Objective
Ehlers–Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and ...tissue fragility. Muscle involvement is plausible based on recently discovered interactions between muscle cells and extracellular matrix molecules; however, muscle symptoms are only sporadically reported. We designed a cross‐sectional study to find out whether neuromuscular features are part of EDS.
Methods
Standardized questionnaires, physical examination, nerve conduction studies, electromyography, muscle ultrasound, and muscle biopsy were performed in 40 EDS patients with the vascular, classic, tenascin‐X (TNX)–deficient type EDS, and hypermobility type of EDS caused by TNXB haploinsufficiency.
Results
Muscle weakness, myalgia, and easy fatigability were reported by the majority of patients. Mild‐to‐moderate muscle weakness (85%) and reduction of vibration sense (60%) were common. Nerve conduction studies demonstrated axonal polyneuropathy in five patients (13%). Needle electromyography myopathic features in nine patients (26%) and a mixed neurogenic‐myopathic pattern in most (60%). Muscle ultrasound showed increased echo‐intensity (48%) and atrophy (50%). Mild myopathic features were seen on muscle biopsy of five patients (28%). Overall, patients with the hypermobility type EDS caused by TNXB haploinsufficiency were least affected.
Interpretation
Mild‐to‐moderate neuromuscular involvement is common in various types of EDS, with a remarkable relation between residual TNX level and degree of neuromuscular involvement, compatible with a dose–effect relation. The findings of this study should increase awareness of neuromuscular symptoms in EDS patients and improve clinical care. They also point to a role of the extracellular matrix in muscle and peripheral nerve function. This is an updated version of this article that originally published online on June 29, 2009. Ann Neurol 2009;65:687–697
Highlights ► Sensory stimulus detection (N1, P2) in the fragile X syndrome brain is characterized by augmented cortical activity. ► Mismatch negativity is significantly reduced in fragile X syndrome ...(FXS) males. ► Involuntary triggering of attentional processes (N2b, P3a) is compromised in FXS.
Aicardi-Goutières syndrome is a mendelian mimic of congenital infection and also shows overlap with systemic lupus erythematosus at both a clinical and biochemical level. The recent identification of ...mutations in TREX1 and genes encoding the RNASEH2 complex and studies of the function of TREX1 in DNA metabolism have defined a previously unknown mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid. Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
CHARGE syndrome is a common cause of congenital anomalies affecting several tissues in a nonrandom fashion. We report a 2.3-Mb de novo overlapping microdeletion on chromosome 8q12 identified by array ...comparative genomic hybridization in two individuals with CHARGE syndrome. Sequence analysis of genes located in this region detected mutations in the gene CHD7 in 10 of 17 individuals with CHARGE syndrome without microdeletions, accounting for the disease in most affected individuals.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A clinically recognizable 9q subtelomeric deletion syndrome has recently been established. Common features seen in these patients are severe mental retardation, hypotonia, brachycephaly, flat face ...with hypertelorism, synophrys, anteverted nares, cupid bow or tented upper lip, everted lower lip, prognathism, macroglossia, conotruncal heart defects, and behavioral problems. The minimal critical region responsible for this 9q subtelomeric deletion (9q
−) syndrome has been estimated to be <1 Mb and comprises the
euchromatin histone methyl transferase 1 gene (
EHMT1). Previous studies suggested that haploinsufficiency for
EHMT1 is causative for 9q subtelomeric deletion syndrome. We have performed a comprehensive mutation analysis of the
EHMT1 gene in 23 patients with clinical presentations reminiscent of 9q subtelomeric deletion syndrome. This analysis revealed three additional microdeletions that comprise the
EHMT1 gene, including one interstitial deletion that reduces the critical region for this syndrome. Most importantly, we identified two de novo mutations—a nonsense mutation and a frameshift mutation—in the
EHMT1 gene in patients with a typical 9q
− phenotype. These results establish that haploinsufficiency of
EHMT1 is causative for 9q subtelomeric deletion syndrome.
Highlights ► Basic information processing in fragile X syndrome (FXS) can be characterized by augmented cortical activity during the early sensory stages in both auditory and visual modalities. ► P3b ...related activity in FXS is significantly reduced in the auditory relative to the visual modality. ► Deficits in selective attention in FXS on a behavioral level can be traced back to event-related cortical activity.
Jeune syndrome (asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal ...mortality as a result of respiratory distress. Renal, hepatic, pancreatic and ocular complications may occur later in life. We describe 13 cases with ages ranging from 9 months to 22 years. Most patients experienced respiratory problems in the first years of their life, three died, one experienced renal complications, and one had hepatic problems. With age, the thoracic malformation tends to become less pronounced and the respiratory problems decrease. The prognosis of ATD seems better than described in literature and in our opinion this justifies long term intensive treatment in the first years. We also propose a follow-up protocol for patients with ATD.
A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to ...have a 2–base-pair deletion in the
Neuroligin 4 gene (
NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to β-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the
NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.
DYNC1H1 encodes the heavy chain protein of the cytoplasmic dynein 1 motor protein complex that plays a key role in retrograde axonal transport in neurons. Furthermore, it interacts with the LIS1 gene ...of which haploinsufficiency causes a severe neuronal migration disorder in humans, known as classical lissencephaly or Miller-Dieker syndrome.
To describe the clinical spectrum and molecular characteristics of DYNC1H1 mutations.
A family based exome sequencing approach was used to identify de novo mutations in patients with severe intellectual disability.
In this report the identification of two de novo missense mutations in DYNC1H1 (p.Glu1518Lys and p.His3822Pro) in two patients with severe intellectual disability and variable neuronal migration defects is described.
Since an autosomal dominant mutation in DYNC1H1 was previously identified in a family with the axonal (type 2) form of Charcot- Marie-Tooth (CMT2) disease and mutations in Dync1h1 in mice also cause impaired neuronal migration in addition to neuropathy, these data together suggest that mutations in DYNC1H1 can lead to a broad phenotypic spectrum and confirm the importance of DYNC1H1 in both central and peripheral neuronal functions.
MicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model ...organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions.
In three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery.
This study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.
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