Duplication and deletion upstream of in autosomal dominant adult-onset leukodystrophy.

OBJECTIVE

To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 ().

METHODS

Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of and its upstream genes. We examined expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed.

RESULTS

We identified 4 patients from 3 families with duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of in patients with duplication was significantly increased. The clinical features of our patients with duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of . Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region.

CONCLUSIONS

We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of . There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of .