Difference between revisions of "Timothy syndrome"

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(Pathophysiology)
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*It is understood that Timothy syndrome both classical and atypical form is the result of a [[missense mutation]] in the [[CACNA1C]] [[gene]].<ref name="pmid28371864">{{cite journal| author=Walsh MA, Turner C, Timothy KW, Seller N, Hares DL, James AF et al.| title=A multicentre study of patients with Timothy syndrome. | journal=Europace | year= 2018 | volume= 20 | issue= 2 | pages= 377-385 | pmid=28371864 | doi=10.1093/europace/euw433 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28371864  }}</ref><ref name="pmid27868338">{{cite journal| author=Baurand A, Falcon-Eicher S, Laurent G, Villain E, Bonnet C, Thauvin-Robinet C et al.| title=Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing. | journal=Am J Med Genet A | year= 2017 | volume= 173 | issue= 2 | pages= 531-536 | pmid=27868338 | doi=10.1002/ajmg.a.38045 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27868338  }}</ref>
 
*It is understood that Timothy syndrome both classical and atypical form is the result of a [[missense mutation]] in the [[CACNA1C]] [[gene]].<ref name="pmid28371864">{{cite journal| author=Walsh MA, Turner C, Timothy KW, Seller N, Hares DL, James AF et al.| title=A multicentre study of patients with Timothy syndrome. | journal=Europace | year= 2018 | volume= 20 | issue= 2 | pages= 377-385 | pmid=28371864 | doi=10.1093/europace/euw433 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28371864  }}</ref><ref name="pmid27868338">{{cite journal| author=Baurand A, Falcon-Eicher S, Laurent G, Villain E, Bonnet C, Thauvin-Robinet C et al.| title=Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing. | journal=Am J Med Genet A | year= 2017 | volume= 173 | issue= 2 | pages= 531-536 | pmid=27868338 | doi=10.1002/ajmg.a.38045 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27868338  }}</ref>
 
*[[CACNA1C]] [[gene]] encodes for [[calcium channel]] α [[subunit]] across [[cell membranes]].
 
*[[CACNA1C]] [[gene]] encodes for [[calcium channel]] α [[subunit]] across [[cell membranes]].
*Any [[missense mutation]] in [[CACNA1C]] [[gene]] results in structural changes of CaV1.2 [[Ion channel|channels]] and delayed [[calcium channel]] α subunit closing and, thus, increased [[cellular]] excitability
+
*Any [[missense mutation]] in exon 8 (atypical form) and exon 8a (classical form) of [[CACNA1C]] [[gene]] results in structural changes of CaV1.2 [[Ion channel|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
 
*[[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
 
*[[Mutation|Mutations]] in CaV1.2 [[Calcium channel|calcium channels]] leads to disruption of the following events in the [[heart]] and other organs:
 
*[[Mutation|Mutations]] in CaV1.2 [[Calcium channel|calcium channels]] leads to disruption of the following events in the [[heart]] and other organs:

Revision as of 15:41, 16 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

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.[1][2]
  • 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 Autosomal dominant Long QT syndrome with syndactyly
Atypical Timothy syndrome CACNA1C 12p13.33 Exon 8a Autosomal dominant A very severe form of long QT syndrome without syndactyly

Pathophysiology

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

Epidemiology and Demographics

Incidence

  • The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
  • In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

Prevalence

  • The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
  • In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
  • The prevalence of [disease/malignancy] is estimated to be [number] cases annually.

Case-fatality rate/Mortality rate

  • In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate/mortality rate of [number range]%.
  • The case-fatality rate/mortality rate of [disease name] is approximately [number range].

Age

  • Patients of all age groups may develop [disease name].
  • The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
  • [Disease name] commonly affects individuals younger than/older than [number of years] years of age.
  • [Chronic disease name] is usually first diagnosed among [age group].
  • [Acute disease name] commonly affects [age group].

Race

  • There is no racial predilection to [disease name].
  • [Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].

Gender

  • [Disease name] affects men and women equally.
  • [Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.

Region

  • The majority of [disease name] cases are reported in [geographical region].
  • [Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

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.[12] One patient with atypical Timothy syndrome was largely normal with the exception of heart arrhythmia.[13] 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.[14][15][12]

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.[13]

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.[13]

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 12.0 12.1 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.
  13. 13.0 13.1 13.2 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.
  14. 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.
  15. 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.



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