Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center

Vilboux, Thierry; Doherty, Dan; Glass, Ian A.; Parisi, Melissa A.; Phelps, Ian G.; Cullinane, Andrew R.; Zein, Wadih M.; Heller, Theo; Soldatos, Ariane; Oden, Neal; Yildirimli, Deniz; Vemulapalli, Meghana; Mullikin, James C.; Program, Nisc Comparative Sequencing; Malicdan, May Christine V.; Gahl, William A.; Gunay‐Aygun, Meral

doi:10.1038/gim.2016.204

Cited by 100 publications

(141 citation statements)

References 29 publications

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“…For instance, patients with EOA who are diagnosed with spinocerebellar ataxia type 29 ( ITPR1 gene mutation), may present with a broad clinical spectrum, including subtle phenotypes with mild, non‐progressive coordination impairment and cognitive disabilities . Furthermore, some patients with Joubert syndrome may present with mild developmental abnormalities, whereas others are severely ataxic . Conversely, features of ataxia are sometimes recognizable in patients with DCD.…”

Section: Discussionmentioning

confidence: 99%

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Paediatric motor phenotypes in early‐onset ataxia, developmental coordination disorder, and central hypotonia

Lawerman

Brandsma

Maurits

et al. 2019

Develop Med Child Neuro

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AIMS To investigate the accuracy of phenotypic early-onset ataxia (EOA) recognition among developmental conditions, including developmental coordination disorder (DCD) and hypotonia of central nervous system origin, and the effect of scientifically validated EOA features on changing phenotypic consensus.METHOD We included 32 children (4-17y) diagnosed with EOA (n=11), DCD (n=10), and central hypotonia (n=11). Three paediatric neurologists independently assessed videotaped motor behaviour phenotypically and quantitatively (using the Scale for Assessment and Rating of Ataxia [SARA]). We determined: (1) phenotypic interobserver agreement and phenotypic homogeneity (percentage of phenotypes with full consensus by all three observers according to the underlying diagnosis); (2) SARA (sub)score profiles; and (3) the effect of three scientifically validated EOA features on phenotypic consensus. RESULTS Phenotypic homogeneity occurred in 8 out of 11, 2 out of 10, and 1 out of 11 patients with EOA, DCD, and central hypotonia respectively. Homogeneous phenotypic discrimination of EOA from DCD and central hypotonia occurred in 16 out of 21 and 22 out of 22 patients respectively. Inhomogeneously discriminated EOA and DCD phenotypes (5 out of 21) revealed overlapping SARA scores with different SARA subscore profiles. After phenotypic reassessment with scientifically validated EOA features, phenotypic homogeneity changed from 16 to 18 patients.

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Section: Discussionmentioning

confidence: 99%

“…For instance, patients with EOA who are diagnosed with ataxic. 30 Conversely, features of ataxia are sometimes recognizable in patients with DCD. Furthermore, at the outpatient clinic, parents cannot always tell whether their child's motor incoordination is progressive or not.…”

Section: Discussionmentioning

confidence: 99%

Paediatric motor phenotypes in early‐onset ataxia, developmental coordination disorder, and central hypotonia

Lawerman

Brandsma

Maurits

et al. 2019

Develop Med Child Neuro

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“…If patient age or cooperation level precluded an adequate measurement of BCVA, a determination of the presence or absence of the following reflexes was documented: 1) fix and follow (FF), 2) central, steady/unsteady and maintained fixation (CSM/CUSM), 3) blink to light (BTL) reflexes. Individuals were determined to have chorioretinal coloboma, retinal degeneration, kidney disease and liver disease based on clinical and laboratory evaluations performed at the NIH Clinical Center [Vilboux et al, 2017]. …”

Section: Participants and Methodsmentioning

confidence: 99%

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center

Summers

Snow

Wiggs

et al. 2017

American J of Med Genetics Pt A

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Objectives Joubert Syndrome (JS) is a genetically heterogeneous ciliopathy characterized by hypo-dysplasia of the cerebellar vermis, a distinct hindbrain/midbrain malformation (molar tooth sign), and intellectual disability. We evaluated the neuropsychological profiles of 76 participants with JS in the context of molecular genetics and clinical covariates. Methods Evaluations included neuropsychological testing, structured parental interviews, DNA sequencing, brain magnetic resonance imaging (MRI), electroencephalography (EEG), ophthalmologic examination, and assessment for renal and hepatic disease. Results On average, participants manifested Full Scale Intelligence Quotients (FSIQ) in the moderately to profoundly low range (M=64.3±15.3). Of the Wechsler index scores, verbal comprehension was least affected and processing speed was most affected. Receptive language was rated as better than expressive language on the Vineland Adaptive Behavior Scales-Second Edition. Those with abnormal EEG had a significantly lower FSIQ (n=15; M=50.7±12.9) compared to participants with normal EEG (n=39; M=64.7±16.3; p=.004). Participants taking psychiatric medications manifested a lower FSIQ (n=20; M=54.8±13.2) than those not taking them (n=42; M=65.0±17.2; p=.022). These correlations were also present in the TMEM67-related JS sub-cohort (n=14). Based on parental assessment, psychiatric and behavioral problems were significantly more common than in the general population for all measures (p<.004 for all). Conclusions The majority (65%) of individuals with JS have some degree of intellectual disability. Abnormal EEG is associated with lower neuropsychological function. Processing speed is a weakness, while verbal comprehension and receptive language are relative strengths. These findings may guide parents, teachers, therapists, and doctors to determine appropriate therapies, accommodations and academic goals for individuals with JS.

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“…Collectively these conditions are caused by recessive mutations in more than 30 autosomal genes, as well as mutations in a few X‐linked genes. Many of these have a role in cilia function, leading to the term “ciliopathies.” Gene panel or exome testing yields a molecular diagnosis in 62% to 94% of cases …”

Section: Cerebellar and Posterior Fossa Abnormalitiesmentioning

confidence: 99%

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

Veyver

2019

Prenatal Diagnosis

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Developmental brain abnormalities are complex and can be difficult to diagnose by prenatal imaging because of the ongoing growth and development of the brain throughout pregnancy and the limitations of ultrasound, often requiring fetal magnetic resonance imaging as an additional tool. As for all major structural congenital anomalies, amniocentesis with chromosomal microarray and a karyotype is the first‐line recommended test for the genetic work‐up of prenatally diagnosed central nervous system (CNS) abnormalities. Many CNS defects, especially neuronal migration defects affecting the cerebral and cerebellar cortex, are caused by single‐gene mutations in a large number of different genes. Early data suggest that prenatal diagnostic exome sequencing for fetal CNS defects will have a high diagnostic yield, but interpretation of sequencing results can be complex. Yet a genetic diagnosis is important for prognosis prediction and recurrence risk counseling. The evaluation and management of such patients is best done in a multidisciplinary team approach. Here, we review general principles of the genetic work‐up for fetuses with CNS defects and review categories of genetic causes of prenatally diagnosed CNS phenotypes.

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Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center

Cited by 100 publications

References 29 publications

Paediatric motor phenotypes in early‐onset ataxia, developmental coordination disorder, and central hypotonia

Paediatric motor phenotypes in early‐onset ataxia, developmental coordination disorder, and central hypotonia

Neuropsychological phenotypes of 76 individuals with Joubert syndrome evaluated at a single center

Prenatally diagnosed developmental abnormalities of the central nervous system and genetic syndromes: A practical review

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