Here, we have represented severe infantile-onset cardiomyopathy in a family with a recently recognized mutation of ALMS1 . Although genotype-phenotype correlation has not been demonstrated for specific clinical spectrum for the individual mutations in ALMS1 in all reported articles to cardiomyopathies, we think that the c.7911dupC (p. Asn2638Glnfs*24) novel mutation may be one of the major determinants of the severe cardiomyopathy.
The cohort of patients with ALMS1 has demonstrated two different major clinical spectrums in relation to cardiomyopathy: those with infantile onset (43%) and those with later onset (18%). Cardiomyopathy has not been diagnosed in the remaining patients (39%, ages 2–33 years). Patients with infantile onset of cardiomyopathy have had apparent recovery of cardiac function within three years . Previous reports have suggested complete recovery of infantile onset cardiomyopathy in Alström syndrome patients .
Bond et al. observed seven families in which heart failure due to dilated cardiomyopathy had been presented as a symptom within the first three months. In that study, all patients responded to conventional supportive therapy, and the cardiomyopathy appeared to resolve spontaneously within six months. The authors suggested that dilated cardiomyopathy in ALMS1 presenting in the first year of life can regress completely .
Brofferio et al. suggested that cardiac involvement in ALMS1 is more common than previously reported. A third (13 of 38) of patients in their study had infantile cardiomyopathy, with EF results ranging from 40 to 66%. The authors proposed longitudinal follow-up studies to determine whether this mild cardiomyopathy progresses into more significant disease in all Alström syndrome patients .
Due to the reported outcomes of cardiomyopathy in ALMS1, most series report cardiac function with a history of infantile cardiomyopathy that improves within the first 2–3 years of life [12,13]. However, we suggest that recovery of cardiac function is not best characterized by time; rather, it is a matter of the type and characterization of the mutation. The severity of cardiomyopathy depends on the truncated protein accordingly the mutation. In our patient series with the ALMS1 c.7911dupC (p. Asn2638Glnfs*24) mutation, cardiomyopathy partially resolved in two cases (Patient D, G) while two patients with the same mutation died despite maximal drug support. Similar to our results Mahamid et al  reported two brothers, 2 and 3 years of age, diagnosed with Alström syndrome during febrile respiratory infection who initially presented in infancy with severe dilated cardiomyopathy. The disease course in the older sibling has mainly resolved while cardiomyopathy in the younger sibling deteriorated despite maximal support with heart failure medications.
Our finding of LV systolic and diastolic dysfunctions in all the children are in accord with previous reports . Phenotypic variation, such as differences in severity of cardiomyopathy among siblings with the same mutation, suggests that besides any variability due to the mutation itself, there is interplay between multitudes of potential genetic modifiers, with environmental factors leading to the range in severity of the Alström syndrome phenotypic spectrum .
In genotype-phenotype correlation studies, researchers have found no association between the location or type of ALMS1 mutations and T2D, body mass index (BMI), or the occurrence of dilated cardiomyopathy [10,17]. In another study, however, Ichihara et al. did identify a link between the polyglutamine repeat in ALMS1 and early onset myocardial infarct .
Despite advances in our knowledge of the spectrum of ALMS1 mutations, we still do not have enough evidence for prognostic predictions based on genotype. Histopathology of affected patients has shown diffuse interstitial fibrosis affecting the myocardium, a finding that was later confirmed by cardiac MRI 5,6. Dilated cardiomyopathy (DCM) can occur suddenly in infancy (in first months of life) due to aberrant differentiation of cardiomyocytes [19, 20]. Histologic findings of infantile cardiomyopathy have not been presented yet, but there are studies in which mitogenic cardiomyopathy is described in patients with Alström syndrome [21,22].
Mitogenic cardiomyopathy is a very rare human phenotype. Shenje et al. showed homozygous or compound heterozygous mutations among six infants with Alström syndrome, suggesting that mitogenic cardiomyopathy is the main cause of lethal cardiomyopathy. They showed that ALMS1 is a key for cell cycle regulation in perinatal cardiomyocytes. The hearts of each of the individuals they studied were removed, either at the time of transplantation due to end-stage heart failure or after death from heart failure . Although we did not perform autopsies, mitogenic cardiomyopathy may be posited as the cause of death of our patient with severe infantile cardiomyopathy. Restrictive cardiomyopathy develops slowly in adolescents and adults . Our first adolescent case (Patient A) died because of restrictive cardiomyopathy, in line with previous reports.
Although intra-familial differences observed in the disease presentation of our patients carrying the same mutation (Patients B, C, D, E and F) complicated our notion about this recently recognized mutation, we suggest that there are mutations which tend to severe cardiomyopathy. Some authors have suggested that environmental and unknown genetic modifiers probably interact with ALMS113 children growing up in the same family with similar environmental factors to support expression patterns of genotype. Further to the evidence from our patients, Hollander et al. showed that the clinical course of Alström syndrome may vary with regard to cardiac disease manifestations even in monozygotic twins .
In a literature review of 44 patients from our country by Ozanturk et al, the authors reported death of two ALMS1 patients with unknown genetic mutation maybe linked to CMP . Our patients had not been displayed in that study. In our ALMS1 cohort, cardiomyopathy appeared to be a primary manifestation.
However, the individuals in current cohort also displayed significant metabolic disturbances, including T2D, vision and hearing loss, elevated triglyceride and cholesterol levels, and obesity. These metabolic disturbances can themselves be significant cardiac risk factors over time. In a study made by Brofferio et al. there were subclinical strain echocardiographic abnormalities in nearly all patients in their cohort, suggesting the presence of myocardial disease in patients without overt cardiomyopathy, including those who have recovered from infantile cardiomyopathy 11. Our findings of abnormal GLS with LV systolic dysfunction and restrictive cardiomyopathy of both ventricles support their results.
In another study, while mild interstitial myocardial fibrosis was present in patients without a prior history of dilated cardiomyopathy, moderate-to-severe interstitial fibrosis was found in ALMS1 patients with history of dilated cardiomyopathy 4. Progressive fibrosis along with cardiac risk factors (obesity, T2DM) can explain restrictive cardiomyopathy of our case (Patient A) diagnosed in adolescence with restrictive cardiomyopathy.