Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication

Abstract

Adult-onset autosomal dominant leukodystrophy (ADLD, OMIM accession number 169500) is a slowly progressive neurological disorder involving early autonomic dysfunction, cognitive impairment, pyramidal lesions, and cerebellar dysfunction. Onset is usually in the fourth or fifth decade of life. The disease is caused by a duplication of a region on chromosome 5q23.2 including the Lamin B1 gene (LMNB1) [1]. Neuroradiological characteristics are symmetrical extensive white matter changes predominantly in the frontal and parietal lobes, middle cerebellar peduncles, and specific brain stem tracts. Furthermore, atrophy of the corpus callosum and the brain stem develop. Sparing or less severe alteration of the periventricular white matter is a typical finding [2]. We report on a 47-year-old male patient with a 2-year history of gait disturbance and micturition problems with imperative strangury and, as mentioned by family members, personality changes and depression. On examination he had moderately severe gait ataxia, symmetrical appendicular ataxia, mild spastic paraparesis, brisk deep tendon reflexes, and bilaterally positive Babinski signs. MR imaging of the brain showed extensive bilateral T2hyperintense lesions in the subcortical and deep cerebral white matter with relative sparing of a periventricular rim and the corpus callosum. The middle cerebellar peduncles, the pyramidal tracts, and medial lemniscus in the midbrain, pons, and medulla, and the decussation of the superior cerebellar peduncles were also affected (Fig. 1). Neuropsychological testing yielded results below average regarding the following domains: verbal fluency and flexibility, verbal memory, verbal recall, working memory, several executive functions, and general working velocity. Lumbar puncture, evoked potentials, nerve conduction studies, and electromyography were without abnormal findings. Blood and urine analysis of amino acids, long-chain fatty acids, and lysosomal enzymes (arylsulfatase A, galactocerebrosidase, alpha-galactosidase) were normal. The pedigree showed numerous affected members of father’s family within three generations. Four out of five uncles and aunts and in the grandparents’ generation, six out of eight family members were affected, mainly by gait disturbance but also by neuropsychiatric symptoms (Fig. 2). Seven affected siblings had died; age at death varied between 46 and 71 years. Because of the mode of inheritance and the clinical and MRI findings, ADLD was supposed and the lamin B1 gene was analyzed. Genomic DNA was extracted from venous blood and hybridized on Affymetrix GeneChip Human Mapping SNP6.0 arrays, following the manufacturer’s instructions. M. M. Dos Santos (&) A. J. Grau Department of Neurology, Klinikum Ludwigshafen, Bremserstrasse 79, 67063 Ludwigshafen, Germany e-mail: santosm@klilu.de