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1.  Extreme clinical variability of dilated cardiomyopathy in two siblings with Alström syndrome 
Pediatric cardiology  2012;34(2):455-458.
Alström syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report on two brothers, 2 and 3 years of age, diagnosed with Alström syndrome who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intra-familial variability. While cardiomyopathy in the older sibling has mainly resolved allowing for the discontinuation of medical therapy, heart function in the younger sibling continues to deteriorate despite maximal drug support with furosemide, carvedilol, captopril and aldospirone. Genetic analysis revealed homozygous mutations, c.8008C>T (R2670X), in ALMS1 resulting in premature protein truncation. This report further emphasizes the exceptional intra-familial variability of ALMS, mainly in the natural course of cardiac disease.
doi:10.1007/s00246-012-0296-6
PMCID: PMC3779600  PMID: 22447358
Alström syndrome; dilated cardiomyopathy; autosomal recessive; ALMS1 gene
2.  Differences in the clinical spectrum of two adolescent male patients with Alström syndrome 
Clinical dysmorphology  2013;22(1):7-12.
Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström’s syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistries, and ophthalmological, audiological, and genetic evaluations. Although both showed typical features of Alström syndrome in childhood, several differences were observed that have not been reported previously. Patient 1 was first studied at the age of 13 years for multisystemic disease and re-evaluated at the age of 15.5 years. Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic–clonic seizures with severe cognitive impairment, features not documented previously in this syndrome. Sequencing analysis indicated two novel ALMS1 mutations in exon 8: p.E1055GfsX4 and p.T1386NfsX15. Metabolic and physiological similarities were observed in both patients, including severe insulin resistance, and truncal obesity with fat loss suggestive of partial lipodystrophy, supporting evidence for a role for ALMS1 in adipose tissue function. The unusual phenotypes of clonic–tonic seizures and severe cognitive abnormalities and lipodystrophy-like adiposity pattern have not been documented previously in Alström syndrome and may be an under-reported abnormality.
doi:10.1097/MCD.0b013e32835b9017
PMCID: PMC3619948  PMID: 23188138
ALMS1; Alström syndrome; hypogonadotropic hypogonadism; partial lipodystrophy; tonic–clonic epilepsy
3.  Novel Alu Retrotransposon Insertion Leading to Alström Syndrome 
Human Genetics  2011;131(3):407-413.
Alström Syndrome is a clinically complex disorder characterized by childhood retinal degeneration leading to blindness, sensorineural hearing loss, obesity, type 2 diabetes mellitus, cardiomyopathy, systemic fibrosis, and pulmonary, hepatic, and renal failure. Alström Syndrome is caused by recessively inherited mutations in the ALMS1 gene, which codes for a putative ciliary protein. Alström Syndrome is characterized by extensive allelic heterogeneity, however founder effects have been observed in some populations. To date, more than 100 causative ALMS1 mutations have been identified, mostly frameshift and nonsense alterations resulting in termination signals in ALMS1. Here we report a complex Turkish kindred in which sequence analysis uncovered an insertion of a novel 333 basepair Alu Ya5 SINE retrotransposon in the ALMS1 coding sequence, a previously unrecognized mechanism underlying mutations causing Alström Syndrome. It is extraordinarily rare to encounter the insertion of an Alu retrotransposon in the coding sequence of a gene. The high frequency of the mutant ALMS1 allele in this isolated population suggests that this recent retrotransposition event spread quickly, and may be used as a model to study the population dynamics of deleterious alleles in isolated communities.
doi:10.1007/s00439-011-1083-9
PMCID: PMC3264847  PMID: 21877133
Alström Syndrome; ALMS1; Alu Ya5; Insertion Mutation; Short Interspersed Nuclear Elements (SINE)
4.  Brain involvement in Alström syndrome 
Background
Alström Syndrome (AS) is a rare ciliopathy characterized by cone–rod retinal dystrophy, sensorineural hearing loss, obesity, type 2 diabetes mellitus and cardiomyopathy. Most patients do not present with neurological issues and demonstrate normal intelligence, although delayed psychomotor development and psychiatric disorders have been reported. To date, brain Magnetic Resonance Imaging (MRI) abnormalities in AS have not been explored.
Methods
We investigated structural brain changes in 12 genetically proven AS patients (mean-age 22 years; range: 6–45, 6 females) and 19 matched healthy and positive controls (mean-age 23 years; range: 6–43; 12 females) using conventional MRI, Voxel-Based Morphometry (VBM) and Diffusion Tensor Imaging (DTI).
Results
6/12 AS patients presented with brain abnormalities such as ventricular enlargement (4/12), periventricular white matter abnormalities (3/12) and lacune-like lesions (1/12); all patients older than 30 years had vascular-like lesions. VBM detected grey and white matter volume reduction in AS patients, especially in the posterior regions. DTI revealed significant fractional anisotropy decrease and radial diffusivity increase in the supratentorial white matter, also diffusely involving those regions that appeared normal on conventional imaging. On the contrary, axial and mean diffusivity did not differ from controls except in the fornix.
Conclusions
Brain involvement in Alström syndrome is not uncommon. Early vascular-like lesions, gray and white matter atrophy, mostly involving the posterior regions, and diffuse supratentorial white matter derangement suggest a role of cilia in endothelial cell and oligodendrocyte function.
doi:10.1186/1750-1172-8-24
PMCID: PMC3584911  PMID: 23406482
Alström syndrome; MRI; DTI; VBM
5.  The progression from obesity to type 2 diabetes in Alström syndrome 
Pediatric Diabetes  2011;13(1):59-67.
Background
Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia and alterations of glucose metabolism that often lead to the development of type 2 diabetes in a young age.
Objective
Relationship between weight and metabolism has been studied in a group of ALMS patients and matched controls.
Research design and methods
Fifteen ALMS patients (8 M, 7 F, aged 3-51 yrs) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic (OGTT) conditions were measured. Further anthropometric and body composition data were obtained from an International group of 27 ALMS patients (13 M, 14 F, age range: 4-29 yrs).
Results
In ALMS we observed an inverse correlation between age and SDS for height, weight and BMI. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, while insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices HOMA-IR, ISI, HOMA%β cell and Insulinogenic Index in ALMS, but unlike the insulin-resistance indices, the beta-cell function indices showed a significant reduction with age.
Conclusions
In ALMS the progression from the early onset obesity towards the impaired fasting glucose or IGT and overt diabetes is mostly due to a progressive failure of β-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.
doi:10.1111/j.1399-5448.2011.00789.x
PMCID: PMC3345208  PMID: 21722283
Alström syndrome; ALMS1; obesity; diabetes; insulin resistance
7.  The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway 
PLoS ONE  2012;7(5):e37925.
Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS.
doi:10.1371/journal.pone.0037925
PMCID: PMC3365098  PMID: 22693585
8.  Arrayed primer extension technology simplifies mutation detection in Bardet–Biedl and Alström syndrome 
Bardet–Biedl syndrome (BBS; OMIM no. 209 900) and Alström syndrome (ALMS; OMIM no. 203 800) are rare, multisystem genetic disorders showing both a highly variable phenotype and considerable phenotypic overlap; they are included in the emerging group of diseases called ciliopathies. The genetic heterogeneity of BBS with 14 causal genes described to date, serves to further complicate mutational analysis. The development of the BBS–ALMS array which detects known mutations in these genes has allowed us to detect at least one mutation in 40.5% of BBS families and in 26.7% of ALMS families validating this as an efficient and cost-effective first pass screening modality. Furthermore, using this method, we found two BBS families segregating three BBS alleles further supporting oligogenicity or modifier roles for additional mutations. We did not observe more than two mutations in any ALMS family.
doi:10.1038/ejhg.2010.207
PMCID: PMC3060323  PMID: 21157496
Bardet–Biedl syndrome; BBS; Alström syndrome; ALMS1; arrayed primer extension; mutation analysis
9.  Alström Syndrome: Genetics and Clinical Overview 
Current Genomics  2011;12(3):225-235.
Alström syndrome is a rare autosomal recessive genetic disorder characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes, hypertriglyceridemia, short stature in adulthood, cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction. Symptoms first appear in infancy and progressive development of multi-organ pathology leads to a reduced life expectancy. Variability in age of onset and severity of clinical symptoms, even within families, is likely due to genetic background.
Alström syndrome is caused by mutations in ALMS1, a large gene comprised of 23 exons and coding for a protein of 4,169 amino acids. In general, ALMS1 gene defects include insertions, deletions, and nonsense mutations leading to protein truncations and found primarily in exons 8, 10 and 16. Multiple alternate splice forms exist. ALMS1 protein is found in centrosomes, basal bodies, and cytosol of all tissues affected by the disease. The identification of ALMS1 as a ciliary protein explains the range of observed phenotypes and their similarity to those of other ciliopathies such as Bardet-Biedl syndrome.
Studies involving murine and cellular models of Alström syndrome have provided insight into the pathogenic mechanisms underlying obesity and type 2 diabetes, and other clinical problems. Ultimately, research into the pathogenesis of Alström syndrome should lead to better management and treatments for individuals, and have potentially important ramifications for other rare ciliopathies, as well as more common causes of obesity and diabetes, and other conditions common in the general population.
doi:10.2174/138920211795677912
PMCID: PMC3137007  PMID: 22043170
ALMS1; Alström syndrome; ciliopathy; truncal obesity.
10.  Bardet-Biedl syndrome with end-stage kidney disease in a four-year-old Romanian boy: a case report 
Background
Bardet-Biedl syndrome is a significant genetic cause of chronic kidney disease in children. Kidney abnormalities are a major cause of morbidity and mortality in Bardet-Biedl syndrome, but the onset of end-stage renal disease at an early age and continuous ambulatory peritoneal dialysis, however, are not commonly mentioned in the literature.
Case presentation
We present the case of a four-year-old Romanian boy who presented to our department with 'febrile seizures'. After an initial evaluation, we diagnosed our patient as having hypertension, severe anemia and end-stage renal disease. He met the major and minor criteria for the diagnosis of Bardet-Biedl syndrome and underwent continuous ambulatory peritoneal dialysis.
Conclusions
Close follow-up for renal involvement in patients with Bardet-Biedl syndrome and Alström syndrome from an early age is highly recommended to prevent end-stage renal disease and so renal replacement therapy can be started immediately.
doi:10.1186/1752-1947-5-378
PMCID: PMC3174128  PMID: 21843323
11.  Protection From Clinical Peripheral Sensory Neuropathy in Alström Syndrome in Contrast to Early-Onset Type 2 Diabetes  
Diabetes Care  2009;32(3):462-464.
OBJECTIVE—Alström syndrome, with type 2 diabetes, and blindness could confer a high risk of foot ulceration. Clinical testing for neuropathy in Alström syndrome and matched young-onset type 2 diabetic subjects was therefore undertaken.
RESEARCH DESIGN AND METHODS—Fifty-eight subjects with Alström syndrome (18 insulin-resistant nondiabetic and 40 diabetic; aged 8–43 years) and 30 young-onset diabetic subjects (aged 13–35 years) were studied. Neuropathy symptom questionnaires were administered. Graded monofilament and 128-MHz tuning fork vibration perception were assessed in both feet.
RESULTS—Neuropathic symptoms, loss of monofilament, and/or vibration perception were reported by 12 of the 30 young-onset type 2 diabetic subjects (6 had neuropathic ulceration) but none of the subjects with Alström syndrome.
CONCLUSIONS—The striking preservation of protective foot sensation in Alström syndrome may provide a clue to the causes of differential susceptibility to neuropathy in the wider diabetic population.
doi:10.2337/dc08-1584
PMCID: PMC2646029  PMID: 19092165
12.  Caloric restriction in Alström syndrome prevents hyperinsulinemia 
Alström syndrome (AS; MIM 203800) is an autosomal recessive disorder characterized by cone-rod dystrophy, dilated cardiomyopathy, sensorineural hearing impairment, developmental delay, and most case had both childhood-onset obesity and hyperinsulinemia. Currently, the pathogenesis of this disease is not clear. Here we report an 18-month-old boy with Alström syndrome. He had obesity but with normal insulin and glucose levels. Molecular analysis of the ALMS1 gene revealed a homozygous deletion 11116_11134 del n(19) in exon 16. His body mass index decreased from 25.0 to 20.7 after calorie restriction for 9 months, and his insulin and glucose levels remained normal. Finding in this case suggests that hyperinsulinemia is a secondary event in Alström syndrome, and early-commenced treatment prevents hyperinsulinemia.
doi:10.1002/ajmg.a.32730
PMCID: PMC2820246  PMID: 19283853
Alström syndrome; ALMS1; obesity; hyperinsulinemia; calorie restriction
13.  ALMS1-Deficient Fibroblasts Over-Express Extra-Cellular Matrix Components, Display Cell Cycle Delay and Are Resistant to Apoptosis 
PLoS ONE  2011;6(4):e19081.
Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions.
doi:10.1371/journal.pone.0019081
PMCID: PMC3082548  PMID: 21541333

Results 1-13 (13)