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Journal of Pediatric Neurology 2023; 21(01): 062-067
DOI: 10.1055/s-0042-1759531
Review Article

Meckel Syndrome: A Clinical and Molecular Overview

Giulia Valentini
1   Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age “G. Barresi,” University Hospital of Messina, Messina, Italy
,
Maria Saia
1   Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age “G. Barresi,” University Hospital of Messina, Messina, Italy
,
Giovanni Farello
2   Pediatric Clinic–Department of Life, Health and Environmental Sciences–Piazzale Salvatore Tommasi 1, Coppito (AQ), Italy
,
Vincenzo Salpietro
3   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Alessio Mancuso
4   Unit of Pediatric Emergency, Department of Human Pathology of the Adult and Developmental Age “Gaetano Barresi,” University of Messina, Messina, Italy
,
Ida Ceravolo
5   Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, Messina, Italy
,
Pia V. Colucci
1   Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age “G. Barresi,” University Hospital of Messina, Messina, Italy
,
Manuela Torre
1   Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age “G. Barresi,” University Hospital of Messina, Messina, Italy
,
Giulia Iapadre
3   Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
,
Gabriella Di Rosa 
1   Unit of Child Neurology and Psychiatry, Department of Human Pathology of the Adult and Developmental Age “G. Barresi,” University Hospital of Messina, Messina, Italy
,
Francesca Cucinotta
6   I.R.C.C.S. Centro Neurolesi Bonino Pulejo, Messina, Italy
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Abstract

Meckel syndrome (MKS) is a lethal, autosomal recessive, congenital syndrome caused by mutations in genes that encode proteins structurally or functionally related to the primary cilium. MKS is a malformative syndrome, most commonly characterized by occipital meningoencephalocele, polycystic kidney disease, liver fibrosis, and post- and (occasionally) preaxial polydactyly. To date, more than 10 genes are known to constitute the molecular background of MKS, displaying genetic heterogeneity. Individuals with MKS may resemble some phenotypic features of Joubert syndrome and related disorders, thus making diagnostic setting quite challenging. Here, we systematically reviewed the main clinical and genetic characteristics of MKS and its role among ciliopathies.

Keywords

Meckel syndrome - MKS - ciliopathy - meningoencephalocele - oligohydramnios

Author Contributions

Conceptualization: G. V., M. S.


Investigation: G. F., V. S.


Resources: F. C.


Data curation: A. M., I. C.


Writing - original draft preparation: P. V. C.


Writing - review and editing: M. T., G. D. R., G. I.


Supervision: F. C.


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 Salonen R. The Meckel syndrome: clinicopathological findings in 67 patients. Am J Med Genet 1984; 18 (04) 671-689
    CrossrefPubMedGoogle Scholar
  • 2 Hartill V, Szymanska K, Sharif SM, Wheway G, Johnson CA. Meckel-Gruber syndrome: an update on diagnosis, clinical management, and research advances. Front Pediatr 2017; 5: 244
    CrossrefPubMedGoogle Scholar
  • 3 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
  • 4 Consugar MB, Kubly VJ, Lager DJ. et al. Molecular diagnostics of Meckel-Gruber syndrome highlights phenotypic differences between MKS1 and MKS3. Hum Genet 2007; 121 (05) 591-599
    CrossrefPubMedGoogle Scholar
  • 5 Delous M, Baala L, Salomon R. et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 2007; 39 (07) 875-881
    CrossrefPubMedGoogle Scholar
  • 6 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
  • 7 Dawe HR, Smith UM, Cullinane AR. et al. The Meckel-Gruber syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum Mol Genet 2007; 16 (02) 173-186
    CrossrefPubMedGoogle Scholar
  • 8 Kyttälä M, Tallila J, Salonen R. et al. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 2006; 38 (02) 155-157
    CrossrefPubMedGoogle Scholar
  • 9 Williams CL, Li C, Kida K. et al. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 2011; 192 (06) 1023-1041
    CrossrefPubMedGoogle Scholar
  • 10 Shi X, Garcia III G, Van De Weghe JC. et al. Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome. Nat Cell Biol 2017; 19 (10) 1178-1188
    CrossrefPubMedGoogle Scholar
  • 11 Hsiao YC, Tong ZJ, Westfall JE, Ault JG, Page-McCaw PS, Ferland RJ. Ahi1, whose human ortholog is mutated in Joubert syndrome, is required for Rab8a localization, ciliogenesis and vesicle trafficking. Hum Mol Genet 2009; 18 (20) 3926-3941
    CrossrefPubMedGoogle Scholar
  • 12 Abdelhamed ZA, Wheway G, Szymanska K. et al. Variable expressivity of ciliopathy neurological phenotypes that encompass Meckel-Gruber syndrome and Joubert syndrome is caused by complex de-regulated ciliogenesis, Shh and Wnt signalling defects. Hum Mol Genet 2013; 22 (07) 1358-1372
    CrossrefPubMedGoogle Scholar
  • 13 Aydin Ozturk P, Asena M, Katar S, Ozturk U. Meckel-Gruber syndrome: a case who lived for 5 months. Pediatr Neurosurg 2019; 54 (04) 277-280
    CrossrefPubMedGoogle Scholar
  • 14 Sergi C, Adam S, Kahl P, Otto HF. Study of the malformation of ductal plate of the liver in Meckel syndrome and review of other syndromes presenting with this anomaly. Pediatr Dev Pathol 2000; 3 (06) 568-583
    CrossrefPubMedGoogle Scholar
  • 15 Chen CP. Meckel syndrome: genetics, perinatal findings, and differential diagnosis. Taiwan J Obstet Gynecol 2007; 46 (01) 9-14
    CrossrefPubMedGoogle Scholar
  • 16 Ferrante MI, Zullo A, Barra A. et al. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 2006; 38 (01) 112-117
    CrossrefPubMedGoogle Scholar
  • 17 Barker AR, Thomas R, Dawe HR. Meckel-Gruber syndrome and the role of primary cilia in kidney, skeleton, and central nervous system development. Organogenesis 2014; 10 (01) 96-107
    CrossrefPubMedGoogle Scholar
  • 18 Paetau A, Salonen R, Haltia M. Brain pathology in the Meckel syndrome: a study of 59 cases. Clin Neuropathol 1985; 4 (02) 56-62
    PubMedGoogle Scholar
  • 19 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
  • 20 Accogli A, Iacomino M, Pinto F. et al. Novel AMPD2 mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities. Neurol Genet 2017; 3 (05) e179
    CrossrefPubMedGoogle Scholar
  • 21 Pinchefsky EF, Accogli A, Shevell MI, Saint-Martin C, Srour M. Developmental outcomes in children with congenital cerebellar malformations. Dev Med Child Neurol 2019; 61 (03) 350-358
    CrossrefPubMedGoogle Scholar
  • 22 Pustorino G, Spano M, Sgro DL. et al. Status gelasticus associated with levetiracetam as add-on treatment. Epileptic Disord 2007; 9 (02) 186-189
    PubMedGoogle Scholar
  • 23 Sepulveda W, Sebire NJ, Souka A, Snijders RJM, Nicolaides KH. Diagnosis of the Meckel-Gruber syndrome at eleven to fourteen weeks' gestation. Am J Obstet Gynecol 1997; 176 (02) 316-319
    CrossrefPubMedGoogle Scholar
  • 24 Nizard J, Bernard JP, Ville Y. Fetal cystic malformations of the posterior fossa in the first trimester of pregnancy. Fetal Diagn Ther 2005; 20 (02) 146-151
    CrossrefPubMedGoogle Scholar
  • 25 Khurana S, Saini V, Wadhwa V, Kaur H. Meckel-Gruber syndrome: ultrasonographic and fetal autopsy correlation. J Ultrasound 2017; 20 (02) 167-170
    CrossrefPubMedGoogle Scholar
  • 26 Manara R, D'Agata L, Rocco MC. et al; Menkes Working Group in the Italian Neuroimaging Network for Rare Diseases. Neuroimaging changes in Menkes disease, part 1. AJNR Am J Neuroradiol 2017; 38 (10) 1850-1857
    CrossrefPubMedGoogle Scholar
  • 27 Chao A, Wong AM, Hsueh C, Chang YL, Wang TH. Integration of imaging and pathological studies in Meckel-Gruber syndrome. Prenat Diagn 2005; 25 (03) 267-268
    CrossrefPubMedGoogle Scholar
  • 28 Quintero RA, Abuhamad A, Hobbins JC, Mahoney MJ. Transabdominal thin-gauge embryofetoscopy: a technique for early prenatal diagnosis and its use in the diagnosis of a case of Meckel-Gruber syndrome. Am J Obstet Gynecol 1993; 168 (05) 1552-1557
    CrossrefPubMedGoogle Scholar
  • 29 Tassano E, Accogli A, Pavanello M. et al. Interstitial 9p24.3 deletion involving only DOCK8 and KANK1 genes in two patients with non-overlapping phenotypic traits. Eur J Med Genet 2016; 59 (01) 20-25
    CrossrefPubMedGoogle Scholar
  • 30 Friedman J, Smith DE, Issa MY. et al. Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy. Nat Commun 2019; 10 (01) 707
    CrossrefPubMedGoogle Scholar
  • 31 Tortora D, Severino M, Accogli A. et al. Moyamoya vasculopathy in PHACE syndrome: six new cases and review of the literature. World Neurosurg 2017; 108: 291-302
    CrossrefPubMedGoogle Scholar
  • 32 Sartori S, Polli R, Bettella E. et al. Pathogenic role of the X-linked cyclin-dependent kinase-like 5 and aristaless-related homeobox genes in epileptic encephalopathy of unknown etiology with onset in the first year of life. J Child Neurol 2011; 26 (06) 683-691
    CrossrefPubMedGoogle Scholar
  • 33 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
  • 34 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
  • 35 Lambacher NJ, Bruel AL, van Dam TJ. et al. TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome. Nat Cell Biol 2016; 18 (01) 122-131
    CrossrefPubMedGoogle Scholar
  • 36 Edvardson S, Shaag A, Zenvirt S. et al. Joubert syndrome 2 (JBTS2) in Ashkenazi Jews is associated with a TMEM216 mutation. Am J Hum Genet 2010; 86 (01) 93-97
    CrossrefPubMedGoogle Scholar
  • 37 Karmous-Benailly H, Martinovic J, Gubler MC. et al. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome. Am J Hum Genet 2005; 76 (03) 493-504
    CrossrefPubMedGoogle Scholar
  • 38 Sang L, Miller JJ, Corbit KC. et al. Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 2011; 145 (04) 513-528
    CrossrefPubMedGoogle Scholar
  • 39 McCaffrey MJ. Trisomy 13 and 18: Selecting the road previously not taken. Am J Med Genet C Semin Med Genet 2016; 172 (03) 251-256
    CrossrefPubMedGoogle Scholar
  • 40 Nowaczyk MJ, Irons MB. Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet C Semin Med Genet 2012; 160C (04) 250-262
    CrossrefPubMedGoogle Scholar
  • 41 Di Rosa G, Deodato F, Loupatty FJ. et al. Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: a novel subtype of 3-methylglutaconic aciduria. J Inherit Metab Dis 2006; 29 (04) 546-550
    CrossrefPubMedGoogle Scholar
  • 42 Mee L, Honkala H, Kopra O. et al. Hydrolethalus syndrome is caused by a missense mutation in a novel gene HYLS1. Hum Mol Genet 2005; 14 (11) 1475-1488
    CrossrefPubMedGoogle Scholar
  • 43 Kaur A, Dhir SK, Goyal G, Mittal N, Goyal RK. Senior Loken syndrome. J Clin Diagn Res 2016; 10 (11) SD03-SD04
    PubMedGoogle Scholar
  • 44 Guilmatre A, Legallic S, Steel G. et al. Type I hyperprolinemia: genotype/phenotype correlations. Hum Mutat 2010; 31 (08) 961-965
    CrossrefPubMedGoogle Scholar
  • 45 Miraglia Del Giudice M, Maiello N, Decimo F. et al. Airways allergic inflammation and L. reuterii treatment in asthmatic children. J Biol Regul Homeost Agents 2012; 26 (1, suppl): S35-S40
    PubMedGoogle Scholar
  • 46 Zollo M, Ahmed M, Ferrucci V. et al. PRUNE is crucial for normal brain development and mutated in microcephaly with neurodevelopmental impairment. Brain 2017; 140 (04) 940-952
    CrossrefPubMedGoogle Scholar
  • 47 Salpietro V, Chimenz R, Arrigo T, Ruggieri M. Pediatric idiopathic intracranial hypertension and extreme childhood obesity: a role for weight gain. J Pediatr 2013; 162 (05) 1084
    CrossrefPubMedGoogle Scholar
  • 48 Lionetti E, Francavilla R, Castellazzi AM. et al. Probiotics and Helicobacter pylori infection in children. J Biol Regul Homeost Agents 2012; 26 (1, suppl): S69-S76
    PubMedGoogle Scholar
  • 49 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
  • 50 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
  • 51 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
  • 52 Salpietro V, Ruggieri M. Pseudotumor cerebri pathophysiology: the likely role of aldosterone. Headache 2014; 54 (07) 1229
    CrossrefPubMedGoogle Scholar
  • 53 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
  • 54 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
  • 55 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
  • 56 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
  • 57 Pizzino G, Irrera N, Galfo F. et al. Effects of the antagomiRs 15b and 200b on the altered healing pattern of diabetic mice. Br J Pharmacol 2018; 175 (04) 644-655
    CrossrefPubMedGoogle Scholar