Familial Type Research Articles

Developing a pathway to clinical trials for CACNA1A-related epilepsies: A patient organization perspective.

CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.

Monogenic Hypertension Linked to the Renin-Angiotensin-Aldosterone System.

Mendelian forms of renin-angiotensin-aldosterone system (RAAS)-related hypertension, commonly referred to as monogenic hypertension, represent a rare but significant subset of hypertensive disorders characterized by genetic mutations that disrupt the normal physiological mechanisms of blood pressure regulation. This review focuses on elucidating the germline mutations affecting RAAS pathways that lead to distinct forms of heritable hypertension. By understanding the pathophysiological basis of conditions such as Gordon's syndrome, Liddle syndrome, congenital adrenal hyperplasia, and familial hyperaldosteronism types, this review aims to highlight the unique clinical features, diagnostic challenges, and therapeutic implications associated with these disorders. Recognizing specific clinical presentations and family histories indicative of monogenic hypertension is crucial for diagnosis, particularly as it often manifests as early-onset hypertension, abnormalities in potassium and blood pH, and occasionally, abnormal sexual development or related syndromes. Therefore, employing a targeted diagnostic approach through next-generation sequencing is essential to pinpoint the responsible genetic mutations, enabling accurate and individualized treatment plans. The critical importance of certain readily available specific channel blockers, such as thiazides or low-dose corticosteroids, in managing these disorders must be emphasized, as they play a key role in preventing serious complications, including cerebrovascular events. As advancements in genetic and molecular sciences continue to evolve, a deeper comprehension of the mechanisms underlying RAAS-related monogenic hypertension promises to revolutionize the management of this complex disorder, offering hope for more effective and individualized treatment options.

Familial partial lipodystrophy resulting from loss-of-function PPARγ pathogenic variants: phenotypic, clinical, and genetic features.

The PPARG gene encodes a member of a nuclear receptor superfamily known as peroxisome proliferator-activated gamma (PPARγ). PPARγ plays an essential role in adipogenesis, stimulating the differentiation of preadipocytes into adipocytes. Loss-of-function pathogenic variants in PPARG reduce the activity of the PPARγ receptor and can lead to severe metabolic consequences associated with familial partial lipodystrophy type 3 (FPLD3). This review focuses on recent scientific data related to FPLD3, including the role of PPARγ in adipose tissue metabolism and the phenotypic and clinical consequences of loss-of-function variants in the PPARG gene. The clinical features of 41 PPARG pathogenic variants associated with FPLD3 patients were reviewed, highlighting the genetic and clinical heterogeneity observed among 91 patients. Most of them were female, and the average age at the onset and diagnosis of lipoatrophy was 21 years and 33 years, respectively. Considering the metabolic profile, hypertriglyceridemia (91.9% of cases), diabetes (77%), hypertension (59.5%), polycystic ovary syndrome (58.2% of women), and metabolic-dysfunction-associated fatty liver disease (87,5%). We also discuss the current treatment for FPLD3. This review provides new data concerning the genetic and clinical heterogeneity in FPLD3 and highlights the importance of further understanding the genetics of this rare disease.

Successful Use of Bortezomib for Recurrent Progressive Familial Intrahepatic Cholestasis Type II After Liver Transplantation: A Pediatric Case with a 9-Year Follow-Up.

Recurrence of progressive familial intrahepatic cholestasis (PFIC) type II poses challenges during postoperative liver transplant care. Posttransplant patients with PFIC type II risk developing recurrent cholestasis with normal gamma-glutamyl transferase activity, which mimics the original bile salt export pump (BSEP) protein deficiency and is related to a form of immunoglobulin G antibody (anti-BSEP)-mediated rejection. Bortezomib effectively induces apoptosis of actively antibody-producing plasma cells that may have a role in antibody-mediated rejection. In this case, we used bortezomib to treat PFIC type II recurrence after liver transplantation in a child.

Clinical characteristics and genetic analysis of two children with Familial glucocorticoid deficiency type 1 due to variants of MC2R gene

To improve the recognition of Familial glucocorticoid deficiency type 1 (FGD1) due to variants of melanocortin 2 receptor (MC2R) gene. Two children with FGD1 diagnosed at the Henan Children's Hospital respectively in 2019 and 2021 were selected as the study subjects. Clinical data, treatment, follow-up and results of genetic testing were collected and retrospectively analyzed. Whole exome sequencing revealed that both children had harbored compound heterozygous variants of the MC2R gene, including c.433C>T (p.R145C) and c.710T>C (p.L237P) in child 1, and c.145delG (p.V49Cfs*35) and c.307G>A (p.D103N) in child 2, among which c.710T>C (p.L237P) and c.145delG (p.V49Cfs*35) were unreported previously. FGD1 is clinically rare, and genetic sequencing is crucial for the definite diagnosis. Discovery of the and novel variants has enriched the mutational spectrum of the FGD1 gene.

Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family

AbstractGenetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998–2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43:c.988 C > T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.

Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as live-cell bioenergetics and metabolic mapping using [13C]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.

Familial myoclonic dystonia type 11 with deep neurostimulator placement in bilateral internal globus pallidus. Case report and literature review

Familial myoclonic dystonia type 11 with deep neurostimulator placement in bilateral internal globus pallidus. Case report and literature review

Severe Neonatal Presentation of Progressive Familial Intrahepatic Cholestasis Type 4 in an Omani Infant

Progressive familial intrahepatic cholestasis type 4 (PFIC4) is a relatively newly described autosomal recessive disorder caused by biallelic mutations in the gene encoding tight junction protein 2 (TJP2) which is located in chromosome 9q21. PFIC4 is characterised by cholestasis with or without other extrahepatic manifestations. Bleeding tendency due to vitamin k deficiency is a well-known complication of cholestasis. We present a neonate who presented to the Emergency Department at a tertiary care hospital in 2021 with cholestasis and multiple intracranial bleeds. He was found to have severe coagulopathy and his genetic work up revealed a homozygous variant mutation in TJP2 gene causing PFIC4. He had persistent cholestasis that necessitated an internal biliary diversion with some clinical improvement. Keywords: Jaundice; Intracranial haemorrhage; Progressive Familial Intrahepatic Cholestasis type 4; Case Report; Oman.

Familial oral lichen planus: A new risk group for oral cancer?

The familial type of oral lichen planus (OLP) is rare, with a paucity of data regarding its clinical significance. Our objective was to characterize patients with familial OLP. Families with at least two members diagnosed with OLP were included. Clinical and demographic data and medical history were recorded. Twenty families, 19 Jewish and 1 Arab, were identified. Of the Jewish families, 57.8% were non-Ashkenazi, originating mainly from central Asia. Of those with OLP there were 14 males and 23 females with an average age of 49.1. Dyslipidemia, cardiovascular, and thyroid disorders (27.7%, 22.2%, and 16.6%, respectively) were the most common comorbidities. Five patients from five distinct families had oral cancer, two with second primary. To the best of our knowledge, this is the largest study describing familial OLP. The predominant and common ethnicity of the families with multiple members diagnosed with OLP may imply an ethnic tendency. The higher tendency of hypothyroidism and the high percentage of OSCC among familial OLP patients might be connected to familial OLP and the latter suggests that this population is predisposed to malignant transformation. Thus, this group should be considered as a high-risk group.

A large in-frame deletion of the calcium-sensing receptor extracellular domain causes familial hypocalciuric hypercalcaemia type 1 (FHH1) and is partially responsive to cinacalcet

A large in-frame deletion of the calcium-sensing receptor extracellular domain causes familial hypocalciuric hypercalcaemia type 1 (FHH1) and is partially responsive to cinacalcet

FRI190 Catching A Chimera: A Case Of Suspected Glucocorticoid Remediable Aldosteronism

Abstract Disclosure: A. Khan: None. B. Ramchandani: None. H.B. Aftab: None. Introduction: Familial hyperaldosteronism type 1 (FH-I), also known as glucocorticoid remediable aldosteronism (GRA) is responsible for 1% of cases of primary aldosteronism (PA). It is caused by a chimeric fusion of the CYP11B2 and CYP11B1 genes resulting in ACTH-sensitive aldosterone production. We describe a case of suspected GRA and outline the diagnosis of this rare condition. Case. A 52-year-old female with history of type 2 diabetes mellitus, obesity, sleep apnea, SVT with ablation presented with long-standing history of resistant hypertension (HTN). HTN was diagnosed in her late twenties. She was previously trialed on eight different classes of antihypertensive medications excluding mineralocorticoid antagonists or potassium-sparing diuretics but HTN remained uncontrolled. Current regimen included hydralazine, nebivolol, and furosemide. Her sister had HTN diagnosed in her forties, a nephew with HTN diagnosed in his early twenties and mother with HTN with unclear age of diagnosis. Her systolic and diastolic BP averaged 150 mmHg and 90 mmHg, respectively, on both home and clinic monitoring. Physical examination was significant for mild cushingoid appearance. Screening tests for pheochromocytoma and hypercortisolism were normal. Plasma aldosterone concentration (PAC) was noted to be at 14.4 ng/dl (<39.2) with a plasma renin activity (PRA) of <0.6 ng/mL/h (2.9 - 10.8), with aldosterone to renin ratio (ARR) of 24. Repeat testing showed PAC of 15.1 ng/dl, PRA<0.6 ng/ml/hr (ARR: 25.1) with potassium of 3.3 mmol/L (3.5 -5.1). PAC levels remained unsuppressed above 10 ng/dL following four-hour, seated, 2 L IV saline suppression test with serum potassium of 3.5 mmol/L. CT abdomen showed normal appearance of the adrenal glands. Given early age of onset of HTN and strong family history, 3-day dexamethasone test was performed using 1 mg oral dexamethasone every 12 hours following which PAC suppressed to <1 ng/dl. Patient was started on spironolactone 25 mg twice daily and at the time of writing is awaiting genetic testing to confirm the diagnosis of GRA. Discussion: GRA is a rare subtype of PA which has an increased risk of cardiovascular and cerebrovascular complications. Our case highlights the importance of screening for GRA in patients who have a personal and/or family history of early onset HTN who have screened positive for PA. Genetic testing for chimeric CYP11B1/B2 gene is the confirmatory step of diagnosis, however, a 3-day dexamethasone suppression test can be used to screen for GRA with a high sensitivity. Elevated levels of urine 18-hydroxycortisol and 18-oxocortisol are also noted but these are not widely available tests. Treatment of GRA is with medical management only; since surgical intervention is not required; proper diagnosis can also save the patient from unnecessary and invasive tests such as adrenal vein sampling. Presentation: Friday, June 16, 2023

OR03-05 Cinacalcet Acts As A Spatially Biased Allosteric Modulator To Enhance CaSR Signaling From Endosomal Membranes

Abstract Disclosure: R. Wyatt: None. C.M. Gorvin: None. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis by activating Gαq/11 and Gαi/o signaling to regulate parathyroid hormone (PTH) release. CaSR can also continue signaling once internalised (known as sustained signaling) to elicit responses that are distinct from those at the plasma membrane. Loss-of-function mutations of CaSR cause familial hypocalciuric hypercalcemia type 1 (FHH1), while Arg15 mutations in the adaptor protein-2 σ-subunit (AP2σ) cause FHH3, by impairing CaSR internalisation and disrupting sustained signaling. However, the sustained signaling pathway has been incompletely defined and the effects of allosteric modulators on the process are unknown. Here we examined CaSR membrane trafficking and G protein activation in different endomembrane compartments using bystander BRET and HILO advanced imaging in HEK293 cells. This showed that internalised CaSR is targeted to Rab5-positive early endosomes and Rab4-positive early-to-recycling membranes, and not to degradation pathways as previously hypothesised. CaSR exclusively recruits active Gq/11 to early endosome membranes to drive sustained signals that produce distinct transcriptional profiles than those from plasma membranes. We next mutated a C-terminal region within CaSR predicted to form a dileucine endocytic motif that interacts with AP2σ. NanoBiT assays confirmed that the CaSR-dileucine mutant disrupted interactions between CaSR and AP2σ to the same magnitude as AP2σ-Arg15 mutations. Moreover, this CaSR-dileucine mutant impaired CaSR internalisation and reduced Gq/11 sustained signals from Rab5 and Rab4 endosomes to similar levels to those observed in cells expressing the FHH3-associated AP2σ-Arg15 mutant. Gi/o and G12/13 responses from plasma membranes were not affected by the CaSR-dileucine mutant. Finally, we assessed whether the CaSR positive allosteric modulator, cinacalcet, affects sustained signalling. When exposed to cinacalcet CaSR significantly increased the recruitment of active Gq/11 to early endosomes, resulting in a significant increase in signaling, while signals from the plasma membrane were not different to vehicle-treated cells. In summary, we have demonstrated that CaSR is targeted to an early-to-recycling endosomal pathway, which could explain how CaSR responds rapidly to fluctutations in serum calcium to maintain calcium homeostasis. Moreover, we have defined the endocytic motif within the CaSR required for sustained signaling and shown that cinacalcet is a spatially-biased allosteric modulator of the CaSR that preferentially enhances signaling from endosomal membranes. Thus, FHH3-associated AP2σ mutations, CaSR dileucine mutants and cinacalcet can be used as tools to better understand CaSR spatiotemporal signaling and define its physiological significance. Presentation: Thursday, June 15, 2023

FRI458 Rare Pathogenic Missense Variants in LMNA Identified in Women with Polycystic Ovary Syndrome (PCOS)

Abstract Disclosure: R. Bauer: None. L. Gorsic: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None. Background: Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility among reproductive age women. In addition to experiencing reproductive symptoms, women with PCOS are at elevated risk of developing obesity, insulin resistance (IR), and type 2 diabetes. Familial partial lipodystrophy type 2 (FPLD2) is a disorder of lipid storage and insulin resistance caused by dominant missense alleles in the gene encoding the intermediate filaments lamin A/C (LMNA). Women with this Mendelian disorder of IR also experience symptoms of PCOS such as amenorrhea and hyperandrogenism. We, therefore, hypothesize that genetic variation in LMNA also contributes to PCOS, which is a common form of IR. In other words, we hypothesize that PCOS falls into the phenotypic spectrum of disorders caused by variation in LMNA.Objective: We aim to identify and evaluate variation in LMNA that underlies PCOS pathogenesis. Methods: To test our hypothesis, we sequenced the LMNA gene in 602 women with PCOS and 125 reproductively healthy women. We comprehensively screened LMNA for genetic variation that is likely to alter the lamin A/C proteins, including missense, nonsense, splicing or frameshift variants. We identified 7 missense variants in 8 cases and no variants in reproductively healthy controls (χ2= 3.1, p=0.081, OR > 1.78, with study controls; χ2= 46.8, p<1x10-8, OR= 8.5 with gnomAD non-Finnish European cohort population controls). To determine which of these variants are pathogenic, we systematically evaluated them according to criteria outlined by the American College of Medical Genetics (ACMG). These guidelines evaluate pathogenicity of variants through multiple lines of evidence, including population data, computational predictions, and functional studies. Results: We identified 5 pathogenic variants in LMNA and 2 that are likely pathogenic. When assessed individually, 6 of the 7 variants are significantly enriched in our cohort when compared to gnomAD non-Finnish European population controls (OR > 5.0). All of the LMNA variants are likely damaging as predicted by 3 computational methods: CADD score ≥ 15, FATHMM prediction of “Damaging”, and MutationTaster classification as “disease causing.” Additionally, many of the variants have previously been identified in individuals with lipodystrophy. Conclusion: Together with previous identification of LMNA variants in women with PCOS by our lab (Urbanek et al. 2009 JCEM) and others (Crespo et al. 2022 JES), this work further establishes LMNA variation as a pathogenic mechanism for PCOS. Presentation Date: Friday, June 16, 2023

LES XANTHOMATOSES HYPERLIPIDEMIQUES: AU-DELA DE LA RARETE, QUELLE PRISE EN CHARGE ?

Xanthomas are benign pseudo tumors, often linked to a disorder of lipoprotein metabolism and which require screening.We report the case of a 33-year-old young adult, with no significant medical history, who consulted for painless yellowish nodules progressively appearing over the past year on the limbs. Cutaneous and mucosal examination reveals small smooth-surfaced nodules, orange-yellow in color, painless, non-pruritic, of varying sizes, located on the forearms, elbows, hands, knees, ears and posterior surface of the neck. The histopathological study of a skin nodule biopsy suggests lipid overload, confirming the diagnosis of xanthomas. The lipid profile, conducted after a 12-hour fast, shows hypertriglyceridemia at 10.28 g/L, hypercholesterolemia at 7.79 g/L, elevated LDL cholesterol levels at 3.64 g/L and decreased HDL cholesterol levels at 0.31 g/L. Thyroid function tests and cardiovascular investigations are unremarkable. The diagnosis of familial combined hyperlipidemia type III, according to the Fredrickson classification is established.The patient is prescribed lifestyle modifications along with treatment consisting of daily pravastatin 40mg and fenofibrate 160mg. The patients condition shows improvement with regression of these lesions.Xanthomatoses linked to familial hypercholesterolemia are very rare. This condition can significantly impact patients lives due to its complications, particularly coronary complications, despite well-managed medical treatment.

Early-Onset Colon Cancer: A Narrative Review of Its Pathogenesis, Clinical Presentation, Treatment, and Prognosis.

Colon cancer remains a leading cause of cancer-related deaths, and there has been a rise in the incidence of early-onset colon cancer or colon cancer diagnosed before the age of 50 years old. Early-onset colon cancerhas several differences in clinical presentation, as well as histopathology, geneticalteration, and molecular profiling. Early-onset colon cancer can be differentiated into familial type that includes hereditary familial syndrome and sporadic type. Demographic variance also exists in both developing and developed countries. Due to the rising incidence of colon cancer diagnosed in younger age, it is imperative to examine the available evidence regarding the mortality rate of early-onset colon cancer. Colon cancer is affected by numerous modifiable and non-modifiable risk factors. Increasing obesity and lifestyle disorders in the younger population, such as smoking, may influence this increasing trend. There are existing guidelines for colon cancer screening in both average-risk and high-risk individuals.This narrative review aims to highlight the pathogenesis of early-onset CRC; its clinical presentation, treatment, prognosis; and how it differs from late-onset CRC.

Postprandial Hyperlipidemia: Its Pathophysiology, Diagnosis, Atherogenesis, and Treatments.

Postprandial hyperlipidemia showing postprandial increases in serum triglyceride (TG) is associated with the development of atherosclerotic cardiovascular disease (ASCVD). To diagnose postprandial hyperlipidemia, the oral fat loading test (OFLT) should be performed; however, this test is very time-consuming and is difficult to perform. Elevated serum TG levels reflect an increase in TG-rich lipoproteins (TRLs), such as chylomicrons (CM), very low-density lipoproteins (VLDL), and their remnants (CM remnants [CMRs] and VLDL remnants [VLDLRs]). Understanding of elevation in CMR and/or VLDLR can lead us to understand the existence of postprandial hyperlipidemia. The measurement of apo B48, which is a constituent of CM and CMR; non-fasting TG, which includes TG content in all lipoproteins including CM and CMR; non-high-density lipoprotein cholesterol (non-HDL-C), which includes TRLs and low-density lipoprotein; and remnant cholesterol are useful to reveal the existence of postprandial hyperlipidemia. Postprandial hyperlipidemia is observed in patients with familial type III hyperlipoproteinemia, familial combined hyperlipidemia, chronic kidney disease, metabolic syndrome and type 2 diabetes. Postprandial hyperlipidemia is closely related to postprandial hyperglycemia, and insulin resistance may be an inducing and enhancing factor for both postprandial hyperlipidemia and postprandial hyperglycemia. Remnant lipoproteins and metabolic disorders associated with postprandial hyperlipidemia have various atherogenic properties such as induction of inflammation and endothelial dysfunction. A healthy diet, calorie restriction, weight loss, and exercise positively impact postprandial hyperlipidemia. Anti-hyperlipidemic drugs such pemafibrate, fenofibrate, bezafibrate, ezetimibe, and eicosapentaenoic acid have been shown to improve postprandial hyperlipidemia. Anti-diabetic drugs including metformin, alpha-glucosidase inhibitors, pioglitazone, dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide 1 analogues have been shown to ameliorate postprandial hyperlipidemia. Although sodium glucose cotransporter-2 inhibitors have not been proven to reduce postprandial hyperlipidemia, they reduced fasting apo B48 and remnant lipoprotein cholesterol. In conclusion, it is important to appropriately understand the existence of postprandial hyperlipidemia and to connect it to optimal treatments. However, there are some problems with the diagnosis for postprandial hyperlipidemia. Postprandial hyperlipidemia cannot be specifically defined by measures such as TG levels 2 h after a meal. To study interventions for postprandial hyperlipidemia with the outcome of preventing the onset of ASCVD, it is necessary to define postprandial hyperlipidemia using reference values such as IGT.

Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis.

Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experience of 6 patients with liver transplantation for hepatocellular carcinoma with background inherited metabolic disease. This is a single-center retrospective, descriptive study. Consecutive patients who underwent liver transplantation for hepatocellular carcinoma with background inherited metabolic disease were included in the study. The record of the patients was accessed, and the following data were extracted: sociodemographic variables, type of metabolic disease, date of liver transplantation, tumor characteristics, laboratory parameters, Model for End-Stage Liver Disease score, immediate- and long-term outcome after transplantation, disease-free survival, and overall survival. Data were analyzed using Statistical Package for the Social Sciences version 25.0. Six patients received liver transplantation for hepatocellular carcinoma with background inherited metabolic liver disease. The median age was 4.5 years. The median Model for End-Stage Liver Disease score was 29.30. The median maximum tumor diameter was 2.15 cm. Three patients had multiple tumor nodules. Half of the patients had microvascular invasion. Four of the patients had a moderately differentiated tumor. Progressive familial intrahepatic cholestasis type II is the commonest inherited metabolic disease seen in 3 patients. Median follow-up is 46.1 months. Half of the patients are currently more than 5 years post liver transplantation with no features of recurrence. The estimated survival rates at 1, 3, and 5 years are 100%, 83.3%, and 83.3%, respectively. Liver transplant for these categories of patients is associated with good disease-free and overall survival, even in the presence of some seemingly poor prognostic features.

Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1.

Familial hypocalciuric hypercalcemia type 1 (FHH-1) defines an autosomal dominant disease, related to mutations in the CASR gene, with mild hypercalcemia in most cases. Cases of FHH-1 with a short QT interval have not been reported to date. Three family members presented with FHH-1 and short QT interval (<360 ms), a condition that could lead to cardiac arrhythmias, and the effects of cinacalcet, an allosteric modulator of the CaSR, in rectifying the abnormal sensitivity of the mutant CaSR and in correcting the short QT interval were determined. CASR mutational analysis was performed by next-generation sequencing and functional consequences of the identified CaSR variant (p.Ile555Thr), and effects of cinacalcet were assessed in HEK293 cells expressing wild-type and variant CaSRs. A cinacalcet test consisting of administration of 30 mg cinacalcet (8 Am) followed by hourly measurement of serum calcium, phosphate, and parathyroid hormone during 8 hours and an electrocardiogram was performed. The CaSR variant (p.Ile555Thr) was confirmed in all 3 FHH-1 patients and was shown to be associated with a loss of function that was ameliorated by cinacalcet. Cinacalcet decreased parathyroid hormone by >50% within two hours, and decreases in serum calcium and increases in serum phosphate occurred within 8 hours, with rectification of the QT interval, which remained normal after 3 months of cinacalcet treatment. Our results indicate that FHH-1 patients should be assessed for a short QT interval and a cinacalcet test used to select patients who are likely to benefit from this treatment.

Autonomic function in sporadic and familial ALS type 8

ObjectiveTo characterize and compare autonomic function in patients with sporadic (sALS) and familial ALS type 8 (fALS8). MethodsWe selected 11 patients with sALS (7 men), 14 with fALS8 (8 men) and 26 controls (15 men). All groups were gender and age-matched. For each subject, Scale for Outcomes in Parkinson's Disease for Autonomic Symptoms (SCOPA-AUT) was applied and data from heart rate variability, Quantitative Sudomotor Axon Reflex Test (QSART) and skin sympathetic response (SSR) were collected. These data were compared across groups using nonparametric tests. P-values < 0.05 were considered significant. ResultsSCOPA-AUT revealed predominant clinical complaints in thermoregulatory, pupillomotor and sexual domains in fALS8 relative to sALS as well as controls. Neurophysiological tests demonstrated significant differences in Valsalva ratio, Expiratory:Inspiratory index and RR minimum values in both ALS groups relative to controls. Sudomotor dysfunction was also observed in sALS and fALS8 groups, as shown by reduced medial forearm and foot QSART volumes and absence of SSR in lower limbs. ConclusionsDysautonomia – cardiac and sudomotor - is part of the phenotype in sALS and fALS8. The profile of autonomic symptoms, however, is different in each group. SignificancePatients with fALS8 and sALS have autonomic dysfunction involving both sympathetic and parasympathetic divisions.