A number sign (#) is used with this entry because progressive leukoencephalopathy (LKENP) with ovarian failure is caused by compound heterozygous mutation in the AARS2 gene (612035) on chromosome 6p21.

Progressive leukoencephalopathy with ovarian failure is an autosomal recessive neurodegenerative disorder characterized by loss of motor and cognitive skills, usually with onset in young adulthood. Some patients may have a history of delayed motor development or learning difficulties in early childhood. Neurologic decline is severe, usually resulting in gait difficulties, ataxia, spasticity, and cognitive decline and dementia. Most patients lose speech and become wheelchair-bound or bedridden. Brain MRI shows progressive white matter signal abnormalities in the deep white matter. Affected females develop premature ovarian failure (summary by Dallabona et al., 2014).

Dallabona et al. (2014) reported 5 unrelated women and 1 man with a progressive leukoencephalopathic neurodegenerative disorder. Two patients, a female and a male, had symptoms in early childhood, 1 manifesting mildly delayed motor development and the other manifesting congenital nystagmus and learning difficulties. These patients developed further neurologic symptoms in their teenage years, including progressive gait ataxia, tremor, spasticity, dystonia, dysarthria, and cognitive decline. The girl developed secondary amenorrhea due to ovarian failure at age 18 years. Four additional women presented with ovarian failure between the ages of 20 and 40, and subsequently developed progressive and severe neurodegeneration resulting in loss of motor skills, speech, and cognition by the mid-thirties to forties. Most of the 6 patients either became wheelchair-bound or bedridden, and 2 died. One patient had no cognitive decline at age 25. Investigation of mitochondrial function performed in 2 patients showed severe isolated cytochrome c oxidase deficiency (15% and 33% residual activity, respectively) in skeletal muscle, although respiratory chain activities were normal in fibroblasts. Ragged-red fibers were not present. Brain MRI of all patients showed patchy and inhomogeneous cerebral white matter abnormalities predominantly affecting the frontal and parietal periventricular and deep white matter, and often affecting the corpus callosum. Cerebellar atrophy was variable. None of the patients had cardiomyopathy.

The transmission pattern of progressive leukoencephalopathy in the families reported by Dallabona et al. (2014) was consistent with autosomal recessive inheritance.

In 6 patients with progressive leukoencephalopathy, including 5 women with premature ovarian failure, Dallabona et al. (2014) identified compound heterozygous mutations in the AARS2 gene (see, e.g., 612035.0004-612035.0007). The mutations in the first 2 patients were found by whole-exome sequencing. Direct sequencing of the AARS2 gene identified pathogenic biallelic mutations in 4 of 11 additional patients with leukodystrophy. Studies of the yeast homologs of 2 variants (612035.0004 and 612035.0005) showed that they resulted in a complete or partial loss of protein function; functional studies of the other variants were not performed.