Knowledge on rare diseases and orphan drugs

To date more than 60 cases have been reported worldwide.

Timothy syndrome (TS) often manifests during the neonatal period. However, in many cases it is diagnosed later, between the ages of 2-4 years old. In TS1, cardiac concerns may become apparent under anesthesia during finger separation surgery. Typical cardiac manifestations in all TS types include a rate corrected QT interval >480 ms, functional 2:1 atrio-ventricular (AV) block associated with bradycardia, tachyarrhythmias and congenital heart defects (patent ductus arteriosus, patent foramen ovale, atrial or ventricular septal defects, tetralogy of Fallot, hypertrophic cardiomyopathy). Facial dysmorphia often includes round face, depressed nasal bridge, low set ears, thin vermilion of the upper lip, and hypoplasic premaxillary. Widely placed teeth with poor enamel is common. Hair is generally sparse. Cutaneous syndactyly is typical of TS1, and often noted in ATS individuals. In TS2, congenital hip abnormalities and/or hypotonia are often noted. Pulmonary health concerns include frequent pneumonia. Gastro-intestinal issues include severe constipation, and in some ATS children, complications of chronic constipation may require surgical removal. Immunodeficiencies are common. Endocrinological concerns includes unusual fluctuations in blood sugar levels resulting in life threatening hypoglycemia, primarily associated with infections, and sleep issues; some children may require growth hormones. Neuronal-developmental concerns can be profound, autism or autistic spectrum disorders are noted, delayed speech and other physical, mental and social developmental milestones are generally delayed.

TS is due to mutations in the CACNA1C gene (12p13.33). The clinical phenotypes correlate with genotype. TS1 is specifically due to a G406R (c.1216 G>A) change in exon 8A. TS2 has the exact same G406R (c. 1216 G>A) change but in the alternatively spliced exon 8. ATS can be recognized by any CACNA1C change (excluding the G406R change) that causes typical multi-system health concerns.

TS diagnosis is based on observed clinical features and molecular genetic testing confirmation.

Non-syndromic autosomal Long QT syndrome, Jervell and Lange-Nielsen syndrome, Andersen-Tawil syndrome, Acquired Long QT syndrome, syndactyly and heart-hand related syndromes, autism associated syndromes.

Echocardiography can often identify fetal distress secondary to cardiac finding of 2:1 AV Block or bradycardia. When the pathogenic CACNA1C variant has been identified in a family member, prenatal genetic testing is possible for at risk pregnancies.

Most cases arise de novo; however, in some cases, TS has been identified as an inherited autosomal dominant trait resulting from parental germline mosaicism.

The main objective is to prevent ventricular fibrillation (VF) and possible sudden death. Interventions should be considered as early as possible and include the combination of left cardiac sympathetic denervation (LCSD) with an implantable cardioverter-defibrillator (ICD). A pacemaker can be placed during the first days of life to control 2:1 AV block and resultant bradycardia. Beta-blockers and/or other antiarrhythmia drugs can be administered to maintain QT interval and prevent ventricular tachyarrhythmias. Drugs that prolong QT interval should be avoided, and all medical procedures requiring anesthesia should be performed with caution. Additional congenital heart defects, respiratory infections, hypoglycemia, and skeletal/smooth muscle anomalies should be managed according to standard protocols. Drugs and dietary practices that could lead to hypoglycemia should be avoided for patients treated with beta-blockers.

Without prompt and appropriate treatment for cardiac concerns, the disease is usually fatal in infancy and early childhood due to arrhythmias precipitated by infections, severe illnesses, hypoglycemia or from complications associated with anesthesia.

Last update: November 2020 - Expert reviewer(s): Pr Peter SCHWARTZ