Severe Leukoencephalopathy with Clinical Recovery Caused by Recessive BOLA3 Mutations

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Leukoencephalopathy with acute neurological regression in infancy is a rare condition.
• Complete clinical recovery is unusual in such cases, prompting investigation into underlying genetic causes.

Purpose of the Study:

• To identify the genetic etiology of a distinct leukoencephalopathy presenting with acute neurological regression and subsequent recovery.
• To characterize the functional consequences of identified genetic variants.

Main Methods:

• Trio whole genome sequencing (WGS) was performed to identify causative variants.
• Mitochondrial function assays, including pyruvate dehydrogenase (PDH) activity and mitochondrial complex analysis, were conducted in patient fibroblasts.
• Plasma glycine levels were measured.

Main Results:

• WGS identified compound heterozygous variants in the BOLA3 gene, including a novel variant.
• Patient fibroblasts showed deficient PDH activity and reduced mitochondrial complex I and II subunits, confirming BOLA3 dysfunction.
• The patient experienced acute neurological regression followed by significant clinical recovery and partial resolution of MRI abnormalities, with elevated plasma glycine.

Conclusions:

• A novel phenotype for Multiple Mitochondrial Dysfunction Syndrome 2 (MMDS2) is described, characterized by leukoencephalopathy and apparently complete clinical recovery.
• A novel BOLA3 variant was identified and functionally validated, expanding the genotypic spectrum of BOLA3-related disorders.
• This case highlights the potential for spontaneous improvement in some genetic leukoencephalopathies.