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Journal of Pediatric Neurology 2023; 21(01): 068-072
DOI: 10.1055/s-0042-1759536
Review Article

Ophthalmological Findings in Joubert Syndrome and Related Disorders

Ida Ceravolo
1   Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
,
Francesca Granata
2   Department of Radiology, University of Messina, Messina, Italy
,
Eloisa Gitto
3   Neonatal and Pediatric Intensive Care Unit, Department of Human Pathology in Adult and Developmental Age “Gaetano Barresi,” University of Messina, Messina, Italy
,
Giulia Iapadre
4   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Roberto Chimenz 
5   Faculty of Medicine and Surgery, University of Messina, Messina, Italy
,
Nino Giannitto
6   Unit of Pediatric Emergency, Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” University of Messina, Messina, Italy
,
Alessio Mancuso
6   Unit of Pediatric Emergency, Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” University of Messina, Messina, Italy
,
Maria Domenica Ceravolo
6   Unit of Pediatric Emergency, Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” University of Messina, Messina, Italy
,
Tommaso La Macchia
7   Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
,
Federico Rissotto
8   Department of Ophthalmology, Scientific Institute San Raffaele Hospital, Milan, Italy
,
Giovanni Farello
9   Pediatric Clinic–Department of Life, Health and Environmental Sciences–Piazzale Salvatore, Coppito (AQ), Italy
,
Caterina Cuppari
6   Unit of Pediatric Emergency, Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” University of Messina, Messina, Italy
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Abstract

Joubert syndrome (JS) is a rare genetic condition characterized by congenital malformation of the mid-hindbrain, cerebellar ataxia, hypotonia, oculomotor apraxia, hypoplasia of the cerebellar vermis resulting in breathing defects, ataxia, and delayed development. Ophthalmological examination reveals eye involvement with nystagmus and retinal defects. Genetic counseling is important for the prevention of new cases. Great advances have been made in recent years. Management is symptomatic and multidisciplinary. In the present review, we discussed the most frequent ophthalmological anomalies associated with JS and speculated on the role of ciliary physiology in eye development.

Keywords

Joubert syndrome - genetic classification - ophthalmological abnormalities

Author Contributions

Conceptualization: R. C., A. M., M. D. C.


Investigation: C. C., I. C., F. R.


Resources: F. G.


Data curation: E. G., G. I.


Writing - original draft preparation: N. G.


Writing - review and editing: T. L. M.


Supervision: G. F.


All authors have read and agreed to the published version of the manuscript.


Data Availability Statement

The data presented in this study are available on request from the corresponding author.




Publication History

Received: 22 August 2022

Accepted: 27 October 2022

Article published online:
05 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Iannicelli M, Brancati F, Mougou-Zerelli S. et al; International JSRD Study Group. Novel TMEM67 mutations and genotype-phenotype correlates in meckelin-related ciliopathies. Hum Mutat 2010; 31 (05) E1319-E1331
    PubMedGoogle Scholar
  • 2 Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 2009; 151C (04) 326-340
    CrossrefPubMedGoogle Scholar
  • 3 Travaglini L, Brancati F, Attie-Bitach T. et al; International JSRD Study Group. Expanding CEP290 mutational spectrum in ciliopathies. Am J Med Genet A 2009; 149A (10) 2173-2180
    CrossrefPubMedGoogle Scholar
  • 4 Travaglini L, Brancati F, Silhavy J. et al; International JSRD Study Group. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders. Eur J Hum Genet 2013; 21 (10) 1074-1078
    CrossrefPubMedGoogle Scholar
  • 5 Valente EM, Logan CV, Mougou-Zerelli S. et al. Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 2010; 42 (07) 619-625
    CrossrefPubMedGoogle Scholar
  • 6 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
  • 7 Valente EM, Salpietro DC, Brancati F. et al. Description, nomenclature, and mapping of a novel cerebello-renal syndrome with the molar tooth malformation. Am J Hum Genet 2003; 73 (03) 663-670
    CrossrefPubMedGoogle Scholar
  • 8 Briguglio M, Pinelli L, Giordano L. et al; CBCD Study Group. Pontine tegmental cap dysplasia: developmental and cognitive outcome in three adolescent patients. Orphanet J Rare Dis 2011; 6: 36
    CrossrefPubMedGoogle Scholar
  • 9 Cherian EV, Shenoy KV, Shetty G, Ambati NR. The child with jerking eyes and gait. BMJ Case Rep 2013; 2013: bcr2012008236
    CrossrefPubMedGoogle Scholar
  • 10 Weiss AH, Doherty D, Parisi M, Shaw D, Glass I, Phillips JO. Eye movement abnormalities in Joubert syndrome. Invest Ophthalmol Vis Sci 2009; 50 (10) 4669-4677
    CrossrefPubMedGoogle Scholar
  • 11 Brancati F, Dallapiccola B, Valente EM. Joubert syndrome and related disorders. Orphanet J Rare Dis 2010; 5: 20
    CrossrefPubMedGoogle Scholar
  • 12 Brancati F, Travaglini L, Zablocka D. et al; International JSRD Study Group. RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders. Clin Genet 2008; 74 (02) 164-170
    CrossrefPubMedGoogle Scholar
  • 13 Brancati F, Iannicelli M, Travaglini L. et al; International JSRD Study Group. MKS3/TMEM67 mutations are a major cause of COACH syndrome, a Joubert syndrome related disorder with liver involvement. Hum Mutat 2009; 30 (02) E432-E442
    CrossrefPubMedGoogle Scholar
  • 14 Romani M, Micalizzi A, Valente EM. Joubert syndrome: congenital cerebellar ataxia with the molar tooth. Lancet Neurol 2013; 12 (09) 894-905
    CrossrefPubMedGoogle Scholar
  • 15 Valente EM, Marsh SE, Castori M. et al. Distinguishing the four genetic causes of Jouberts syndrome-related disorders. Ann Neurol 2005; 57 (04) 513-519
    CrossrefPubMedGoogle Scholar
  • 16 Valente EM, Brancati F, Silhavy JL. et al; International JSRD Study Group. AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol 2006; 59 (03) 527-534
    CrossrefPubMedGoogle Scholar
  • 17 Brancati F, Barrano G, Silhavy JL. et al; International JSRD Study Group. CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders. Am J Hum Genet 2007; 81 (01) 104-113
    CrossrefPubMedGoogle Scholar
  • 18 Singla V, Reiter JF. The primary cilium as the cell's antenna: signaling at a sensory organelle. Science 2006; 313 (5787): 629-633
    CrossrefPubMedGoogle Scholar
  • 19 Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet 2007; 28 (03) 113-125
    CrossrefPubMedGoogle Scholar
  • 20 Parisi M, Glass I. Joubert syndrome. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2021
    Google Scholar
  • 21 Parisi MA, Doherty D, Eckert ML. et al. AHI1 mutations cause both retinal dystrophy and renal cystic disease in Joubert syndrome. J Med Genet 2006; 43 (04) 334-339
    CrossrefPubMedGoogle Scholar
  • 22 Westfall JE, Hoyt C, Liu Q. et al. Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1. J Neurosci 2010; 30 (26) 8759-8768
    CrossrefPubMedGoogle Scholar
  • 23 Sturm V, Leiba H, Menke MN. et al. Ophthalmological findings in Joubert syndrome. Eye (Lond) 2010; 24 (02) 222-225
    CrossrefPubMedGoogle Scholar
  • 24 Wang SF, Kowal TJ, Ning K. et al. Review of ocular manifestations of Joubert syndrome. Genes (Basel) 2018; 9 (12) 605
    CrossrefPubMedGoogle Scholar
  • 25 Makino S, Tampo H. Ocular findings in two siblings with Joubert syndrome. Clin Ophthalmol 2014; 8: 229-233
    CrossrefPubMedGoogle Scholar
  • 26 Brodsky MC, Donahue SP, Vaphiades M, Brandt T. Skew deviation revisited. Surv Ophthalmol 2006; 51 (02) 105-128
    CrossrefPubMedGoogle Scholar
  • 27 Couch SM, Brodie SE, Leavitt JA, Brodsky MC. Something to sink your teeth into. Surv Ophthalmol 2011; 56 (06) 544-549
    CrossrefPubMedGoogle Scholar
  • 28 Khan AO, Oystreck DT, Seidahmed MZ. et al. Ophthalmic features of Joubert syndrome. Ophthalmology 2008; 115 (12) 2286-2289
    CrossrefPubMedGoogle Scholar
  • 29 Manole A, Jaunmuktane Z, Hargreaves I. et al. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy. Brain 2017; 140 (11) 2820-2837
    CrossrefPubMedGoogle Scholar
  • 30 Pedullà M, Miraglia Del Giudice M, Fierro V. et al. Atopy as a risk factor for thyroid autoimmunity in children. J Biol Regul Homeost Agents 2012; 26 (1, Suppl): S9-S14
    PubMedGoogle Scholar
  • 31 Ruggieri M, Polizzi A, Strano S. et al. Mixed vascular nevus syndrome: a report of four new cases and a literature review. Quant Imaging Med Surg 2016; 6 (05) 515-524
    CrossrefPubMedGoogle Scholar
  • 32 Bruno L, Ceravolo G, Ceravolo MD. et al. Genetic cardiac channelopathies and SIDS. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 55-58
    PubMedGoogle Scholar
  • 33 Giacobbe A, Granese R, Grasso R. et al. Association between maternal serum high mobility group box 1 levels and pregnancy complicated by gestational diabetes mellitus. Nutr Metab Cardiovasc Dis 2016; 26 (05) 414-418
    CrossrefPubMedGoogle Scholar
  • 34 Salpietro V, Phadke R, Saggar A. et al. Zellweger syndrome and secondary mitochondrial myopathy. Eur J Pediatr 2015; 174 (04) 557-563
    CrossrefPubMedGoogle Scholar
  • 35 Loddo I, Barbera F, Di Gesaro G. et al. Genetics and cardiovascular disease. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 17-22
    PubMedGoogle Scholar
  • 36 Pavlidou E, Salpietro V, Phadke R. et al. Pontocerebellar hypoplasia type 2D and optic nerve atrophy further expand the spectrum associated with selenoprotein biosynthesis deficiency. Eur J Paediatr Neurol 2016; 20 (03) 483-488
    CrossrefPubMedGoogle Scholar
  • 37 Efthymiou S, Salpietro V, Malintan N. et al; SYNAPS Study Group. Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination. Brain 2019; 142 (10) 2948-2964
    CrossrefPubMedGoogle Scholar
  • 38 Coleman J, Jouannot O, Ramakrishnan SK. et al. PRRT2 regulates synaptic fusion by directly modulating SNARE complex assembly. Cell Rep 2018; 22 (03) 820-831
    CrossrefPubMedGoogle Scholar
  • 39 Nascimben F, Peri FM, Impellizzeri P. et al. Role of oxidative stress in the pathogenesis of congenital cardiopathies. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 85-90
    PubMedGoogle Scholar
  • 40 Leu C, Stevelink R, Smith AW. et al; Epi25 Consortium. Polygenic burden in focal and generalized epilepsies. [published correction appears in Brain. 2020;143(7):e61] Brain 2019; 142 (11) 3473-3481
    CrossrefPubMedGoogle Scholar
  • 41 Niccolini F, Mencacci NE, Yousaf T. et al. PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology. Mov Disord 2018; 33 (12) 1961-1965
    CrossrefPubMedGoogle Scholar
  • 42 Chirico V, Rigoli L, Lacquaniti A. et al. Endocrinopathies, metabolic disorders, and iron overload in major and intermedia thalassemia: serum ferritin as diagnostic and predictive marker associated with liver and cardiac T2* MRI assessment. Eur J Haematol 2015; 94 (05) 404-412
    CrossrefPubMedGoogle Scholar
  • 43 Chelban V, Wilson MP, Warman Chardon J. et al; Care4Rare Canada Consortium and the SYNaPS Study Group. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. Ann Neurol 2019; 86 (02) 225-240
    CrossrefPubMedGoogle Scholar
  • 44 Ruggieri M, Polizzi A, Schepis C. et al. Cutis tricolor: a literature review and report of five new cases. Quant Imaging Med Surg 2016; 6 (05) 525-534
    CrossrefPubMedGoogle Scholar
  • 45 Granata F, Morabito R, Mormina E. et al. 3T double inversion recovery magnetic resonance imaging: diagnostic advantages in the evaluation of cortical development anomalies. Eur J Radiol 2016; 85 (05) 906-914
    CrossrefPubMedGoogle Scholar
  • 46 Chimenz R, Manti S, Fede C. et al. Primary nocturnal enuresis in children with allergic rhinitis and severe adenotonsillar hypertrophy: a single center pilot study. J Biol Regul Homeost Agents 2015; 29 (2, suppl 1): 73-79
    PubMedGoogle Scholar
  • 47 Cuppari C, Amatruda M, Ceravolo G. et al. Myocarditis in children - from infection to autoimmunity. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 37-41
    PubMedGoogle Scholar
  • 48 Carotenuto M, Roccella M, Pisani F. et al. Polysomnographic findings in fragile X syndrome children with EEG abnormalities. Behav Neurol 2019; 2019: 5202808
    CrossrefPubMedGoogle Scholar
  • 49 Bell S, Rousseau J, Peng H. et al. Mutations in ACTL6B cause neurodevelopmental deficits and epilepsy and lead to loss of dendrites in human neurons. Am J Hum Genet 2019; 104 (05) 815-834
    CrossrefPubMedGoogle Scholar
  • 50 Salpietro V, Lin W, Delle Vedove A. et al; SYNAPS Study Group. Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome. Ann Neurol 2017; 81 (04) 597-603
    CrossrefPubMedGoogle Scholar
  • 51 Chimenz R, Chirico V, Cuppari C. et al. Fabry disease and kidney involvement: starting from childhood to understand the future. Pediatr Nephrol 2022; 37 (01) 95-103
    CrossrefPubMedGoogle Scholar
  • 52 Piard J, Umanah GKE, Harms FL. et al. A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy. Brain 2018; 141 (03) 651-661
    CrossrefPubMedGoogle Scholar
  • 53 Salpietro V, Ruggieri M. Pseudotumor cerebri pathophysiology: the likely role of aldosterone. Headache 2014; 54 (07) 1229
    CrossrefPubMedGoogle Scholar
  • 54 Pavone P, Briuglia S, Falsaperla R. et al. Wide spectrum of congenital anomalies including choanal atresia, malformed extremities, and brain and spinal malformations in a girl with a de novo 5.6-Mb deletion of 13q12.11-13q12.13. Am J Med Genet A 2014; 164A (07) 1734-1743
    CrossrefPubMedGoogle Scholar
  • 55 Salpietro V, Zollo M, Vandrovcova J. et al; SYNAPS Study Group. The phenotypic and molecular spectrum of PEHO syndrome and PEHO-like disorders. Brain 2017; 140 (08) e49
    CrossrefPubMedGoogle Scholar
  • 56 Loddo I, Cutrupi MC, Concolino D. et al. Cardiac defects in RASopathies: a review of genotype- phenotype correlations. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 23-30
    PubMedGoogle Scholar
  • 57 Chirico V, Lacquaniti A, Salpietro V, Buemi M, Salpietro C, Arrigo T. Central precocious puberty: from physiopathological mechanisms to treatment. J Biol Regul Homeost Agents 2014; 28 (03) 367-375
    PubMedGoogle Scholar
  • 58 Toldo I, Brunello F, Morao V. et al. First attack and clinical presentation of hemiplegic migraine in pediatric age: a multicenter retrospective study and literature review. Front Neurol 2019; 10: 1079
    CrossrefPubMedGoogle Scholar
  • 59 Sestito S, Roppa K, Parisi F. et al. The heart in Anderson-Fabry disease. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 63-69
    PubMedGoogle Scholar
  • 60 Sheldon CA, Paley GL, Xiao R. et al. Pediatric idiopathic intracranial hypertension: age, gender, and anthropometric features at diagnosis in a large, retrospective, multisite cohort. Ophthalmology 2016; 123 (11) 2424-2431
    CrossrefPubMedGoogle Scholar
  • 61 Casto C, Dipasquale V, Ceravolo I. et al. Prominent and regressive brain developmental disorders associated with Nance-Horan syndrome. Brain Sci 2021; 11 (09) 1150
    CrossrefPubMedGoogle Scholar
  • 62 Papandreou A, Schneider RB, Augustine EF. et al. Delineation of the movement disorders associated with FOXG1 mutations. Neurology 2016; 86 (19) 1794-1800
    CrossrefPubMedGoogle Scholar
  • 63 Salpietro V, Perez-Dueñas B, Nakashima K. et al. A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. Mov Disord 2018; 33 (03) 482-488
    CrossrefPubMedGoogle Scholar
  • 64 Salpietro V, Ruggieri M, Sancetta F. et al. New insights on the relationship between pseudotumor cerebri and secondary hyperaldosteronism in children. J Hypertens 2012; 30 (03) 629-630
    CrossrefPubMedGoogle Scholar
  • 65 Ghosh SG, Becker K, Huang H. et al. Biallelic mutations in ADPRHL2, encoding ADP-ribosylhydrolase 3, lead to a degenerative pediatric stress-induced epileptic ataxia syndrome. [published correction appears in Am J Hum Genet. 2018;103(5):826] [published correction appears in Am J Hum Genet. 2021;108(12):2385] Am J Hum Genet 2018; 103 (03) 431-439
    CrossrefPubMedGoogle Scholar
  • 66 Gramaglia SMC, Cuppari C, Salpietro C. et al. Congenital heart disease in Down syndrome. J Biol Regul Homeost Agents 2020; 34 (4, suppl 2): 31-35
    PubMedGoogle Scholar
  • 67 Riva A, Gambadauro A, Dipasquale V. et al. Biallelic variants in KIF17 associated with microphthalmia and coloboma spectrum. Int J Mol Sci 2021; 22 (09) 4471
    CrossrefPubMedGoogle Scholar
  • 68 Salpietro V, Efthymiou S, Manole A. et al. A loss-of-function homozygous mutation in DDX59 implicates a conserved DEAD-box RNA helicase in nervous system development and function. Hum Mutat 2018; 39 (02) 187-192
    CrossrefPubMedGoogle Scholar
  • 69 Nicita F, Ruggieri M, Polizzi A. et al. Seizures and epilepsy in Sotos syndrome: analysis of 19 Caucasian patients with long-term follow-up. Epilepsia 2012; 53 (06) e102-e105
    CrossrefPubMedGoogle Scholar
  • 70 Greco M, Ferrara P, Farello G, Striano P, Verrotti A. Electroclinical features of epilepsy associated with 1p36 deletion syndrome: a review. Epilepsy Res 2018; 139: 92-101
    CrossrefPubMedGoogle Scholar