A novel autosomal dominant leukodystrophy with specific MRI pattern.

Area of Science:

• Neurology
• Genetics
• Radiology

Background:

• Etiologic diagnosis of adult-onset leukodystrophies presents significant challenges in clinical neurology.
• Autosomal dominant leukodystrophies are a heterogeneous group of inherited white matter disorders.

Purpose of the Study:

• To describe the unique clinico-radiological features of a novel autosomal dominant leukodystrophy within a single family.
• To investigate the genetic basis of this newly observed leukodystrophy.

Main Methods:

• Clinical and Magnetic Resonance Imaging (MRI) features were systematically recorded across three generations of one family.
• Exome sequencing was performed on two affected individuals and one unaffected family member.
• Extensive metabolic screening and targeted sequencing of known dominant leukodystrophy genes were conducted.

Main Results:

• Four affected relatives exhibited homogeneous MRI findings: extensive, symmetrical T2-weighted white matter hyperintensities with posterior predominance.
• Key areas of white matter involvement included the middle cerebellar peduncles, corpus callosum, and posterior limb of the internal capsules.
• Metabolic screening and sequencing of NOTCH3, LMNB1, GFAP, and CSF1R genes were negative; exome sequencing did not identify a causative mutation.

Conclusions:

• This family presents a unique form of adult-onset autosomal dominant leukodystrophy with characteristic radiological findings.
• The absence of mutations in known genes and negative exome sequencing results highlight the need for further investigation into novel genetic mechanisms underlying this disorder.