Filamin C is a large dimeric actin-binding protein, most prevalent in skeletal and cardiac muscle Z-discs, where it participates in sarcomere mechanical stabilization and intracellular signaling, ...interacting with numerous binding partners. Dominant heterozygous mutations of Filamin C gene cause several forms of myopathy and structural or arrhythmogenic cardiomyopathy. In this report we describe clinical and molecular findings of two Italian patients, in whom we identified two novel missense variants located within the Filamin C actin binding domain. Muscle imaging, histological and ultrastructural findings are also reported. Our results underline the extreme inter- and intrafamilial variability of clinical manifestations, hence the need to extend the investigation also to asymptomatic relatives, and the relevance of a broad diagnostic approach involving muscle electron microscopy, skeletal muscle magnetic resonance imaging and next generation sequencing techniques.
Abstract
Background
Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare disorder characterized by recurrent epistaxis, telangiectasias and systemic ...arteriovenous malformations (AVMs). HHT is associated with mutations in genes encoding for proteins involved in endothelial homeostasis such as
ENG
(endoglin) and
ACVRL1
(activin receptor-like kinase-1).
Case presentation
Here we describe a 22-year-old male presenting with a transient episode of slurred speech and left arm paresis. Brain MRI displayed polymicrogyria. A right-to-left shunt in absence of an atrial septum defect was noted. Chest CT revealed multiple pulmonary AVMs, likely causing paradoxical embolism manifesting as a transient ischemic attack.
The heterozygous
ENG
variant, c.3G > A (p.Met1lle), was detected in the patient. This variant was also found in patient’s mother and in his younger brother who displayed cortical dysplasia type 2.
Conclusions
The detection of cortical development malformations in multiple subjects from the same pedigree may expand the phenotypic features of ENG-related HHT patients. We suggest considering HHT in young patients presenting with acute cerebral ischemic events of unknown origin.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To reach a molecular diagnosis for a family with two consecutive fetuses presenting with multiple congenital anomalies.
Methods
The two fetuses underwent prenatal ultrasound, autopsy, ...radiologic, and genetic investigation. Genetic analysis included karyotype and array‐CGH for both fetuses and trio‐based whole exome sequencing (WES) only for the second fetus.
Results
WES results, initially focusing on recessive or dominant de novo variants, were negative.However, as a result of new relevant information regarding family history, the variant c.648_651dup in the PTCH1 gene was identified as causative of the fetal phenotype.
Conclusions
This case further highlights how WES data analysis and interpretation strongly rely on family history and robust genotype–phenotype correlation. This is even more relevant in the prenatal setting, where access to fetal phenotype is limited and prenatal recognition of many morbid genes is not fully explored. We also provide a detailed description of the prenatal manifestations of Basal Cell Nevus Syndrome.
Key points
What's already known about this topic?
The diagnosis of BCNS is usually reached postnatally and its prenatal manifestations are mostly known from familial cases
What does this study add?
We provide a thorough picture of the prenatal presentation of BCNS in two fetuses
We underline how a comprehensive autoptic fetal examination may disclose diagnostic handles
We stress that the prenatal diagnosis of BCNS may be underestimated due to the current knowledge of this condition
White matter (WM) abnormalities and ventricular enlargement in brain MRI are well-known features in infantile-onset Pompe disease (IOPD) in the era of enzyme replacement therapy (ERT). In this ...multicentric observational retrospective study, we report a small cohort of IOPD subjects under ERT treatment (
= 5, median age at MRI = 7.4 years, median period of treatment = 85 months) that showed the classic features of extensive supratentorial WM abnormalities but also unusual findings such as early infratentorial WM abnormalities and late supratentorial U-fiber involvement. Given the recent implementation of ERT and the rarity of the disease, a complete spectrum of presentation and understanding of progressive pathology in the brain of IOPD subjects in treatment remains underacknowledged. The availability of long-term follow-up of IOPD subjects under ERT treatment allows a better insight into the evolution of brain abnormalities in such disease.
An early diagnosis of CHARGE syndrome is challenging, especially for the primary care physicians who often take care of neonates with multiple congenital anomalies. Here we report eight cases of ...CHARGE syndrome whose diagnosis was made early in life with the intent to identify the most helpful features allowing a prompt clinical diagnosis.
Medical records of patients with CHARGE syndrome whose diagnosis was made at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in Milan, Italy were retrospectively reviewed.
Taken together, these patients reflect the considerable phenotypic variability of the syndrome; in one patient, the diagnosis was made immediately after birth because all the major criteria were met. In six patients, presenting with relatively nonspecific defects, a temporal bone computerized tomography scan was essential to achieve the correct diagnosis. In one patient, the diagnosis was made later than the others were. A careful examination revealed the presence of outer, middle, and inner ear anomalies: these elements, in the absence of any additional major criteria, represented for us an important diagnostic clue.
This article suggests that an accurate evaluation of the ear should be made every time CHARGE syndrome is considered as a likely diagnosis even when the standard criteria are not fulfilled.
ABSTRACT
Introduction
The aim of this study was to evaluate the muscle MRI pattern of 9 patients (median age: 6.5 ± 2.74 years) affected by classic infantile‐onset Pompe disease who were treated with ...enzyme replacement therapy.
Methods
We performed and qualitatively scored T1‐weighted (T1‐w) sequences of the facial, shoulder girdle, paravertebral, and lower limb muscles and short‐tau inversion recovery (STIR) sequences of the lower limbs using the Mercuri and Morrow scales, respectively.
Results
On T1‐w images, mild (grade 1) or moderate (grade 2) involvement was found in the tongue in 6 of 6 patients and in the adductor magnus muscle in 6 of 9. STIR hyperintensity was detected in all areas examined and was categorized as limited to mild in 5 of 8 patients.
Conclusions
On T1‐w sequences, mild/moderate adipose substitution in the adductor magnus and tongue muscles was documented. STIR edema‐like alterations of thigh and calf muscles are novel findings. Correlations with biopsy findings and clinical parameters are needed to fully understand these findings. Muscle Nerve 55: 841–848, 2017
Usually overlooked by physicians, olfactory abnormalities are not uncommon. Olfactory malformations have recently been reported in an emerging group of genetic disorders called Mendelian Disorders of ...the Epigenetic Machinery (MDEM). This study aims to determine the prevalence of olfactory malformations in a heterogeneous group of subjects with MDEM. We reviewed the clinical data of 35 patients, 20 females and 15 males, with a mean age of 9.52 years (SD 4.99). All patients had a MDEM and an already available high-resolution brain MRI scan. Two experienced neuroradiologists reviewed the MR images, noting abnormalities and classifying olfactory malformations. Main findings included Corpus Callosum, Cerebellar vermis, and olfactory defects. The latter were found in 11/35 cases (31.4%), of which 7/11 had Rubinstein-Taybi syndrome (RSTS), 2/11 had CHARGE syndrome, 1/11 had Kleefstra syndrome (KLFS), and 1/11 had Weaver syndrome (WVS). The irregularities mainly concerned the olfactory bulbs and were bilateral in 9/11 patients. With over 30% of our sample having an olfactory malformation, this study reveals a possible new diagnostic marker for MDEM and links the epigenetic machinery to the development of the olfactory bulbs.
Some missense mutations and small deletions in the NOTCH3 gene, not involving cysteine residues, have been described in patients considered to be affected by paucisymptomatic CADASIL. However, the ...significance of such molecular variants is still unclear. We describe a 49-year-old woman with a CADASIL-like phenotype, carrying a novel cysteine-sparing mutation in exon 29 of the NOTCH3 gene, and discuss the possible pathogenetic role of this molecular variant. Even though atypical clinical and MRI findings make a diagnosis of CADASIL unlikely in this patient, our report nevertheless underlines the intriguing genotype-phenotype relationship in NOTCH3 mutations and the importance of functional investigation to ascertain the role of new NOTCH3 mutations in CADASIL pathogenesis.
Somatoform disorders (SDs) are a heterogeneous group of psychiatric syndromes characterized by common symptoms, which may mimic a physical condition but they are not explained by a medical condition. ...Although the biologic nature of this disorder has been widely accepted, the neuroanatomical correlates characterizing SDs are still inconclusive.
This study aims to explore gray matter (GM) volume alterations in SD patients compared to healthy controls and their possible association with clinical and cognitive measures.
We used voxel-based morphometry to examine regional GM volumes in 20 inpatients with SDs and 24-matched healthy controls. Only for SD patients, we employed multiple instruments to assess psychopathology and cognitive functioning, which were then used to explore their association with GM volume deficits.
Compared to healthy controls, SD patients showed GM volume reductions in the hypothalamus, left fusiform gyrus, right cuneus, left inferior frontal gyrus, left posterior cingulate, and right amygdala (p < 0.05, cluster Family Wise Error corrected). Additionally, in SD, Symptom Checklist-90-Phobia and Hamilton Depressive Rating Scale scores negatively correlated with specific fronto-temporoparietal regions whereas Symptom Checklist-90-Sleep scores positively correlated with anterior cingulate cortex. Lastly, the Boston Naming Test negatively correlated with fronto-temporoparietal and striatal volumes whereas Free and Cued Selective Reminding Test and Stroop scores positively correlated with superior temporal gyrus and cuneus, respectively (all p < 0.05, cluster Family Wise Error corrected).
Our results suggest that SDs might be characterized by selective impairments in specific cortico-limbic regions associated to two overlapping circuits, the neuromatrix of pain and the emotion regulation system.
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