Cardiogenetics 2012; volume 2:e2 Cardiac electrical system regulation with hypogonadism), liver, pul- monary, and renal disease over time. Correspondence: Richard J. Czosek, Cincinnati involvement in Individuals can be identified with developmen- Children’s Hospital Medical Center, Pediatric Alström syndrome: tal delay, which may be due to vision and hear- Cardiology, MLC 2003, 3333 Burnett Avenue, uncommon causes ing impairments. It is likely that Alström syn- Cincinnati, OH 45229, USA. drome is underdiagnosed as individuals with Tel. +1.513.636.2237 - Fax: +1.513.636.7996. E-mail: [email protected] of dilated cardiomyopathies this disorder are frequently followed by various specialty services, without consideration of a Richard J. Czosek,1 Paula Goldenberg,1 Funding: JAT and SMW are funded by National unifying diagnosis. Institutes of Health grants R01 HL087000-01A1 1 1 Erin M. Miller, Robert Spicer, Alström syndrome, an autosomal recessive (JAT, SWM), the Children’s Cardiomyopathy Jeffrey A. Towbin,1 Stephanie M. Ware1,2 disorder, is one of a group of disorders of cilia, Foundation (SMW), and Burroughs Wellcome 1Division of Pediatric Cardiology; collectively termed ciliopathies.1-3 Mutations of Fund Clinical Scientist Award in Translational Research #1008496 (SMW). 2Division of Molecular Cardiovascular the ALMS1 gene cause Alström syndrome4,5 The role of this gene in disease pathology is Biology, The Heart Institute, Cincinnati Key words: Alström syndrome, arrhythmia, car- Children’s Hospital Medical Center, OH, unclear, but it is hypothesized to play a role in diomyopathy. 6 USA intracellular trafficking. Mouse models (Alms1 -/-) have similar manifestations includ- Contributions: RJC, PG, EM, RS, JAT, SMW, data ing obesity, hypogonadism, hyperinsulinemia, acquisition, analysis and interpretation, manu- retinal dysfunction, and late-onset hearing script drafting/revision; RJC, SMW, project con- loss. In these murine models ALMS1 appears to ception and design. All authors have approved the Abstract have a role in planar cell polarity signaling in final version of the manuscript. the cochlea, adipogenesis, and rhodopsin traf- Conflicts of interests: the authors declare no Alström syndrome is a rare autosomal reces- 6-8 ficking. potential conflicts of interests. sive disorder with dilated cardiomyopathy in The diagnosis of Alström syndrome can be 60% of patients. Despite the frequency of car- difficult because of its rarity and similarity to Received for publication: 7 November 2011. diac involvement in Alström syndrome, con- other syndromic conditions. Bardet-Biedl syn- Revisiononly received: 16 January 2012. duction system abnormalities or arrhythmias drome is another ciliopathy associated with Accepted for publication: 17 January 2012. have not been characterized previously. We cone-rod dystrophy, polydactyly, obesity, dia- report two siblings with Alström syndrome betes, and hypogonadism, however cardiomy- This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY- with conduction system involvement with left opathy is infrequently associated withuse this NC 3.0). bundle branch block on electrocardiogram condition. Kearns-Sayre syndrome is a pro- (ECG). One patient had first degree atrioven- gressive mitochondrial disorder associated ©Copyright R.J. Czosek et al., 2012 tricular block in addition to bundle branch with pigmentary retinal degeneration, com- Licensee PAGEPress, Italy block and underwent pacemaker implantation. plete heart block, cardiomyopathy, sen- Cardiogenetics 2012; 2:e2 This same patient developed intra-atrial re- sorineural hearing loss, diabetes mellitus, and doi:10.4081/cardiogenetics.2012.e2 entry tachycardia requiring anti-arrhythmic renal Fanconi disease that can have a very medication and eventual trans-catheter abla- similar phenotypic presentation. tion. The second patient developed atrial and Despite the frequent incidence of dilated outpatient follow-up visit, he demonstrated ventricular arrhythmias and underwent place- cardiomyopathy reported in patients with improved ventricular function with a shorten- 6 ment of a bi-ventricular defibrillator. These Alström syndrome (60%), conduction system ing fraction of 30%. He was initially diagnosed findings suggest that cardiac conduction sys- involvement or cardiac arrhythmias have not with tachycardia-mediated cardiomyopathy. tem involvement and clinical arrhythmia may been described in this patient population to His cardiac function was thought to likely be significant yet under-recognized complica- date and the longitudinal cardiac features have improve in time with management of the tions in patients with Alström syndrome. been poorly documented. We report two sib- arrhythmia. Patients should be routinely screened with lings with Alström syndrome whose phenotype Six months later he was noted to have con- ECG and Holter monitoring in additionNon-commercial to included conduction system involvement and cerning left ventricular (LV) dilation and a pro- echocardiographic assessment and a cardiolo- significant clinical arrhythmias. gressive widening of his QRS interval (148 ms gist experienced with cardiomyopathy should combined; PR interval of 196 ms) with stable be an integral part of the care team. function (Figure 3A). These new electrocardio- gram (ECG) findings in the context of his previ- Case Reports ously noted retinitis pigmentosa raised concern for Kearns-Sayre syndrome. He was referred to Introduction Case #1 a pediatric geneticist and a cardiologist with The first patient is a 20-year-old male who cardiomyopathy experience. On exam he was Alström syndrome is a rare autosomal reces- initially presented to cardiology at the age of noted to have short stature (2%ile). Additional sive disorder. Its hallmark features include 17 years for tachycardia (Figure 1A). Prior to testing demonstrated high frequency sen- dilated cardiomyopathy, nystagmus and pig- his evaluation by cardiology, he had been diag- sorineural hearing loss and glucose intolerance. mentary retinopathy, childhood obesity with- nosed with retinitis pigmentosa and had mtDNA testing in blood for common out hyperphagia, and sensorineural hearing severe visual impairment. Upon presentation deletions/duplications including Kearns-Sayre loss. This disorder has progressive multi-sys- he had moderate ventricular dysfunction with syndrome was normal. A cardiac biopsy showed temic effects with patients developing meta- a shortening fraction (SF) of 23% and mild left displacement of myofibrils. By electron bolic syndrome (hypercholesterolemia, hyper- atrial enlargement (Figure 2A). During this microscopy, the intermyofibril spaces were triglyceridemia, insulin resistant diabetes), admission, the patient was started on digoxin filled with increased numbers of mitochondria endocrine (thyroid, growth, sex hormone dys- for treatment of his tachycardia. At his initial with striking proliferative features and, in some [page 6] [Cardiogenetics 2012; 2:e2] Brief Report areas, glycogen granules, consistent with a and electrophysiological data. Patient informa- mitochondrial disorder. He developed progres- Materials and Methods tion was collected as part of a clinical registry sive first degree AV block, and underwent place- study approved by the Institutional Review ment of a dual chamber pacemaker. A skeletal Patient, family and medical history were Board of Cincinnati Children’s Hospital. muscle biopsy was performed while under anes- evaluated in two siblings with Alström syn- Patient consent was obtained for photography thesia for his pacemaker placement. Testing of drome including genetic, echocardiographic and publication. the muscle biopsy for deletions, the gold stan- dard diagnostic test for Kearns-Sayre, was nor- mal. Given this patient’s constellation of symp- toms, Alström syndrome was considered. He was found to have two ALMS1 mutations (c.7369_7370delGA (p.Asp2457Stop) and c.7374_7375delGA (p.Asp2459Stop)) which con- firmed a diagnosis of Alström syndrome. Over the next two years this patient devel- oped progressive QRS widening with a left bundle branch block pattern and was admitted for atrial flutter which was successfully car- dioverted. Five months following his device implantation he developed atrial flutter refrac- tory to electrical cardioversion or amiodarone therapy, and required trans-venous ablation of several intra-atrial reentry circuits (Figure 3B). To date he remains clinically stable in only sinus rhythm with mild LV dysfunction on a medical regimen of atenolol, lisinopril, met- Figure 1. Clinical facial features of described patients with Alström syndrome. A) Case #1; formin and lasix. B) Case #2. use Case #2 The second patient is a 25-year-old female (Figure 1B) who initially presented for cardiac evaluation at the age of 23 years following the diagnosis of dilated cardiomyopathy in her younger brother (Patient #1). Prior to evalua- tion in the cardiology clinic, she had been diagnosed with retinitis pigmentosa, systemic hypertension and Type II diabetes mellitus. Upon initial evaluation, her echocardiogram demonstrated borderline normal ventricular function with a SF of 27% and mild left atrial dilation (Figure 2B). Initial ECG demonstrated a left bundle branch block pattern with a QRS duration of 125 ms (Figure 3C). She was start- ed on carvedilol in addition to herNon-commercial prior regi- men of lisinopril and metformin. ALMS1 testing was performed on this patient for her known familial mutations which confirmed a