Transcriptomic Analysis of Patients With Clinical Suspicion of Maturity-onset Diabetes of the Young (MODY) With a Negative Genetic Diagnosis

BackgroundThe personalized management of each type of Mature-onset diabetes of the young (MODY), a non-autoimmune monogenic form of diabetes mellitus, achieves both avoiding invasive therapies and better defining the patient's prognosis and reducing future misdiagnoses by performing a screening family. Positive genetic diagnosis is achieved in only around 50% of patients with clinical characteristics of this disease, which leads us to propose in this study to evaluate the diagnostic utility of transcriptomic analysis in patients with clinical suspicion of MODY but a negative genetic diagnosis using Nanostring nCounter technology.ResultsWe conducted transcriptomic analysis of 19 MODY-associated genes in peripheral blood samples from 19 patients and 8 healthy controls. Normalized gene expression was compared between patients and controls and correlated with each patient’s biochemical and clinical variables. Z-scores were calculated to identify significant changes in gene expression in patients versus controls. Only 7 of the genes analyzed were detected in peripheral blood. HADH expression was significantly lower in patients versus controls. Among patients with suspected MODY, GLIS3 expression was higher in obese versus non-overweight patients, and in patients aged <25 versus >25 years at diabetes onset. Significant alteration with respect to controls of any gene was observed in 31.6% of patients. ConclusionsAlthough blood does not appear to be an adequate sample for transcriptomic analysis of patients with suspected MODY, it does allow identification of potential molecular targets causing the disease in a considerable proportion of cases.

Transient Neonatal Diabetes Mellitus and Seizure with an Unknown Etiology

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.

Migraine: Calcium Channels and Glia

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel.

Molecular causes of congenital anomalies of the kidney and urinary tract (CAKUT)

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 0.5–1/100 newborns and as a group they represent the most frequent cause for chronic kidney failure in children. CAKUT comprise clinically heterogeneous conditions, ranging from mild vesicoureteral reflux to kidney aplasia. Most forms of CAKUT share the pathophysiology of an impaired developmental interaction of the ureteric bud (UB) and the metanephric mesenchyme (MM). In most cases, CAKUT present as an isolated condition. They also may occur as a component in rare multi-organ syndromes. Many CAKUT probably have a multifactorial etiology. However, up to 20% of human patients and > 200 transgenic mouse models have a monogenic form of CAKUT, which has fueled our efforts to unravel molecular kidney (mal-)development. To date, genetic variants in more than 50 genes have been associated with (isolated) CAKUT in humans. In this short review, we will summarize typical imaging findings in patients with CAKUT and highlight recent mechanistic insight in the molecular pathogenesis of monogenic forms of CAKUT.

Relative adipose tissue failure in Alström syndrome drives obesity-induced insulin resistance

Obesity is a major risk factor for insulin resistance (IR) and its attendant complications. The pathogenic mechanisms linking them remain poorly understood, partly due to a lack of intermediary monogenic human phenotypes. Here, we report on a monogenic form of IR-prone obesity, Alström syndrome (ALMS). Twenty-three subjects with monogenic or polygenic obesity underwent hyperinsulinaemic-euglycemic clamping with concomitant adipose tissue (AT) microdialysis and an in-depth analysis of subcutaneous AT histology. We have shown a relative adipose tissue failure in monogenic obese cohort; a finding supported by observations in a novel conditional mouse model (<i>Alms^flin/flin</i>) and ALMS1-silenced human primary adipocytes. Whereas, selective reactivation of ALMS1 gene in adipose tissue of an ALMS conditional knockdown mice model (<i>Alms^flin/flin;Adipo-Cre^+/-</i>) restores systemic insulin sensitivity and glucose tolerance. Hence, we show for the first time the relative adipose tissue failure in human obese cohorts to be a major determinant of accelerated IR without evidence of lipodystrophy. These new insights into adipocyte driven insulin resistance may assist development of adipose tissue targeted therapeutic strategies for diabetes.

Adaptive Status, Autistic Symptoms and Cognitive Profile in Patients with Monogenic Form of Autism Spectrum Disorders – Fragile X Syndrome.

The article analyzes psychological data of a large group (55 males and 6 females) of subjects with monogenic form of hereditary cognitive impairment with autistic symptoms – Martin-Bell syndrome (FXS) at different age ranges (from 2 to 34 years old). As a result of the analysis, significant cognitive impairments were identified, which persisted throughout the studied age interval (IQ 50 ± 2.1 in males and 60 ± 5.6 in females). Autistic disorders were observed on average in 60% of subjects (less in females) and were most pronounced at 8-12 years. Use of Autism Diagnostic Observation Scale-2 (ADOS-2) allowed us to show that “Social Affect” scale makes the main contribution to overall score of autistic manifestations. Almost all subjects showed a significantly reduced level of adaptive skills. The lowest scores on “Communication”, “Socialization” and “Everyday life skills” scales were observed at the age of 8-12 years. With increase in age, subjects improved only on “Daily Life Skills” scale. It was also shown that a higher degree of adaptation and better nonverbal intelligence was observed in children with less severe autistic symptoms.

CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) presenting as psychosis

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is the most common monogenic form of cerebral small-vessel disease characterised by recurrent strokes. Behavioural disturbance also presents in a significant proportion of subjects as neurotic spectrum disorders and psychotic features are rarely reported. In this case report, we highlight a 32-year-old man with CADASIL syndrome, who had overt psychotic symptoms with neurological signs later on.

To diet or not to diet in neonatal diabetes responding to sulfonylurea treatment

Background Neonatal diabetes mellitus (NDM) is defined as a monogenic form of diabetes that occurs in the first 6 months of life. As information on diet in NDM patients successfully treated with sulfonylurea is not yet available, we aimed to investigate the hypothesis that a carb-restricted diet is not needed in such cases. Case presentation In this case report, we present a successful implementation of a completely liberalized diet in a young patient with NDM, developmental delay and epilepsy (DEND syndrome), who was also switched to sulfonylurea treatment. The excellent metabolic control during follow-up despite completely ignoring any diet suggests that at least in some patients this approach might work. Conclusions If our proposed hypothesis is also confirmed by other reports, it might add significantly to the quality of life of these patients and broaden the knowledge in this medical field.