Parkinson's disease is associated with gastrointestinal motility abnormalities favoring the occurrence of local infections. The aim of this study was to investigate whether small intestinal bacterial overgrowth contributes to the pathophysiology of motor fluctuations. Thirty-three patients and 30 controls underwent glucose, lactulose, and urea breath tests to detect small intestinal bacterial overgrowth and Helicobacter pylori infection. Patients also underwent ultrasonography to evaluate gastric emptying. The clinical status and plasma concentration of levodopa were assessed after an acute drug challenge with a standard dose of levodopa, and motor complications were assessed by Unified Parkinson's Disease Rating Scale-IV and by 1-week diaries of motor conditions. Patients with small intestinal bacterial overgrowth were treated with rifaximin and were clinically and instrumentally reevaluated 1 and 6 months later. The prevalence of small intestinal bacterial overgrowth was significantly higher in patients than in controls (54.5% vs. 20.0%; P = .01), whereas the prevalence of Helicobacter pylori infection was not (33.3% vs. 26.7%). Compared with patients without any infection, the prevalence of unpredictable fluctuations was significantly higher in patients with both infections (8.3% vs. 87.5%; P = .008). Gastric half-emptying time was significantly longer in patients than in healthy controls but did not differ in patients based on their infective status. Compared with patients without isolated small intestinal bacterial overgrowth, patients with isolated small intestinal bacterial overgrowth had longer off time daily and more episodes of delayed-on and no-on. The eradication of small intestinal bacterial overgrowth resulted in improvement in motor fluctuations without affecting the pharmacokinetics of levodopa. The relapse rate of small intestinal bacterial overgrowth at 6 months was 43%. 2013 Movement Disorder Society.
Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth syndromes generally present with inherent health concerns and, in some instances, an increased risk of tumor predisposition that necessitate prompt diagnosis and appropriate referral. In this review, we introduce some of the more common overgrowth syndromes, along with their molecular mechanisms, diagnostics, and medical complications for improved recognition and management of patients affected with these disorders.
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Figure 2. Chromosomal arrangement of the 11p15.5 locus. Maternal allele on top (in pink) and paternal allele below (blue) are represented. IC1, imprinting center 1, attracts the non-methylated form CTCF (transcription repressors of the CCCTC-binding family), which activates transcription of H19, a non-coding RNA, which represses growth. When the imprinting center is methylated, as normally occurring on the paternal allele, H19 is not transcribed, and the downstream enhancer elements can act on IGF2, which similar to IGF-1, promotes growth, particularly in the perinatal phase. Imprinting center 2 represses the expression of the potassium channel gene, KCNQ1, via transcription of its antisense (KCNQ1OT1) and the nearby CDKN1C, a growth-repressing cycline. Therefore, when IC2 is methylated, as seen on the maternal allele, CDKN1C is expressed, and growth is attenuated. On the paternal allele, IC2 is not methylated, and CDKN1C along with KCNQ1 are repressed, allowing growth. Either via expression of IGF2 or silencing of CDKN1C, the paternal allele promotes growth. Hypermethylation of IC1 on the maternal allele resulting in IGF2 overexpression is the mechanism seen in the patient in Figure 1 (right). This causes the maternal allele to function similar to the paternal allele, resulting in overgrowth with macroglossia. Loss of methylation of the maternal IC2 resulting in CDKN1C repression will also result in BWSp. Note: IC2 is depicted in this figure in juxtaposition to the KCNQ1 gene for simplification; its true position is within the KCNQ1 gene.
Figure 4. The cellular response to growth factor (GF) via its receptor. Upon dimerization of the receptor, IRS1 (insulin receptor substrate 1) is phosphorylated and activates (via its SH2 domain) downstream effectors, particularly PI3K (phosphatidylinositol 3-kinase). The latter, in turn, phosphorylates the second messenger PIP2 (phosphatidylinositol 4,5-bisphosphate), resulting in the activation of AKT (protein kinase B), which activates the mTORC1 (mammalian target of rapamycin complex 1). This pathway promotes cellular proliferation (via AKT) and also promotes angiogenesis and protein synthesis via the mTORC1 effector. Overactivation of the catalytic unit of PI3K, called PIK3CA, or AKT1 may result in uncontrolled activation of this pathway and signal-independent (over) growth. The former is seen in PIK3CA-related overgrowth spectrum (PROS) and the latter in Proteus syndrome, both are segmental overgrowth syndromes. A similar picture can be seen with biallelic deactivation of PTEN which is a growth repressor, as it dephosphorylates PIP3 back to its inactive form PIP2. This condition is seen in PTEN hamartoma tumor syndrome (PHTS). Not shown in the figure, but similar to PHTS, other growth repressors are the TSC1/2 complexes (tuber sclerosis complex), which inhibit mTORC1, but themselves are inhibited by AKT. The pathogenesis of variants in TSC1/2 is different, resulting in discrete tuberous growth of the cutaneous and CNS tissues, and predispose to variety of cancers. Of note, the PI3K/AKT/mTOR pathway is one pathway in which the growth factor activates.
Bacteria can compete for available food. And compounds produced through the bacterial break-down of stagnant food can also trigger diarrhea. Together, these effects of bacterial overgrowth result in diarrhea, malnutrition and weight loss.
The overgrowth of bacteria can result in B-12 deficiency that can lead to weakness, fatigue, tingling, and numbness in your hands and feet and, in advanced cases, to mental confusion. Damage to your central nervous system resulting from B-12 deficiency may be irreversible.
Genetic testing for genes associated with segmental and/or generalized overgrowth, including macrocephaly. The genetic heterogeneity associated with these conditions can make it difficult to use phenotype as the sole criterion to select a definitive cause. Broad panel testing allows for an efficient evaluation of several potential genes based on a single clinical indication. Some genes in this test may also be associated with additional unrelated disorders, which are not included in the list of disorders tested. This panel is not intended to detect disorders caused by postzygotic mosaicism when performed in DNA from blood, buccal swabs or saliva.
CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
A patent application (WO2017140828A1) has been filed by INSERM (Institut National de la Sant et de la Recherche Mdicale), Centre National De La Recherche Scientifique (CNRS), Universit Paris Descartes, and Assistance Publique-Hpitaux De Paris (AP-HP) for the use of BYL719 (alpelisib) in the treatment of PIK3CA-related overgrowth spectrum (PROS/CLOVES syndrome). G.C. is the inventor.
On April 5, 2022, the Food and Drug Administration granted accelerated approval to alpelisib (Vijoice, Novartis Pharmaceuticals) for adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy.
Those changes and the overgrowth they cause can happen in many parts of the body, including the skin, blood vessels, bones, fat, and brain. PROS can have a variety of symptoms, depending on which type it is and which parts of the body are affected. Often, these symptoms are visible when a baby is born, so doctors can diagnose a child with a PROS condition at birth. Sometimes it happens later in childhood.
Megalencephaly-capillary malformation (MCAP) syndrome. This form of PROS causes overgrowth of the brain and other body parts, such as blood vessels and parts of the face. People with MCAP syndrome may have a developmental delay and unusual fingers and toes.
Facial infiltrating lipomatosis. This disorder includes painless swelling or overgrowth of part of the face. It often happens on only one side of the head. Sometimes, masses grow from nerves, or part of the tongue is bigger than usual. Bones and teeth also may be affected.
What is small intestinal bacterial overgrowth?Small intestinal bacterial overgrowth (SIBO) is also commonly referred to as small bowel bacterial overgrowth. The small intestine and large intestine both contain bacteria that help with normal function of the intestine including digestion and immunity. Normally, the large intestine has a much larger number of bacteria than the small intestine. In SIBO, the small intestine develops a much higher number of bacteria than the large intestine. One of the primary roles of the small intestine is to absorb nutrients that the body needs. Over time, the change seen in the small intestine due to the increased number of bacteria can lead to poor absorption of nutrients in the small bowel and malnutrition. 0852c4b9a8
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