Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

Hearing loss in children with mitochondrial disorders.

OBJECTIVE: At least 1-5 children per 1000 suffer from congenital hearing loss, and 50% of these cases can be attributed to genetic causes. It has been estimated that 1% of pre-lingual hearing loss is due to mutations in mitochondrial DNA. Previous literature reports audiometric data for few patients, usually less than 20 per study. The goal of this study was to characterize the hearing loss associated with mitochondrial mutations and determine whether previously characterized patterns of hearing loss in these patients (progressive, sensorineural, high frequency losses) are found in our population as well. METHODS: An IRB-approved retrospective chart review of the electronic medical records in the Nemours/Alfred I. dupont Hospital for Children system from January 2004 to October 2009 (a five-year period) was undertaken using ICD-9 codes 277.87 (mitochondrial disorder) and 359.89BA (mitochondrial myopathy). These 149 records were then evaluated for audiologic data, resulting in 26 charts with both a mitochondrial disorder and hearing evaluation. RESULTS: Of 26 patients with known mitochondrial disorders and audiometric documentation, 15 (58%) had hearing loss, and 11 patients had normal hearing (42%). Ten patients had sensorineural hearing loss (38%), two patients had conductive hearing loss (7.7%), one patient had a mixed hearing loss (3.8%), and two patients had an as yet undefined hearing loss (ABR had not yet been performed at the time of this study) (7.7%). CONCLUSION: In comparison with previous studies, generally including less than 20 patients, this is one of the largest collections of audiometric data on children with mitochondrial disorders. Unlike prior studies describing a progressive, sensorineural loss across all frequencies or mainly affecting high frequencies, the hearing loss in our patients was more variable including low frequency losses, mid-frequency losses, and conductive losses and was often not progressive or even improved. Our overall 38% rate of sensorineural hearing loss correlates well with previous case series; this study clearly justifies the use of routine audiometric screening in children with mitochondrial disorders, including use of ABR and OAEs as ASND can be seen in this population, as well as repeat testing over time to evaluate for progression.