Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the “molar tooth sign”), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.

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The PLAN-associated phenotypes and the challenges of diagnosing the childhood-onset form are delineated, and a common North African founder mutation is identifed.

Introduction RNA polymerase III (Pol III)‐related leukodystrophies are a group of autosomal recessive neurodegenerative disorders caused by mutations in POLR3A and POLR3B. Recently a recessive mutation in POLR1C causative of Pol III‐related leukodystrophies was identified. Methods We report the case of a Tunisian girl of 14 years of age who was referred to our department for evaluation of progressive ataxia that began at the age of 5. Genetic diagnosis was performed by NGS and Sanger analysis. In silico predictions were performed using SIFT, PolyPhen‐2, and Mutation Taster. Results Neurological examination showed cerebellar and tetrapyramidal syndrome, mixed movement disorders with generalized dystonia and severe myoclonus leading to death at 25 years. Brain MRI scans showed diffuse hypomyelination associated with cerebellar atrophy. It also showed bilateral T2 hypointensity of the ventrolateral thalamus, part of the posterior limb of the internal capsule, the substantia nigra and the subthalamic nucleus. Next generation sequencing leukodystrophy panel including POLR3A and POLR3B was negative. Sanger sequencing of the coding regions of POLR1C revealed a novel homozygous mutation. Conclusion The clinical and imaging findings of patients with POLR1C hypomyelinating leukodystrophy are reviewed. Interestingly, severe myoclonic dystonia and T2 hypointensity of the substantia nigra and the subthalamic nucleus are not reported yet and could be helpful for the diagnosis of POLR1C hypomyelinating leukodystrophy.