Chromosomal Preimplantation Genetic Diagnosis: 25 Years and Counting.

Preimplantation genetic diagnosis (PGD), first successfully carried out in humans in the early 1990s, initially involved the PCR sexing of embryos by Y- (and later also X-) chromosome specific detection. Because of the problems relating to misdiagnosis and contamination of this technology however the PCR based test was superseded by a FISH-based approach involving X and Y specific probes. Sexing by FISH heralded translocation screening, which was shortly followed by preimplantation genetic screening (PGS) for Aneuploidy. Aneuploidy is widely accepted to be the leading cause of implantation failure in assisted reproductive technology (ART) and a major contributor to miscarriage, especially in women of advanced maternal age. PGS (AKA PGD for aneuploidy PGD-A) has had a chequered history, with conflicting lines of evidence for and against its use. The current practice of trophectoderm biopsy followed by array CGH or next generation sequencing is gaining in popularity however as evidence for its efficacy grows. PGS has the potential to identify viable embryos that can be transferred thereby reducing the chances of traumatic failed IVF cycles, miscarriage or congenital abnormalities and facilitating the quickest time to live birth of chromosomally normal offspring. In parallel to chromosomal diagnoses, technology for PGD has allowed for improvements in accuracy and efficiency of the genetic screening of embryos for monogenic disorders. The number of genetic conditions available for screening has increased since the early days of PGD, with the human fertilization and embryology authority currently licensing 419 conditions in the UK [1]. A novel technique known as karyomapping that involves SNP chip screening and tracing inherited chromosomal haploblocks is now licensed for the PGD detection of monogenic disorders. Its potential for the universal detection of chromosomal and monogenic disorders simultaneously however, has yet to be realized

Early onset torsion dystonia (Oppenheim's dystonia)

Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities