Timothy syndrome

Timothy syndrome
Classification and external resources
OMIM	601005
DiseasesDB	34006

Timothy syndrome is a rare autosomal dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly (webbing of fingers and toes) and autism spectrum disorders.

Timothy syndrome often ends in early childhood death.

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.^[1]^[2]^[3]

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 fibrillation. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had a 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.^[4]

Children with Timothy syndrome tend to be born via caesarean section due to fetal distress.^[1]^[2]

Diagnosis

Syndactyly and other deformities are typically observed and diagnosed at birth. 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. Sequencing of the CACNA1C gene further confirms the diagnosis.

Pathophysiology

Timothy syndrome has an autosomal dominant pattern of inheritance.

There are two recognized types of Timothy syndrome, classical (type-1) and atypical (type-2). They are both caused by mutations in CACNA1C, the gene encoding the calcium channel Ca_v1.2 α subunit. Timothy syndrome mutations in CACNA1C cause delayed channel closing and, thus, increased cellular excitability.

Both classical and atypical Timothy syndromes are caused by mutations in CACNA1C. These mutations are in exon 8 (atypical form) and exon 8a (classical form), an alternatively spliced exon. Exon 8a is highly expressed in the heart, brain, gastrointestinal system, lungs, immune system and smooth muscle. Exon 8 is also expressed in these regions and its level is approximately 5-fold higher than exon 8a expression.

There is one mutation found in patients with classical Timothy syndrome, G406R, located just past the 6th membrane spanning segment of domain 1 (D1S6). The conserved glycine at this position seems to be vital for proper voltage dependent inactivation as the mutant is lacking in this respect.^[3] Atypical Timothy syndrome mutations are similar, one being the identical G406R mutation in the other splice form and the second mutation being G402S, located a few amino acids upstream. The effect of these mutations on channel function is identical to the G406R mutation in classical Timothy syndrome.^[4] The lack of proper voltage-dependent inactivation in these mutants causes prolonged inward current and depolarization during cardiac action potentials. This leads to long QT syndrome and resultant arrhythmia. Because exon 8 has greater expression in the heart versus exon 8a, patients with atypical Timothy syndrome have worsened cardiac defects compared to those with the classical form.

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.^[4]

Prognosis

The prognosis for patients diagnosed with Timothy syndrome is very poor. 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.^[3] One patient with atypical Timothy syndrome was largely normal with the exception of heart arrhythmia.^[4] 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.

History

Some of the abnormalities observed in Timothy syndrome were described in the 1990s. However, it was linked with calcium channel abnormalities in 2004, and the disorder was thence named "Timothy syndrome" in honor of Katherine W. Timothy, who was among the first to identify a case and performed much of the phenotypic analysis that revealed other abnormalities.^[3]

External links

References

1 2 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. doi:10.1016/0735-1097(94)00318-K. PMID 7798527.
1 2 Marks M, Trippel D, Keating M (1995). "Long QT syndrome associated with syndactyly identified in females". Am J Cardiol 76 (10): 744–745. doi:10.1016/S0002-9149(99)80216-1. PMID 7572644.
1 2 3 4 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. doi:10.1016/j.cell.2004.09.011. PMID 15454078.
1 2 3 4 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 USA 102 (23): 8089–8096. doi:10.1073/pnas.0502506102. PMC 1149428. PMID 15863612.

Congenital abnormality syndromes (Q87, 759.7)

Craniofacial

Acrocephalosyndactylia Apert syndrome/Pfeiffer syndrome Saethre–Chotzen syndrome Carpenter syndrome Sakati–Nyhan–Tisdale syndrome

other:	Möbius syndrome Goldenhar syndrome Cyclopia Baller–Gerold syndrome

Short stature

Limbs

Adducted thumb syndrome Holt–Oram syndrome Klippel–Trénaunay–Weber syndrome Nail–patella syndrome Rubinstein–Taybi syndrome

Gastrulation/mesoderm:	Caudal regression syndrome ectromelia Sirenomelia VACTERL association

Overgrowth

Laurence–Moon–Bardet–Biedl

Combined/other,
known locus

2 (Feingold syndrome)
3 (Zimmermann–Laband syndrome)
4/13 (Fraser syndrome)
8 (Branchio-oto-renal syndrome, CHARGE syndrome)
12 (Keutel syndrome, Timothy syndrome)
15 (Marfan syndrome)
19 (Donohue syndrome)
Multiple
- Fryns syndrome

Diseases of ion channels

Calcium channel

Voltage-gated	CACNA1A Familial hemiplegic migraine 1 Episodic ataxia 2 Spinocerebellar ataxia type-6 CACNA1C Timothy syndrome Brugada syndrome 3 Long QT syndrome 8 CACNA1F Ocular albinism 2 CSNB2A CACNA1S Hypokalemic periodic paralysis 1 Thyrotoxic periodic paralysis 1 CACNB2 Brugada syndrome 4

Ligand gated	RYR1 Malignant hyperthermia Central core disease RYR2 CPVT1 ARVD2

Sodium channel

Voltage-gated	SCN1A Familial hemiplegic migraine 3 GEFS+ 2 Febrile seizure 3A SCN1B Brugada syndrome 6 GEFS+ 1 SCN4A Hypokalemic periodic paralysis 2 Hyperkalemic periodic paralysis Paramyotonia congenita Potassium-aggravated myotonia SCN4B Long QT syndrome 10 SCN5A Brugada syndrome 1 Long QT syndrome 3 SCN9A Erythromelalgia Febrile seizure 3B Paroxysmal extreme pain disorder Congenital insensitivity to pain

Constitutively active	SCNN1B/SCNN1G Liddle's syndrome SCNN1A/SCNN1B/SCNN1G Pseudohypoaldosteronism 1AR

Potassium channel

Voltage-gated	KCNA1 Episodic ataxia 1 KCNA5 Familial atrial fibrillation 7 KCNC3 Spinocerebellar ataxia type-13 KCNE1 Jervell and Lange-Nielsen syndrome Long QT syndrome 5 KCNE2 Long QT syndrome 6 KCNE3 Brugada syndrome 5 KCNH2 Short QT syndrome KCNQ1 Jervell and Lange-Nielsen syndrome Romano–Ward syndrome Short QT syndrome Long QT syndrome 1 Familial atrial fibrillation 3 KCNQ2 BFNS1

Inward-rectifier	KCNJ1 Bartter syndrome 2 KCNJ2 Andersen–Tawil syndrome Long QT syndrome 7 Short QT syndrome) KCNJ11 TNDM3 KCNJ18 Thyrotoxic periodic paralysis 2

Chloride channel

TRP channel

TRPC6
- FSGS2
TRPML1
- Mucolipidosis type IV

Connexin

Porin

AQP2
- Nephrogenic diabetes insipidus 2

See also: ion channels

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