Context:
Several patients with Beckwith-Wiedemann Syndrome (BWS) with multiple imprinting defects found by genetic analysis have been described. However, only two cases have been described with both ...genetic and clinical signs and symptoms of multiple diseases caused by imprinting defects.
Case Description:
The girl in this case presented at the age of 6 months with morbid obesity (body mass index, +7.5 SDS) and a large umbilical hernia. Genetic analysis showed BWS (hypomethylation of the KCNQ1OT1 gene). Calcium homeostasis was normal, and she had no signs of Albright hereditary osteodystrophy. At the age of 10 years, she presented with fatigue, and laboratory analyses showed marked hypocalcemia with signs of PTH resistance, but without evidence for Albright hereditary osteodystrophy, thus suggesting pseudohypoparathyroidism type 1B. Consistent with this diagnosis, methylation analysis of the GNAS complex revealed hypomethylation (about 20%) of the GNAS exon 1A, NESPAS, and GNASXL loci and hypermethylation (100% methylation) of the NESP locus.
Conclusions:
Imprinting defects at several different loci can occur in some patients, thus causing multiple different diseases. Symptoms of pseudohypoparathyroidism type 1B may be absent at diagnosis of BWS, yet prolonged subclinical hypocalcemia and/or hyperphosphatemia can have negative consequences (eg, intracerebral calcifications, myocardial dysfunction). We therefore suggest that patients with an imprinting disorder should be monitored for elevations in PTH, and epigenetic analysis of the GNAS complex locus should be considered.
Although thyroid dysgenesis is the most common cause of congenital hypothyroidism (CH), its molecular basis remains largely elusive. Indeed, in only a minority of cases with thyroid dysgenesis ...(2%-3%) was it possible to identify an underlying genetic defect. The objective of this study was to screen the PAX8 gene and the PAX2 gene in a family with six cases of CH spanning three generations and presenting urogenital malformations. Herein, we report a case series and in vitro characterization of the PAX8 gene mutation.
Investigations were conducted at a tertiary care referral center. The index case was diagnosed to have congenital hypothyroidism at 7 months of age when he presented with severe impairment of suckling, constipation, and poor development. Treatment with levothyroxine corrected the symptoms and was associated with catch-up growth. His progeny, including two sons, one daughter, and two granddaughters, were affected by CH, and three of them received the diagnosis at neonatal screening. Ultrasound demonstrated normally located thyroid glands with reduced volumes. Five of the six affected family members, including the index case, had urogenital malformations, including incomplete horseshoe kidney, undescended testicles, hydrocele, and ureterocele. Strabismus was found in three out of six affected patients. No other somatic malformations were found.
Direct sequencing of the PAX8 gene revealed a new heterozygous mutation (c.74C > G) in all affected individuals. This mutation leads to substitution of proline with arginine at codon 25 (P25R). Fluorescence microscopy showed that P25R is normally located in the nucleus. In transient transfection studies, this mutation causes reduced transcriptional activation ability when using a luciferase reporter construct under the control of a thyroglobulin promoter. This diminished transactivation ability is due to loss of DNA binding capability as shown in electrophoresis mobility shift assay. The sequencing analysis of the PAX2 gene was normal.
We conclude that this novel PAX8 mutation is responsible for a severe form of dominantly inherited CH. The mutation seems to be associated with abnormalities of the urogenital tract.
Desmoplakin is a cytoplasmic desmosomal protein that plays a vital role in normal intercellular adhesion. Mutations in desmoplakin can result in devastating skin blistering diseases and ...arrhythmogenic right ventricular cardiomyopathy, a heart muscle disorder associated with ventricular arrhythmias, heart failure, and sudden death. The desmoplakin N-terminal region is a 1056-amino-acid sequence of unknown structure. It mediates interactions with other desmosomal proteins, is found in a variety of plakin proteins, and spans what has been termed the “plakin domain,” which includes residues 180–1022 and consists of six spectrin repeats (SRs) and an Src homology 3 domain. Herein we elucidate the architecture of desmoplakin's plakin domain, as well as its constituent tandem SRs. Small-angle X-ray scattering analysis shows that the entire plakin domain has an “L” shape, with a long arm and a short arm held at a perpendicular angle. The long arm is 24.0 nm long and accommodates four stably folded SRs arranged in tandem. In contrast, the short arm is 17.9 nm in length and accommodates two independently folded repeats and an extended C-terminus. We show that mutations linked to arrhythmogenic right ventricular cardiomyopathy (K470E and R808C) cause local conformational alterations, while the overall folded structure is maintained. This provides the first structural and mechanistic insights into an entire plakin domain and provides a basis for understanding the critical role of desmoplakin in desmosome function.
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Abstract Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1 , and TRPS II, caused by a ...contiguous gene deletion affecting (amongst others) TRPS1 and EXT1 . We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype–phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1 . Other mutations are located anywhere in exons 4–7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1 , but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1 , but numbers are too small to allow firm conclusions.
Background & Aims
Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be ...fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR‐dependent expression of genes involved in biotransformation and secretion in vitro.
Methods
Thirteen patients (age 18–81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1–10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 μmol/L).
Results
Serum bilirubin of patients with PHSF ranged from 264 to 755 μmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 μmol/L after 1–10 weeks of rifampicin treatment. In vitro, rifampicin PXR‐dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTβ.
Conclusion
Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR‐dependent induction of CYP3A4, UGT1A1, MRP2 and OSTβ could contribute to the anticholestatic effect of rifampicin in PHSF.
Clinical Reasoning: Heart to swallow van Westerloo, David J; Barge-Schaapveld, Daniela Q; Bikker, Hennie ...
Neurology,
2016-May-17, 2016-05-17, 20160517, Letnik:
86, Številka:
20
Journal Article
Recenzirano
Odprti dostop
A 55-year-old woman was admitted to our intensive care department after intoxication with lithium. Her medical history was relevant for bipolar disorder for which she received medical treatment with ...lithium, haloperidol, and citalopram. In the week before admission, she had developed a clinical picture of gastroenteritis with diarrhea and vomiting, which resulted in dehydration and a marked deterioration in kidney function. During the last days before admission, she had become progressively lethargic and had developed dysarthria as well as postural tremors of the extremities. The tremors were coarse and irregular, most clearly present in the hands with a frequency of approximately 8 Hz. At admission, she opened her eyes spontaneously, localized pain, and showed normal verbal responses (E4M5V5). Physical examination showed severe dysarthria, ataxia, and no focal neurologic deficits. Reflexes were normal. Laboratory investigation revealed a de novo elevated creatinine level (220 mumol/L, normal 49-90) corresponding to an estimated glomerular filtration rate of 22 mL/min/1.73 m super(2)(normal >60) and a lithium level that was 5.8 mmol/L (target value 0.6-0.8 mmol/L). ECG at admission was normal except for a prolonged QTc interval of 533 milliseconds (normal <450).
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to ...assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13 years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene were screened. After genetic analysis, phenotypic characteristics of desmosomal versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C (42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T waves in leads V4 to V6 (p <0.001), and additional structural (p = 0.007) or functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation carriers had more solitary right ventricular abnormalities. The revised TFC included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC, including 7 PLN mutation carriers. In conclusion, there is a substantial contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of patients (19 of 59) with genetically unexplained proven ARVD/C, this nondesmosomal mutation was found. PLN mutation carriers have ARVD/C characteristics, including important right ventricular involvement, and additionally more often low-voltage electrocardiograms, inverted T waves in the left precordial leads, and left ventricular involvement.
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