Diabetic ketoacidosis with SGLT2 inhibitor use - a patient series. / Diabetisk ketoacidose ved bruk av SGLT2-hemmer ­ en pasientserie.

BACKGROUND: Inhibitors of sodium glucose cotransporter 2 (SGLT2 inhibitors) are increasingly being used to treat type 2 diabetes. Results from previous studies suggest a rising incidence of diabetic ketoacidosis with the use of this medication. MATERIAL AND METHOD: We performed a diagnosis search in the electronic patient records at Haukeland University Hospital for the period 1 January 2013-31 May 2021 with the aim of identifying patients with diabetic ketoacidosis who used SGLT2 inhibitors. A total of 806 patient records were reviewed. RESULTS: Twenty-one patients were identified. Thirteen had severe ketoacidosis, and ten had normal blood glucose levels. Probable triggering causes were found in 10 of the 21, with recent surgery being the most common (n = 6). Three of the patients were not tested for ketones, and 9 were not tested for antibodies to rule out type 1 diabetes. INTERPRETATION: The study showed that severe ketoacidosis occurs in patients with type 2 diabetes using SGLT2 inhibitors. It is important to be aware of this risk and the fact that ketoacidosis can occur without hyperglycaemia. Arterial blood gas and ketone tests must be performed to make the diagnosis.

Thoracoscopic esophagectomy for stenosis of thoracic esophagus due to acute esophageal necrosis associated with alcoholic ketoacidosis.

Acute esophageal necrosis (AEN) is a rare disease characterized by the appearance of diffuse black mucosa on upper gastrointestinal endoscopy; the condition often progresses to esophageal stenosis in the chronic phase. A 70-year-old man was admitted to a neighborhood hospital with the diagnosis of alcoholic ketoacidosis and an upper gastrointestinal endoscopy performed to investigate the symptom of esophageal tightness revealed AEN. The patient developed esophageal stenosis with scarring in the chronic phase and was referred to our hospital for surgery 6 months after the diagnosis of AEN. We performed thoracoscopic esophagectomy with the patient in the prone position. Although the esophagus was thickened and strong adhesions were present around the esophagus due to inflammation, we were able to complete the surgical procedure thoracoscopically. In patients presenting with benign esophageal stenosis developing after AEN, thoracoscopic esophagectomy may be a useful treatment option, even in the presence of severe fibrosis.

Anti-programmed Cell Death Protein-1 Therapy in Intrahepatic Cholangiocarcinoma Induced Type 1 Diabetes: A Case Report and Literature Review.

Immune checkpoint inhibitors, widely used in the treatment of malignancies, can improve the prognosis of patients, while it also can induce various immune-related adverse events, and type 1 diabetes induced by anti-programmed cell death protein-1 is a rare but severe complication. Here we reported a case of type 1 diabetes induced by anti-PD-1 which was to treat intrahepatic cholangiocarcinoma. The case was a 61-year-old female who developed diabetes and ketoacidosis symptoms at the 16th week after anti-PD-1 therapy. Her blood glucose was 30.32 mmol/L, HBA1c was 8.10%, and C-peptide was <0.10 ng/ml. The patient was diagnosed as fulminant type 1 diabetes mellitus complicated with ketoacidosis induced by anti-PD-1, and was treated with massive fluid rehydration, intravenous infusion of insulin and correction of acid-base electrolyte disorder. Hepatectomy was performed after stabilization, and the patient was treated with long-term insulin. Through the case report and literature review, this study aims to improve oncologists' understanding of anti-PD-1 induced type 1 diabetes, so as to make early diagnosis and treatment of the complications and ensure medical safety.

Association of Agenesis of the Dorsal Pancreas With HNF1B Heterozygote Mutation: A Case Report.

Background: Agenesis of the dorsal pancreas (ADP) is a rare disease, the pathogenic mechanism of which is partially related to variants of hepatocyte nuclear factor 1B (HNF1B) gene. Case Presentation: We report a case of ADP, which presented with acute ketoacidosis, hyperuricemia, and liver dysfunction. In this case, the HNF1B score was estimated as 16 and a heterozygous variant of HNF1B in exon 2 (c.513G>A-p.W171X) was identified through gene sequencing. Conclusions: A good understanding of the clinical comorbidities of ADP is essential for avoiding missed diagnosis to a great extent. Moreover, estimation of HNF1B score is recommended before genetic testing.

Accidental ketosis-induced polyuria in a toddler: a case report.

BACKGROUND: In the pediatric population, parental concern of recent onset frequent or large volume urination in young children is common. CASE PRESENTATION: A 2-year-old male with no significant past medical history and unremarkable family history was brought to his pediatrician by his mother who reports that the child had been "soaking through his diapers" for the previous two to 3 days. Mother states that patient has not had an appreciable change in the number of wet diapers per day, just the perceived weight/volume of each diaper. The patient's mother denied any recent illness, apparent abdominal pain, dysuria, or recent changes in his bowel movements. She similarly denied polydipsia, polyphagia, or gross hematuria in the patient. Patient's diet consists of eating a low carbohydrate with mostly high protein and fat diet that was similar to the paleo-type diet consumed by her and her husband. Meals over the recent days were even lower in carbohydrates than usual as the family was actively trying to consume healthier food options. On physical exam the child was found to be afebrile with a normal physical exam. A urine dipstick was performed and was positive for 2+ ketones and 1+ protein. Urine leukocytes and nitrites were negative, as was urinary glucose. A fingerstick blood glucose sample was 83 mg/dL. Based on the patient's physical examination, laboratory findings, and the history which revealed a very-low carbohydrate diet, a preliminary diagnosis of ketosis-induced polyuria was made. The patient's mother was advised to incorporate a greater portion of carbohydrates into her son's diet, with a follow-up scheduled for the following week. At the follow-up appointment the mother reports that she had continued the patient's carbohydrate intake and the excessive urine amount per wet diaper has not returned. Repeat urine dipstick confirmed the resolution of the ketonuria and proteinuria. CONCLUSION: This case illustrates the inadvertent consequences that can occur when parents impose new fad diets on their young children. The recent increase in the popularity of fad diets makes the consideration of alternative diets important to review in the patient history and subsequently include in the differential diagnosis of polyuria.

Metabolic Acidosis in Postsurgical Patient on Canagliflozin and Metformin: A Case Report.

Canagliflozin is a novel drug for diabetes mellitus with the mechanisms of inducing glucosuria through inhibition of the sodium-glucose cotransporter 2 in the kidney independent of insulin activity. We are reporting euglycemic ketoacidosis with severe life-threatening metabolic acidosis. The 2 patients described had type 2 diabetes mellitus and were in a state of relative starvation after abdominal surgery. The first patient had been given an oral diet but was restricted with regard to calorie and sugar intake. The second patient had been nil per os since the operation.

Cuidados pós-ressuscitação-cardiopulmonar (RCP) / Post-cardiopulmonary resuscitation (CPR) care

Evitar novos episódios de parada cardiorrespiratória (PCR). Identificar e tratar as causas que levaram o paciente à PCR. Oferecer suportes ventilatório, hemodinâmico, neurológico e metabólico. Realizar a modulação terapêutica de temperatura para todos os pacientes que retornaram à circulação espontânea. Indicação de cateterismo cardíaco para pacientes sem causa estabelecida de PCR quando a causa pode ser um evento coronariano

Avoid further episodes of cardiopulmonary arrest (CPA). Identify and treat the causes of the patient's CPA. Provide ventilatory, hemodynamic, neurological and metabolic support. Perform therapeutic temperature modulation for all patients who have resumed spontaneous circulation. Indication of cardiac catheterization for patients with no established cause of CPA when the cause may be a coronary event

Carga ácida potencial renal de la dieta servida a pacientes en un hospital privado. Caracas, Venezuela / Acid load renal potential of the diet served to patients in a private hospital. Caracas Venezuela

La acidosis metabólica sub clínica resultante de una carga ácida de la dieta puede constituir un factor de riesgo para diversas patologías. El objetivo fue determinar la Carga Acida Potencial Renal (CAPR) de las dietas servidas a pacientes hospitalizados en el Centro Médico Docente La Trinidad. Se analizó el contenido en proteínas, grasas, carbohidratos, kilocalorías y CAPR de cuatro tipos de dietas: completa (C), de protección gástrica (PG), hiposódica (H) y para diabéticos (D). Se calculó la CAPR de los alimentos disponibles, de los ofrecidos en dos menús representativos y de las dietas seleccionadas por los pacientes. Adicionalmente se plantearon tres combinaciones para lograr dietas con baja carga ácida. La CAPR (X mEq/día) fue: 1) alimentos disponibles: C 100,51; PG 57,16; H 82,4; D 73,15. 2) para los menús 1 y 2: C 38,88 y 27,22; PG 48,3 y 24,45; H 21,54 y 8,24; D 36,53 y 46,22. 3) para las dietas elegidas por los pacientes: C 28,27; PG 25,77; H 7,19; D 15,63. 4) para las combinaciones propuestas: C -17,43; PG -24,17; H -15,83; D -16,29. La CAPR se correlacionó directamente con el contenido de proteínas de los cuatro tipos de dietas (p<0.001) e inversamente con el peso en gramos de frutas y hortalizas (p<0.01). La CAPR de las dietas elegidas por los pacientes fue positiva. Sin embargo, es posible lograr combinaciones que resulten en dietas con baja carga ácida. Se recomienda educar a los pacientes en relación a la importancia de evitar dietas de elevado contenido ácido(AU)

Subclinical metabolic acidosis as a result of an acid dietary load may represent a risk factor for multiple pathologies. The objective of this study was to determine the Potential Renal Acid Load (PRAL) of diets served to patients hospitalized at the Centro Médico Docente La Trinidad. Protein, fat, carbohydrate, energy and PRAL of four types of diets were analyzed. The four types of diets were the following: complete (C), gastric protection (GP), low sodium (LS) and for diabetic patients (D). PRAL was calculated for available foods, for foods in two types of menus (1 and 2) and for diets selected by patients. Additionally, food combinations for diets with low acid load were proposed. PRAL (X mEq/day) was: 1) for available foods: C 100,51; GP 57,16; LS 82,4; D 73,15. 2); for patients selection: C 28,27; GP 25,77; LS 7,19; D 15,6; 3) for menus 1 and 2: C 38,88 and 27,22; PG 48,3 and 24,45; H 21,54 and 8,24; D 36,53 and 46,22. 4) for proposed combinations: C -17,43; GP -24,17; LS -15,83; D -16,29. There was a direct and significant correlation between PRAL and protein content (p<0.001) and an inverse and significant correlation with fruits and vegetables (p<0.01). PRAL of patient selected diets was positive. However, it is possible to achieve food combinations for diets with a low acid load. Appropriate strategies should be designed in order to educate patients in relation to the importance of avoiding diets with elevated acid load(AU)

Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity.

In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.

Starvation Ketoacidosis as a Cause of Unexplained Metabolic Acidosis in the Perioperative Period.

BACKGROUND Besides providing anesthesia for surgery, the anesthesiologist's role is to optimize the patient for surgery and for post-surgical recovery. This involves timely identification and treatment of medical comorbidities and abnormal laboratory values that could complicate the patient's perioperative course. There are several potential causes of anion and non-anion gap metabolic acidosis in surgical patients, most of which could profoundly affect a patient's surgical outcome. Thus, the presence of an acute acid-base disturbance requires a thorough workup, the results of which will influence the patient's anesthetic management. CASE REPORT An otherwise-healthy 24-year-old female presented for elective spine surgery and was found to have metabolic acidosis, hypotension, and polyuria intraoperatively. Common causes of acute metabolic acidosis were investigated and systematically ruled out, including lactic acidosis, diabetic ketoacidosis, drug-induced ketoacidosis, ingestion of toxic alcohols (e.g., methanol, ethylene glycol), uremia, and acute renal failure. Laboratory workup was remarkable only for elevated serum and urinary ketone levels, believed to be secondary to starvation ketoacidosis. Due to the patient's unexplained acid-base disturbance, she was kept intubated postoperatively to allow for further workup and management. CONCLUSIONS Starvation ketoacidosis is not widely recognized as a perioperative entity, and it is not well described in the medical literature. Lack of anesthesiologist awareness about this disorder may complicate the differential diagnosis for acute intraoperative metabolic acidosis and lead to a prolonged postoperative stay and an increase in hospital costs. The short- and long-term implications of perioperative ketoacidosis are not well defined and require further investigation.

Right Ventricle Mass Removal from Tricuspid Valve Apparatus: An Unusual Thromboembolic Complication of Severe Ketoacidosis.

The presence of a pathologic mass in the right ventricle (RV) may lead to hemodynamic consequences and to a life-threatening incident of pulmonary embolism. The diagnosis of an unstable thrombus in the right heart chamber usually necessitates intensive treatment to dissolve or remove the pathology. We present a report of an unusual complication of severe ketoacidosis: thrombus in the right ventricle, removed from the tricuspid valve (TV) apparatus. A four-year-old boy was diagnosed with diabetes mellitus (DM) type I de novo. During hospitalization, a 13.9 × 8.4 mm tumor in the RV was found in a routine cardiac ultrasound. The patient was referred for surgical removal of the floating lesion from the RV. The procedure was performed via midline sternotomy with extracorporeal circulation (ECC) and mild hypothermia. Control echocardiography showed complete tumor excision with normal atrioventricular valves and heart function. Surgical removal of the thrombus from the tricuspid valve apparatus was effective, safe, and a definitive therapy for thromboembolic complication of pediatric severe ketoacidosis.

Host-iron assimilation: pathogenesis and novel therapies of mucormycosis.

Mucormycosis is a fungal infection caused by organisms belonging to the order Mucorales. Although considered uncommon, mucormycosis has been steadily increasing in incidents for the last two decades. Mortality of the disease is unacceptably high despite antifungal therapy and surgical interventions. The lack of understanding of the pathogenesis of the disease and the absence of rapid diagnostic assay contribute to the poor prognosis of mucormycosis. The hyper susceptibility of patients with elevated available serum iron points to the critical role of the ability of Mucorales to acquire host iron as a critical virulence factor. Specifically patients with deferoxamine-therapy, hyperglycaemic with or without ketoacidosis, or other forms of acidosis are uniquely predisposed to mucormycosis. In this review, we discuss the molecular mechanisms of infection in these patient categories in an attempt to identify novel therapies for a disease with poor prognosis. Emphasis on the effect of glucose and free iron on host-pathogen interactions are also covered.

Hyperglycaemia and ketosis in a non-diabetic patient--an unusual cause of delayed recovery.

We report a case of hyperglycaemia and ketosis developing in a non-diabetic patient who underwent a neurosurgical procedure under general anaesthesia. A 52-year-old non-diabetic female patient underwent excision of acoustic neuroma under general anaesthesia. Pancreatic function was not disturbed and she received a single dose of dexamethasone (8 mg) and paracetamol (1 g). Delayed recovery from anaesthesia occurred. On investigation, she was found to have hyperglycaemia and ketosis. She was further managed on the line of diabetic ketoacidosis. After 24 hours, when blood glucose had normalised and ketosis abated, she could be weaned from mechanical ventilation and extubated. The patient did not receive any drugs known to cause such a condition. To the best of our knowledge, hyperglycaemia and ketosis developing in a non-diabetic patient causing delayed recovery and extubation is here reported for the first time.

Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis.

OBJECTIVE: Currently, there is no consensus on the definition of hyperemesis gravidarum (HG; protracted vomiting in pregnancy) and no single widely used set of diagnostic criteria for HG. The various definitions rely on symptoms, sometimes in combination with laboratory tests. Through a systematic review, we aimed to summarize available evidence on the diagnostic value of biomarkers for HG. This could assist diagnosis and may shed light on the, as yet, not understood cause of the disorder. STUDY DESIGN: We searched Medline and Embase for articles about diagnostic biomarkers for either the presence or severity of HG or nausea and vomiting of pregnancy. We defined HG as any combination of nausea, vomiting, dehydration, weight loss, or hospitalization for nausea and/or vomiting in pregnancy, in the absence of any other obvious cause for these complaints. RESULTS: We found 81 articles on 9 biomarkers. Although 65% of all studies included only HG cases with ketonuria, we did not find an association between ketonuria and presence or severity of HG in 5 studies reporting on this association. Metaanalysis, with the use of the hierarchical summary receiver operating characteristics model, yielded an odds ratio of 3.2 (95% confidence interval, 2.0-5.1) of Heliobacter pylori for HG, as compared with asymptomatic control subjects (sensitivity, 73%; specificity, 55%). Studies on human chorionic gonadotropin and thyroid hormones, leptin, estradiol, progesterone, and white blood count showed inconsistent associations with HG; lymphocytes tended to be higher in women with HG. CONCLUSION: We did not find support for the use of ketonuria in the diagnosis of HG. H pylori serology might be useful in specific patients.

Ketoacidosis and trace amounts of isopropanol in a chronic alcoholic patient.

BACKGROUND: Alcohol ketoacidosis is a frequently missed diagnosis, but is well described in the literature. We present a case of ketoacidosis, likely alcohol ketoacidosis, in a 40 y-old chronic alcoholic patient. The detection of trace serum isopropanol prompted a discussion of alcohol ketoacidosis versus toxic isopropanol ingestion or a combination of both, including comparisons with citations in current literature. METHODS: The automated instruments used to analyze the patient's urine, blood, and serum samples are described. RESULTS: The initial impression was severe metabolic acidosis with an increased anion gap and normal serum glucose and whole blood lactate. Testing for potential toxic ingestions detected only increased serum acetone and trace serum isopropanol. A urinalysis positive for ketones and an increased serum ß-hydroxybutyrate concentration clenched the diagnosis of ketoacidosis. CONCLUSION: Ketoacidosis with an increased anion gap in the absence of hyperglycemia or glycosuria in a chronic alcoholic patient should prompt the evaluation for alcohol ketoacidosis. Trace serum isopropanol may be worrisome for a toxic ingestion, but this finding in severe ketoacidosis may be explained by the reversible action of the enzyme alcohol dehydrogenase. Markedly increased serum isopropanol with a low serum acetone:isopropanol ratio would be more indicative of a toxic isopropanol ingestion.

Conduta nutricional no trauma para o clínico / Conduct in nutrition on trauma for clinical

JUSTIFICATIVA E OBJETIVOS: Trauma é um evento agudo que altera a homeostase do organismo, por desencadear reações neuroendócrinas e imunológicas que visam a manutenção da volemia, do débito cardíaco, da oxigenação tecidual e da oferta e utilização de substratos energéticos. Todas têm em comum um evento inicial agudo, alterando todo o equilíbrio do organismo e uma resposta fisiopatológica complexa. O objetivo deste estudo foi alertar sobre as necessidades energético-proteicas no trauma, consumo metabólico,formas mais seguras de administração da dieta e as possíveis complicações do suporte nutricional inadequado nessas situações. CONTEÚDO: A nutrição deve ser integrada no tratamento global do paciente criticamente doente a fim de minimizar as complicações de um tratamento mais prolongado. As prioridades imediatas após o trauma são: reanimação volêmica, oxigenação e a interrupção da hemorragia. Associados a esses fatores estão o estado hiperdinâmico da resposta ao trauma, bem como a dor, febre, exposição ao frio, acidose e hipovolemia, e possíveis infecções, aumentando a demanda metabólica. O suporte nutricional é parte essencial do tratamento metabólico desses pacientes. Ele deve ser instituído antes que haja perda significativa de peso, de preferência nas primeiras 24h da admissão no hospital, através de dietas orais ou enterais preferencialmente e parenterais, quando necessário. CONCLUSÃO: Uma dieta bem administrada é capaz de manter a massa celular corporal e a limitação da perda de peso a menos de 10% do peso na pré-lesão. O importante é o paciente ser constantemente reavaliado para ajuste da dieta de acordo com as necessidades diárias. Dentre as consequências de uma inadequada abordagem destes pacientes, tem-se a síndrome de realimentação, a cetose e a desnutrição.

BACKGROUND AND OBJECTIVES: Trauma is an acute event that alters the body's homeostasis, neuroendocrine and for triggering immune responses aimed at maintaining blood volume, cardiac output, tissue oxygenation and the supply and use of energy substrates. All have in common an acute initial event, changing the whole balance of the body and a complex pathophysiological response. The objective of this study was to make aware of the protein-energy needs in trauma, metabolic consumption, the bests ways of diet administration and the possible complications of inadequate nutritional support in these situations. CONTENTS: Nutrition must be integrated into the overal ltreatment of critically ill patients in order to minimize the complications of a longer treatment. The immediate priorities are thefollowing trauma fluid resuscitation, oxygenation and stopping the bleeding. These factors are associated with the state of a hyperdynamic response to trauma, as well as pain, fever, exposure to cold, acidosis and hypovolemia, and possible infections, increasing the metabolic demand. Nutritional support is an essential part of the metabolic treatment of these patients. It must be established before there is significant loss of weight, preferably within 24 hours of admission to the hospital, through diet or oral enteral and parenteral preferably when necessary. CONCLUSION: A well-managed diet is able to maintain body cell mass and limiting the weight loss to less than 10% weight inthe pre-injury. The important thing is to be constantly reassessed the patient to adjust the diet according to the daily needs. Among the consequences of an inadequate approach to these patients, are: Refeeding syndrome, ketosis, and malnutrition.

Ketonuria after fasting may be related to the metabolic superiority.

Obese individuals are less able to oxidize fat than non-obese individuals. Caloric reduction or fasting can detect ketonuria. We investigated the differences of metabolic parameters in the presence of ketonuria after a minimum 8 hr fast in a cross-sectional analysis of 16,523 Koreans (6,512 women and 10,011 men). The relationship between the presence of ketonuria of all subjects and prevalence of obesity, central obesity, metabolic syndrome, and obesity-related metabolic parameters were assessed. The ketonuria group had lower prevalence of obesity, central obesity, and metabolic syndrome than the non-ketonuria group. In addition, all metabolic parameters (including body weight, waist circumference, blood glucose, high-density lipoprotein, triglyceride, blood pressure, and insulin) were favorable in the ketonuria group than in the non-ketonuria group, even after adjustment for age, tobacco use, and alcohol consumption. The odds ratios of having obesity (odds ratio [OR]=1.427 in women, OR=1.582 in men, P<0.05), central obesity (OR=1.675 in women, OR=1.889 in men, P<0.05), and metabolic syndrome (OR=3.505 in women, OR=1.356 in men, P<0.05) were increased in the non-ketonuria group compared to the ketonuria group. The presence of ketonuria after at least an 8 hr fast may be indicative of metabolic superiority.

Two novel POLG mutations causing hepatic mitochondrial DNA depletion with recurrent hypoketotic hypoglycaemia and fatal liver dysfunction.

BACKGROUND: Inherited mtDNA depletion syndromes (MDS) are a group of severe mitochondrial disorders resulting from defects in nucleus-encoded factors and often associated with severe or fatal liver failure. PATIENT: In this article, we describe the case of an 18-month-old patient with recurrent hypoketotic hypoglycaemia and fatal hepatic dysfunction with liver mtDNA depletion. METHODS: The assessment of mtDNA copy number was performed on leucocytes, liver and muscle biopsy by Quantitative Real Time PCR and total RNA from liver biopsy was used as a template to amplify the cDNA of the POLG1 gene. RESULTS: Sequence analysis identified two previously undescribed mutations (1868T>G and 2263A>G) located in the gene coding the catalytic subunit of mitochondrial DNA polymerase gamma (POLG), predicting an L623W and K755E amino acid change, respectively. Both mutations were located in the highly conserved linker region of the protein and were absent in more than 200 healthy unrelated control subjects. The identification of these two mutations allowed us to perform genetic counselling and prenatal diagnosis. CONCLUSION: Our data further expand the spectrum of POLG1 gene mutations and the unique phenotype reported (late onset isolated liver disease without lactic acidosis) increase the variability of clinical presentations associated with mutations in this gene.