aging brain. Part II. Pathologic conditions
Radiology
Outbreak of life-threatening thiamine deficiency in infants in Israel caused by a defective soy-based formula
Pediatrics
The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter
Nat. Genet.
Thiamine, riboflavin, pyridoxine, and vitamin C status in premature infants receiving parenteral and enteral nutrition
J. Pediatr. Gastroenterol. Nutr.
Wernicke encephalopathy: MR findings in five patients
AJNR Am. J. Neuroradiol.
The blood-brain barrier and selective vulnerability in experimental thiamine-deficiency encephalopathy in the mouse
Metab. Brain Dis.
Hair cell synaptic ribbons are essential for synchronous auditory signalling
Nature
Cited by (9)
Effect of perinatal and postnatal thiamine deficiency on auditory pathway of the Wistar-Albino rats
2023, Brazilian Journal of OtorhinolaryngologyCitation Excerpt :Temporary or permanent, unilateral or bilateral, stable or progressive hearing loss can be observed due to thiamine deficiency.2 Recently, thiamine deficiency has been linked with auditory neuropathy;1,2 however, few studies have explored this issue. In this study, we created an animal model to explore factors influencing the hearing pathways of new-borns during pregnancy and lactation by inducing a maternal dietary thiamine deficiency.
The limitation of risk factors as a means of prognostication in auditory neuropathy spectrum disorder of perinatal onset
2020, International Journal of Pediatric OtorhinolaryngologyCitation Excerpt :It is also important to consider that factors associated with NICU stay other than those analysed in this study may be responsible for transient or permanent hearing deficit from ANSD. Hypoxia [23], riboflavin depletion [24], which can be exacerbated by phototherapy for hyperbilirubinemia [25], thiamin deficiency [26], noise exposure [27] are examples of other potential etiologic factors. Resolution of a contributory nutritional deficiency could conceivably promote restoration of normal hearing [28], but maturation of auditory pathways and false positive ABR testing should also be considered as possible reasons for normalization of hearing.
Translational issues in cochlear synaptopathy
2017, Hearing ResearchThe hunt for hidden hearing loss in humans: From preclinical studies to effective interventions
2022, Frontiers in NeuroscienceAuditory neuropathy and prematurity: modern view of the issue (literature review)
2022, Vestnik Otorinolaringologii