Download PDF
CC BY 4.0 · Glob Med Genet 2023; 10(03): 190-193
DOI: 10.1055/s-0043-1771184
Case Report

Molecular Evaluation of Joubert Syndrome and Hearing Impairment in a Patient with Ataxic Cerebral Palsy

N. Sreedevi
1   Department of Speech-Language Sciences, All India Institute of Speech and Hearing, Mysore, India
,
N. Swapna
2   Department of Speech-Language Pathology, All India Institute of Speech and Hearing, Mysore, India
,
Santosh Maruthy
1   Department of Speech-Language Sciences, All India Institute of Speech and Hearing, Mysore, India
,
T. Jayakumar
1   Department of Speech-Language Sciences, All India Institute of Speech and Hearing, Mysore, India
,
Charles Sylvester 
3   Unit for Human Genetics, All India Institute of Speech and Hearing, Mysore, India
› Author Affiliations Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
› Further Information
Also available at
   Permissions and Reprints

Abstract

Joubert syndrome (JBTS) is a rare autosomal recessive or X-linked congenital brain malformation with strong genetic heterogeneity. Other neurological features of JBTS include hypotonia, ataxia, developmental delay, and cognitive impairment. Hearing loss with JBTS has been reported in the literature. We present the case of a 3.5-year-old boy born to a healthy consanguineous South Indian couple who was presented with ataxic cerebral palsy (CP) and hearing impairment; medical reports confirmed typical brain malformations of JBTS. Hearing impairment was screened by audiological assessment, which confirmed the presence of severe-profound hearing loss with outer hair cell dysfunction. Whole-exome sequencing (WES) was performed to know the molecular aspects of the condition and to detect any novel mutations. The homozygous mutation AHI1 c.2023G > A associated with JBTS type 3 and GJB2 c.71G > A mutation associated with hearing impairment were identified. Sanger sequencing was performed to validate the result and it identified heterozygous AHI1 c.2023G > A and GJB2 c.71G > A in the patient's parents. This study confirms the diagnosis of JBTS by WES helps identify the genetic causes of hereditary disorders that accelerate genetic evaluation and counseling for at-risk families.

Keywords

Joubert syndrome - hearing loss - AHI1 - GJB2

Ethical Approval

The study was approved by the Ethics Committee of All India Institute of Speech and Hearing, Mysore, India.


Author Contribution

N. Sreedevi was responsible for conceptualization, supervision, and project administration. N Swapna contributed to conceptualization. Santosh Maruthy was responsible for supervision and project administration. T. Jayakumar contributed to supervision. Charles Sylvester was responsible for the methodology, molecular biology, bioinformatics, and writing the original manuscript.




Publication History

Received: 12 May 2023

Accepted: 20 June 2023

Article published online:
17 July 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Radha Rama Devi A, Naushad SM, Lingappa L. Clinical and molecular diagnosis of Joubert syndrome and related disorders. Pediatr Neurol 2020; 106: 43-49
    CrossrefPubMedGoogle Scholar
  • 2 Harion M, Qebibo L, Riquet A. et al. New insights into CC2D2A-related Joubert syndrome. J Med Genet 2023; 60: 578-586
    CrossrefPubMedGoogle Scholar
  • 3 Maria BL, Hoang KB, Tusa RJ. et al. “Joubert syndrome” revisited: key ocular motor signs with magnetic resonance imaging correlation. J Child Neurol 1997; 12 (07) 423-430
    CrossrefPubMedGoogle Scholar
  • 4 Bachmann-Gagescu R, Dempsey JC, Phelps IG. et al; University of Washington Center for Mendelian Genomics. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. J Med Genet 2015; 52 (08) 514-522
    CrossrefPubMedGoogle Scholar
  • 5 Jain D, Ravishankar V. Ocular manifestations leading to a diagnosis of Joubert syndrome related disorder. Nepal J Ophthalmol 2022; 14 (27) 173-177
    CrossrefPubMedGoogle Scholar
  • 6 Salman MS, Chodirker BN. Neuro-ophthalmological findings in children and adolescents with chronic ataxia. Neuroophthalmology 2015; 39 (03) 125-131
    CrossrefPubMedGoogle Scholar
  • 7 Nuovo S, Bacigalupo I, Ginevrino M. et al; JS Italian Study Group. Age and sex prevalence estimate of Joubert syndrome in Italy. Neurology 2020; 94 (08) e797-e801
    CrossrefPubMedGoogle Scholar
  • 8 Sattar S, Gleeson JG. The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders. Dev Med Child Neurol 2011; 53 (09) 793-798
    CrossrefPubMedGoogle Scholar
  • 9 Kher AS, Chattopadhyay A, Divekar A, Khambekar K, Bharucha BA. Joubert syndrome with polydactyly and optic coloboma in two sibs. Indian J Pediatr 1994; 61 (06) 729-732
    CrossrefPubMedGoogle Scholar
  • 10 Kroes HY, Van Zanten BG, De Ru SA. et al. Is hearing loss a feature of Joubert syndrome, a ciliopathy?. Int J Pediatr Otorhinolaryngol 2010; 74 (09) 1034-1038
    CrossrefPubMedGoogle Scholar
  • 11 Huang L, Szymanska K, Jensen VL. et al. TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone. Am J Hum Genet 2011; 89 (06) 713-730
    CrossrefPubMedGoogle Scholar
  • 12 Ferland RJ, Eyaid W, Collura RV. et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 2004; 36 (09) 1008-1013
    CrossrefPubMedGoogle Scholar
  • 13 Dixon-Salazar T, Silhavy JL, Marsh SE. et al. Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 2004; 75 (06) 979-987
    CrossrefPubMedGoogle Scholar
  • 14 Azadegan-Dehkordi F, Bahrami T, Shirzad M. et al. Mutations in GJB2 as major causes of autosomal recessive non-syndromic hearing loss: first report of c. 299–300delAT mutation in Kurdish population of Iran. J Audiol Otol 2019; 23 (01) 20-26
    CrossrefPubMedGoogle Scholar
  • 15 Lee JY, In SI, Kim HJ, Jeong SY, Choung YH, Kim YC. Hereditary palmoplantar keratoderma and deafness resulting from genetic mutation of connexin 26. J Korean Med Sci 2010; 25 (10) 1539-1542
    CrossrefPubMedGoogle Scholar
  • 16 Anzai T, Fukunaga I, Hatakeyama K. et al. Deformation of the outer hair cells and the accumulation of caveolin-2 in connexin 26 deficient mice. PLoS One 2015; 10 (10) e0141258
    CrossrefPubMedGoogle Scholar
  • 17 Santarelli R, Cama E, Scimemi P, Dal Monte E, Genovese E, Arslan E. Audiological and electrocochleography findings in hearing-impaired children with connexin 26 mutations and otoacoustic emissions. Eur Arch Otorhinolaryngol 2008; 265 (01) 43-51
    CrossrefPubMedGoogle Scholar
  • 18 Chen GD, Tanaka C, Henderson D. Relation between outer hair cell loss and hearing loss in rats exposed to styrene. Hear Res 2008; 243 (1–2): 28-34
    CrossrefPubMedGoogle Scholar
  • 19 Mistrík P, Ashmore JF. Reduced electromotility of outer hair cells associated with connexin-related forms of deafness: an in silico study of a cochlear network mechanism. J Assoc Res Otolaryngol 2010; 11 (04) 559-571
    CrossrefPubMedGoogle Scholar
  • 20 Hill RS, Walsh CA. Molecular insights into human brain evolution. Nature 2005; 437 (7055): 64-67
    CrossrefPubMedGoogle Scholar
  • 21 Walsh CA. Molecular genetics of human developmental brain disorders of the Arabian Gulf region. J Med Sci 2009; 2 (01) 5-12
    Google Scholar
  • 22 Dekair LH, Kamel H, El-Bashir HO. Joubert syndrome labeled as hypotonic cerebral palsy. Neurosciences (Riyadh) 2014; 19 (03) 233-235
    Google Scholar
  • 23 Dan B. How useful is the diagnosis of ataxic cerebral palsy?. Dev Med Child Neurol 2020; 62 (03) 264
    CrossrefPubMedGoogle Scholar
  • 24 Gunzler SA, Stoessl AJ, Egan RA, Weleber RG, Wang P, Nutt JG. Joubert syndrome surviving to adulthood associated with a progressive movement disorder. Mov Disord 2007; 22 (02) 262-265
    CrossrefPubMedGoogle Scholar
  • 25 Atsumi M, Takeda T, Misaki Y, Ogata H. Joubert syndrome diagnosed based on sleep-disordered breathing in a 25-year-old man: case report. Brain Nerve 2008; 60 (02) 195-198
    PubMedGoogle Scholar