Pathophysiology
The profound sensorineural hearing loss observed in this patient may have been due to a coexisting nonsense mutation in Microphthalmia-associated transcription factor (MITF) [PMID:25850411].
Mutations identified in MCT8, such as G221R, P321L, D453V, and P537L, result in partial or complete loss of transport activity for T3 and T4, while others like insV236, G282C, and G558D primarily disturb protein expression and trafficking [PMID:23550058].
Clinical Presentation
We report a case of Allan-Herndon-Dudley syndrome presenting with profound sensorineural hearing loss, an uncommon manifestation not usually associated with the condition [PMID:25850411].
The siblings presented with psychomotor retardation, congenital hypotonia, spasticity, and no speech acquisition, consistent with the clinical features of monocarboxylate transporter 8 deficiency [PMID:23235483].
Diagnosis
Mutations causing predominantly endoplasmic reticulum localization (e.g., insV236, G282C, G558D) versus plasma membrane localization (e.g., P537L) may aid in distinguishing specific subtypes of AHDS through detailed protein analysis [PMID:23550058].
Two siblings diagnosed with monocarboxylate transporter 8 deficiency showed reduced regional cerebral blood flow in bilateral frontal cortex and cerebellum on (99m)Tc ethyl cysteinate dimer SPECT imaging [PMID:23235483].
MRI revealed delayed myelination and cortical atrophy, predominantly in the frontal lobes, alongside SPECT findings, contributing to the diagnosis of monocarboxylate transporter 8 deficiency in the siblings [PMID:23235483].
Differential Diagnosis
This case highlights the importance of considering additional genetic mutations, such as MITF, in the differential diagnosis of sensorineural hearing loss in AHDS patients [PMID:25850411].
Management
Dimethylsulfoxide, 4-phenylbutyric acid, and genistein have been shown to increase T3 uptake into cells expressing the MCT8 ΔPhe501 mutant, suggesting potential therapeutic avenues [PMID:26368820].
Genistein, available as a nutritional supplement, effectively stabilizes the MCT8-ΔPhe501 mutant at concentrations achievable clinically [PMID:26368820].
Given that different MCT8 mutations affect transport activity and cellular localization differently, personalized therapeutic approaches based on the specific mutation identified could be beneficial [PMID:23550058].
Prognosis & Follow-up
Given that stabilizing agents like 4-phenylbutyric acid have shown promise in other genetic disorders, similar interventions might offer prognostic benefits for patients with MCT8 mutations [PMID:26368820].
References
1 Braun D, Schweizer U. Efficient Activation of Pathogenic ΔPhe501 Mutation in Monocarboxylate Transporter 8 by Chemical and Pharmacological Chaperones. Endocrinology 2015. link 2 Gagliardi L, Nataren N, Feng J, Schreiber AW, Hahn CN, Conwell LS et al.. Allan-Herndon-Dudley syndrome with unusual profound sensorineural hearing loss. American journal of medical genetics. Part A 2015. link 3 Kersseboom S, Kremers GJ, Friesema EC, Visser WE, Klootwijk W, Peeters RP et al.. Mutations in MCT8 in patients with Allan-Herndon-Dudley-syndrome affecting its cellular distribution. Molecular endocrinology (Baltimore, Md.) 2013. link 4 Goto M, Ito K, Okamoto N, Sato N, Sasaki M. Cerebral blood flow on (99m)Tc ethyl cysteinate dimer SPECT in 2 siblings with monocarboxylate transporter 8 deficiency. Clinical nuclear medicine 2013. link