Sozos Papasozomenos

CMT4A: identification of a Hispanic GDAP1 founder mutation.

Mutations of the ganglioside‐induced differentiation‐associated protein 1 gene (GDAP1) cause autosomal recessive Charcot–Marie–Tooth disease type 4A. We report four additional families with recessive mutations (487C→T, Q163X; 359G→A, R120Q) of GDAP1; Q163X occurred in three unrelated Hispanic families that had the same haplotype suggesting a Spanish founder mutation. Both the Q163X and the R120Q mutation cause demyelination and axonal loss. The patients had symptoms within the first two years of life and involvement of cranial, sensory, and enteric nerves. Neuropathology showed loss of large myelinated fibers, onion bulb formations and focal folding of the outer myelin lamina. Ann Neurol 2003;53:400–405

The activation of heat shock transcription factor 1 is differentially regulated in the brain of estrogen- and testosterone-treated heat-shocked rats.

One hundred and fifteen rats were ovariectomized, given daily injections of 10 microg of 17beta-estradiol 3-benzoate (EB), 250 microg of testosterone propionate (TP), or 10 microg of EB + 250 microg of TP in sesame oil (SO) or SO alone for 1, 1.5 and 2 mo, and heat shocked at 42 degrees C for 15 min. Immediately after heat shock, the increase in inducibly hyperphosphorylated heat shock transcription factor 1 (pHSF1) was highest in TP-treated and least in EB-treated rats. Heat shock transcription factor 1 (HSF1) also accumulated in the nuclei of neurons in TP-treated and exit the nuclei in EB-treated rats. While the subnuclear distribution of HSF1 was uniform and similar in control and heat-shocked EB-treated rats, it localized predominantly on euchromatin in heat-shocked TP-treated rats. An antibody, which preferentially recognized pHSF1, stained almost exclusively cell nuclei and demonstrated irregularly-shaped and round neuronal nuclei of heat-shocked TP- and EB-treated rats, respectively. Concomitantly, synthesis of the inducible heat shock protein Hsp70 was lowest in EB- and highest in TP-treated rats. In this model, testosterone prevents the heat shock-induced hyperphosphorylation of tau. Because HSF1 delays aging, its enhanced activation by testosterone strengthens the argument for a therapeutic role of androgens in Alzheimers disease.

Reorganization of Axonal Cytoskeleton Following β, β′-Iminodipropionitrile (IDPN) Intoxication

β,β ′-Iminodipropionitri1e (IDPN), NH=(CH2CH2CN)2, is a synthetic compound closely related to the osteolathyrogen B-aminopropionitrile (NH2CH2CH2CN). Intoxication of various experimental animals with IDPN produces the excitement, circling and choreathetosis (ECC) or waltzing syndrome (Selye, 1957), a permanent symptom complex indicating irreparable damage to the central nervous system (CNS). Early histopathological studies have described large, amorphous bodies in the anterior horn cells of spinal cord and in other large neurons throughout the nervous system. These amorphous bodies were originally misinterpreted as degenerated neuronal perikarya and were called “ghost cells” (Bachhuber et al., 1955; Ule, 1962). It was shown subsequently by Chou and Hartman (1964; 1965) that the “ghost cells” were actually huge balloons and swollen axons connected to the cell body by an apparently normal initial segment (Fig. 1). They suggested that “axostasis,” caused by a “plug” of particulate organelles in the proximal axon, produced the axonal swellings.

NGTS-04SUGGESTION OF TP53 GERMLINE GENETIC TESTING BASED ON RESULTS FROM NEXT GENERATION SEQUENCING OF TUMOR SPECIMEN: A CASE REPORT

Molecular testing provides clinicians with a unique characterization of a patients tumor. Next generation sequencing (NGS) based genetic analysis is the most commonly used tool for multiple cancer pathologies and has implications for better understanding tumorigenesis and designing potential targeted treatments. We report the case of a 52-year-old male diagnosed with anaplastic oligodendroglioma at age 50. NGS analysis of tumor specimen detected two mutations in the tumor suppressor gene TP53. Somatic TP53 mutations are frequently identified in a variety of human cancers, including primary brain tumors. Germline TP53 mutations are associated with Li-Fraumeni Syndrome (LFS), a condition in which individuals are at high risk for developing multiple primary tumors during their lifetime, typically at earlier ages of onset than the general population. Germline genetic testing is indicated when an individuals personal and/or family history raises the clinicians suspicion for the disease. Our patients past medical history and family history were noncontributory and his presentation of disease was consistent with an isolated lesion. However, Knudsons two-hit hypothesis states that cells with pre-existing germline mutations in key genes are at high risk to become tumor cells when a somatic mutation occurs in the second allele. Therefore, the presence of two somatic TP53 mutations raised the question of whether one was also present in the germline. Subsequent germline genetic testing did detect one of the TP53 mutations, consistent with a diagnosis of LFS. This case is an example of another application of molecular tumor testing to individualize patient care. Further investigation of patients with known LFS and other hereditary cancer syndromes revealed similar molecular results in their tumor samples. While some individuals may have two somatic TP53 mutations and negative germline testing, this molecular finding may raise the clinicians awareness that further genetic work-up is warranted.

Vein of Galen aneurysmal malformations associated with high output cardiac failure: Report of three autopsy cases

Vein of Galen aneurysmal malformations (VGAMs) are rare congenital vascular, malformation. The malformation usually develops between the 6th to 11th wk of gestation. We report three autopsy cases, all prenatally diagnosed by ultrasound or fetal magnetic resonance imaging with VGAM with associated high-output cardiac failure. Prenatal fetal echocardiogram on two patients showed cardiomegaly, ventricular dilatation, pulmonary hypertension and reversed aortic flow. The cause of death in all the three patients was high-output cardiac failure due to VGAM. The autopsy findings confirmed feeding arteries from posterior cerebral arteries to VGAM in all patients. Other significant neuropathologic findings at autopsy were severe hydrocephalus, polymicrogyria, germinal matrix hemorrhage, periventricular leukomalacia, and microcalcification. The findings support that VGAM may be due to abnormal arterial venous communication and the most common cause of death in these patients is high-output cardiac failure. The presence of other associated brain abnormalities indicates a poor prognosis.