1 European Journal of Human Genetics 2007 Vol: 15(5):511-521. DOI: 10.1038/sj.ejhg.5201648

Joubert syndrome (and related disorders) (OMIM 213300)

Joubert syndrome (JS) and related disorders are characterized by the 'molar tooth sign' (cerebellar vermis hypoplasia and brainstem anomalies) on MRI, hypotonia, developmental delay, ataxia, irregular breathing pattern and abnormal eye movements. Combinations of additional features such as polydactyly, ocular coloboma, retinal dystrophy, renal disease, hepatic fibrosis, encephalocele, and other brain malformations define clinical sub-types. Recent identification of the NPHP1, AHI1, and CEP290 genes has started to reveal the molecular basis of JS, which may implicate the primary cilium in these disorders. Additional genes remain to be identified.

Mentions
Figures
Figure 1: Diagnostic and management algorithm for JSRD. See text for details. This proposed testing strategy is likely to change with the discovery of additional genes and refined genotype–phenotype correlations. *Renal, juvenile nephronophthisis or renal concentrating defect; RD, retinal dystrophy; LCA, Leber congenital amaurosis. 1AHI1 mutations are estimated to cause JSRD in 11% of subjects; sequencing of all coding exons is available. 2Homozygous NPHP1 deletions are estimated to cause JSRD in 1–2% of subjects; testing by fluorescence in situ hybridization (FISH) or marker analysis to identify homozygous deletions is available.3CEP290 mutations are estimated to cause JSRD in 10% of subjects; sequencing of all coding exons is currently available. JSRD, Joubert syndrome and related disorders, DD/MR, developmental delay/mental retardation, abn. eye mvts., abnormal eye movements (including nystagmus, OMA), irreg. breathing, irregular breathing pattern (tachypnea and/or apnea). Figure 2: MRI images showing the (a) normal appearance of the cerebellum in comparison with (b) the typical MTS circled in black (top), with elevation of the fourth ventricle and vermis hypoplasia (white arrow) shown on sagittal image (bottom). (c) In the patient with a homozygous NPHP1 deletion, the superior cerebellar peduncles are thin (black arrows, above) and there is less vermis hypoplasia and fourth ventricular elevation (below). Figure 3: AHI1 protein with identified mutations. Mutations resulting in protein termination are indicated in yellow boxes above the protein. Splice-site mutations are indicated by blue boxes above the protein, starting with 'IVS' to designate the intronic change. Missense mutations and one in-frame deletion are indicated as pink boxes below the protein. Protein motifs include an amino-terminal coiled-coil domain, six WD40 domains, and a carboxy-terminal Src-homology 3 (SH3) domain. Numbers in parentheses indicate number of families in which the mutation has been identified. From Dixon-Salazar et al15, Parisi et al28, Ferland et al39, Romano et al41, Utsch et al42, Valente et al.43
Altmetric
References
  1. Maria BL, Quisling RG, Rosainz LC et al: Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance. J Child Neurol 1999; 14: 368-376 , .
  2. Saraiva JM, Baraitser M: Joubert syndrome: a review. Am J Med Genet 1992; 43: 726-731 , .
  3. Steinlin M, Schmid M, Landau K, Boltshauser E: Follow-up in children with Joubert syndrome. Neuropediatr 1997; 28: 204-211 , .
    • . . . JS is associated with the 'molar tooth sign' (MTS), a radiologic finding that includes cerebellar vermis hypoplasia and malformation of the brainstem.1 An irregular breathing pattern in the newborn period and abnormal eye movements may be observed.2, 3, 4 Typically, the hypotonia is most prominent during infancy, and cerebellar ataxia develops later . . .
    • . . . Although diagnostic criteria for JS have not been established, the clinical features often cited as necessary for the diagnosis of classic JS include:2, 3, 4, 5, 6 . . .
    • . . . In one series, the average age of independent sitting was 19 months and the average age of walking was 4 years for those who developed these skills;5 another series reported three outcomes: early mortality, those with developmental quotients <30, and those with developmental quotients 60–85.3 Ataxia and speech dyspraxia are typical and likely due to the cerebellar malformation . . .
    • . . . Third nerve palsy has also been observed.19 Retinal disease consisting of a pigmentary retinopathy has been documented in some children with JS,2, 3 and some infants manifest a severe form of congenital blindness with markedly flattened electroretinogram (ERG) traces, analogous to what is termed Leber congenital amaurosis.20, 21 Ocular colobomas are present in some children at birth and usually affect the choroid and retina;2 these are a common feature of the JSRD known as COACH syndrome.8, 22 . . .
  4. Joubert M, Eisenring JJ, Robb JP, Andermann F: Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 1969; 19: 813-825 , .
    • . . . JS is associated with the 'molar tooth sign' (MTS), a radiologic finding that includes cerebellar vermis hypoplasia and malformation of the brainstem.1 An irregular breathing pattern in the newborn period and abnormal eye movements may be observed.2, 3, 4 Typically, the hypotonia is most prominent during infancy, and cerebellar ataxia develops later . . .
    • . . . Although diagnostic criteria for JS have not been established, the clinical features often cited as necessary for the diagnosis of classic JS include:2, 3, 4, 5, 6 . . .
    • . . . Central nervous system involvement may also include fluid collections in the posterior fossa resembling Dandy–Walker malformation and is observed in 10% of subjects.12 Although hydrocephalus is uncommon in JS, a few patients develop hydrocephalus requiring shunting even in the absence of a Dandy–Walker malformation.13 Occipital encephaloceles or meningoceles have been observed,2, 4, 8 as well as agenesis of the corpus callosum.14 Polymicrogyria and/or cortical dysplasia has been described in a few subjects with AHI1 mutations (see below under Molecular and genetic basis of disease),8, 15 but does not appear to be a common finding in JSRD, nor among a wider cohort of subjects with AHI1 mutations . . .
  5. Maria BL, Boltshauser E, Palmer SC, Tran TX: Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol 1999; 14: 583-590; discussion 590-591 , .
  6. Parisi MA, Glass IA: Joubert syndrome; In: GeneReviews at GeneTests-GeneClinics: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997-2006. Available at Link 2006 , .
  7. 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: 423-430 , .
  8. Gleeson JG, Keeler LC, Parisi MA et al: Molar tooth sign of the midbrain-hindbrain junction: occurrence in multiple distinct syndromes. Am J Med Genet 2004; 125A: 125-134; discussion 117 , .
  9. 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: 663-670 , .
    • . . . The disorders that share the MTS have been termed JSRD.8 JS may also be considered an oculo-cerebello-renal syndrome because of the coincident involvement of all three organ systems.9 Certain clinical features tend to occur in distinctive patterns, such as the combination of retinal and renal involvement, lending support to this proposed nosologic framework;8, 10, 11 however, these associations have not always been consistent . . .
    • . . . Several of these affected individuals developed retinal dystrophy, but renal disease has not been described.14, 52 An extended consanguineous Italian family9 and several Arab families53 showed linkage to a locus on the pericentromeric region of chromosome 11, termed the CORS2 (JBTS2) locus . . .
  10. Chance PF, Cavalier L, Satran D, Pellegrino JE, Koenig M, Dobyns WB: Clinical nosologic and genetic aspects of Joubert and related syndromes. J Child Neurol 1999; 14: 660-666; discussion 669-672 , .
    • . . . The disorders that share the MTS have been termed JSRD.8 JS may also be considered an oculo-cerebello-renal syndrome because of the coincident involvement of all three organ systems.9 Certain clinical features tend to occur in distinctive patterns, such as the combination of retinal and renal involvement, lending support to this proposed nosologic framework;8, 10, 11 however, these associations have not always been consistent . . .
  11. Satran D, Pierpont ME, Dobyns WB: Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: more than just variants of Joubert syndrome. Am J Med Genet 1999; 86: 459-469 , .
    • . . . The disorders that share the MTS have been termed JSRD.8 JS may also be considered an oculo-cerebello-renal syndrome because of the coincident involvement of all three organ systems.9 Certain clinical features tend to occur in distinctive patterns, such as the combination of retinal and renal involvement, lending support to this proposed nosologic framework;8, 10, 11 however, these associations have not always been consistent . . .
    • . . . In some of these conditions, the MTS is always present, whereas in others (such as juvenile nephronophthisis or Senior–Løken syndrome), only a subset of individuals with the diagnosis manifests the MTS.11 This nosologic classification is inherently limited by the lack of genotype–phenotype correlations and awaits the identification of additional causative genes to provide molecular clarification . . .
    • . . . Cystic dysplasia appears as multiple cysts of various sizes in immature kidneys with fetal lobulations on ultrasound and may be present at birth.2, 11, 23, 24 This finding is characteristic of the JSRD known as Dekaban–Arima syndrome (Table 1) . . .
  12. Maria BL, Bozorgmanesh A, Kimmel KN, Theriaque D, Quisling RG: Quantitative assessment of brainstem development in Joubert syndrome and Dandy-Walker syndrome. J Child Neurol 2001; 16: 751-758 , .
    • . . . Central nervous system involvement may also include fluid collections in the posterior fossa resembling Dandy–Walker malformation and is observed in 10% of subjects.12 Although hydrocephalus is uncommon in JS, a few patients develop hydrocephalus requiring shunting even in the absence of a Dandy–Walker malformation.13 Occipital encephaloceles or meningoceles have been observed,2, 4, 8 as well as agenesis of the corpus callosum.14 Polymicrogyria and/or cortical dysplasia has been described in a few subjects with AHI1 mutations (see below under Molecular and genetic basis of disease),8, 15 but does not appear to be a common finding in JSRD, nor among a wider cohort of subjects with AHI1 mutations . . .
  13. Genel F, Atlihan F, Ozdemir D, Targan S: Development of hydrocephalus in a patient with Joubert syndrome. J Postgrad Med 2004; 50: 153 , .
    • . . . Central nervous system involvement may also include fluid collections in the posterior fossa resembling Dandy–Walker malformation and is observed in 10% of subjects.12 Although hydrocephalus is uncommon in JS, a few patients develop hydrocephalus requiring shunting even in the absence of a Dandy–Walker malformation.13 Occipital encephaloceles or meningoceles have been observed,2, 4, 8 as well as agenesis of the corpus callosum.14 Polymicrogyria and/or cortical dysplasia has been described in a few subjects with AHI1 mutations (see below under Molecular and genetic basis of disease),8, 15 but does not appear to be a common finding in JSRD, nor among a wider cohort of subjects with AHI1 mutations . . .
  14. Valente EM, Marsh SE, Castori M et al: Distinguishing the four genetic causes of jouberts syndrome-related disorders. Ann Neurol 2005; 57: 513-519 , .
  15. 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: 979-987 , .
    • . . . Central nervous system involvement may also include fluid collections in the posterior fossa resembling Dandy–Walker malformation and is observed in 10% of subjects.12 Although hydrocephalus is uncommon in JS, a few patients develop hydrocephalus requiring shunting even in the absence of a Dandy–Walker malformation.13 Occipital encephaloceles or meningoceles have been observed,2, 4, 8 as well as agenesis of the corpus callosum.14 Polymicrogyria and/or cortical dysplasia has been described in a few subjects with AHI1 mutations (see below under Molecular and genetic basis of disease),8, 15 but does not appear to be a common finding in JSRD, nor among a wider cohort of subjects with AHI1 mutations . . .
    • . . . The AHI1 (Abelson Helper-Integration site 1) gene has 28 exons (26 coding), encodes a protein called Jouberin, and was found to harbor JS-causing mutations based on mapping studies in several inbred families.15, 39, 40 A variety of nonsense, missense, splice-site, and insertion mutations have been identified in JS subjects15, 28, 39, 41, 42, 43 (Figure 3) . . .
    • . . . In a cohort of 117 JS subjects screened for AHI1 mutations by a combination of haplotype analysis and gene sequencing, 11% had mutations.28 Polymicrogyria of the cerebral cortex has been observed in two individuals with AHI1 mutations.15 Retinal dystrophy was reported in 11 out of 12 families with AHI1 mutations;28 however, no subjects exhibited the variable JSRD features of encephalocele, polydactyly, coloboma, or liver fibrosis . . .
    • . . . From Dixon-Salazar et al15, Parisi et al28, Ferland et al39, Romano et al41, Utsch et al42, Valente et al.43 . . .
  16. Holroyd S, Reiss AL, Bryan RN: Autistic features in Joubert syndrome: a genetic disorder with agenesis of the cerebellar vermis. Biol Psychiatry 1991; 29: 287-294 , .
    • . . . A few children with autism have been reported,16, 17 although other surveys suggest that classic autism is not typical in JS.18 Behavioral disturbances, when present, are most likely to include impulsivity and temper tantrums.19 . . .
  17. Ozonoff S, Williams BJ, Gale S, Miller JN: Autism and autistic behavior in Joubert syndrome. J Child Neurol 1999; 14: 636-641 , .
    • . . . A few children with autism have been reported,16, 17 although other surveys suggest that classic autism is not typical in JS.18 Behavioral disturbances, when present, are most likely to include impulsivity and temper tantrums.19 . . .
  18. Takahashi TN, Farmer JE, Deidrick KK, Hsu BS, Miles JH, Maria BL: Joubert syndrome is not a cause of classical autism. Am J Med Genet A 2005; 132: 347-351 , .
    • . . . A few children with autism have been reported,16, 17 although other surveys suggest that classic autism is not typical in JS.18 Behavioral disturbances, when present, are most likely to include impulsivity and temper tantrums.19 . . .
  19. Hodgkins PR, Harris CM, Shawkat FS et al: Joubert syndrome: long-term follow-up. Dev Med Child Neurol 2004; 46: 694-699 , .
  20. Tusa RJ, Hove MT: Ocular and oculomotor signs in Joubert syndrome. J Child Neurol 1999; 14: 621-627 , .
    • . . . Disturbances of ocular motility such as OMA are very common and were documented in all children evaluated with comprehensive ophthalmologic testing in one survey.20 OMA typically manifests with dysconjugate eye movements and head thrusting to compensate for the inability to initiate saccades.19 Nystagmus (horizontal, torsional, and/or rotatory) is often present at birth and may improve with age . . .
    • . . . Third nerve palsy has also been observed.19 Retinal disease consisting of a pigmentary retinopathy has been documented in some children with JS,2, 3 and some infants manifest a severe form of congenital blindness with markedly flattened electroretinogram (ERG) traces, analogous to what is termed Leber congenital amaurosis.20, 21 Ocular colobomas are present in some children at birth and usually affect the choroid and retina;2 these are a common feature of the JSRD known as COACH syndrome.8, 22 . . .
  21. Ivarsson SA, Bjerre I, Brun A, Ljungberg O, Maly E, Taylor I: Joubert syndrome associated with Leber amaurosis and multicystic kidneys. Am J Med Genet 1993; 45: 542-547 , .
    • . . . Third nerve palsy has also been observed.19 Retinal disease consisting of a pigmentary retinopathy has been documented in some children with JS,2, 3 and some infants manifest a severe form of congenital blindness with markedly flattened electroretinogram (ERG) traces, analogous to what is termed Leber congenital amaurosis.20, 21 Ocular colobomas are present in some children at birth and usually affect the choroid and retina;2 these are a common feature of the JSRD known as COACH syndrome.8, 22 . . .
  22. Verloes A, Lambotte C: Further delineation of a syndrome of cerebellar vermis hypo/aplasia, oligophrenia, congenital ataxia, coloboma, and hepatic fibrosis. Am J Med Genet 1989; 32: 227-232 , .
  23. Steinlin M, Blaser S, Boltshauser E: Cerebellar involvement in metabolic disorders: a pattern-recognition approach. Neuroradiology 1998; 40: 347-354 , .
    • . . . Cystic dysplasia appears as multiple cysts of various sizes in immature kidneys with fetal lobulations on ultrasound and may be present at birth.2, 11, 23, 24 This finding is characteristic of the JSRD known as Dekaban–Arima syndrome (Table 1) . . .
  24. Dekaban AS: Hereditary syndrome of congenital retinal blindness (Leber), polycystic kidneys and maldevelopment of the brain. Am J Ophthalmol 1969; 68: 1029-1037 , .
    • . . . Cystic dysplasia appears as multiple cysts of various sizes in immature kidneys with fetal lobulations on ultrasound and may be present at birth.2, 11, 23, 24 This finding is characteristic of the JSRD known as Dekaban–Arima syndrome (Table 1) . . .
  25. Hildebrandt F, Nothwang HG, Vossmerbaumer U et al: Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B. Pediatr Nephrol 1998; 12: 16-19 , .
    • . . . In contrast, juvenile nephronophthisis is characterized by microscopic cysts affecting the renal tubules and usually presents with urine concentrating defects in the first or second decade of life manifested by polydipsia, polyuria, anemia, and growth failure, with progression to end-stage renal disease by 13 years of age.25, 26 Small, scarred, and echogenic kidneys on ultrasound are only visible late in the course of the disease . . .
  26. Saunier S, Salomon R, Antignac C: Nephronophthisis. Curr Opin Genet Dev 2005; 15: 324-331 , .
    • . . . In contrast, juvenile nephronophthisis is characterized by microscopic cysts affecting the renal tubules and usually presents with urine concentrating defects in the first or second decade of life manifested by polydipsia, polyuria, anemia, and growth failure, with progression to end-stage renal disease by 13 years of age.25, 26 Small, scarred, and echogenic kidneys on ultrasound are only visible late in the course of the disease . . .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
    • . . . NPHP1 and other nephrocystin gene products associated with juvenile nephronophthisis are known to localize to the cell–cell junctions and the primary cilium and basal body apparatus of renal epithelial cells.26, 47 These nephrocystin gene products form multiprotein complexes with microtubules, adherens proteins, and other cytoskeletal components, and may play a role as mechanosensors in cellular signaling processes or in intraflagellar transport.26 Although a precise role for these proteins has not yet been elucidated in the cerebellum, it is known that most neurons and glia in the mammalian brain contain a primary cilium, an organelle that is present on almost all cells.48, 49 A role for the AHI1 protein in ciliary function has not been identified . . .
  27. Kumada S, Hayashi M, Arima K et al: Renal disease in Arima syndrome is nephronophthisis as in other Joubert-related Cerebello-oculo-renal syndromes. Am J Med Genet A 2004; 131: 71-76 , .
    • . . . Although these two renal lesions have been considered distinct, one report reviewed the renal pathology that had been described as cystic dysplasia in subjects with Dekaban–Arima syndrome and found it to be indistinguishable from nephronophthisis.27 Thus, it is possible that the renal manifestations in JSRD represent a continuum . . .
  28. 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: 334-339 , .
    • . . . The renal cystic disease recently described in some subjects with JS due to AHI1 mutations suggests that the onset of a nephronophthisis-like disorder may be delayed to as late as the third decade.28 A general association between retinal and renal involvement has been observed, although this is not absolute.2, 23, 29 . . .
    • . . . The NPHP1 mutation detection rate for the purely renal disorder is approximately 30%,34 in contrast to a rate of approximately 1–2% in patients with JS based on several case series.28, 35, 37 However, the likelihood of detecting a causative NPHP1 deletion may be increased in subjects with JS who also have juvenile nephronophthisis . . .
    • . . . The AHI1 (Abelson Helper-Integration site 1) gene has 28 exons (26 coding), encodes a protein called Jouberin, and was found to harbor JS-causing mutations based on mapping studies in several inbred families.15, 39, 40 A variety of nonsense, missense, splice-site, and insertion mutations have been identified in JS subjects15, 28, 39, 41, 42, 43 (Figure 3) . . .
    • . . . In a cohort of 117 JS subjects screened for AHI1 mutations by a combination of haplotype analysis and gene sequencing, 11% had mutations.28 Polymicrogyria of the cerebral cortex has been observed in two individuals with AHI1 mutations.15 Retinal dystrophy was reported in 11 out of 12 families with AHI1 mutations;28 however, no subjects exhibited the variable JSRD features of encephalocele, polydactyly, coloboma, or liver fibrosis . . .
    • . . . Renal disease consistent with nephronophthisis has been observed in several older subjects with JS and AHI1 mutations.28, 42 Thus, individuals with AHI1 mutations are at risk to develop both retinal dystrophy and progressive kidney disease. . . .
    • . . . From Dixon-Salazar et al15, Parisi et al28, Ferland et al39, Romano et al41, Utsch et al42, Valente et al.43 . . .
    • . . . The NPHP1 and AHI1 genes combined accounted for <15% of causative mutations in a cohort of 117 subjects, strongly suggesting that other genes for JS remain to be identified.28 In another study, the CEP290 gene was causative in seven out of 96 individuals with JSRD (7%).44 Linkage analysis has implicated two additional loci in JSRD (Table 2) . . .
    • . . . Clinical molecular testing for the homozygous deletion of the NPHP1 gene associated with juvenile nephronophthisis,35, 56 identified in only 1–2% of subjects with JS, is available by FISH or microsatellite marker analysis28 (see http://www.genetests.org for a list of testing laboratories) . . .
  29. King MD, Dudgeon J, Stephenson JB: Joubert's syndrome with retinal dysplasia: neonatal tachypnoea as the clue to a genetic brain-eye malformation. Arch Dis Child 1984; 59: 709-718 , .
  30. Gentile M, Di Carlo A, Susca F et al: COACH syndrome: report of two brothers with congenital hepatic fibrosis, cerebellar vermis hypoplasia, oligophrenia, ataxia, and mental retardation. Am J Med Genet 1996; 64: 514-520 , .
  31. Quisling RG, Barkovich AJ, Maria BL: Magnetic resonance imaging features and classification of central nervous system malformations in Joubert syndrome. J Child Neurol 1999; 14: 628-635; discussion 669-672 , .
  32. Hildebrandt F, Otto E, Rensing C et al: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 1997; 17: 149-153 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
  33. Saunier S, Calado J, Benessy F et al: Characterization of the NPHP1 locus: mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am J Hum Genet 2000; 66: 778-789 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
  34. Hoefele J, Otto E, Felten H et al: Clinical and histological presentation of 3 siblings with mutations in the NPHP4 gene. Am J Kidney Dis 2004; 43: 358-364 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
    • . . . The NPHP1 mutation detection rate for the purely renal disorder is approximately 30%,34 in contrast to a rate of approximately 1–2% in patients with JS based on several case series.28, 35, 37 However, the likelihood of detecting a causative NPHP1 deletion may be increased in subjects with JS who also have juvenile nephronophthisis . . .
  35. Parisi MA, Bennett CL, Eckert ML et al: The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 2004; 75: 82-91 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
    • . . . The NPHP1 mutation detection rate for the purely renal disorder is approximately 30%,34 in contrast to a rate of approximately 1–2% in patients with JS based on several case series.28, 35, 37 However, the likelihood of detecting a causative NPHP1 deletion may be increased in subjects with JS who also have juvenile nephronophthisis . . .
    • . . . Clinical molecular testing for the homozygous deletion of the NPHP1 gene associated with juvenile nephronophthisis,35, 56 identified in only 1–2% of subjects with JS, is available by FISH or microsatellite marker analysis28 (see http://www.genetests.org for a list of testing laboratories) . . .
  36. Betz R, Rensing C, Otto E et al: Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J Pediatr 2000; 136: 828-831 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
  37. Castori M, Valente EM, Donati MA et al: NPHP1 gene deletion is a rare cause of Joubert syndrome related disorders. J Med Genet 2005; 42: e9 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
    • . . . Two subjects with the homozygous NPHP1 deletion had retinal dystrophy in addition to nephronophthisis, comprising Senior–Løken syndrome.37, 38 Thus far, the MTS in these individuals appears to be less striking with less extensive cerebellar vermis hypoplasia and elongated, but not thickened, superior cerebellar peduncles (Figure 2); the significance of this finding is not clear, as few JS subjects with NPHP1 deletions have been identified . . .
  38. Caridi G, Dagnino M, Rossi A et al: Nephronophthisis type 1 deletion syndrome with neurological symptoms: prevalence and significance of the association. Kidney Int 2006; 70: 1342-1347 , .
    • . . . The 30-exon NPHP1 (Nephronophthisis 1) gene and a portion of another gene of unknown function reside within a homozygous deletion of 290 kb flanked by large inverted repeat elements on chromosome 2q13 that has been identified in the renal disorder, juvenile nephronophthisis.26, 32, 33 Compound heterozygosity for the deletion combined with a point mutation in the NPHP1 gene has been identified in some subjects with nephronophthisis.34 The common NPHP1 deletion has also been identified in a few patients with JS,35, 37, 38 as well as some individuals with congenital OMA known as Cogan syndrome.36 The deletion appears to be identical in the different disorders . . .
  39. 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: 1008-1013 , .
    • . . . The AHI1 (Abelson Helper-Integration site 1) gene has 28 exons (26 coding), encodes a protein called Jouberin, and was found to harbor JS-causing mutations based on mapping studies in several inbred families.15, 39, 40 A variety of nonsense, missense, splice-site, and insertion mutations have been identified in JS subjects15, 28 . . .
    • . . . From Dixon-Salazar et al15, Parisi et al28, Ferland et al39, Romano et al41, Utsch et al42, Valente et al.43 . . .
  40. Lagier-Tourenne C, Boltshauser E, Breivik N et al: Homozygosity mapping of a third Joubert syndrome locus to 6q23. J Med Genet 2004; 41: 273-277 , .
    • . . . The AHI1 (Abelson Helper-Integration site 1) gene has 28 exons (26 coding), encodes a protein called Jouberin, and was found to harbor JS-causing mutations based on mapping studies in several inbred families.15, 39, 40 A variety of nonsense, missense, splice-site, and insertion mutations have been identified in JS subjects15, 28, 39, 41, 42, 43 (Figure 3) . . .
  41. Romano S, Boddaert N, Desguerre I et al: Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study. Neuropediatrics 2006; 37: 42-45 , .
    • . . . The AHI1 (Abelson Helper-Integration site 1) gene has 28 exons (26 coding), encodes a protein called Jouberin, and was found to harbor JS-causing mutations based on mapping studies in several inbred families.15, 39, 40 A variety of nonsense, missense, splice-site, and insertion mutations have been identified in JS subjects15, 28, 39, 41, 42, 43 (Figure 3) . . .
    • . . . From Dixon-Salazar et al15, Parisi et al28, Ferland et al39, Romano et al41, Utsch et al42, Valente et al.43 . . .
  42. Utsch B, Sayer JA, Attanasio M et al: Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome. Pediatr Nephrol 2006; 21: 32-35 , .
    • . . . The AHI1 (Abelson Helper-Integration site 1) gene has 28 exons (26 coding), encodes a protein called Jouberin, and was found to harbor JS-causing mutations based on mapping studies in several inbred families.15, 39, 40 A variety of nonsense, missense, splice-site, and insertion mutations have been identified in JS subjects15, 28, 39, 41, 42, 43 (Figure 3) . . .
    • . . . From Dixon-Salazar et al15, Parisi et al28, Ferland et al39, Romano et al41, Utsch et al42, Valente et al.43 . . .
  43. Valente EM, Brancati F, Silhavy JL et al: AHI1 gene mutations cause specific forms of Joubert syndrome-related disorders. Ann Neurol 2006; 59: 527-534 , .
  44. Sayer JA, Otto EA, O'Toole J F et al: The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet 2006; 38: 674-681 , .
    • . . . The 55-exon CEP290 gene (Centrosomal Protein, 290 kDa) was identified as causative in seven of 96 individuals with JSRD in one series (7%).44 The affected individuals in the majority of families have had retinal dystrophy or congenital blindness, and renal disease consistent with nephronophthisis or renal cortical cysts has also been present.44, 45 Thus, the form of JSRD in many families with CEP290 mutations overlaps with Senior–Løken syndrome or Joubert-LCA like . . .
    • . . . Other findings in some affected individuals include ocular colobomas and encephaloceles.44 Almost all of the JSRD-associated CEP290 mutations have included nonsense, splice-site, or insertions/deletions resulting in frameshift mutations.43, 44 Mutations in CEP290 have also been identified in 21% of patients with Leber congenital amaurosis without the MTS or cognitive impairment; in these individuals, a common point mutation creates an aberrant splice product but some residual production of wild-type protein is hypothesized to account for the milder phenotype than the complete loss-of-function mutations found in JSRD patients.46 . . .
    • . . . However, CEP290 localizes to the centrosome at the base of the cilium and is present in the cerebellum during mouse embryogenesis; expression defects in zebrafish result in aberrant retinal, cerebellar, and renal development.44, 45 The centrosome is known to be important in chromosome segregation and may play a role in cell-cycle regulation . . .
    • . . . The NPHP1 and AHI1 genes combined accounted for <15% of causative mutations in a cohort of 117 subjects, strongly suggesting that other genes for JS remain to be identified.28 In another study, the CEP290 gene was causative in seven out of 96 individuals with JSRD (7%).44 Linkage analysis has implicated two additional loci in JSRD (Table 2) . . .
    • . . . Mutations in both AHI1 and CEP290 are more likely to be associated with retinal disease, with CEP290 implicated in some cases with congenital blindness or Leber amaurosis.44, 46 In rare families with a large number of affected children and/or known consanguinity, linkage analysis may be feasible on a research basis. . . .
  45. Valente EM, Silhavy JL, Brancati F et al: Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 2006; 38: 623-625 , .
    • . . . The 55-exon CEP290 gene (Centrosomal Protein, 290 kDa) was identified as causative in seven of 96 individuals with JSRD in one series (7%).44 The affected individuals in the majority of families have had retinal dystrophy or congenital blindness, and renal disease consistent with nephronophthisis or renal cortical cysts has also been present.44, 45 Thus, the form of JSRD in many families with CEP290 mutations overlaps with Senior–Løken syndrome or Joubert-LCA like . . .
    • . . . However, CEP290 localizes to the centrosome at the base of the cilium and is present in the cerebellum during mouse embryogenesis; expression defects in zebrafish result in aberrant retinal, cerebellar, and renal development.44, 45 The centrosome is known to be important in chromosome segregation and may play a role in cell-cycle regulation . . .
  46. den Hollander AI, Koenekoop RK, Yzer S et al: Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber Congenital Amaurosis. Am J Hum Genet 2006; 79: 556-561 , .
  47. Watnick T, Germino G: From cilia to cyst. Nat Genet 2003; 34: 355-356 , .
    • . . . NPHP1 and other nephrocystin gene products associated with juvenile nephronophthisis are known to localize to the cell–cell junctions and the primary cilium and basal body apparatus of renal epithelial cells.26, 47 These nephrocystin gene products form multiprotein complexes with microtubules, adherens proteins, and other cytoskeletal components, and may play a role as mechanosensors in cellular signaling processes or in intraflagellar transport.26 Although a precise role for these proteins has not yet been elucidated in the cerebellum, it is known that most neurons and glia in the mammalian brain contain a primary cilium, an organelle that is present on almost all cells.48, 49 A role for the AHI1 protein in ciliary function has not been identified . . .
    • . . . The functions of this complex organellar structure are many and varied, and mutations in proteins that form the centrosome/basal body apparatus and primary cilium are emerging as important causes of diseases such as Bardet–Biedl syndrome, OFD syndrome 1, Meckel-Gruber syndrome polycystic kidney disease, and lissencephaly,47, 50 some of which have clinical overlap with JSRD. . . .
  48. Fuchs JL, Schwark HD: Neuronal primary cilia: a review. Cell Biol Int 2004; 28: 111-118 , .
    • . . . NPHP1 and other nephrocystin gene products associated with juvenile nephronophthisis are known to localize to the cell–cell junctions and the primary cilium and basal body apparatus of renal epithelial cells.26, 47 These nephrocystin gene products form multiprotein complexes with microtubules, adherens proteins, and other cytoskeletal components, and may play a role as mechanosensors in cellular signaling processes or in intraflagellar transport.26 Although a precise role for these proteins has not yet been elucidated in the cerebellum, it is known that most neurons and glia in the mammalian brain contain a primary cilium, an organelle that is present on almost all cells.48, 49 A role for the AHI1 protein in ciliary function has not been identified . . .
  49. Whitfield JF: The neuronal primary cilium - an extrasynaptic signaling device. Cell Signal 2004; 16: 763-767 , .
    • . . . NPHP1 and other nephrocystin gene products associated with juvenile nephronophthisis are known to localize to the cell–cell junctions and the primary cilium and basal body apparatus of renal epithelial cells.26, 47 These nephrocystin gene products form multiprotein complexes with microtubules, adherens proteins, and other cytoskeletal components, and may play a role as mechanosensors in cellular signaling processes or in intraflagellar transport.26 Although a precise role for these proteins has not yet been elucidated in the cerebellum, it is known that most neurons and glia in the mammalian brain contain a primary cilium, an organelle that is present on almost all cells.48, 49 A role for the AHI1 protein in ciliary function has not been identified . . .
  50. Badano JL, Teslovich TM, Katsanis N: The centrosome in human genetic disease. Nat Rev Genet 2005; 6: 194-205 , .
    • . . . The functions of this complex organellar structure are many and varied, and mutations in proteins that form the centrosome/basal body apparatus and primary cilium are emerging as important causes of diseases such as Bardet–Biedl syndrome, OFD syndrome 1, Meckel-Gruber syndrome polycystic kidney disease, and lissencephaly,47, 50 some of which have clinical overlap with JSRD. . . .
  51. Saar K, Al-Gazali L, Sztriha L et al: Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity. Am J Hum Genet 1999; 65: 1666-1671 , .
    • . . . Two consanguineous Arab families from Oman showed linkage to 9q34,51 identifying the JBTS1 locus . . .
  52. Sztriha L, Al-Gazali LI, Aithala GR, Nork M: Joubert's syndrome: new cases and review of clinicopathologic correlation. Pediatr Neurol 1999; 20: 274-281 , .
    • . . . Several of these affected individuals developed retinal dystrophy, but renal disease has not been described.14, 52 An extended consanguineous Italian family9 and several Arab families53 showed linkage to a locus on the pericentromeric region of chromosome 11, termed the CORS2 (JBTS2) locus . . .
  53. Keeler LC, Marsh SE, Leeflang EP et al: Linkage analysis in families with Joubert syndrome plus oculo-renal involvement identifies the CORS2 locus on chromosome 11p12-q13.3. Am J Hum Genet 2003; 73: 656-662 , .
    • . . . Several of these affected individuals developed retinal dystrophy, but renal disease has not been described.14, 52 An extended consanguineous Italian family9 and several Arab families53 showed linkage to a locus on the pericentromeric region of chromosome 11, termed the CORS2 (JBTS2) locus . . .
  54. Innes AM, Parboosingh J, Roccamatisi D et al: Joubert Syndrome (JS) and Meckel-Gruber syndrome (MGS) are the same disorder in the Hutterite Brethren [abstract 602]. Presented at the annual meeting of The American Society of Human Genetics, October 29, 2004, Toronto, Ontario, Canada. Available from Link 2004 , .
    • . . . The identification of consanguineous families that do not map to any of these five loci suggests the presence of additional causative genes.14, 54, 55 . . .
  55. Janecke AR, Muller T, Gassner I et al: Joubert-like syndrome unlinked to known candidate loci. J Pediatr 2004; 144: 264-269 , .
  56. Hildebrandt F, Rensing C, Betz R et al: Establishing an algorithm for molecular genetic diagnostics in 127 families with juvenile nephronophthisis. Kidney Int 2001; 59: 434-445 , .
    • . . . Clinical molecular testing for the homozygous deletion of the NPHP1 gene associated with juvenile nephronophthisis,35, 56 identified in only 1–2% of subjects with JS, is available by FISH or microsatellite marker analysis28 (see http://www.genetests.org for a list of testing laboratories) . . .
  57. Raynes HR, Shanske A, Goldberg S, Burde R, Rapin I: Joubert syndrome: monozygotic twins with discordant phenotypes. J Child Neurol 1999; 14: 649-654; discussion 669-672 , .
  58. Wang P, Chang FM, Chang CH, Yu CH, Jung YC, Huang CC: Prenatal diagnosis of Joubert syndrome complicated with encephalocele using two-dimensional and three-dimensional ultrasound. Ultrasound Obstet Gynecol 1999; 14: 360-362 , .
    • . . . In the presence of a family history, prenatal diagnosis of JS has been accomplished as early as the first trimester on the basis of extracranial anomalies, such as polydactyly or renal cysts and major structural CNS malformations such as encephalocele.58 Early diagnosis is more challenging when extracranial abnormalities are not present, because cerebellar vermis hypoplasia cannot be reliably diagnosed until 18–20 weeks gestation,59 and the MTS has not been observed before 27 weeks gestation.60 In the absence of a family history, one example of prenatal diagnosis has been published; at 32 weeks gestation, Aslan et al61 observed vermian agenesis, bilateral ventriculomegaly, postaxial polydactyly, and episodes of tachypnea, strongly suggesting a diagnosis of JS . . .
  59. Bromley B, Nadel AS, Pauker S, Estroff JA, Benacerraf BR: Closure of the cerebellar vermis: evaluation with second trimester US. Radiology 1994; 193: 761-763 , .
    • . . . In the presence of a family history, prenatal diagnosis of JS has been accomplished as early as the first trimester on the basis of extracranial anomalies, such as polydactyly or renal cysts and major structural CNS malformations such as encephalocele.58 Early diagnosis is more challenging when extracranial abnormalities are not present, because cerebellar vermis hypoplasia cannot be reliably diagnosed until 18–20 weeks gestation,59 and the MTS has not been observed before 27 weeks gestation.60 In the absence of a family history, one example of prenatal diagnosis has been published; at 32 weeks gestation, Aslan et al61 observed vermian agenesis, bilateral ventriculomegaly, postaxial polydactyly, and episodes of tachypnea, strongly suggesting a diagnosis of JS . . .
  60. Fluss J, Blaser S, Chitayat D et al: Molar tooth sign in fetal brain magnetic resonance imaging leading to the prenatal diagnosis of Joubert syndrome and related disorders. J Child Neurol 2006; 21: 320-324 , .
    • . . . In the presence of a family history, prenatal diagnosis of JS has been accomplished as early as the first trimester on the basis of extracranial anomalies, such as polydactyly or renal cysts and major structural CNS malformations such as encephalocele.58 Early diagnosis is more challenging when extracranial abnormalities are not present, because cerebellar vermis hypoplasia cannot be reliably diagnosed until 18–20 weeks gestation,59 and the MTS has not been observed before 27 weeks gestation.60 In the absence of a family history, one example of prenatal diagnosis has been published; at 32 weeks gestation, Aslan et al61 observed vermian agenesis, bilateral ventriculomegaly, postaxial polydactyly, and episodes of tachypnea, strongly suggesting a diagnosis of JS . . .
  61. Aslan H, Ulker V, Gulcan EM et al: Prenatal diagnosis of Joubert syndrome: a case report. Prenatal Diagn 2002; 22: 13-16 , .
    • . . . In the presence of a family history, prenatal diagnosis of JS has been accomplished as early as the first trimester on the basis of extracranial anomalies, such as polydactyly or renal cysts and major structural CNS malformations such as encephalocele.58 Early diagnosis is more challenging when extracranial abnormalities are not present, because cerebellar vermis hypoplasia cannot be reliably diagnosed until 18–20 weeks gestation,59 and the MTS has not been observed before 27 weeks gestation.60 In the absence of a family history, one example of prenatal diagnosis has been published; at 32 weeks gestation, Aslan et al61 observed vermian agenesis, bilateral ventriculomegaly, postaxial polydactyly, and episodes of tachypnea, strongly suggesting a diagnosis of JS . . .
  62. Doherty D, Glass IA, Siebert JR et al: Prenatal diagnosis in pregnancies at risk for Joubert syndrome by ultrasound and MRI. Prenat Diagn 2005; 25: 442-447 , .
  63. Wang X, Gattone II V, Harris PC, Torres VE: Effectiveness of vasopressin V2 receptor antagonists OPC-31260 and OPC-41061 on polycystic kidney disease development in the PCK rat. J Am Soc Nephrol 2005; 16: 846-851 , .
  64. Dejneka NS, Rex TS, Bennett J: Gene therapy and animal models for retinal disease. Dev Ophthalmol 2003; 37: 188-198 , .
  65. Beales PL: Lifting the lid on Pandora's box: the Bardet-Biedl syndrome. Curr Opin Genet Dev 2005; 15: 315-323 , .
    • . . . In this regard, JS is remarkably similar to Bardet–Biedl syndrome, with at least 11 different loci/genes identified, whose gene products all play a role in the basal body/ciliary apparatus.65 Discovery of genes for JS may provide further information about the function of the centrosome, basal body, and primary cilium and may also lead to valuable insights into mechanisms of cerebellar, renal, and ocular development. . . .
  66. Baala L, Romano S, Khaddour R et al: The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome. Am J Hum Genet 2007; 80: 186-194 , .
    • . . . While all of the affected individuals manifest cerebellar vermis hypoplasia and/or the MTS, two of them lack the classic features of Meckel-Gruber syndrome (encephalocele, renal cysts, Polydactyly, and hepatic fibrosis).66 Clinical testing for mutations in MKS3 is available. . . .
Expand