Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex

The TSC1-TSC2-TBC1D7 complex is an important negative regulator of the mechanistic target of rapamycin complex 1 that controls cell growth in response to environmental cues. Inactivating TSC1 and TSC2 mutations cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterised by the occurrence of benign tumours in various organs and tissues, notably the brain, skin and kidneys. TBC1D7 mutations have not been reported in TSC patients but homozygous inactivation of TBC1D7 causes megaencephaly and intellectual disability. Here, using an exon-specific deletion strategy, we demonstrate that some regions of TSC1 are not necessary for the core function of the TSC1-TSC2 complex. Furthermore, we show that the TBC1D7 binding site is encoded by TSC1 exon 22 and identify amino acid residues involved in the TSC1-TBC1D7 interaction

Follow-up nationwide survey on predictive genetic testing for late-onset hereditary neurological diseases in Japan

A follow-up nationwide survey on predictive genetic testing for late-onset neurological diseases in Japan was conducted. A questionnaire was sent to 89 institutional members of the Japan's National Liaison Council for Clinical Sections of Medical Genetics, and was returned by 60 (67.4%). A total of 301 clients with an interest in predictive testing were accumulated from April 2006 to March 2011. The greatest interest was shown for spinocerebellar degeneration (SCD, n = 110), followed by myotonic dystrophy type 1 (DM1, n = 69), Huntington's disease (HD, n = 52) and familial amyloid polyneuropathy (FAP, n = 35). The ratios of clients who actually underwent predictive testing were: SCD, 21.8%; DM1, 39.1%; HD, 26.9%; and FAP, 74.3%, indicating that predictive testing was conducted very cautiously for untreatable neurological diseases in Japan. Clinical geneticists were predominantly involved in genetic counseling, whereas the participation of non-medical doctor (non-MD) staff, including nurses, clinical psychologists and genetic counselors, was not common. Lack of non-MD counseling staff was one of the most serious issues in conducting predictive testing, which has not been improved since the previous survey performed in 2006. Institutional arrangements, such as revision of medical insurance system regarding genetic testing and counseling, might be necessary to resolve this issue.ArticleJOURNAL OF HUMAN GENETICS. 58(8):560-563 (2013)journal articl

Huntington's disease: a clinical review

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide

A Decade of Genetic Counseling in Frontotemporal Dementia Affected Families: Few Counseling Requests and much Familial Opposition to Testing

A decade of genetic counseling of frontotemporal dementia (FTD) affected families has generated two important observations. First, the uptake rate for presymptomatic testing for FTD is low in our department of Clinical Genetics at the Erasmus Medical Center in the Netherlands. Second, FTD at-risk counselees reported substantial familial opposition to genetic testing, which is distinct from the attitude in Huntington Disease affected families. We hypothesize that the low acceptance for FTD genetic counseling is consequential to the familial opposition and explain this within the theoretical framework of separation-individuation. Furthermore, we hypothesize that separation-individuation problems do not similarly influence the acceptance of HD genetic counseling, due to the educative role of the well-organised patient organization for HD in the Netherlands. We offer counseling recommendations that serve to facilitate the individuation of the counselee with respect to the FTD genetic test

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations

Early-onset Parkinson’s disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin