Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the "molar tooth sign" on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

We conducted a retrospective study to determine whether the presence of moyamoya collaterals influenced the risk of recurrence of cerebrovascular events (CVEs: stroke or transient ischemic attack) in patients with sickle cell disease placed on chronic transfusions after a stroke. Forty-three patients with homozygous sickle cell anemia (HbSS) and 1 with HbSO Arab (16 females, 28 males) who had suffered strokes while under the age of 18 were studied. All patients had been on transfusions aimed at maintaining the sickle hemoglobin (HbS) level below 30%. They were followed for a mean of 6.6 years (2.2 to 20.4 years). The presence of collaterals was diagnosed based on either magnetic resonance angiography or conventional angiography. Eighteen (41%) of the 44 patients suffered recurrent CVEs. Nineteen (43%) (6 females, 13 males) patients had moyamoya collaterals. Eleven (58%) of these 19 experienced 21 total recurrent CVEs, including 4 strokes in 4 patients (21%). In comparison, 7 (28%) of 25 patients without moyamoya collaterals experienced 9 recurrent CVEs (P < .05) with only 1 recurrent stroke (4%). Moyamoya patients were also more likely to have 2 recurrent CVEs (42% vs 8%,