Timothy syndrome

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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; TS

Overview

Timothy syndrome is a rare syndrome that follows autosomal dominant inheritance pattern. Timothy syndrome is a multisystem disorder 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	Protein involved	Location	Mutations	Inheritance pattern	Symptoms
Classic Timothy syndrome	CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	12p13.33	Exon 8 a	Autosomal dominant	Long QT syndrome with syndactyly
Atypical Timothy syndrome	CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	12p13.33	Exon 8	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 exon 8 (atypical form) and exon 8a (classical form) of CACNA1C gene results in structural changes of Ca(V)1.2channels and delayed calcium channel α subunit closing and, thus, increased cellular excitability.
• There is one more mutation in G406R that is associated with the timothy syndrome.
• The location of G406R is in domain one segment six (D1S6) which holds glycine at this position and plays a very important role in voltage-dependent inactivation.
• Calcium channel α subunit especially Ca(V)1.2 involved 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 Ca(V)1.2 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

• Due to the fact that exon 8(atypical Timothy syndrome) is more expressed in heart muscles than that of exon 8a(classic Timothy syndrome) patients with exon 8 mutation have a severe form of long QT interval.

Causes

Genetic Causes

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

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).

Epidemiology and Demographics

Incidence

• The incidence of timothy syndrome is unknown worldwide.
• Only 20 cases were reported worldwide.

Prevalence

• The prevalence of timothy syndrome is less than 1 per 100,000 individuals worldwide.

Mortality rate

• In patients with timothy syndrome the average age of death is 2.5 years

Age

• Timothy syndrome commonly affects individuals of younger age group, the median age of diagnosis is usally within the first few days after birth.

Race

• There is no racial predilection to Timothy syndrome.

Gender

• Timothy syndrome affects men and women equally.

Risk Factors

• There are no established risk factors for Timothy syndrome.

Screening

• There is insufficient evidence to recommend routine screening for Timothy syndrome.

Natural History, Complications, Prognosis

Natural History

• The symptoms of Timothy syndrome usually develop in the first decade of life, and start with symptoms such as cardiac, hand/foot, facial, and neurodevelopmental symptoms.

Complications

• Common complications of Timothy syndrome include:
  • Ventricular tachyarrhythmia which includes both ventricular tachycardia and ventricular fibrillation is the cause of death in most of the patients with Timothy syndrome
  • Severe infections due to weakened immune system(despite aggressive antibiotic therapy)
  • Intractable hypoglycemia

Prognosis

• The prognosis for patients diagnosed with Timothy syndrome is grim.

• The average age of death is 2.5 years in patients with Timothy syndrome.

Diagnosis

Diagnostic study of choice

• Sequence analysis(100% detectable), Targeted analysis for pathogenic variants(>95% detectable), Gene-targeted deletion/duplication analysis of CACNA1C gene testing is the gold standard test for the diagnosis of Timothy syndrome.
• Along with the genetic testing patients also evaluate for following recommendations:
  • Electrocardiogram(ECG)
  • Echocardiogram
  • Developmental and neurological assessment for autism and Intellectual disability
  • Skeletal abnormalities

Symptoms

Common Symptoms

Common symptoms of Timothy syndrome include:

• Torsade de pointes
• Syncopal events usually self-terminating
• Arrhythmias
• Palpitations
• Neuropsychiatric symptoms such as autism and Intellectual disability
• Seizures
• Hypotonia

Less Common Symptoms

Less common symptoms of Timothy syndrome include:

• Ventricular fibrillation
• Cardiac arrest
• Sudden death

Electrocardiogram

• 

  Trimonth syndrome ECG after birth showed a prolonged QT interval (QTc 600 ms), 2:1 atrioventricular block and significant bradycardia (ventricular rate 60/min). Case courtesy by U. Krause Et Al

  An ECG is helpful in the diagnosis of Timothy syndrome. Findings on an ECG diagnostic of Timothy syndrome include the following:

  • 

    A boy with a heart rate at 58/min, QT 498 ms and QTc 490 ms in long Qt syndrome. Case courtesy by Thomas Hof Et Al

    Prolongation of the QTc interval with an average QTc of 580 ms in classic Timothy syndrome
  • Prolongation of the QTc interval with an average QTc of 640 ms in atypical Timothy syndrome
  • Macroscopic T-wave alternans
  • Tachyarrhythmias: due to abnormal cardiac depolarization and cardiac repolarization
  • Ventricular tachycardia
  • AV block
  • Torsade de pointes ventricular tachycardia

  • 

    Bilateral cutaneous syndactyly of the third, fourth, and fifth fingers. Case courtesy by Hyo Soon An Et Al

    Ventricular fibrillation

Physical Examination

Characteristic phenotypic features of Timothy syndrome: bald head and lower–set ears, webbing of fingers and toes. Case courtesy by U. Krause Et Al

HEENT

• HEENT examination of patients with Timothy syndrome is usually shows characteristic Craniofacial features such as:
  • Bald head
  • Depressed nasal bridge
  • Premaxillary underdevelopment
  • Low-set ears
  • Thin vermilion border of the upper lip
  • Round face
  • Poor dental enamel with widely spaced teeth

Heart

• Cardiovascular manifestations of Timothy Syndrome may include:
  • Functional 2:1 AV block
  • Tachyarrhythmias
  • Signs of congenital heart disease which include: PDA(Patent ductus arteriosus), PFO(patent foramen ovale), VSD(Ventricular septal defect), TOF(Tetralogy of Fallot), HCM(Hypertrophic cardiomyopathy)

Neurodevelopmental

• Neurodevelopmental examination of patients with Timothy syndrome shows signs of the following:
  • Autism
  • Autism spectrum disorder
  • Severe language delay
  • Mild language delay

Extremities

• Extremities examination of patients with Timothy syndrome shows webbed fingers(syndactyly) and toes.
• Syndactyly is due to the failure of apoptosis on the apical ectodermal ridge.

Laboratory Findings

• There are no diagnostic laboratory findings associated with Timothy syndrome.

Ultrasound

• Ultrasound may be helpful in the diagnosis of syndactyly during pregnancy with Timothy syndrome patients.

X Ray, CT scan and MRI scan

• There are no x-ray, CT scan and MRI scan findings associated with Timothy syndrome.

Medical Therapy

• Verapamil, mexiletine and ranolazine are also effective in treating the patients of Timothy syndrome.
• Beta-blockers helps in controlling the QT interval prolongation which in-turn helps in preventing ventricular tachycardia, which is the main cause of death in patients with Timothy syndrome.
• In patients with Timothy syndrome despite treated with the beta-blockers risk of cardiac events still persists.
  • Preferred regimen (1): Nadolol 1–1.5 mg/kg/day administered once a day in patients ≥12 years of age, divided twice daily in infants and children
  • Preferred regimen (2): Verapamil 120 mg twice a day and by decreasing the beta blocker dosage to half.

Interventions

• The feasibility of interventions depends on the severity of Timothy syndrome patients at the time of diagnosis which include:

Implantable cardioverter-defibrillators (ICDs)

• ICDs are single most effective method for preventing sudden death in patients with Timothy syndrome.
• ICDs are reserved for the patients who undergone cardiac arrest resuscitation.

• ICDs are good alternative choice of treatment for the patients who are resistant to beta blockers.

Left cardiac sympathetic denervation (LCSD)

• LCSDs are reserved for the patients who are not compatible with beta blocker or Implantable cardioverter-defibrillators (ICDs).

Pacemaker

• In patients with Timothy syndrome placing a pacemaker is going to help in controlling the 2:1 AV block and bradycardia.

Surgery

• Surgery is not the first-line treatment option for patients with Timothy syndrome. Surgery is usually reserved for patients with either:
  • Syndactyly: Surgical release of syndactyly.

Primary Prevention

• There are no established measures for the primary prevention of Timothy syndrome.

Secondary Prevention

• Effective measures for the secondary prevention of Timothy syndrome include:
  • Taking special care while giving the anesthesia due to the risk of cardiac arrhythmias.
  • Monitoring of serum glucose levels due to intractable hypoglycemia in patients with Timothy syndrome.