Identification of genomic deletions spanning the PCDH19 gene in two unrelated girls with intellectual disability and seizures.

Recently, missense and truncating mutations in the gene PCDH19 have been reported to cause female-restricted epilepsy with mental retardation (EFMR). EFMR (MIM#300088) is an X-linked disorder characterized by early onset seizures and intellectual disability (ID). Interestingly, unlike typical X-linked mode of inheritance, the phenotype is restricted to females, and males are unaffected carriers. PCDH19 is highly expressed in brain, and the encoded protein belongs to the cadherin superfamily. Here we report two unrelated female patients with deletions spanning PCDH19 identified by copy number variation (CNV) analysis and validated by qPCR. In one, we have identified a 3 Mb interstitial deletion at Xq21.33-q22.1 which spans PCDH19, LOC442459 & TNMD. This patient had her first seizure at 8 months old, and also has ID and aggressive behavior. In another female patient we identified a de novo 603 kb heterozygous deletion in a female patient with fits (since 1 year of age), ID, hyperactivity and aggressive behavior. The deletion spans the entire PCDH19 gene (also TNMD, SRPX2, TSPAN6 and SYTL4). In conclusion, our results suggest that deletions at PCDH19 also cause EFMR.

Unsuccessful treatment attempt: cord blood stem cell transplantation in a patient with Niemann-Pick disease type A.

Niemann-Pick disease type A (NP-A; OMIM 257200) is an autosomal recessive lysosomal storage disorder caused by deficiency of acid sphingomyelinase and resulting in accumulation of sphingomyelin, unesterified cholesterol, and other complex lipids in many tissues. It is characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course culminating in death by 3 years of age. There is no known effective treatment. We report the case of a prenatally diagnosed girl who underwent cord blood stem cell transplantation (CBSCT) at 3 months of age. She was neurologically intact at the time of CBSCT. Hepatosplenomegaly, was detected at 6 weeks of age; the splenomegaly resolved following CBSCT. Recovery was complicated by graft-versus-host disease. She subsequently developed and continues to show marked global developmental delay, generalized hypotonia, and signs of neurological regression, despite continued engraftment. Bilateral cherry red spots were detected at 10 months of age, 7 months post-CBSCT. Although she is doing better than her affected brother, she shows little overall benefit from CBSCT.