1. Joubert Syndrome in Three Siblings Martine K.F. Docx 1, Bart Loeys 2, Heidi Hoeben 3, Mark Helbert 3, Johan Vande Walle 4 1 Department of Paediatric Nephrology and Chronic Paediatric Diseases Queen Paola Children’s Hospital Antwerp, 2 Center for Medical Genetics, Antwerp and University of Antwerp, 3 Department of Nephrology AZM Middelheim Hospital Antwerp, 4 Department of Paediatric Nephrology and Rheumatology, Safepedrug, Ghent University Hospital, Ghent, Belgium.

2. Patients  missense mutation c.1888 T>C in gene TMEM 67 on chromosome 8q 22.1 14-year-old Girl -Mental Retardation -Ataxia -Left Eye Ablatio Retinae -NPHP ( 12 years ESRF) PD -Liver Fibrosis with Oesophageal Varices -Pancytopenia 3-year-old Twin Girl -Mental Retardation -Retinal Dystrophia -Liver Fibrosis -NPHP 3-year-old Twin Girl -Mental Retardation -Nystagmus + Retinal Dystrophia -Liver Fibrosis -NPHP 2

3. Introduction 3

4. Figure 2 The Lancet Neurology 2013 12, 894-905DOI: (10.1016/S1474-4422(13)70136-4) Copyright © 2013 Elsevier Ltd Terms and Conditions Terms and Conditions Figure 2 Schematic representation of the structure of the primary cilium and its protein complexes Most proteins that are mutated in Joubert syndrome and Meckel syndrome cluster in large complexes at the basal body or the transition zone of the cilium. These complexes participate in the regulation of ciliogenesis, control the trafficking of specific pools of molecules targeted to the cilium, and are implicated in signalling pathways mediated by the cilium. IFT=intraflagellary transport.

5. Classification of Joubert Syndrome and Related Disorders 5

6. Schematic approach to the diagnosis and management of JSRD. Left: clinical manifestations that - in variable association - may lead to the diagnostic suspicion of JSRD. Middle: the detection of the MTS by brain magnetic resonance imaging confirms the diagnosis; in a subset of patients, other CNS defects may be identified. Right: proposed evaluation protocol for multiorgan involvement. *by water restriction or Desmopressin test. Brancati et al. Orphanet Journal of Rare Diseases 2010 5:20 doi:10.1186/1750-1172-5-20 6

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9. Conclusions All 3 siblings diagnosed with a missense mutation in the gene TMEM 67, encoding the transmembrane protein 67. The gene and protein are also called MKS3 ( Meckelin). This mutation is typical for JS type 6. Other ciliopathies with a mutation in the gene TMEM 67 are Meckel-Gruber syndrome type 3, COACH syndrome, nephronopthisis type 11 and Bardet-Biedl syndrome type 14. Otto et al.(2009) “ Hypomorphic mutations in meckelin ( MKS3/TMEM 67) cause nephronophtisis with liver fibrosis. our 3 patients severe neurologic abnormalities together with nephronophtisis and liver fibrosis. 9