Presentation is loading. Please wait.

Presentation is loading. Please wait.

Auditory findings in Smith-Lemli-Opitz syndrome (SLOS)

Similar presentations


Presentation on theme: "Auditory findings in Smith-Lemli-Opitz syndrome (SLOS)"— Presentation transcript:

1 Auditory findings in Smith-Lemli-Opitz syndrome (SLOS)
Tiffany Pointon, MD Deborah Hayes, PhD Ellen Roy Elias, MD

2 Introduction Autosomal recessive disorder- mutations in DHCR7 gene Results in cholesterol deficiency and accumulation of precursors 7- and 8-dehydrocholesterol (7-DHC and 8- DHC)1,2,3 Cholesterol is vital for production of bile acids and hormones, cell membranes and cell signaling. 7-DHC is oxidized 4,5,6 forming oxysterols that have been shown to reduce cell viability7,8

3 SLOS clinical characteristics
Cognitive/developmental disability Cleft palate 2-3 toe syndactyly Photosensitivity Sensorineural hearing loss has been described in case reports9,10 hearing and auditory function have not been further characterized.

4 SLOS treatment Cholesterol supplementation
Improves biochemical parameters, photosensitivity, growth, infection tolerance Oxysterols may play a role in SLOS Antioxidants decrease oxysterol levels11,12 AquADEKs™ antioxidant preparation chosen as antioxidant of choice as it has proven safe in pediatric patients

5 The goal of this study was:
Analyze hearing status and auditory pathway function in SLOS Determine if treatment with cholesterol and the antioxidant preparation AquADEKs™ has an effect on auditory outcomes over time

6 Methods Participants 24 patients with biochemically and/or genetically confirmed SLOS were enrolled in the COMIRB approved protocol at Children’s Hospital Colorado between and 2016. 15 males, 9 females Average age was 10 years (range 13 days to 49 years)

7 Methods Auditory Brainstem Response (ABR)13

8 Methods Tympanometry: an objective test of middle ear function conducted by varying air pressure in the external ear canal and measuring acoustic energy transmission through the middle ear. Otoacoustic emissions (OAEs): an objective test of cochlear sensory cell function obtained by measuring acoustic energy produced when outer hair cells, which act as a cochlear amplifier, vibrate in response to stimulation. Auditory steady state response (ASSR): an auditory evoked potential elicited by modulated pure-tones which can be used to predict the pure-tone audiogram

9 Methods Treatment – started at enrollment
Cholesterol suspension (200 mg/ml and/or other cholesterol sources) with doses of mg/kg/day divided tid AquADEKs™ Vitamins A, D, E, K Vitamin C B Vitamins Selenium Coenzyme Q10

10 Average sterol labs at diagnosis grouped by sterol ratio severity
Mild N=7 Moderate N=10 Severe Serum Cholesterol (mg/dL) 152.6 (93-193) 129 (88-191) 47.9 (12-83) 7-DHC (mg/dL) 1.1 ( ) 5.2 ( ) 21.3 ( ) 8-DHC (mg/dL) 0.9 ( ) 4.51 ( ) 14.3 ( ) Sterol Ratio (%) ( ) 7.8 ( ) 186.1 ( ) Sterol ratio ranges: Mild (0-3.5), Moderate (3.6-17), Severe (>17). Sterol Ratio : (7-DHC+ 8-DHC)/ cholesterol x 100 7-DHC reference range: mg/dL. Ranges listed in parentheses

11 Baseline hearing status in patients with SLOS
N=47 ears 57% (27/47 ears) with normal hearing 19% (9/47 ears) with sensorineural hearing loss 15% (7/47 ears) with conductive hearing loss 9% (4/47 ears) with mixed hearing loss

12 Characteristics of patients at baseline grouped by hearing status
Normal Hearing Sensorineural HL Conductive HL Mixed HL N=27 N=9 N=7 N=4 Average Age (years) 9.9 (0.6-28) 11.3 (0.3-23) 4.1 (0.8-21) 25.4 (1.8-49) Baseline cholesterol level (mg/dL) 130.5 (32-193) 94.3 (53-154) 98.1 (31-190) 73.5 (12-135) Baseline Sterol Ratio (%) 13.8 ( ) 22.3 ( ) 23.6 ( ) 283.32 ( ) Hearing loss at birth 2 Submucosal cleft palate 6 1 Hard palate cleft palate 3 Cholesterol supplementation >6months at baseline 7 *Ranges listed in parentheses

13 Longitudinal Hearing Hearing status was relatively stable over time on Cholesterol and AquADEKs™ in 21/24 patients Of the 3 patients with changes: One moderately affected patient with unilateral sensorineural hearing loss at baseline had normal hearing at repeat testing on treatment Two pediatric patients with normal/borderline hearing showed sensorineural hearing loss at follow-up

14 Baseline Auditory Brainstem Response (ABR)
36% (17/47 ears) had a prolonged wave I-V interval 53% (25/47 ears) had normal I-V intervals 11% (5/47) had undetectable Wave I Due to profound hearing loss

15 Characteristics of patients at baseline ABR
Normal I-V interval Prolonged I-V interval (N=25) (N=17) Average Age (years) 9.7 (0.6-28) 6.7 (0.3-15) Baseline cholesterol level (mg/dL) 116.7 (31-191) 108.4 (12-193) Baseline 7-DHC (mg/dL) 5.5 ( ) 10.5 ( ) Baseline Sterol ratio (%) 15 ( ) 79.6 ( ) * Ranges listed in parentheses

16 Wave I-V interval and hearing status
Prolonged I-V interval was not limited to individuals with hearing loss 59% (10/17 ears) with prolonged I-V interval had normal hearing 29% (5/17) with prolonged I-V interval had sensorineural hearing loss.

17 Longitudinal ABR 7 out of 11 patient’s ABR results were unchanged over time while on cholesterol and AquADEKs™ 4 patients’ ABR results changed over time 2 moderately affected patients with normal/borderline baseline ABR’s developed prolonged ABR on cholesterol and AquADEKs™ 1 mildly affected patient with normal baseline ABR developed a mildly prolonged ABR on cholesterol only 1 patient with prolonged baseline ABR had normal ABR on repeat testing after initiating cholesterol and AquADEKs™ treatment

18 Discussion- Hearing loss
Sensorineural hearing loss in Smith-Lemli-Opitz syndrome (SLOS) has only previously been described in case reports In our study, baseline hearing loss was observed in 43% (20/47 ears) 19% (9/47 ears) showed sensorineural hearing loss 9% (4/47 ears) showed mixed hearing loss This suggests that hearing loss is likely associated with SLOS Patients with SLOS may benefit from regular hearing screenings

19 Discussion- ABR Wave I-V intervals measure conduction time through the auditory brainstem pathway, from the auditory nerve to the inferior colliculus 36% (17/47 ears) had a prolonged wave I- V interval at baseline Of those with prolonged intervals, 59% had normal hearing and 29% had sensorineural hearing loss Prolonged conduction in the auditory pathway is likely associated with SLOS, and it is not limited to individuals with hearing loss

20 Discussion- Auditory outcomes in SLOS
The cause of hearing loss and prolonged I-V intervals in SLOS is unknown at this time Potential contributing factors: Cholesterol deficiency may be associated with decreased myelination in the central nervous system, membrane instability and/or altered functioning of ion channels 7-DHC oxidation leads to accumulation of oxysterols which are felt to decrease cell viability  could this occur in the auditory system too?

21 Discussion- Sterol Ratios
Sterol ratio calculation [7-DHC + 8-DHC]/ cholesterol level x 100% Average baseline sterol ratios by hearing status Normal hearing (N=27 ears): 13.8 Sensorineural hearing loss (N=9 ears): 22.3 Mixed hearing loss (N= 4 ears): 283 Average baseline sterol ratios by ABR results Normal I-V interval (N= 25 ears): 15 Prolonged I-V interval (N= 17 ears): 79.6

22 Discussion- Sterol Ratios
These data show that higher sterol ratios may be associated with a higher risk of hearing loss and prolonged wave I-V intervals Use of sterol ratios in the clinical setting may prove beneficial in understanding SLOS patients’ severity of disease.

23 Discussion- Longitudinal data
No clear evidence that treatment with cholesterol and AquADEKs™ improves auditory outcomes over time Potential explanations Oxysterols may not play a role in auditory changes and AquADEKs™ may not have an effect on auditory outcomes Also possible that AquADEKs™ may stabilize auditory outcomes from worsening over time, but not improve outcomes ? Sensitivity of ABR?

24 Summary Hearing loss and prolonged neural conduction through the auditory pathway are seen in a subset of patients with Smith- Lemli-Opitz syndrome Increased sterol ratios may be associated with higher risk of hearing loss and prolonged auditory neural conduction Prolonged auditory neural conduction is not limited to individuals with hearing loss No clear evidence that AquADEKs improves auditory outcomes

25 References Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet May 29;341(8857):1414. PubMed PMID: Tint GS, Irons M, Elias ER, Batta AK, Salen G, Frieden R, Chen TS (1994): Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330:107–113. Elias ER, Irons M. Abnormal cholesterol metabolism in Smith-Lemli-Opitz syndrome. Curr Opin Pediatr Dec;7(6): Review. PubMed PMID: Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids Apr;30(4): Review. PubMed PMID: Yin H, Porter NA. New insights regarding the autoxidation of polyunsaturated fatty acids. Antioxid Redox Signal Jan-Feb;7(1-2): Review. PubMed PMID: Xu L, Korade Z, Porter NA. Oxysterols from free radical chain oxidation of 7- dehydrocholesterol: product and mechanistic studies. J Am Chem Soc Feb 24;132(7): doi: /ja PubMed PMID: ; PubMed Central PMCID: PMC

26 Lemaire-Ewing S, Prunet C, Montange T, Vejux A, Berthier A, Bessède G, Corcos L, Gambert P, Néel D, Lizard G. Comparison of the cytotoxic, pro-oxidant and pro- inflammatory characteristics of different oxysterols. Cell Biol Toxicol Mar;21(2): PubMed PMID: Korade, Z., L. Xu, R. Shelton, and N. A. Porter. Biological activities of 7- dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome a. J.Lipid Res. 51: 3259–3269 Di Berardino, F., Alpini, D., Ambrosetti, U., Amadeo, C., Cesarani, A. Sensorineural hearing-loss in the Smith—Lemli-Opitz syndrome. International Journal of Pediatric Otorhinolaryngology ; 2: Krakowiak PA, Nwokoro NA, Wassif CA, Battaile KP, Nowaczyk MJ, Connor WE, Maslen C, Steiner RD, Porter FD. Mutation analysis and description of sixteen RSH/Smith-Lemli- Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping. Am J Med Genet Sep 18;94(3): Korade Z, Xu L, Harrison FE, et al. Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz Syndrome (SLOS). Biological psychiatry b;75(3): /j.biopsych Fliesler SJ. Antioxidants: The Missing Key to Improved Therapeutic Intervention in Smith- Lemli-Opitz Syndrome? Hereditary genetics : current research. 2013;2(2):119. Seyede Faranak Emami and Nasrin Gohari. The Vestibular-Auditory Interaction for Auditory Brainstem Response to Low Frequencies. ISRN Otolaryngology, vol. 2014, Article ID


Download ppt "Auditory findings in Smith-Lemli-Opitz syndrome (SLOS)"

Similar presentations


Ads by Google