Characteristics of cardiomyopathy in Alström syndrome: Prospective single-center data on 38 patients

Abstract

Background Alström syndrome (AS) is a rare monogenetic disorder with multi-organ involvement. Complex metabolic disturbances are common and cardiomyopathy is a well-recognized feature in infants as well as in older children and adults. Although the mechanism of cardiomyopathy is not known, previous reports suggest that individuals with infantile-onset cardiac disease recover completely. Methods In this single center prospective series of 38 children and adults (age range 1.7 to 37.9 years; 20 females) with AS, we evaluated cardiac manifestations in detail, in the context of specific ALMS1 mutations and multisystem involvement. All patients underwent ALMS1 sequencing, biochemical testing, electrocardiogram, and echocardiographic imaging with speckle tracking to evaluate systolic strain; 21 patients underwent cardiac magnetic resonance imaging with T1 mapping. Results Approximately half of patients (17/38) had a previous diagnosis of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in 94% of patients and correlated with body mass index (r = 0.602, p = 0.002) and C-reactive protein level (r = 0.56, p = 0.004), but only in children. Electrocardiographic abnormalities were seen in two-thirds of patients, and left ventricular dilatation and/or dysfunction was present in 4 adults and 4 children. Conclusion AS patients with a history of resolved infantile cardiomyopathy continue to have residual impairment in cardiac function. For patients with a normal ejection fraction and no prior cardiac history, strain can be abnormal, suggesting subclinical cardiac involvement. Close cardiac screening and aggressive modification of other manifestations of AS that are risk factors for cardiac disease, including obesity, inflammation, diabetes and dyslipidemia, are essential in caring for patients with AS.

Genomic knockout ofalms1in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

“…Closer examination revealed a loss of ventricular wall integrity in the alms1 −/− fish (Fig 2C”). These findings are consistent with cardiomyopathy in Alström, including the reported variability in phenotypic presentation in patients (19).…”

“…Having confirmed the presence of previously reported prominent multi-organ features in the alms1 −/− zebrafish (4,18,19), we explored the possibility of metabolic defects. Alström patients exhibit high rates of early onset obesity coupled with hyperinsulinemia and progression to frank T2DM, often as early as the second decade of life (4).…”

“…Nearly two-thirds of Alström syndrome patients present with dilated cardiomyopathy and congestive heart failure contributes to a significant portion of the reported mortality (19). The earliest manifestation of cardiomyopathy in zebrafish is cardiac edema, which results from failed contractility, loss of vascular integrity or ventricular malformations and can develop by 48 hpf (20).…”

Clinical characteristics of individual organ system disease in non-motile ciliopathies

“…Two different forms of myocardial disease occur in AS [82,87]. A subset of AS patients present in early infancy with severe infantile cardiomyopathy characterized by mitogenic histopathological features including cardiomyocyte hyperplasia and proliferation [88].…”

ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits

“…Dilated cardiomyopathy (DCM) may arise in infancy, then often resolve or at least abate within 3 years. However, it may recur, or manifest for the first time, in adolescence or adulthood [2, 3, 4, 7]. Other common features include hepatic, renal and pulmonary dysfunction, chronic otitis media in childhood, abnormal spinal curvature (scoliosis, kyphosis or lordosis) arising in adolescence, short stature in adulthood, gastrointestinal disturbances and neurological disturbances such as absence seizures [3–6].…”