Ovarian failure related to eukaryotic initiation factor 2B mutations

Abstract

Ovarian failure (OF) at age <40 years occurs in approximately 1% of all women. Other than karyotype abnormalities, very few genes are known to be associated with this ovarian dysfunction. We studied eight patients who presented with premature OF and white-matter abnormalities on magnetic resonance imaging. Neurological signs may be absent or present after OF. In seven patients, we report for the first time mutations in three of the five EIF2B genes (EIF2B2, -4, and -5) that were recently shown to cause childhood ataxia with central nervous system hypomyelination/vanishing white-matter disease leukodystrophy. The correlation we observed between the age at onset of the neurological deterioration and the severity of OF suggests a common pathophysiological pathway.

Figure 1

Cerebral MRI of affected patients. Images of patients 941-2 (A, B, and C), 944 (D, E, and F), and 1014 (G, H, and I), obtained when patients were, respectively, 24, 33, and 16 years of age. In the hemispheric white matter, the following anomalies were observed: an abnormal diffuse signal, characterized by a decreased signal on T1 weighted sequence imaging (A, D, E, and G) and an increased signal on T2 (B and H) and on fluid attenuated inversion recovery (FLAIR) sequences imaging (C, F, and I). Patients 941-2 and 944, who had early school difficulties, have cerebral atrophy involving the cerebral cortex, hemispheric white matter (with ventricular dilatation), and corpus callosum. Abnormal signal within the abnormal white matter on FLAIR sequence imaging is extensive in the frontal white matter of patient 941-2 (C, arrowhead), limited in patient 944 (F, arrowhead), and absent in patient 1014, who experienced secondary amenorrhea and episodes of headache but had normal results on neurological examination at age 16 years.