Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings

Louw, Jacoba; Corveleyn, Anniek; Jia, Yaojuan; Iqbal, Sajid; Boshoff, Derize; Gewillig, Marc; Peeters, Hilde; Moerman, Philippe; Devriendt, Koenraad

doi:10.1016/j.ejmg.2014.06.004

Cited by 34 publications

(48 citation statements)

References 17 publications

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“…While fibrosis may be an important player in late onset cardiomyopathy in AS, the acute infantile cardiomyopathy in this disorder appears to have a different pathophysiology. A mitogenic cardiomyopathy associated with an increased number of cardiomyocytes in mitosis was part of the histopathology of two siblings with AS [26]. Consistent with this observation, Shenje et al showed increased cardiomyocyte proliferation in two-week old homozygous Alms1 -mutant mice and concluded that deficiency of ALMS1 protein impairs postnatal cardiomyocyte cell cycle arrest [7].…”

Section: Discussionmentioning

confidence: 85%

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

Brofferio

Sachdev

Hannoush

et al. 2017

Molecular Genetics and Metabolism

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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.

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Section: Discussionmentioning

confidence: 85%

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

Brofferio

Sachdev

Hannoush

et al. 2017

Molecular Genetics and Metabolism

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“…Beyond optimization of the patient’s care, recognition of recessive inheritance as the underlying mechanism for sporadic disease, conferring a 25% recurrence risk, has informed family planning. Insights into the pathobiology of mitogenic cardiomyopathy, a form of DCM in Alström syndrome characterized by myocyte nuclear hypertrophy and marked mitotic activity, are emerging [Chang et al, 2010, Shenje et al, 2014, Louw et al, 2014], but further research will be required to develop individualized, mechanism-based therapy beyond traditional reverse cardiac remodeling drugs.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non‐syndromic dilated cardiomyopathy

Long

Evans

Olson

2015

American J of Med Genetics Pt A

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Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care.

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“…Intriguingly, biallelic mutations in ALMS1 also cause mitogenic cardiomyopathy, an ultra-rare form of DCM characterised by delayed cell cycle arrest of neonatal cardiomyocytes [15, 16]. This condition is fatal in the first months of life, before other clinical features of AS normally manifest.…”

Section: Introductionmentioning

confidence: 99%

“…Alms1 also appears to be required for timely postnatal cell cycle arrest of cardiomyocytes in mice [15]. Thus, mitogenic cardiomyopathy is most likely an extreme form of the infantile DCM often observed in AS [15, 16]. Mechanisms regulating cardiomyocyte cell cycle arrest are of great interest partly because reversing this process could provide a way to stimulate cardiac regeneration after injury [17].…”

Section: Introductionmentioning

confidence: 99%

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

Hearn

2018

J Mol Med

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Alström syndrome (AS) is characterised by metabolic deficits, retinal dystrophy, sensorineural hearing loss, dilated cardiomyopathy and multi-organ fibrosis. Elucidating the function of the mutated gene, ALMS1, is critical for the development of specific treatments and may uncover pathways relevant to a range of other disorders including common forms of obesity and type 2 diabetes. Interest in ALMS1 is heightened by the recent discovery of its involvement in neonatal cardiomyocyte cell cycle arrest, a process with potential relevance to regenerative medicine. ALMS1 encodes a ~ 0.5 megadalton protein that localises to the base of centrioles. Some studies have suggested a role for this protein in maintaining centriole-nucleated sensory organelles termed primary cilia, and AS is now considered to belong to the growing class of human genetic disorders linked to ciliary dysfunction (ciliopathies). However, mechanistic details are lacking, and recent studies have implicated ALMS1 in several processes including endosomal trafficking, actin organisation, maintenance of centrosome cohesion and transcription. In line with a more complex picture, multiple isoforms of the protein likely exist and non-centrosomal sites of localisation have been reported. This review outlines the evidence for both ciliary and extra-ciliary functions of ALMS1.

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Homozygous loss-of-function mutation in ALMS1 causes the lethal disorder mitogenic cardiomyopathy in two siblings

Cited by 34 publications

References 17 publications

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

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

Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non‐syndromic dilated cardiomyopathy

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

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