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17.05.2017 | Original Article | Ausgabe 5/2017

Journal of Inherited Metabolic Disease 5/2017

Developmental window of sensorineural deafness in biotinidase-deficient mice

Journal of Inherited Metabolic Disease > Ausgabe 5/2017
Kathleen June Maheras, Kirit Pindolia, Barry Wolf, Alexander Gow
Wichtige Hinweise
Responsible editor: Gajja Salomons

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10545-017-0049-z) contains supplementary material, which is available to authorized users.


Biotinidase deficiency is an autosomal recessively inherited disorder that results in the inability to recycle the vitamin, biotin. If untreated, the disorder can result in a range of neurological and cutaneous symptoms, including sensorineural deficits and deafness. To understand early mechanistic abnormalities that may precede more generalized and nonspecific effects of metabolic deficits such as weight loss and acidosis, we have analyzed auditory brainstem responses (ABRs) in biotinidase-deficient knockout (Btd −/− ) mice in the periweaning period with or without dietary biotin supplementation. We find significant increases in the latency of wave V of the ABR elicited by pure tone stimuli at one octave intervals, which precede substantial increases in ABR thresholds. Finer interpeak latency analyses of these changes indicate they are confined to the latter ABR waves associated with the CNS and likely reflect slowed brainstem transmission time. In contrast, peripheral nervous system conduction velocity appears normal. Further, we find that biotin-supplementation after the onset of symptoms reverses the latency shifts, which has significant relevance for early treatment in patients. Finally, ABR latencies in Btd −/− mice fed a biotin-supplemented diet for the first month of life appear refractory to transmission time slowing during a subsequent bout of biotin deficiency. These data suggest a transient vulnerability window for biotin deficiency in the auditory brainstem. Finally, we also observe a developmental vulnerability window involving follicular melanosome production or melanocyte survival. Sensorineural deafness precedes peripheral hearing loss in developmental biotinidase deficiency and is transient if rescued by dietary biotin within a short developmental window.

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