Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

Joubert syndrome (JS) is a neurodevelopmental disorder characterized by hypotonia and developmental delay, as well as the obligatory molar tooth sign on brain imaging. Since hypotonia and developmental delay are nonspecific features, there must be a high level of clinical suspicion of JS so that the diagnostic brain imaging and/or molecular testing for the >38 genes associated with JS is/are obtained. The goal of this study was to analyze clinical photographs of a cohort of patients with JS to define a list of physical examination features that should prompt investigation for JS. Analysis of photographs from 94 individuals with JS revealed that there is a recognizable pattern of facial features in JS that changes over time as individuals age. Macrocephaly, head tilting even when looking straight ahead, eye movement abnormalities (oculomotor apraxia, nystagmus, strabismus), and ptosis are common in those with JS. Distinctive features in younger children include triangular-shaped open mouth with tongue protrusion; in older children and adults, mandibular prognathia and prominent nasal bridge are common.

Gain-of-function mutations in ALPK1 cause an NF-κB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome.

OBJECTIVES: To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation in ALPK1, is an autoinflammatory disease. METHODS: This cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect of ALPK1 mutations on immune signalling. Clinical, immunologic and radiographical examinations were performed, and 10 patients were empirically initiated on anticytokine therapy and monitored. Exome sequencing was used to identify a new pathogenic variant. Cytokine profiling, transcriptomics, immunoblotting and knock-in mice were used to assess the impact of ALPK1 mutations on protein function and immune signalling. RESULTS: The majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with the Alpk1 T237M mutation exhibited subclinical inflammation.Clinical features not conventionally attributed to inflammation were also common in the cohort and included short dental roots, enamel defects and decreased salivary flow. CONCLUSION: ROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in ALPK1 and some features of disease are amenable to immunomodulatory therapy.

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.

The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature.

The spectrum of peroxisomal disorders is wide and comprises individuals that die in the first year of life, as well as people with sensorineural hearing loss, retinal dystrophy and amelogenesis imperfecta. In this article, we describe three patients; two diagnosed with Heimler syndrome and a third one with a mild-intermediate phenotype. We arrived at these diagnoses by conducting complete ophthalmic (National Eye Institute), auditory (National Institute of Deafness and Other Communication Disorders), and dental (National Institute of Dental and Craniofacial Research) evaluations, as well as laboratory and genetic testing. Retinal degeneration with macular cystic changes, amelogenesis imperfecta, and sensorineural hearing loss were features shared by the three patients. Patients A and C had pathogenic variants in PEX1 and Patient B, in PEX6. Besides analyzing these cases, we review the literature regarding mild peroxisomal disorders, their pathophysiology, genetics, differential diagnosis, diagnostic methods, and management. We suggest that peroxisomal disorders are considered in every child with sensorineural hearing loss and retinal degeneration. These patients should have a dental evaluation to rule out amelogenesis imperfecta as well as audiologic examination and laboratory testing including peroxisomal biomarkers and genetic testing. Appropriate diagnosis can lead to better genetic counseling and management of the associated comorbidities.

Healthcare recommendations for Joubert syndrome.

Joubert syndrome (JS) is a recessive neurodevelopmental disorder defined by a characteristic cerebellar and brainstem malformation recognizable on axial brain magnetic resonance imaging as the "Molar Tooth Sign". Although defined by the neurological features, JS is associated with clinical features affecting many other organ systems, particularly progressive involvement of the retina, kidney, and liver. JS is a rare condition; therefore, many affected individuals may not have easy access to subspecialty providers familiar with JS (e.g., geneticists, neurologists, developmental pediatricians, ophthalmologists, nephrologists, hepatologists, psychiatrists, therapists, and educators). Expert recommendations can enable practitioners of all types to provide quality care to individuals with JS and know when to refer for subspecialty care. This need will only increase as precision treatments targeting specific genetic causes of JS emerge. The goal of these recommendations is to provide a resource for general practitioners, subspecialists, and families to maximize the health of individuals with JS throughout the lifespan.

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

PURPOSE: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. METHODS: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). RESULTS: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. CONCLUSION: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.Genet Med advance online publication 26 January 2017.

Defective ciliogenesis in INPP5E-related Joubert syndrome.

Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium. Here, we report the detailed clinical phenotypes of two sisters with a novel homozygous variant in INPP5E (NM_019892.4: c.1565G>C, NP_063945.2: p.Gly552Ala), expanding the phenotype associated with Joubert syndrome type 1. Expression studies using patient-derived fibroblasts showed changes in mRNA and protein levels. Analysis of fibroblasts from patients revealed that a significant number of cells had shorter or no cilia, indicating defects in ciliogenesis, and cilia maintenance.

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

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. 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. 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). 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.