Forbes D. Porter

Bio: Forbes D. Porter is an academic researcher from United States Department of Health and Human Services. The author has contributed to research in topics: Smith–Lemli–Opitz syndrome & Lathosterolosis. The author has an hindex of 17, co-authored 25 publications receiving 1106 citations. Previous affiliations of Forbes D. Porter include Washington University in St. Louis & National Institutes of Health.

Smith–Lemli–Opitz syndrome: pathogenesis, diagnosis and management

Abstract: Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome due to a deficiency of 7-dehydrocholesterol reductase (DHCR7). DHCR7 primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. In SLOS, this results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the clinical aspects and diagnosis of SLOS, therapeutic interventions and the current understanding of pathophysiological processes involved in SLOS.

Malformation syndromes due to inborn errors of cholesterol synthesis

Abstract: Cholesterol has long been known to function as both a structural lipid and a precursor molecule for bile acid and steroid hormone synthesis. In addition, this ubiquitous lipid is now known to contribute fundamentally to the development and function of the CNS and the bones, and, as detailed in other articles in this Perspective series, it plays major roles in signal transduction, sperm development, and embryonic morphogenesis. Over the past decade, the identification of multiple congenital anomaly/mental retardation syndromes due to inborn errors of cholesterol synthesis has underscored the importance of cholesterol synthesis in normal development. The prototypical example of a human malformation syndrome that results from a defect in cholesterol synthesis is the RSH/Smith-Lemli-Opitz syndrome (SLOS). To date, five additional human syndromes resulting from impaired cholesterol synthesis have been described. These include desmosterolosis, X-linked dominant chondrodysplasia punctata type 2 (CDPX2), CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma/nevus and limb defects), Greenberg dysplasia, and, most recently, Antley-Bixler syndrome. Natural mouse mutations corresponding to CDPX2 (tattered) and CHILD syndrome (bare patches and striated) have been identified, and mouse models corresponding to SLOS and lathosterolosis have been produced by gene disruption. Identification of the biochemical defects present in these disorders has given insight into the role that cholesterol plays in normal embryonic development, has provided the initial step in understanding the pathophysiological processes underlying these malformation syndromes, and has given rise to treatment protocols for patients with SLOS. Cholesterol is synthesized from lanosterol, the first sterol in the cholesterol synthesis pathway, via a series of enzymatic reactions shown in Figure 1. These include the demethylation at C4α, C4β, and C14, which converts the C30 molecule lanosterol to C27 cholesterol; isomerization of the ∆ 8(9) double bond to a ∆ 7 double bond; desaturation to form a ∆ 5 double bond; and finally, reduction of ∆ 14 , ∆ 24 , and ∆ 7 double bonds (Figure 1). Analyses of human and murine syndromes resulting from cholesterol synthetic defects have helped illuminate both the normal functions of cholesterol and a range of normal and teratogenic functions of the various precursor sterols that accumulate in these disorders. Here, I consider the clinical, molecular, biochemical, and developmental aspects of these disorders, focusing on the five malformation syndromes presented in Table 1.

Klippel‐Trenaunay‐Weber syndrome associated with a 5:11 balanced translocation

Abstract: We report on a case of Klippel-Trenaunay Weber syndrome (KTWS) associated with a reciprocal translocation [46,XX,t (5;11) (q13.3;p15.1)]. The patient has developmental delay and minor anomalies in addition to classic findings of KTWS. These data support the notion that Klippel-Trenaunay-Weber syndrome may be due to a single gene defect and suggests the possible localization of a Klippel-Trenaunay-Weber gene(s) to 5q or 11p.

Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker

Abstract: Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.

Pathology and genetics of tumours of the lung , pleura, thymus and heart

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Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

Abstract: Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles.

Cleft lip and palate: understanding genetic and environmental influences.

Abstract: Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the aetiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research.