Timothy syndrome: Difference between revisions

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== Physical Examination ==
== Physical Examination ==
Physical examination of patients with [disease name] is usually normal.  OR  Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].  OR  The presence of [finding(s)] on physical examination is diagnostic of [disease name].  OR  The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
=== Appearance of the Patient ===
* Patients with [disease name] usually appear [general appearance].
=== Vital Signs ===
=== Vital Signs ===


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* [[Bradycardia]] with regular pulse or (ir)regularly irregular pulse
* [[Bradycardia]] with regular pulse or (ir)regularly irregular pulse
* Tachypnea / bradypnea
* Tachypnea / bradypnea
* Kussmal respirations may be present in _____ (advanced disease state)
* Kussmaul respirations may be present in _____ (advanced disease state)
* Weak/bounding pulse / pulsus alternans / paradoxical pulse / asymmetric pulse
* Weak/bounding pulse / pulsus alternans / paradoxical pulse / asymmetric pulse
* High/low blood pressure with normal pulse pressure / [[wide pulse pressure]] / [[narrow pulse pressure]]
* High/low blood pressure with normal pulse pressure / [[wide pulse pressure]] / [[narrow pulse pressure]]

Revision as of 14:54, 21 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

  • 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.[3]

Classification

  • Timothy syndrome may be classified into 2 groups as follows:[4][5][6]
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

  • 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

Differentiating Timothy syndrome from other Diseases

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

Screening

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

Natural History, Complications, Prognosis

Natural History

Complications

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.[22] [23]

Diagnosis

Diagnostic study of choice

Symptoms

Common Symptoms

Common symptoms of Timothy syndrome include:

Less Common Symptoms

Less common symptoms of Timothy syndrome include

Electrocardiogram

Physical Examination

Vital Signs

  • High-grade / low-grade fever
  • Hypothermia / hyperthermia may be present
  • Tachycardia with regular pulse or (ir)regularly irregular pulse
  • Bradycardia with regular pulse or (ir)regularly irregular pulse
  • Tachypnea / bradypnea
  • Kussmaul respirations may be present in _____ (advanced disease state)
  • Weak/bounding pulse / pulsus alternans / paradoxical pulse / asymmetric pulse
  • High/low blood pressure with normal pulse pressure / wide pulse pressure / narrow pulse pressure

Skin

  • Skin examination of patients with [disease name] is usually normal.

OR

  • UploadedImage-01.jpg Description (Adapted from Dermatology Atlas)
  • Description (Adapted from Dermatology Atlas)

HEENT

  • HEENT examination of patients with Timothy syndrome is usually shows characteristic facial features such as:[29]

OR

  • Abnormalities of the head/hair may include ___
  • Evidence of trauma
  • Icteric sclera
  • Nystagmus
  • Extra-ocular movements may be abnormal
  • Pupils non-reactive to light / non-reactive to accommodation / non-reactive to neither light nor accommodation
  • Ophthalmoscopic exam may be abnormal with findings of ___
  • Hearing acuity may be reduced
  • Weber test may be abnormal (Note: A positive Weber test is considered a normal finding / A negative Weber test is considered an abnormal finding. To avoid confusion, you may write "abnormal Weber test".)
  • Rinne test may be positive (Note: A positive Rinne test is considered a normal finding / A negative Rinne test is considered an abnormal finding. To avoid confusion, you may write "abnormal Rinne test".)
  • Exudate from the ear canal
  • Tenderness upon palpation of the ear pinnae/tragus (anterior to ear canal)
  • Inflamed nares / congested nares
  • Purulent exudate from the nares
  • Facial tenderness
  • Erythematous throat with/without tonsillar swelling, exudates, and/or petechiae

Neck

  • Neck examination of patients with [disease name] is usually normal.

OR

Lungs

  • Pulmonary examination of patients with [disease name] is usually normal.

OR

  • Asymmetric chest expansion OR decreased chest expansion
  • Lungs are hyporesonant OR hyperresonant
  • Fine/coarse crackles upon auscultation of the lung bases/apices unilaterally/bilaterally
  • Rhonchi
  • Vesicular breath sounds OR distant breath sounds
  • Expiratory wheezing OR inspiratory wheezing with normal OR delayed expiratory phase
  • Wheezing may be present
  • Egophony present/absent
  • Bronchophony present/absent
  • Normal/reduced tactile fremitus

Heart

  • Cardiovascular examination of patients with [disease name] is usually normal.

OR

  • Chest tenderness upon palpation
  • PMI within 2 cm of the sternum (PMI) / Displaced point of maximal impulse (PMI) suggestive of ____
  • Heave / thrill
  • Friction rub
  • S1
  • S2
  • S3
  • S4
  • Gallops
  • A high/low grade early/late systolic murmur / diastolic murmur best heard at the base/apex/(specific valve region) may be heard using the bell/diaphgram of the stethoscope

Abdomen

  • Abdominal examination of patients with [disease name] is usually normal.

OR

Back

  • Back examination of patients with [disease name] is usually normal.

OR

  • Point tenderness over __ vertebrae (e.g. L3-L4)
  • Sacral edema
  • Costovertebral angle tenderness bilaterally/unilaterally
  • Buffalo hump

Genitourinary

  • Genitourinary examination of patients with [disease name] is usually normal.

OR

  • A pelvic/adnexal mass may be palpated
  • Inflamed mucosa
  • Clear/(color), foul-smelling/odorless penile/vaginal discharge

Neuromuscular

  • Neuromuscular examination of patients with [disease name] is usually normal.

OR

  • Patient is usually oriented to persons, place, and time
  • Altered mental status
  • Glasgow coma scale is ___ / 15
  • Clonus may be present
  • Hyperreflexia / hyporeflexia / areflexia
  • Positive (abnormal) Babinski / plantar reflex unilaterally/bilaterally
  • Muscle rigidity
  • Proximal/distal muscle weakness unilaterally/bilaterally
  • ____ (finding) suggestive of cranial nerve ___ (roman numerical) deficit (e.g. Dilated pupils suggestive of CN III deficit)
  • Unilateral/bilateral upper/lower extremity weakness
  • Unilateral/bilateral sensory loss in the upper/lower extremity
  • Positive straight leg raise test
  • Abnormal gait (describe gait: e.g. ataxic (cerebellar) gait / steppage gait / waddling gait / choeiform gait / Parkinsonian gait / sensory gait)
  • Positive/negative Trendelenburg sign
  • Unilateral/bilateral tremor (describe tremor, e.g. at rest, pill-rolling)
  • Normal finger-to-nose test / Dysmetria
  • Absent/present dysdiadochokinesia (palm tapping test)

Extremities

  • Extremities examination of patients with Timothy syndrome shows webbed fingers(syndactyly) and toes.[30]

Signs and symptoms

.[31][32][22][23]

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.[23]

References

  1. ↑ 1.0 1.1 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. ↑ Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L; et al. (2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome". Am J Med Genet A. 158A (1): 182–7. doi:10.1002/ajmg.a.34355. PMC 3319791. PMID 22106044.
  4. ↑ Schultz D, Mikala G, Yatani A, Engle DB, Iles DE, Segers B; et al. (1993). "Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart". Proc Natl Acad Sci U S A. 90 (13): 6228–32. doi:10.1073/pnas.90.13.6228. PMC 46901. PMID 8392192.
  5. ↑ Soldatov NM, Bouron A, Reuter H (1995). "Different voltage-dependent inhibition by dihydropyridines of human Ca2+ channel splice variants". J Biol Chem. 270 (18): 10540–3. doi:10.1074/jbc.270.18.10540. PMID 7737988.
  6. ↑ Lyford GL, Strege PR, Shepard A, Ou Y, Ermilov L, Miller SM; et al. (2002). "alpha(1C) (Ca(V)1.2) L-type calcium channel mediates mechanosensitive calcium regulation". Am J Physiol Cell Physiol. 283 (3): C1001–8. doi:10.1152/ajpcell.00140.2002. PMID 12176756.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ Dixon RE, Cheng EP, Mercado JL, Santana LF (2012). "L-type Ca2+ channel function during Timothy syndrome". Trends Cardiovasc Med. 22 (3): 72–6. doi:10.1016/j.tcm.2012.06.015. PMC 3640256. PMID 22999068.
  11. ↑ Dick IE, Joshi-Mukherjee R, Yang W, Yue DT (2016). "Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca(2+)-dependent inactivation". Nat Commun. 7: 10370. doi:10.1038/ncomms10370. PMC 4740114. PMID 26822303.
  12. ↑ 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.
  13. ↑ Betzenhauser MJ, Pitt GS, Antzelevitch C (2015). "Calcium Channel Mutations in Cardiac Arrhythmia Syndromes". Curr Mol Pharmacol. 8 (2): 133–42. doi:10.2174/1874467208666150518114857. PMC 4762596. PMID 25981977.
  14. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L; et al. (2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome". Am J Med Genet A. 158A (1): 182–7. doi:10.1002/ajmg.a.34355. PMC 3319791. PMID 22106044.
  22. ↑ 22.0 22.1 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.
  23. ↑ 23.0 23.1 23.2 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.
  24. ↑ Gillis J, Burashnikov E, Antzelevitch C, Blaser S, Gross G, Turner L; et al. (2012). "Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome". Am J Med Genet A. 158A (1): 182–7. doi:10.1002/ajmg.a.34355. PMC 3319791. PMID 22106044.
  25. ↑ Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S; et al. (2011). "Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals". J Am Coll Cardiol. 57 (1): 51–9. doi:10.1016/j.jacc.2010.07.038. PMC 3332533. PMID 21185501.
  26. ↑ Marks ML, Whisler SL, Clericuzio C, Keating M (1995). "A new form of long QT syndrome associated with syndactyly". J Am Coll Cardiol. 25 (1): 59–64. doi:10.1016/0735-1097(94)00318-k. PMID 7798527.
  27. ↑ Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH; et al. (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. doi:10.1073/pnas.0502506102. PMC 1149428. PMID 15863612.
  28. ↑ "Sudden Cardiac Arrest during Anesthesia in a 30-Month-Old Boy with Syndactyly: A Case of Genetically Proven Timothy Syndrome".
  29. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301577.
  30. ↑ An HS, Choi EY, Kwon BS, Kim GB, Bae EJ, Noh CI; et al. (2013). "Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome". J Korean Med Sci. 28 (5): 788–91. doi:10.3346/jkms.2013.28.5.788. PMC 3653096. PMID 23678275.
  31. ↑ 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.
  32. ↑ 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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