Timothy syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Synonyms and keywords: Long QT syndrome 8; LQT8; Long QT syndrome with syndactyly

Overview

Timothy syndrome is a rare disease that follows autosomal dominant inheritance pattern. Timothy syndrome is characterized by physiological and developmental defects which include long QT-prolongation, arrhythmias, structural heart defects, syndactyly and autism spectrum disorders. Timothy syndrome may be classified into 2 groups, classical form(type-1) and atypical form(type-2). Timothy syndrome caused by mutations in CACNA1C, which encodes for calcium channel α subunit. Timothy syndrome often ends in early death. The United States of America in order to categorize a condition as a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed in 1983 by congress for the rare diseases. Today an average of 25-30 million Americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.

Historical Perspective

• Timothy syndrome was first discovered by Reichenbach and Marks, in 1992.

• In 1995, Splawski, Reichenbach, and Marks were the first to give the name Timothy syndrome in the honor of Dr. Katherine W. Timothy who did the phenotypic analysis.

Classification

• Timothy syndrome may be classified into 2 groups as follows:

Type	Gene	Location	Inheritance pattern	Symptoms
Classic Timothy syndrome	CACNA1C	12p13.33	Autosomal dominant	Long QT syndrome with syndactyly
Atypical Timothy syndrome	CACNA1C	12p13.33	Autosomal dominant	A very severe form of long QT syndrome without syndactyly

Pathophysiology

• It is understood that Timothy syndrome both classical and atypical form is the result of a missense mutation in the CACNA1C gene.
• CACNA1C gene encodes for calcium channel α subunit across cell membranes.
• Any missense mutation in CACNA1C gene results in structural changes of CaV1.2 channels and delayed calcium channel α subunit closing and, thus, increased cellular excitability
• Calcium channel α subunit especially CaV1.2 involves in transporting positively charged calcium ions into the cells across a cell membrane which plays a critical role in the normal function of heart and brain cells
• Mutations in CaV1.2 Calcium channels leads to disruption of the following events in the heart and other organs:
  • Cell-to-cell communication
  • Muscle contraction
  • Normal regulation of certain genes

Causes

Genetic Causes

• Timothy syndrome is caused by a missense mutation in the CACNA1C gene.

Life-threatening Causes[edit | edit source]

• Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated. There are no life-threatening causes of disease name, however, complications resulting from untreated disease names are common.
• Life-threatening causes of [symptom/manifestation] include [cause1], [cause2], and [cause3].
• [Cause] is a life-threatening cause of [disease].

Common Causes[edit | edit source]

Common causes of [disease name] may include:

• [Cause1]
• [Cause2]
• [Cause3]

Differentiating Timothy syndrome from other Diseases

• Timothy syndrome must be differentiated from Jervell and Lange-Nielsen syndrome (JLNS), Romano-Ward syndrome, , Andersen-Tawil syndrome, Brugada syndrome, and Sudden infant death syndrome (SIDS).

Natural History, Complications, Prognosis

The prognosis for patients diagnosed with Timothy syndrome is grim. Of 17 children analyzed in one study, 10 died at an average age of 2.5 years. Of those that did survive, 3 were diagnosed with autism, one with an autism spectrum disorder and the last had severe delays in language development. One patient with atypical Timothy syndrome was largely normal with the exception of heart arrhythmia. Likewise, the mother of two Timothy syndrome patients also carried the mutation but lacked any obvious phenotype. In both of these cases, however, the lack of severity of the disorder was due to mosaicism.

Diagnosis

Signs and symptoms

The most striking sign of Timothy syndrome is the co-occurrence of both syndactyly (~0.03% of births) and long QT syndrome (1% per year) in a single patient. Other common symptoms of Timothy syndrome are cardiac arrhythmia (94%), heart malformations (59%), autism or an autism spectrum disorder (80% who survive long enough for evaluation). Facial dysmorphologies such as flattened noses also occur in approximately half of patients. Children with this disorder have small teeth which, due to poor enamel coating, are prone to dental cavities and often require removal. The average age of death due to complications of these symptoms is 2.5 years.

Atypical Timothy syndrome has largely the same symptoms as the classical form. Differences in the atypical form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and atrial fibrillations. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had body development discrepancy wherein her upper body was normally developed (that of a 6-year-old) while her lower half resembled a 2 or 3-year-old.

Interestingly, children with Timothy syndrome tend to be born via cesarean section due to fetal distress.

Physical Examination

Extremities

Syndactyly and other deformities are typically observed and diagnosed at birth.

Electrocardiogram

Long QT syndrome sometimes presents itself as a complication due to surgery to correct syndactyly. Other times, children collapse spontaneously while playing. In all cases, it is confirmed with ECG measurements. The sequencing of the CACNA1C gene further confirms the diagnosis.

Treatment

Surgery is typically used to correct structural heart defects and syndactyly. Propanolol or beta-adrenergic blockers are often prescribed as well as insertion of a pacemaker to maintain proper heart rhythm. With the characterization of Timothy syndrome mutations indicating that they cause defects in calcium currents, it has been suggested that calcium channel blockers may be effective as a therapeutic agent.