Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.

About 10% of infertile/subfertile women are diagnosed with diminished ovarian reserve (DOR), of which < 5% will become pregnant spontaneously. Fragile X (FMR1) genetic testing may provide a reason for her early ovarian aging and/or have reproductive implications. Seven women with DOR (genetic study subset) and the male partners of six of these women were separately interviewed about the experience of being asked to undergo this unanticipated genetic test. Three interviews were conducted (before, within 1 week after, and 3 months after learning the test results). None of the participants carried the FMR1 premutation (largest FMR1 allele 27–50 CGG repeats).For women, their pregnancy-seeking journey was long and exhausting. Women understood the reproductive implications of carrying the FMR1 premutation, and hoped for a negative result. Being offered a genetic test caused women to pause and re-think their future reproductive plans. Husbands viewed the infertility journey as filled with unknowns, of which the genetic test results would be one more puzzle piece. The expense of fertility testing/treatment was mentioned by both spouses, though more notably by husbands. The introduction of a possible genetic cause of infertility, with additional potential health consequences for future biological children, caused women to re-think their quest for pregnancy. In contrast, the genetic test was viewed as an additional source of information for their husbands as opposed to raising concern regarding potential reproductive ramifications.

Diminished ovarian reserve (DOR) and premature ovarian failure are associated with elevated FMR1 CGG repeat alleles. We assessed pretest attitudes about potentially carrying the FMR1 premutation (FXP) (>55 CGG repeats) among reproductive age women compared with attitudes after learning their non-carrier status. Ninety-two women with DOR, regular menses and no family history of Fragile X Syndrome underwent FMR1 testing and completed attitudinal questionnaires before (T1) and 3 months after learning the test results (T2). The analysis utilized signed rank tests and α=0.05. Very few women thought they were likely to have a FXP (6.6%). More participants thought FMR1 premutations were “serious” at T2 (62.9%) than at T1 (46.1%, p<0.0003). When asked at T1 to “describe your feelings when you consider that you are potentially a carrier” of a FXP, 10% had negative feelings, 50% felt ambivalent, and 40% had positive feelings. At T2, feelings about not being a carrier were significantly more favorable (p<0.0001): negative (0%), ambivalent (6.5%), positive (93%). Corroborating prior reports, few women had a negative view of FXP, perhaps anticipating that carrying the FXP explains their infertility. Perception of the seriousness of FXP increased after learning they did not carry the FXP, which would be predicted by health belief models.

One cannot predict patients' screening preferences, thus both FTS and IS should be offered. Given non-directive counselling, patients are generally satisfied with their screening choices.

No abstract