De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy.

BACKGROUND: Mutations in the SPG3A gene (atlastin protein) cause approximately 10% of autosomal-dominant hereditary spastic paraplegia. For many subjects with an SPG3A mutation, spastic gait begins in early childhood and does not significantly worsen even over many years. Such subjects resemble those with spastic diplegic cerebral palsy. To date, only 9 SPG3A mutations have been reported. OBJECTIVE: To analyze the SPG3A coding sequence in an individual with childhood-onset spastic gait, who, prior to the birth of her similarly affected child, had no previous family history of hereditary spastic paraplegia. METHODS: The SPG3A coding sequence was analyzed in DNA samples from the proband, her affected child, her unaffected parents, and control subjects by polymerase-chain-reaction amplification of each exon followed by direct DNA sequencing. Seventeen microsatellite polymorphisms were amplified and analyzed to confirm reported paternity. RESULTS: We identified a novel SPG3A mutation (L157W) in the proband and her affected child. This mutation was absent in the proband's unaffected parents. Results of microsatellite polymorphism analysis were consistent with paternity as reported. These results indicate that this novel SPG3A mutation arose de novo in the proband. CONCLUSIONS: We report the de novo occurrence of a novel SPG3A mutation in a subject with childhood-onset, nonprogressive, spastic diplegia who had no previous family history of hereditary spastic paraplegia until the birth of her similarly affected son. Although rare, the occurrence of a de novo hereditary spastic paraplegia gene mutation must be considered in subjects with spastic diplegic cerebral palsy for whom no other cause is identified. This is extremely important for correct genetic counseling because recurrence risk may be as high as 50% when a mutation is detected.

Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1.

Transcription activity of genes is related to their replication timing, accordingly gene activation is coupled with a shift from late replication to early replication and vice versa. The relationship between replication timing and gene expression is best manifested by monoallelically expressed genes which show an asynchronous pattern of allelic replication, with the active allele replicating earlier than the inactive counterpart. Biallelically expressed genes, which normally replicate highly synchronously, when present in lymphocytes derived from patients with various types of malignancies or premalignancies, replicate highly asynchronously, similar to monoallelically expressed genes. Since neurofibromatosis-type 1 (NF1) patients are at an increased risk to develop malignancies, we used the fluorescence in situ hybridization (FISH) replication assay and evaluated the level of replication synchrony of three cancer-implicated genes (RB1, AML1, and CMYC) in lymphocytes derived from patients with NF1 without malignancy. Each gene, which normally displayed synchrony in allelic replication, in the patients' cells displayed loss of synchrony. The loss of replication synchrony, of each gene, in the patients' cells was achieved by an advanced replication of a single allele, which replicated remarkably earlier than its normal scheduled timing. In addition, the second allele showed slightly earlier replication timing than that normal for the gene. Thus, it is assumed that the NF1 condition is associated with activation of cancer-implicated genes that may be the cause for increased risk of patients to develop malignancies. As loss of synchrony in allelic replication timing differentiates well between NF1 patients and control subjects, this marker may have a potential use for identification of presymptomatic carriers of NF1 disorders.

Congenital hypothyroidism with Prader-Willi syndrome.

We report a 1 year-old female patient with severe hypotonia who has congenital hypothyroidism and Prader-Willi syndrome (PWS). At birth she was found to have congenital hypothyroidism caused by an ectopic sublingual thyroid gland and was commenced on thyroid replacement therapy. She continued to have severe motor delay and therefore further diagnostic evaluation was performed. PWS was confirmed by DNA and fluorescence in situ hybridization (FISH) analysis. This report emphasizes the need to further investigate patients who are found to have congenital hypothyroidism and do not improve adequately on treatment.

Reduced recombination in maternal meiosis coupled with non-disjunction at meiosis II leading to recurrent 47,XXX.

We determined the meiotic origin and the stage of non-disjunction of the extra X chromosomes in two sisters with 47,XXX chromosomal complements. Segregation of the X chromosomes in all family members was analyzed using X-linked short tandem repeat polymorphic (STRP) markers. Densitometric analysis of two STRP markers confirmed that both sisters had three copies of the X chromosome and the extra X chromosomes were maternally derived. Both sisters did not share the same maternal homologue suggesting that the recurrent trisomy is non-homologous X chromosome-specific. Haplotype analysis demonstrated a reduction to homozygosity for markers examined, covering most of the length of the X chromosomes in both sisters. These findings suggested that the extra X chromosomes have derived from meiotic II non-disjunction following a nullitransitional meiosis I (MI). A lack of recombination in the X chromosomes of both sisters suggests a possible maternal genetic defect leading to an erratic recombination at MI. This information may contribute to further understanding of mechanisms leading to X chromosome non-disjunction and may assist in counseling of families with this chromosomal rearrangement.

Factors affecting performance of prenatal genetic testing by Israeli Jewish women.

The number of prenatal genetic tests that are being offered to women is constantly increasing. However, there is little national data as to who is performing the tests and the reasons for doing or not doing so. This study evaluated the proportion of Jewish women in Israel who perform the various prenatal genetic tests and the factors affecting the performance of these tests. It was found that 60.9% of the women performed the triple test, 50.8% of women older than 35 years performed amniocentesis, while 63.3 and 24.3% of women performed Tay-Sachs and fragile-X carrier testing respectively. Ninety-six percent of the secular women compared to only 6.7% of the ultrareligious women performed the triple test. It was also found that94.4% of the secular women, 36.4% of the religious, and none of the ultrareligious women older than 35 years performed amniocentesis. In the stepwise regression analysis, being secular, having a higher income, fewer children, and being of Ashkenazi origin remained significant factors in determining performance of Tay-Sachs carrier testing. As regards fragile-X carrier testing, being secular, having fewer than four children, and having a higher income and a supplementary medical insurance remained significant factors. The main reason reported by the women for not performing amniocentesis or the triple test was for religious or moral grounds (53.3 and 67% respectively). The main reason given for not performing Tay-Sachs or fragile-X testing was that they were not referred for the tests (76 and 82% respectively). Consideration should be given to providing first trimester prenatal diagnosis to the ultrareligious group, including state subsidized fragile-X testing and educating the primary care givers about the importance of prenatal genetic testing. The information from the present study is vital for the planning of an equitable prenatal genetic service and provides guidelines for the implementation of such services in other countries.

Asynchronous replication of biallelically expressed loci: a new phenomenon in Turner syndrome.

PURPOSE: Transcriptional activity of genes is related to their replication timing; alleles showing the common biallelic mode of expression replicate synchronously, whereas those with a monoallelic mode of expression replicate asynchronously. Here the level of synchronization in replication timing of alleles was determined in subjects with Turner syndrome. METHODS: Fluorescence in situ hybridization was used for three loci not linked to X chromosome, in lymphocytes derived from 12 controls, 3 individuals with Turner, and 4 with mosaic Turner syndrome. RESULTS: In cells derived from controls, each pair of alleles replicated synchronously; yet these same alleles replicated asynchronously in cells monosomic for X chromosome derived from Turner and mosaic Turner patients. When the level of 45,X was low in the mosaic samples, the replication pattern of the 46,XX cells was normal. However, in samples with a high level of mosaicism, a significantly increased asynchronous replication was detected in the 46,XX cells. CONCLUSION: An altered temporal replication control in Turner syndrome affecting the aneuploid and euploid cells is shown. This alteration may potentially be involved in the determination of the syndrome.

A founder COL17A1 splice site mutation leading to generalized atrophic benign epidermolysis bullosa in an extended inbred Palestinian family from Israel.

PURPOSE: Generalized atrophic benign epidermolysis bullosa is a nonlethal form of junctional EB with an autosomal recessive inheritance. There is generalized cutaneous blister formation at sites of trauma, atrophic alopecia affecting scalp, eyelash and eyebrow, dystrophic nail changes, and tooth abnormalities. In this study, we have studied a five-generation Palestinian family affected with generalized atrophic benign epidermolysis bullosa. METHODS: We have performed linkage analysis to genes that are mutated in generalized atrophic benign epidermolysis bullosa, followed by direct sequencing of patient genomic DNA. RESULTS: We have shown that the disease is caused by a newly detected homozygous donor splice site mutation, IVS51+1G>A, in the type XVII collagen gene, COL17A1. CONCLUSION: The effect of a founder mutation introduced 3 to 4 generations before a disease appearance is demonstrated in this inbred family.