Homozygosity analysis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) may appear to be familial or sporadic, with recognised dominant and recessive inheritance in a proportion of cases. Sporadic ALS may be caused by rare homozygous recessive mutations. We studied patients and controls from the UK and a multinational pooled analysis of GWAS data on homozygosity in ALS to determine any potential recessive variant leading to the disease. Six-hundred and twenty ALS and 5169 controls were studied in the UK cohort. A total of 7646 homozygosity segments with length >2 Mb were identified, and 3568 rare segments remained after filtering ‘common'' segments. The mean total of the autosomal genome with homozygosity segments was longer in ALS than in controls (unfiltered segments, P=0.05). Two-thousand and seventeen ALS and 6918 controls were studied in the pooled analysis. There were more regions of homozygosity segments per case (P=1 × 10⁻⁵), a greater proportion of cases harboured homozygosity (P=2 × 10⁻⁵), a longer average length of segment (P=1 × 10⁻⁵), a longer total genome coverage (P=1 × 10⁻⁵), and a higher rate of these segments overlapped with RefSeq gene regions (P=1 × 10⁻⁵), in ALS patients than controls. Positive associations were found in three regions. The most significant was in the chromosome 21 SOD1 region, and also chromosome 1 2.9–4.8 Mb, and chromosome 5 in the 65 Mb region. There are more than twenty potential genes in these regions. These findings point to further possible rare recessive genetic causes of ALS, which are not identified as common variants in GWAS.     

Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called "type-1 fibrillinopathies." In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.     

Divergent coverage,frequency and costs of organised and opportunistic Pap testing in Finland

We evaluated the overall coverage, frequency and costs of Pap testing by screening modality and health care provider in Finland. Information about Pap testing in the Finnish female population of 2.7 million was obtained from nationwide population‐based registry data. Among women aged 25–69 years, 87% had had a Pap test taken within or outside the organised programme at least once during the last 5 years and half of those screened in the organised programme had also had at least one Pap test taken outside the programme. Of the annual average of 530,000 Pap tests taken, 84% were taken for screening purposes and 16% as follow‐up. Forty percent of the 446,000 annual screening tests were taken in the organised programme, 55% as opportunistic tests in public primary or student health care or by private providers and 5% in public secondary health care. One‐fifth of all opportunistic screening Pap tests were taken from women aged <25. The voluminous opportunistic Pap testing in public primary health care was concentrated in young women aged 25–29 whereas the bulk of opportunistic testing in private health occurred in age groups eligible for organised screening. The total cost of all screening Pap tests was €22.4 million, of which 71% incurred in opportunistic screening. Of the 84,000 annual follow‐up Pap tests and their €8.3 million total costs, ～60% incurred in organised screening or in secondary health care.     

Assessment of Traub formula and ketone bodies in cause of death investigations

Diabetes and alcohol abuse may cause severe metabolic disturbances that can be fatal. These may be difficult to diagnose in autopsies based solely on macroscopical and histological findings. In such cases, metabolic markers, such as postmortem glucose and ketone levels, can provide supporting information. Glucose or combined glucose and lactate, the Traub value, is often used to indicate hyperglycemia. The use of the Traub value, however, has been questioned by some, because the lactate levels are known to elevate in postmortem samples also due to other reasons than glycolysis of glucose molecules. Ketoacidosis can be detected by analyzing ketone body levels, especially beta-hydroxybutyric acid (BHB). Acetone is also elevated in severe cases of ketoacidosis. Here, we have evaluated the value of these biomarkers for postmortem determination of the metabolic disturbances. Retrospective data of 980 medico-legal autopsies performed in Finland, where glucose, lactate and ketone bodies were analyzed, was collected. Our findings show that the Traub value indicates hyperglycemia, even when glucose levels are low. For diagnosis, evaluation of complementing markers, e.g. ketone bodies and glycated hemoglobin is needed. Our results show that BHB can be used for screening and diagnosis of ketoacidosis. Acetone alone is not sufficient, since it is elevated only in the most severe cases. We also found that alcohol abuse rarely causes severe ketoacidosis. However, sporadic cases do exist where ketone body levels are extremely high. Despite this, alcoholic ketoacidosis is very rarely diagnosed as the cause of death.