Genetic leukodystrophies (gLD), encompassing inherited disorders affecting cerebral white matter, are a heterogeneous group of diseases.1 While they classically first manifest in childhood, adolescent and adult-onset forms are increasingly recognised.2 3 Different pathological mechanisms produce white matter abnormalities (WMAs) depending on the affected gene.1 Hypomyelinating gLD (H-gLD) share the common histological feature of decreased myelin formation in the brain, in contrast to demyelinating gLD (loss of previously formed myelin), dysmyelinating gLD (deposition of structurally abnormal myelin) and myelinolytic disorders (vacuolisations disrupting myelin integrity).1 MRI characteristics help discriminate hypomyelination from other WMAs. In H-gLD, WMAs are widespread, mildly hyperintense on T2/fluid attenuation inversion recovery and associated with diffuse T1 hyperintense, isointense or mildly hypointense signal relative to the grey matter.4 In other gLD, WMAs can be focal or confluent, often with regional predominance, and prominent T2 hyperintensity with marked T1 hypointensity.2 4 H-gLD typically present in the neonatal period with axial hypotonia, followed by spastic paraparesis and delayed motor development in early childhood.2 4 Nystagmus, cerebellar ataxia, extrapyramidal syndrome and cognitive impairment can later develop.3 4 Depending on the gene defect, extraneurological signs have been described.4 Adolescent/adult-onset H-gLD are exceptionally reported.2 We report findings in three unrelated patients with late-onset neurological symptoms and hypomyelinating features on brain MRI. ### Case reports Brain MRI of our patients are shown in figure 1, all showing diffuse WMAs suggestive of isolated hypomyelination. Candidate variants detected by next-generation sequencing (NGS), clinical and electrophysiological features are summarised in online supplementary table 1. The genes included in the panels are listed in online supplementary table 2. Genetic methodology, molecular characteristics and bioinformatics prediction tools of …

Mutations in the EIF2B1–5 genes encoding the subunits of the ubiquitously expressed eukaryotic initiation factor 2B (EIF2B) 1 Van der Knaap M.S. Leegwater P.A. Könst A.A. et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol. 2002; 51: 264-270 Crossref PubMed Scopus (291) Google Scholar have been reported in a group of clinically heterogeneous autosomal recessive multisystem diseases, frequently including leukodystrophy, termed EIF2B-related disorders. 2 Van der Knaap M.S. van Berkel C.G.M. Herms J. et al. eIF2B related disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet. 2003; 73: 1199-1207 Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar Childhood ataxia with central hypomyelination and vanishing white matter disease were first described in the 1990s. 3 Schiffmann R. Moller J.R. Trapp B.D. et al. Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol. 1994; 35: 331-340 Crossref PubMed Scopus (212) Google Scholar , 4 Van der Knaap M.S. Barth P.G. Gabreels F.J. et al. A new leukoencephalopathy with vanishing white matter. Neurology. 1997; 48: 845-855 Crossref PubMed Google Scholar Onset is most often in childhood, but vanishing white matter disease may also start at adulthood. 5 Labauge P. Horzinski L. Ayrignac X. et al. Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain. 2009; 132: 2161-2169 Crossref PubMed Scopus (93) Google Scholar , 6 Bugiani M. Boor I. Powers J.M. et al. Leukoencephalopathy with vanishing white matter: a review. J Neuropathol Exp Neurol. 2010; 69: 987-996 Crossref PubMed Scopus (131) Google Scholar Classically, neurological signs are predominant, dominated by cerebellar ataxia and spasticity with a chronic progressive course and additional episodes of rapid deterioration after minor head trauma and febrile infections that may lead to coma. 7 Van der Knaap M.S. Pronk J.C. Scheper G.C. Vanishing white matter disease. Lancet Neurol. 2006; 5: 413-423 Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar Brain magnetic resonance imaging (MRI) shows abnormal hyper-T2 signal of all or almost all cerebral white matter. Progressively, there is a rarefaction and cystic degeneration of the affected white matter, which is replaced by cerebrospinal fluid. 4 Van der Knaap M.S. Barth P.G. Gabreels F.J. et al. A new leukoencephalopathy with vanishing white matter. Neurology. 1997; 48: 845-855 Crossref PubMed Google Scholar , 7 Van der Knaap M.S. Pronk J.C. Scheper G.C. Vanishing white matter disease. Lancet Neurol. 2006; 5: 413-423 Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar Later, initial symptoms such as psychiatric manifestations or primary ovarian failure were also described, as well as oligohydramnios, intrauterine growth retardation, cataracts, pancreatitis, hepatosplenomegaly, and hypoplastic kidneys. 2 Van der Knaap M.S. van Berkel C.G.M. Herms J. et al. eIF2B related disorders: antenatal onset and involvement of multiple organs. Am J Hum Genet. 2003; 73: 1199-1207 Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar , 5 Labauge P. Horzinski L. Ayrignac X. et al. Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain. 2009; 132: 2161-2169 Crossref PubMed Scopus (93) Google Scholar

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.

Les leuco-encéphalopathies hypomyélinisantes (LEhypo) font partie des leuco-encéphalopathies héréditaires (LEH) débutant habituellement dans l'enfance. Malgré une sémiologie IRM caractéristique, les LEhypo de début adulte sont peu reconnues. Décrire les caractéristiques cliniques, radiologiques et génétiques de patients avec leuco-encéphalopathie de sémiologie hypomyélinisante en IRM et début des symptômes neurologiques à l'âge adulte. Quatre patients suspects de LEH avec début adulte sont rapportés du fait de caractéristiques hypomyélinisantes en IRM cérébrale : hypersignal T2 diffus de la substance blanche d'intensité modérée associé à un hypersignal T1 (habituellement hyposignal T1 dans les leuco-encéphalopathies démyélinisantes (LEdem) plus fréquentes). Ces patients ont eu un bilan étiologique large incluant le séquençage en NGS d'un panel de 131 gènes impliqués dans les LEH. Leurs données cliniques et paracliniques ont été collectées rétrospectivement. Le bilan métabolique était négatif pour tous les patients. Une mutation hétérozygote a été trouvée dans les gènes TUBB4A, SPG15, HSPD1 chez trois patients, deux dans le gène POLR3A chez un quatrième. Toutes les cinq mutations étaient faux sens, quatre n'ont jamais été rapportées. La présentation clinique était atypique chez tous les patients comparée à la forme pédiatrique. Par exemple la patiente avec deux mutations POLR3A présentait un syndrome frontal comportemental isolé sans signe moteur. Les LEhypo ont été très rarement rapportée avec début à l'âge adulte, et principalement avec mutations POLR3A/B. Avec cette série de quatre patients, nous montrons que d'autres gènes uniquement décrits chez des patients pédiatriques peuvent être impliqués, révélant souvent de nouvelles mutations. L'identification en IRM d'une LEhypo rend inutile le bilan étiologique notamment métabolique recherchant une cause de LEdem. La LEhypo débutant à l'âge adulte est une entité existante avec différents gènes impliqués. Reconnaître ses caractéristiques IRM est essentielle pour une approche diagnostique spécifique.

Objective To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families. Methods Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts. Results We identified a biallelic mutation in a gene coding for a Pol III-specific subunit, POLR3K (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in POLR3A- and POLR3B-related leukodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%-80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control. Conclusions These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.

Sengers syndrome is a rare autosomal recessive metabolic disorder caused by lack of acylglycerol kinase due to mutations in the AGK gene. It is characterized by congenital cataract, hypertrophic cardiomyopathy, myopathy and lactic acidosis. Two clinical forms have been described: a severe neonatal form, and a more benign form displaying exercise intolerance. We describe two siblings with congenital cataract, cardiomyopathy, hypotonia, intellectual disability and lactic acidosis. Whole exome sequencing revealed a homozygous c.1035dup mutation in the two siblings, supporting a diagnosis of Sengers syndrome. Our patients presented an intermediate form with intellectual deficiency, an unusual feature in Sengers syndrome. This permitted a prenatal diagnosis for a following pregnancy.