Characterization of the thymus in Lrp4 myasthenia gravis: Four cases

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Most patients have pathogenic autoantibodies against the acetylcholine receptor (AChR). In the last years a novel subpopulation of MG patients has been described that harbors antibodies against low-density lipoprotein receptor-related protein 4 (Lrp4), another postsynaptic neuromuscular antigen. In early-onset AChR MG (EOMG), the thymus plays an important role in immunopathogenesis, and early thymectomy is beneficial. It is still unknown if the thymus plays any role in Lrp4-MG. In this pilot study, we compared thymus samples from four patients with Lrp4-MG (one pre-treated with immunosuppressive drugs), four non-MG controls and five EOMG patients (not pretreated with immunosuppressive drugs). Immunohistochemistry of the Lrp4-MG thymi revealed normal architecture, with normal numbers and distribution of B-cells, lymphoid follicles and Hassall's corpuscles. Primary CD23⁺ lymphoid follicles were similarly infrequent in Lrp4-MG and control thymic sections. In none of the control or Lrp4-MG thymi did we find secondary follicles with CD10⁺ germinal centers. These were evident in 2 of the 5 EOMG thymi, where primary lymphoid follicles were also more frequent on average, thus showing considerable heterogeneity between patients. Even if characteristic pathological thymic changes were not observed in the Lrp4 subgroup, we cannot exclude a role for the thymus in Lrp4-MG pathogenesis, since one Lrp4-MG patient went into clinical remission after thymectomy alone (at one year follow-up) and one more improved after thymectomy in combination with immunosuppressive therapy.     

Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene

Mutations in the TUBB4A gene have been identified so far in two neurodegenerative disorders with extremely different clinical features and course: whispering dysphonia, also known as dystonia type 4 (DYT4), and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We describe a patient with slowly progressive spastic paraparesis, segmental dystonia, intellectual disability, behavioral problems, and evidence of permanent, incomplete myelination associated with progressive cerebellar atrophy. Whole exome sequencing revealed a novel E410K de novo heterozygous mutation in the TUBB4A gene. The clinical and radiological picture of our patient is different from the classic phenotype; thus, it expands the phenotypic variation of TUBB4A-gene-related disorders.     

Effects of placentation on selected type A behaviors in adult males in the national heart,lung, and blood institute (NHLBI) twin study

A dermatoglyphic index derived from monozygotic (MZ) twins of known placental type was used to estimate placentation retrospectively in a sample of adult male MZ twins. Examination of behavioral test scores with respect to placentation showed that the within-pair difference of most measures of type A behavior was smaller in presumed monochorionic than presumed dichorionic pairs. Measures of cognitive function and hostility were not related to placental type. Intraclass correlations in the monochorionic subgroup of MZ twins were greater than the correlations reported for the full sample of MZ twins. The trends were strongest for the Adjective Check List scales taken at two different exams 5 years apart and, to a lesser extent, for the Framingham type A scale. Our results are most consistent with greater intrauterine environmental covariance in monochorionic MZ twins as an explanation for inflation of the MZ twin correlation relative to dizygotic (DZ) correlation reported for some type A measures.     

The Cook and Medley HO scale: a heritability analysis in adult male twins

Thirty-seven pairs of monozygotic (MZ) and 60 pairs of dizygotic (DZ) middle-aged, male, American twins were studied to determine the heritability of the Cook and Medley Hostility (HO) scale and its two subscales, Cynicism and Paranoid Alienation. No clear evidence for a significant genetic component was indicated for the full HO scale and the Paranoid Alienation subscale. Scores on these scales were found to be associated with age, socioeconomic status, the twinning condition, and the Minnesota Multiphasic Personality Inventory (MMPI) K scale. DZ twins scored higher than MZ on HO and Cynicism, and lower on the MMPI K scale. Statistical adjustments for age and socioeconomic status removed twin mean differences and weakened MZ intrapair correlations on the HO scale but did not change overall conclusions regarding heritability. After the association with K was partialled out from these scales and retested for heritability, both HO and Paranoid Alienation showed a weaker twin pair similarity than that observed in the unadjusted scales. However, Cynicism, the scale with the greatest item overlap with the K scale, was not affected by the adjustment. Since no genetic component was evident for the K scale in this sample it was concluded that if a genetic influence in these MMPI scales is present, it is mostly in the Cynicism subscale of HO.     

Prenatal exclusion of Leigh syndrome due to T8993C mutation in the mitochondrial DNA

Leigh syndrome (LS) is a mitochondrial encephalopathy that is caused by a mutation either in the mitochondrial DNA (mtDNA) or in the nuclear encoded genes of the mitochondrial proteins. Prenatal diagnosis of defects in the mtDNA is usually problematic because of mtDNA heteroplasmy and tissue specificity. However, the mutations T8993 G/C in the ATP synthase subunit 6 gene of the mtDNA show a more even tissue distribution and do not appear to change significantly over time. There are only few reports of prenatal diagnosis of the T8993G mutation in Leigh disease. Here we describe the first prenatal genetic testing of T8993C in a fetus of a mother whose previous child had died of Leigh syndrome due to the T8993C mutation. Mutant load in the chorionic villus sample (CVS) as well as in amniocytes was undetectable, thus predicting a very high likelihood of an unaffected outcome, indicative of a healthy baby. The diagnosis was confirmed after birth. Gathering data on the prenatal diagnosis of mtDNA mutations is of great importance so that prenatal diagnosis of both T8993G and T8993C mutations can be offered routinely.     

Changes in Mini-Mental State Exam in community-dwelling older persons over 6 years: relationship to health and neuropsychological measures

Although cognitive screening test scores change with advanced age, the significance of these changes (particularly decline in score) needs to be defined in terms of general health and neuropsychological functioning. Such analysis was undertaken in a subgroup of 287 healthy older men (mean age at baseline = 70.7 years) from the Western Collaborative Group Study, an ongoing cardiovascular and aging research project. Time from baseline to follow-up study averaged 6.0 years (SD = 0.5 years). Mini-Mental State Examination (MMSE) scores indicated that 15% of participants declined by three or more points (a 1+ standard deviation change among all change scores), 5% of participants improved by three or more points, and 80% of the sample remained within two points of their initial score. In health terms, decliners were significantly older, less active at follow-up, rated their health more poorly, and reported more depressive symptoms than non-decliners. Decliners also performed more poorly on several neuropsychological tests administered at follow-up. Results suggest that a decline of three or more points on the MMSE in community-dwelling, older persons without acute illness may signify important changes in health and cognition.