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AJNR Am J Neuroradiol. 2019 May;40(5):788-791. doi: 10.3174/ajnr.A6036. Epub 2019 Apr 25.

GJA1 Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination.

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From the Department of Genetics (L.S.-V., T.C., P.C., F.M.).
Department of Neurology and Reference Center for Neurogenetic Diseases (C.V.), Angers University Hospital, Angers, France.
Department of Neurology (M.C.), Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière University Hospital, Paris, France.
Sorbonne Université (M.C.), Centre National de la Recherche Scientifique UMR 7622, Institut National de la Santé et de la Recherche Médicale ERL 1156, Institut de Biologie Paris-Seine, Paris, France.
Baylor Scott & White Research Institute (R.S.), Dallas, Texas.
Department of Neuropediatrics and Reference Center for Leukodystrophy and Leukoencephalopathy (O.B.-T.), Assistance Publique-Hôpitaux de Paris, Robert-Debré University Hospital, Paris, France.
From the Department of Genetics (L.S.-V., T.C., P.C., F.M.)
Reference Center for Adult Neurometabolic Diseases (F.M.).
Groupe de Recherche Clinique No. 13, Neurométabolisme (F.M.), Sorbonne Université, Paris, France.
Sorbonne Université (F.M.), Université Pierre-et-Marie-Curie-Paris 6, UMR S 1127 and Institut National de la Santé et de la Recherche Médicale U 1127, and Centre National de la Recherche Scientifique UMR 7225, and Brain and Spine Institute, F-75013, Paris, France.


Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.


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