Antisense oligonucleotide therapeutic approach for Timothy syndrome.

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

Current updates on arrhythmia within Timothy syndrome: genetics, mechanisms and therapeutics.

Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene CACNA1C encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of CACNA1C gene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation-transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.

Long-term follow-up of a patient with type 2 Timothy syndrome and the partial efficacy of mexiletine.

We report a detailed case of type 2 TS due to a p.(Gly402Ser) mutation in exon 8 of the CACNA1C gene. The patient shows a marked prolongation of repolarization with a mean QTc of 540 ms. He shows no structural heart disease, syndactyly, or cranio-facial abnormalities. However, he shows developmental delays, without autism, and dental abnormalities. The cardiac phenotype is very severe, with a resuscitated cardiac arrest at 2.5 years of age, followed by 26 appropriate shocks during nine years of follow-up. Adding mexiletine to nadolol resulted in a reduction of the QTc and a slight decrease in the number of appropriate shocks.

Generalised hypomineralisation of enamel in oculodentodigital dysplasia: comprehensive dental management of a case.

Oculodentodigital dysplasia (ODDD) is a rare congenital disorder characterised by developmental abnormalities of the eye, dentition and digits of the hands and feet, with neurological symptoms reported in 30% of individuals. Dental anomalies associated with ODDD include enamel hypoplasia and subsequent caries, microdontia, missing teeth, amelogenesis imperfecta, pulp stones and delayed tooth development. Here, we describe the comprehensive dental management of a 3-year-old girl who presented with rapid deterioration of the primary dentition due to generalised enamel hypomineralisation. Conservative, comprehensive restorative management was performed under general anaesthesia. Within 6 months, further breakdown of the remaining unrestored enamel was noted. This case documents the challenges of conservative management in dental anomalies that are not well documented due to the extreme rarity of the disorder.

Clinical Outcomes and Modes of Death in Timothy Syndrome: A Multicenter International Study of a Rare Disorder.

OBJECTIVES: The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations. BACKGROUND: TS is an extremely rare genetic disorder of the L-type cardiac channel Cav1.2 encoded by CACNA1C. The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms. METHODS: Patients diagnosed with TS between January 1, 1994, and April 1, 2016, from 12 international tertiary care pediatric centers were included in this retrospective study. Data were gathered via survey from the patients' electrophysiologists. RESULTS: Seventeen patients diagnosed with TS were identified. Length of follow-up was 4.9 years (range 3.0 to 19.0 years). Mean QTc was 640 ms (range 500 to 976 ms). All patients were treated with beta-blockers; 13 patients (76%) were also treated with an implantable defibrillator. Eleven patients experienced an episode of aborted cardiac arrest, 6 associated with general anesthesia and 2 with hypoglycemia. Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia. CONCLUSIONS: This study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.

A multicentre study of patients with Timothy syndrome.

Aims: Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS. Methods and results: All patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties. Conclusion: Timothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.

FATCO Syndrome (Fibular Aplasia, Tibial Campomelia, Oligosyndactyly with Talar Aplasia). A Case Study.

FATCO syndrome consists of fibular hemimelia, tibial campomelia and oligosyndactyly. FATCO syndrome can also be associated with other congenital anomalies; therefore, every case needs thorough evaluation so as to make the management of the patient easier. A few cases of this syndrome have been described in literature but only two cases have been reported in India so far. We present a 3-year-old male child born of a non-con-sanguinous marriage with FATCO syndrome and ipilateral talar aplasia without any other congenital anomalies.

From disease to treatment: from rare skeletal disorders to treatments for osteoporosis.

During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis.

A Simple Alternative Treatment for Syndactyly of the Toe.

Toe syndactyly is a common congenital malformation affecting approximately 1 in 2000 people and can cause significant emotional and psychological distress for the patient. We report a case of a 41-year-old female who was concerned about the aesthetic appearance of her bilateral second and third toe with incomplete, simple syndactyly and had requested surgical correction. A number of operative techniques have been described in the orthopedic and plastic surgery data, with no one technique proving superior. We used medical tattooing to create the appearance of a complete interdigital cleft. This low-risk, and low-cost procedure resulted in a satisfactory outcome for the patient. To the best of our knowledge, this is the first reported case using this technique, which we propose as a simple alternative to surgical correction of toe syndactyly.

Miscellaneous Bone Disorders.

This chapter deals with a few of the important childhood bone disorders associated with high bone mass as well as conditions associated with fragility fractures and limb deformities that have not been addressed in previous chapters. A couple of skeletal dysplasias that can sometimes be confused with rickets are also dealt with in this chapter.

Lily's Story: STAR Syndrome.

BACKGROUND: Lily was born 7 years ago with an illness that did not have a name; she had only a constellation of anomalies. The hope of happiness that most parents experience when expecting a baby was lost halfway through my pregnancy when we heard the words "survival" and "termination of the pregnancy." Lily did survive and has taught us, her parents, and members of her medical team the meaning of courage and collaboration. PURPOSE: This article describes our journey. Today that lesson has blossomed into a patient/parent/family engagement program changing the culture of healthcare and the future for hospitalized infants. IMPLICATIONS FOR PRACTICE: We share our story so that others might learn from our experiences. Hope and survival are so important to parents and families and health professionals need to be aware that taking away hope can devastate a family. IMPLICATIONS FOR RESEARCH: More research is needed about when a baby who was expected to die lives anyway and how that experience can best be supported for families. This is an area where the experience is unique and little is really known.

Sclerostin: current knowledge and future perspectives.

In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.

Aparato de compresión-distracción modelo 1 (ACD-1) en el tratamiento de la sindactilia. Informe de 2 casos / Compression-distraction device model 1 (ACD-1) for treatment of syndactily. report of 2 cases

El objetivo de este artículo es demostrar la utilidad del empleo del ACD-1 en la formación de piel como primera etapa, por un proceso de distracción dosificada en el tratamiento quirúrgico de la sindactilia. Se estudiaron 2 hombres sanos mayores de 20 años que acudieron voluntariamente quirúrgico basado en el uso del ACD-1. A cada paciente fueron montados 3 apartas ACD-1, en las falanges proximal, media y distal de cada uno de los dedos afectados, para inmediatamante después llevar a cabo un proceso de distracción en cada uno de los aparatos a razón de 1 mm diario, hasta obtener la suficiente piel para llevar a cabo la plástica. En los dos casos el resultado fue satisfactorio, conservándose la actividad de los dedos durante el proceso de distracción, evitando de esta manera complicaciones postoperatorias como contracturas, necrosis o desgarros

The preoperative use of extra-tissue expander for syndactyly.

To our knowledge, this is the first report of a method of stretching the interdigital skin of syndactyly by means of a pincer. The pincer, a U-shaped metal spring plate with a sponge cushion, is applied before the operation for about two months; pressure is placed against both sides of the interdigital fusion to expand the skin and to develop hollows. Use of the pincer facilitates a syndactyly operation by allowing defect coverage with a local flap only. Four patients successfully treated by this method are reported. The method has the great advantage of not requiring skin grafts, which often have unfavorable results both functionally and cosmetically.