Timothy syndrome: Difference between revisions
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* Timothy syndrome affects men and women equally. | * Timothy syndrome affects men and women equally. | ||
== Risk Factors == | |||
* There are no established risk factors for Timothy syndrome. | |||
==Natural History, Complications, Prognosis== | ==Natural History, Complications, Prognosis== | ||
Revision as of 02:57, 17 January 2020
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
- 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 | Mutations | Inheritance pattern | Symptoms |
| Classic Timothy syndrome | CACNA1C | 12p13.33 | Exon 8 a | Autosomal dominant | Long QT syndrome with syndactyly |
| Atypical Timothy syndrome | CACNA1C | 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.[3][4]
- 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 CaV1.2 channels and delayed calcium channel α subunit closing and, thus, increased cellular excitability.[5]
- There is one more mutation in G406R that is associated with the timothy syndrome.[6]
- 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 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
- 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).[7][8][9][10][11][12][13]
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.
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 (despite aggressive antibiotic therapy)
- Intractable hypoglycemia
Prognosis
- The prognosis for patients diagnosed with Timothy syndrome is grim.
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.[16][17][14]
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.[15]
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.[15]
References
- ↑ Reichenbach H, Meister EM, Theile H (1992). "[The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet]". Kinderarztl Prax. 60 (2): 54–6. PMID 1318983.
- ↑ Marks ML, Trippel DL, Keating MT (1995). "Long QT syndrome associated with syndactyly identified in females". Am J Cardiol. 76 (10): 744–5. doi:10.1016/s0002-9149(99)80216-1. PMID 7572644.
- ↑ Walsh MA, Turner C, Timothy KW, Seller N, Hares DL, James AF; et al. (2018). "A multicentre study of patients with Timothy syndrome". Europace. 20 (2): 377–385. doi:10.1093/europace/euw433. PMID 28371864.
- ↑ Baurand A, Falcon-Eicher S, Laurent G, Villain E, Bonnet C, Thauvin-Robinet C; et al. (2017). "Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing". Am J Med Genet A. 173 (2): 531–536. doi:10.1002/ajmg.a.38045. PMID 27868338.
- ↑ Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R; et al. (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. doi:10.1016/j.cell.2004.09.011. PMID 15454078.
- ↑ De Oliveira CC, Figueiredo EA, Gazzinelli G, Howells RE, Pellegrino J (1975). "Biochemical changes in the transformation of Schistosoma mansoni cercariae to schistosomules". Comp Biochem Physiol B. 51 (4): 417–20. doi:10.1016/0305-0491(75)90031-0. PMID 1149428.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
- ↑ Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC; et al. (2001). "Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome". JAMA. 286 (18): 2264–9. doi:10.1001/jama.286.18.2264. PMID 11710892.
- ↑ Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C; et al. (2007). "Prevalence of long-QT syndrome gene variants in sudden infant death syndrome". Circulation. 115 (3): 361–7. doi:10.1161/CIRCULATIONAHA.106.658021. PMID 17210839.
- ↑ Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C; et al. (2001). "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias". Circulation. 103 (1): 89–95. doi:10.1161/01.cir.103.1.89. PMID 11136691.
- ↑ Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C; et al. (2006). "Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study". Int J Legal Med. 120 (3): 129–37. doi:10.1007/s00414-005-0019-0. PMID 16012827.
- ↑ Juang JJ, Horie M (2016). "Genetics of Brugada syndrome". J Arrhythm. 32 (5): 418–425. doi:10.1016/j.joa.2016.07.012. PMC 5063259. PMID 27761167.
- ↑ Thomas D, Wimmer AB, Karle CA, Licka M, Alter M, Khalil M; et al. (2005). "Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome". Cardiovasc Res. 67 (3): 487–97. doi:10.1016/j.cardiores.2005.05.003. PMID 15950200.
- ↑ 14.0 14.1 Splawski I, Timothy K, Sharpe L, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz P, Joseph R, Condouris K, Tager-Flusberg H, Priori S, Sanguinetti M, Keating M (2004). "Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism". Cell. 119 (1): 19–31. PMID 15454078.
- ↑ 15.0 15.1 15.2 Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A, Sanguinetti M, Keating M (2005). "Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations". Proc Natl Acad Sci U S A. 102 (23): 8089–96, discussion 8086-8. PMID 15863612.
- ↑ Marks M, Whisler S, Clericuzio C, Keating M (1995). "A new form of long QT syndrome associated with syndactyly". J Am Coll Cardiol. 25 (1): 59–64. PMID 7798527.
- ↑ Marks M, Trippel D, Keating M (1995). "Long QT syndrome associated with syndactyly identified in females". Am J Cardiol. 76 (10): 744–5. PMID 7572644.