Frances Elmslie

Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss

We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.

Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis.

To the Editor: Tuberous sclerosis is an autosomal dominant disorder characterized by hamartomatous growths in many organs and caused by inherited mutations of the TSC1 or TSC2 gene. Acquired (somatic) mutations of either gene occur within pathologic cells in patients with sporadic lymphangioleiomyomatosis. Renal angiomyolipomas occur in both disorders, resulting in substantial morbidity and mortality.1 The proteins TSC1 and TSC2 regulate signaling through the mammalian target of rapamycin (mTOR) pathway to control processes including growth, cell-cycle progression, apoptosis, and autophagy. Constitutive activation of mTOR and its downstream targets occurs in lesions associated with tuberous sclerosis or lymphangioleiomyomatosis, suggesting that mTOR .xa0.xa0.

Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome

We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.

Angiomyolipomata: challenges, solutions, and future prospects based on over 100 cases treated.

Study Type – Therapy (case series) Level of Evidenceu20034

De novo mutations in MLL cause Wiedemann-Steiner syndrome.

Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.

How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Carbimazole embryopathy: an emerging phenotype

Concerns about the safety of carbimazole in pregnancy were raised in 1985 [Milham ( 1985 ): Teratology 32:321]. Since this time many reports of children believed to have been affected by carbimazole in utero have appeared in the medical literature. Initial reports were of an increased incidence of scalp defects in the infants of treated mothers, but many other anomalies have now been described. Choanal atresia, gastrointestinal anomalies‐particularly esophageal atresia, athelia/hypothelia, developmental delay, hearing loss, and dysmorphic facial features have all been reported. The phenotype associated with exposure to carbimazole appears to be rare but specific with distinctive facial features. We report on two new cases of carbimazole embryopathy with strikingly similar facial features.

Molecular and phenotypic characterization of ring chromosome 22.

We performed a phenotype study of 35 individuals (19 males, 16 females) with ring chromosome 22 or r(22) with a mean age of 10 years. In common with other studies, a phenotype of moderate‐to‐profound learning difficulties and delay or absence of speech affected all individuals with the exception of the case with the smallest deletion. Autistic traits were significantly associated with r(22), as shown by an autism screening questionnaire. Mild and variable dysmorphic features, predominantly craniofacial and distal limb, were observed. Internal organ involvement was uncommon. Even though ring chromosomes are reportedly associated with growth abnormalities, only 2 out of 24 individuals showed evidence of growth failure, while 2 showed accelerated growth. Chromosome 22 long arm deletions, as determined by hemizygosity for informative microsatellite markers, varied from <67 kb to 10.2 Mb in size (or <0.15 to 21% of total chromosome length), with no significant differences in the parental origin of the ring chromosome. Few phenotypic features correlated with deletion size suggesting a critical gene, or genes, of major effect lies close to the telomere. Loss of the SHANK3/PROSAP2 gene has been proposed to be responsible for the main neurological developmental deficits observed in 22q13 monosomies. This study supports this candidate gene by identifying a phenotypically normal r(22) individual whose ring chromosome does not disrupt SHANK3. All other r(22) individuals were hemizygous for SHANK3, and we propose it to be a candidate gene for autism or abnormal brain development.

Two cases of sudden unexpected death in epilepsy in a GEFS+ family with an SCN1A mutation

Discussion of basic mechanisms of the epilepsies constitutes an important part of every epilepsy congress or symposium. Investigators working in the laboratory made significant contributions to the International Epilepsy Congress last July. This article summarizes some of the new insights into the mechanisms of epileptogenesis and the novel strategies for therapeutic intervention emerging from the basic science sessions at the 27th International Epilepsy Congress in Singapore. Each of the following paragraphs also includes the names of those investigators (in parentheses) who presented this material at the Congress. Much emphasis has been given to the role of KCNQ channels and their associated M-currents in providing inhibitory control over neuronal discharges. These channels control the generation and frequency of action potentials, are strategically concentrated at brain regions relevant to epilepsy, and loss of function mutations in KCNQ2/3 channels underlie epileptic seizures in neonates (i.e., benign familial neonatal convulsions). This insight, together with the broad-spectrum anticonvulsant activity of drugs enhancing M-currents in animal models of seizures, suggests that these channels represent novel molecular targets for developing antiepileptic drugs (Y. Yaari, J. Kempfle). Interactions of steroid hormones with seizures were presented with particular attention to the mechanisms involved in the neuroprotective action of β-estradiol (J. Veliskova). Long-term treatment with low doses of β-estradiol delays seizure onset in rats and dramatically reduces seizureinduced hippocampal damage; these effects appear to depend on the ability of β-estradiol to enhance neuropeptide Y levels in hilar interneurons, which in turn leads to increased inhibition in the dentate gyrus. Neurosteroid compounds synthetized within the brain and acting in a nonclassical fashion (via actions that do not involve nuclear hormone receptors) have been described as potent allosteric modulators of GABAA receptors. Fluctuations in neurosteroid levels may contribute to seizure exacerbation at times of stress or in catamenial epilepsy (M. Rogawski). Recent studies show that neurosteroids can retard epileptogenesis following status epilepticus. Ganaxolone, a neurosteroid analog, is currently undergoing clinical trials for the treatment of infantil spasms and adult partial epilepsy. Among the novel targets for seizure inhibition, inflammation and the blood–brain barrier (BBB) have an emerging role: selective inhibitors of inflammatory pathways activated by brain injury or by status epilepticus have been shown to reduce seizures and retard epileptogenesis in various experimental models (T. Ravizza, S. Balosso, Y. Murashima, M. Fukuda); a novel molecular pathway activated by serum components, such as albumin, under conditions of increased BBB permeability may trigger epileptogenesis, via activation of TGF-β receptors (A. Friedman). The data suggest that serum albumin is taken up by astrocytes via TGF-β receptors, leading to down-regulation of Kir-4.1 channels and glutamate transporter, and these events may be involved in the development of epileptiform activity. Targeting of the BBB has also been proposed as a strategy to contrast pharmacoresistance (H.Potschka, L. Chen). Noncompetitive inhibitors of multidrug transport proteins, which are overexpressed in endothelium of brain vessels and the associated astrocitic endfeet in epileptic tissue, enhance the brain levels and the efficacy of phenytoin and phenobarbital in experimental models of drug-resistant seizures. Recently, a pilot functional PET imaging study in pharmacoresistant epileptic patients showed a reduced uptake of verapamil, a P-glycoprotein substrate in the focal epileptogenic area, supporting a functional upregulation of drug efflux activity in the BBB (Langer et al., Epilepsia 2007;48:1774–1784). Gene therapy approaches have been described in models of focal epilepsies using viral vectors expressing neuroprotective peptides (such as NPY or galanin) (F. Noe’, M. Kokaia, M. During), or the GABAA receptor alpha1subunit (A. Brooks-Kayal). Experimental findings report either a decreased risk of developing epilepsy or a strong reduction in spontaneous seizure frequency and the arrest in seizure progression, highlighting the possibility of using gene therapy not only to suppress seizures but also to interfere with epileptogenesis. Imaging studies in experimental models of seizures suggest a predictive value of MRI for the development of epilepsy (J. Jansen, I. Kharatishvili). Quantitative measurements of water diffusion in the rat hippocampus ipsilateral to neocortical fluid-percussion injury (a model of traumatic brain injury) positively correlates with the increased seizure susceptibility developing in rats 12 months postinjury. This correlation could be established as soon

Different mutations in the NF1 gene are associated with Neurofibromatosis-Noonan syndrome (NFNS)

The association of the Noonan phenotype with neurofibromatosis type 1 (NF1) was first noted by Allanson et al. [Am J Med Genet 1985;21:457–462.] and 30 further cases have subsequently been reported. It has been suggested that this phenotype is more common than previously appreciated, as Colley et al. [Clin Genet 1996;49:59–64.] examined 94 sequentially identified patients with NF1 from their genetic register and found Noonan features in 12. A 3‐bp deletion of exon 17 of the NF1 neurofibromin gene was described in one family by Carey et al. [Proc Greenwood Genet Center 1997;17:52–53]. However, it remains unclear whether Neurofibromatosis–Noonan syndrome (NFNS) represents a form of NF1 (with mutations in the NF1 neurofibromin gene) or a separate syndrome. We have used a new, rapid sequence analysis technique—comparative sequence analysis (CSA)—to examine the NF1 gene in six patients with NFNS. None of the six patients had the previously identified mutation, nor did we observe other mutations within this exon. However, two other mutations were found: in exon 25, a 3‐bp deletion 4312 del GAA, and in exon 23‐2, a 2‐bp insertion 4095 ins TG. The PTPN11 gene, now known to cause over 50% of Noonan syndrome was also examined in four cases of NFNS, and no mutations were found. These results show that NFNS can in some cases result from different mutations in the NF1 gene and therefore represents a variant form of NF1.