Primary Genetic Mutations Research Articles

From Circulating Tumor Cells to Mirna: New Challenges in the Diagnosis and Prognosis of Medullary Thyroid Cancer.

Medullary thyroid carcinoma (MTC) is a malignant tumor that arises from parafollicular C cells, which are responsible for producing calcitonin. The majority (75%) of MTC cases are sporadic forms, while the remaining (25%) have a hereditary component. In these hereditary cases, MTC can occur in conjunction with other endocrine disorders (i.e., pheochromocytoma) or as an isolated condition known as familial medullary thyroid carcinoma. The primary genetic mutation associated with the development of MTC, regardless of its hereditary or sporadic nature, is a point mutation in the RET gene. Evaluation of serum calcitonin levels represents the most reliable and sensitive marker for both the initial diagnosis and the postsurgical monitoring of MTC. Unfortunately, most patients do not achieve normalization of postsurgical serum calcitonin (CT) levels after surgery. Therefore, there is a need to find new biomarkers to be used with serum CT in order to increase test sensitivity and specificity. In this review, we summarize the literature from 2010 to 2023 to review the role of circulating tumor cells, cell-free DNA, and miRNA and their application in diagnosis, outcome of MTC, and response to treatments.

Плексиформная нейрофиброма наружных гениталий и промежности у девочки

We report a case of plexiform neurofibroma of the external genitalia and perineum in a 11-year-old girl with no family history of this disease. The patient was diagnosed with neurofibromatosis type 1 upon admission to the clinic. Surgery was performed by a team of a pediatric surgeon and gynecologist after the examination. The postoperative period was uneventful. No signs of neurofibroma recurrence were observed 2 years postoperatively. The description of the diagnostic and treatment stages in this case resulting from a primary genetic mutation is of interest to pediatricians and pediatric surgeons. Key words: neurofibromatosis, perineum, child

HLH-Like Syndrome and Rhabdomyolysis in an Adolescent Patient

Hemophagocytic lymphohistiocytosis (HLH) is a rare heterogeneous group of disorders characterized by immune overactivation. It can occur because of primary genetic mutations or secondary to almost any inflammatory or infectious process. The clinical manifestations of this syndrome are varied and life-threatening and resemble those of many malignancies, infections, sepsis, and multisystem inflammatory syndrome in children. Laboratory abnormalities often are not diagnostic for HLH until late in the disease course, and the laboratory studies are send-out tests at most institutions. Thus, quickly and accurately diagnosing pediatric patients with HLH presents significant challenges to the clinician. Furthermore, there has been recent discussion in the literature regarding the use of diagnostic criteria for HLH. In this case report, we detail an adolescent male individual who developed persistent unexplained fever, rhabdomyolysis, and regional ischemic immune myopathy. To our knowledge, there is no previous report of a pediatric patient with this rare myopathy or HLH presenting with persistent rhabdomyolysis in the literature. The patient was hospitalized for a total of 61 days, with multiple treatments attempted throughout during his course of illness. In this report, we highlight the importance of using diagnostic flexibility when HLH is suspected in pediatric patients and provide insight into the unique challenges of identifying this condition.

The strengths of the genetic approach to understanding neural systems development and function: Ray Guillery's synthesis.

The organization and function of sensory systems, especially the mammalian visual system, has been the focus of philosophers and scientists for centuries—from Descartes and Newton onward. Nevertheless, the utility of understanding development and its genetic foundations for deeper insight into neural function has been debated: Do you need to know how something is assembled—a car, for example—to understand how it works or how to use it—to turn on the ignition and drive? This review addresses this issue for sensory pathways. The pioneering work of the late Rainer W. (Ray) Guillery provides an unequivocal answer to this central question: Using genetics for mechanistic exploration of sensory system development yields essential knowledge of organization and function. Ray truly built the foundation for this now accepted tenet of modern neuroscience. His work on the development and reorganization of visual pathways in albino mammals—all with primary genetic mutations in genes for pigmentation—defined the genetic approach to neural systems development, function and plasticity. The work that followed his lead in a variety of sensory systems, including my own work in the developing olfactory system, proceeds directly from Ray's fundamental contributions.

Increased polyamines as protective disease modifiers in congenital muscular dystrophy.

Most Mendelian disorders, including neuromuscular disorders, display extensive clinical heterogeneity that cannot be solely explained by primary genetic mutations. This phenotypic variability is largely attributed to the presence of disease modifiers, which can exacerbate or lessen the severity and progression of the disease. LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a fatal degenerative muscle disease resulting from mutations in the LAMA2 gene encoding Laminin-α2. Progressive muscle weakness is predominantly observed in the lower limbs in LAMA2-CMD patients, whereas upper limbs muscles are significantly less affected. However, very little is known about the molecular mechanism underlying differential pathophysiology between specific muscle groups. Here, we demonstrate that the triceps muscles of the dy2j/dy2j mouse model of LAMA2-CMD demonstrate very mild myopathic findings compared with the tibialis anterior (TA) muscles that undergo severe atrophy and fibrosis, suggesting a protective mechanism in the upper limbs of these mice. Comparative gene expression analysis reveals that S-Adenosylmethionine decarboxylase (Amd1) and Spermine oxidase (Smox), two components of polyamine pathway metabolism, are downregulated in the TA but not in the triceps of dy2j/dy2j mice. As a consequence, the level of polyamine metabolites is significantly lower in the TA than triceps. Normalization of either Amd1 or Smox expression in dy2j/dy2j TA ameliorates muscle fibrosis, reduces overactive profibrotic TGF-β pathway and leads to improved locomotion. In summary, we demonstrate that a deregulated polyamine metabolism is a characteristic feature of severely affected lower limb muscles in LAMA2-CMD. Targeted modulation of this pathway represents a novel therapeutic avenue for this devastating disease.

Pulmonary Emboli and Deep Venous Thrombosis during Adolescence

Pulmonary emboli (PE) and deep venous thrombus (DVT) are two conditions considered to affect primarily adults. These conditions, however, can and do affect neonates, toddlers, school-age children, and adolescents. Factors contributing to the development of PE and DVT are often associated with genetic mutations in Antithrombin III, Protein C, and Protein S. This article presents a primary care case study of an adolescent who was diagnosed with and underwent treatment for bilateral PE and a DVT, and reviews the underlying primary genetic mutations, diagnostic workup, and management of his clinical condition.

Practice Bulletin No. 182 Summary: Hereditary Breast and Ovarian Cancer Syndrome.

Hereditary breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome characterized by multiple family members with breast cancer, ovarian cancer, or both. Based on the contemporary understanding of the origins and management of ovarian cancer and for simplicity in this document, ovarian cancer also refers to fallopian tube cancer and primary peritoneal cancer. Clinical genetic testing for gene mutations allows more precise identification of those women who are at an increased risk of inherited breast cancer and ovarian cancer. For these individuals, screening and prevention strategies can be instituted to reduce their risks. Obstetrician-gynecologists play an important role in the identification and management of women with hereditary breast and ovarian cancer syndrome. If an obstetrician-gynecologist or other gynecologic care provider does not have the necessary knowledge or expertise in cancer genetics to counsel a patient appropriately, referral to a genetic counselor, gynecologic or medical oncologist, or other genetics specialist should be considered (1). More genes are being discovered that impart varying risks of breast cancer, ovarian cancer, and other types of cancer, and new technologies are being developed for genetic testing. This Practice Bulletin focuses on the primary genetic mutations associated with hereditary breast and ovarian cancer syndrome, BRCA1 and BRCA2, but also will briefly discuss some of the other genes that have been implicated.

Practice Bulletin No 182: Hereditary Breast and Ovarian Cancer Syndrome.

Hereditary breast and ovarian cancer syndrome is an inherited cancer-susceptibility syndrome characterized by multiple family members with breast cancer, ovarian cancer, or both. Based on the contemporary understanding of the origins and management of ovarian cancer and for simplicity in this document, ovarian cancer also refers to fallopian tube cancer and primary peritoneal cancer. Clinical genetic testing for gene mutations allows more precise identification of those women who are at an increased risk of inherited breast cancer and ovarian cancer. For these individuals, screening and prevention strategies can be instituted to reduce their risks. Obstetrician-gynecologists play an important role in the identification and management of women with hereditary breast and ovarian cancer syndrome. If an obstetrician-gynecologist or other gynecologic care provider does not have the necessary knowledge or expertise in cancer genetics to counsel a patient appropriately, referral to a genetic counselor, gynecologic or medical oncologist, or other genetics specialist should be considered (1). More genes are being discovered that impart varying risks of breast cancer, ovarian cancer, and other types of cancer, and new technologies are being developed for genetic testing. This Practice Bulletin focuses on the primary genetic mutations associated with hereditary breast and ovarian cancer syndrome, BRCA1 and BRCA2, but also will briefly discuss some of the other genes that have been implicated.

Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations.

Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN. The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy. Animal models knocked out for MTM1 show severe reduction of ryanodine receptor 1 mediated calcium release but, since knocking out genes in animal models does not necessarily replicate the human phenotype, we considered it important to study directly the effect of MTM1 mutations on patient muscle cells. The results of the present study show that at the level of myotubes MTM1 mutations do not dramatically affect calcium homeostasis and calcium release mediated through the ryanodine receptor 1, though they do affect myotube size and nuclear content. On the other hand, mature muscles such as those obtained from patient muscle biopsies exhibit a significant decrease in expression of the ryanodine receptor 1, a decrease in muscle-specific microRNAs and a considerable up-regulation of histone deacetylase-4. We hypothesize that the latter events consequent to the primary genetic mutation, are the cause of the severe decrease in muscle strength that characterizes these patients.

Gastrointestinal dysfunction in autism spectrum disorder: the role of the mitochondria and the enteric microbiome.

Autism spectrum disorder (ASD) affects a significant number of individuals worldwide with the prevalence continuing to grow. It is becoming clear that a large subgroup of individuals with ASD demonstrate abnormalities in mitochondrial function as well as gastrointestinal (GI) symptoms. Interestingly, GI disturbances are common in individuals with mitochondrial disorders and have been reported to be highly prevalent in individuals with co-occurring ASD and mitochondrial disease. The majority of individuals with ASD and mitochondrial disorders do not manifest a primary genetic mutation, raising the possibility that their mitochondrial disorder is acquired or, at least, results from a combination of genetic susceptibility interacting with a wide range of environmental triggers. Mitochondria are very sensitive to both endogenous and exogenous environmental stressors such as toxicants, iatrogenic medications, immune activation, and metabolic disturbances. Many of these same environmental stressors have been associated with ASD, suggesting that the mitochondria could be the biological link between environmental stressors and neurometabolic abnormalities associated with ASD. This paper reviews the possible links between GI abnormalities, mitochondria, and ASD. First, we review the link between GI symptoms and abnormalities in mitochondrial function. Second, we review the evidence supporting the notion that environmental stressors linked to ASD can also adversely affect both mitochondria and GI function. Third, we review the evidence that enteric bacteria that are overrepresented in children with ASD, particularly Clostridia spp., produce short-chain fatty acid metabolites that are potentially toxic to the mitochondria. We provide an example of this gut–brain connection by highlighting the propionic acid rodent model of ASD and the clinical evidence that supports this animal model. Lastly, we discuss the potential therapeutic approaches that could be helpful for GI symptoms in ASD and mitochondrial disorders. To this end, this review aims to help better understand the underlying pathophysiology associated with ASD that may be related to concurrent mitochondrial and GI dysfunction.

Modifiers of heart and muscle function: where genetics meets physiology

New Findings What is the topic of this review? Genetic modifiers act on many different physiological aspects of muscle disease. Understanding and identifying such modifiers is important because their discovery may help to predict the course of muscle disease and also indicate pathways to be exploited in designing new therapeutics. What advances does it highlight? Genetic modifiers have been identified that act primarily on limb skeletal muscles. Newer modifiers, where the responsible gene has yet to be identified, alter the course of cardiopulmonary dysfunction in muscular dystrophy. Distinct modifiers that act differentially on limb skeletal muscles versus heart and respiratory muscles reflect underlying physiological differences of these muscle groups. Many single-gene disorders are associated with a range of symptoms that cannot be explained solely by the primary genetic mutation. Muscular dystrophy is a genetic disorder associated with variable outcomes that arise from both the primary genetic mutation and the contribution from environmental and genetic modifiers. Disruption of the dystrophin complex occurs in Duchenne muscular dystrophy and limb girdle muscular dystrophy, producing heart and muscle disease through a cellular injury process characterized by plasma membrane disruption and fibrosis. Multiple modifier loci have been mapped by using a mouse model of muscular dystrophy. These modifiers exert their effect often on specific muscle groups targeted by the muscular dystrophy process, possibly reflecting distinct pathophysiological processes among muscle groups. Genetic modifiers act on both cardiac and respiratory muscle parameters, suggesting genetic and physiological integration of cardiopulmonary function. Skeletal muscles of the limbs are modified by a locus on mouse chromosome 7. This region of chromosome 7 harbours an insertion/deletion polymorphism in Ltbp4, the gene encoding latent transforming growth factor β binding protein 4. LTBP4 exerts its effect in muscle disease by acting on plasma membrane stability and fibrosis, thereby linking instability of the sarcolemma directly to fibrosis. In the human muscle disease Duchenne muscular dystrophy, protein coding single-nucleotide polymorphisms in LTBP4 associate with prolonged ambulation, demonstrating that modifiers identified from mouse studies translate to human disease.

G.P.13.03 Can VLA-4 be applied as a biomarker for prognosis and therapeutic target in Duchenne muscular dystrophy?

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, affecting about 1 in 3500 male births, caused by mutations or deletions in the dystrophin gene. Even though the primary genetic mutation causes a modification in the resistance of the muscle fibers to damage, studies in animal models as well as in DMD patients have strongly suggested that the immune response observed in this disease could also contribute to the progressive fibrosis and fat infiltration observed in the muscles. The molecular mechanisms that could be involved in this intense migration of immune cells into the damaged muscle have not yet been established. We have followed a cohort of 49 boys with DMD which was subdivided according to the severity of the disease. Each group was studied for the expression of the integrin-type extracellular matrix (ECM) receptors on the surface of the T cells obtained from the blood, as well as for the ECM-driven migratory response of these T cells in vitro. In addition the inflammatory infiltrate in the muscle tissue of DMD patients has been characterized. We observed a positive correlation between the percentage of T cells expressing high levels of the fibronectin receptor in CD4+ T cells in the blood according to the severity of the disease. In addition, the relative numbers of VLA-4hi T cells was positively correlated with a more rapid evolution and therefore a more severe outcome. We have also demonstrated that the mononuclear cells obtained from patients either with a poor prognosis or in an advanced phase of the disease had a higher fibronectin-driven migratory response when compared with mildly affected patients and with control individuals. Importantly, this process could be blocked by pre-treatment with an anti-VLA-4 monoclonal antibody. Thus, we propose that VLA-4 can be considered a target molecule for prognosis and its blockage as a possible therapeutic option in DMD.

The pseudohypoparathyroidism type lb locus is linked to a region including GNAS1 at 20q13.3.

Pseudohypoparathyroidism (PHP) is characterized by biochemical hypoparathyroidism with elevated parathyroid hormone levels owing to reduced target tissue responsiveness to parathyroid hormone. Patients with PHP la have somatic defects termed Albright's hereditary osteodystrophy (AHO) and exhibit resistance to additional hormones because of heterozygous mutations in the GNAS1 gene that lead to a generalized deficiency of the a subunit of Gs, the heterotrimeric G protein that couples receptors to adenylyl cyclase. By contrast, patients with PHP 1b lack AHO and have selective parathyroid hormone (PTH) resistance, presumably because of an imprinting defect that impairs expression of G(s)alpha in the proximal renal tubule. Although an epigenetic defect in GNAS1 has been identified in subjects with PHP1b, the genetic defect is unknown. To define the genetic defect in PHP 1b, we performed a genome-wide linkage analysis in five multi-generational PHP lb families. Of the 408 polymorphic microsatellite markers examined, markers located on chromosome 20q13.3, the region containing GNAS1, demonstrated linkage to PHP lb. Fine-mapping and multipoint linkage analysis of this region demonstrated linkage to a 5.7-cM region between 907rep2 and the telomere. Haplotype analysis established that affected individuals shared a 5-cM region including part of the GNAS1 gene to the telomere. Our data confirm that PHP1b is linked to a region that includes GNAS1, and further refine the locus, although the primary genetic mutation(s) that causes defective imprinting of GNAS1 remains undefined.

Neuraminidase in mucolipidoses: Normal activity in frozen autopsy tissues from three patients with I-cell disease and adult β-galactosidase deficiency

Neuraminidase was assayed in the frozen autopsy tissues from three patients with I-cell disease and an adult patient with cherry-red spots, myoclonus, cerebellar ataxia and β-galactosidase deficiency. Both diseases showed normal neuraminidase activity toward neuramine lactose and fetuin in cerebral gray matter, liver and kidney. These results suggest that the neuraminidase deficiency is limited only to some tissues and that this biochemical abnormality is not caused by a primary genetic mutation in these diseases.

Joseph disease: protein patterns in fibroblasts and brain.

The separation of brain and fibroblast proteins was analyzed on two-dimensional acrylamide gels. Proteins were examined from skin fibroblast cultures and brain homogenates from the frontal cerebral cortex, putamen, and cerebellum. Protein species from skin fibroblast cultures of controls and patients with Joseph disease or Huntington disease were not significantly different. The proteins from homogenates of the cerebral cortex, putamen, and cerebellum from controls differed from those of one Joseph disease patient. Two major classes of proteins were increased in the patient's putamen and cerebellum. Proteins of 40,000 and 50,000 daltons--including the glial filamentous acidic protein complex (molecular weight 50,000), and two proteins which migrated near actin--were increased in the cerebellum. The glial filamentous acidic protein complex increased 3.7-fold in the putamen of the patient. These protein changes probably represent gliosis, but may also be an expression of the primary genetic mutation.