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Jan D. Marshall - One of the best experts on this subject based on the ideXlab platform.
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Alstrom Syndrome renal findings in correlation with obesity insulin resistance dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the nih clinical center
Molecular Genetics and Metabolism, 2018Co-Authors: Meryl Waldman, Jurgen K Naggert, Joan C Han, Daniela P Reyescapo, Joy Bryant, Kathryn A Carson, Baris Turkbey, Peter L Choyke, William A Gahl, Jan D. MarshallAbstract:Abstract Alstrom Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR 2 and proteinuria); all were adults with median age of 32.8 (20.6–37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the Syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alstrom Syndrome, identification of novel targeted therapies is needed.
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comprehensive endocrine metabolic evaluation of patients with Alstrom Syndrome compared with bmi matched controls
The Journal of Clinical Endocrinology and Metabolism, 2018Co-Authors: Jan D. Marshall, Joan C Han, Daniela P Reyescapo, Joy Bryant, Chiaying Liu, James C Reynolds, Evrim B Turkbey, Ismail B Turkbey, Juergen K NaggertAbstract:Background Alstrom Syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body-associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. Objective We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)-matched controls. Methods We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. Results Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic Syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). Conclusion Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.
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characteristics of cardiomyopathy in Alstrom Syndrome prospective single center data on 38 patients
Molecular Genetics and Metabolism, 2017Co-Authors: Alessandra Brofferio, Juergen K Naggert, Jan D. Marshall, Joy Bryant, Vandana Sachdev, Hwaida Hannoush, Stanislav Sidenko, Anna Noreuil, Arlene Sirajuddin, Joan C HanAbstract:Abstract Background Alstrom 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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respiratory manifestations in 38 patients with Alstrom Syndrome
Pediatric Pulmonology, 2017Co-Authors: Caroline Boerwinkle, Jan D. Marshall, Joy Bryant, William A Gahl, Kenneth N Olivier, Meral GunayaygunAbstract:Summary Objectives: Alstrom Syndrome (AS) is a rare, multi-system condition characterized by retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, hypertriglyceridemia, cardiomyopathy, hepatorenal disease, and recurrent respiratory infections. It belongs to a group of genetic disorders known as primary ciliopathies, which includes autosomal dominant and recessive polycystic kidney diseases, as well as Joubert and Bardet–Biedl Syndromes. Prior studies have suggested phenotypic overlap between primary ciliopathies affecting the non-motile, sensory cilia, and primary ciliary dyskinesia (PCD), a motile ciliopathy characterized by respiratory tract disease. Methods: We describe the burden of oto-sino-pulmonary disease in 38 individuals with AS and examines the degree of clinical overlap between PCD and AS. Evaluation at the NIH Clinical Center included clinical examination, chest imaging, and clinical history surveys, as well as measurement of nasal nitric oxide (nNO) in nine patients. Results: Recurrent otitis media was ubiquitous in the AS cohort (92%) with 50% requiring pressure equalization tube placement. A history of bronchitis/pneumonia and sinusitis was reported in 61% and 50% of individuals, respectively. PCD-characterizing symptoms (laterality defects, unexplained neonatal respiratory distress, year-round nasal congestion, and wet cough) were far less prevalent in the AS cohort compared to PCD, and the average nNO production in the AS cohort was 232 ± 57.1 nl/min compared to a cut-off of <77 nl/min for PCD. Conclusions: These data suggest that the oto-sino-respiratory complications in AS are prominent enough to warrant increased clinical attention, but significantly impaired respiratory cilia function as seen in PCD is unlikely in AS. (www.clinicaltrials.gov, trial NCT00068224) Pediatr Pulmonol. 2017;52:487–493. © 2016 Wiley Periodicals, Inc.
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long term clinical follow up and molecular testing for diagnosis of the first tunisian family with Alstrom Syndrome
European Journal of Medical Genetics, 2016Co-Authors: A Chakroun, Jan D. Marshall, Mariem Ben Said, Amine Ennouri, I Achour, M Mnif, Mohamed Abid, A Ghorbel, Jurgen K Naggert, Saber MasmoudiAbstract:Abstract Alstrom Syndrome is a clinically complex disorder characterized by progressive degeneration of sensory functions, resulting in visual and audiological impairment as well as metabolic disturbances. It is caused by recessively inherited mutations in the ALMS1 gene, which codes for a centrosomal/basal body protein. The purpose of this study was to investigate the genetic and clinical features of two Tunisian affected siblings with Alstrom Syndrome. Detailed clinical examinations were performed including complete ophthalmic examination, serial audiograms and several biochemical and hormonal blood tests. For the molecular study, first genomic DNA was isolated using a standard protocol. Then, linkage analysis with microsatellite markers was performed and DNA array was used to detect known mutations. Subsequently, all ALMS1 exons were simultaneously sequenced for one affected patient with the TaGSCAN targeted sequencing panel. Finally, segregation of the causal variant was performed by Sanger sequencing. Both affected siblings had cone rod dystrophy with impaired visual acuity, sensorineural hearing loss and truncal obesity. One affected individual showed insulin resistance without diabetes mellitus. Other clinical features including cardiac and pulmonary dysfunction, hypothyroidism, hyperlipidemia, acanthosis nigricans, renal and hepatic dysfunction were absent. Genetic analysis showed the presence of a homozygous splice site mutation (c.10388-2A > G) in both affected siblings. Although Alstrom Syndrome is relatively well characterized disease, this Syndrome is probably misdiagnosed in Tunisia. Here, we describe the first report of Tunisian patients affected by this Syndrome and carrying a homozygous ALMS1 mutation. The diagnosis was suspected after long-term clinical follow-up and confirmed by genetic testing.
Gayle B. Collin - One of the best experts on this subject based on the ideXlab platform.
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pituitary morphovolumetric changes in Alstrom Syndrome
Journal of Neuroradiology, 2016Co-Authors: Valentina Citton, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Alessandro Baglione, Roberto Vettor, Renzo ManaraAbstract:Summary Purpose Alstrom Syndrome (AS) is a rare monogenic ciliopathy characterized by cone-code dystrophy, leading to early blindness, and obesity. Early endocrinological dysfunctions, especially growth hormone deficiency and hypogonadism, are detected in about half of AS patients. This MRI study investigates the presence of pituitary gland abnormalities in a large cohort of AS patients. Methods Pituitary morphological changes (gland flattening with partial or total empty sella) were evaluated on midsagittal high-resolution T1-weighted images of 32 AS patients (mean-age 23.2 ± 9.4 years; range: 6–45, 15 females) and 21 unrelated healthy subjects (mean age 23.2 ± 11.2 years; range: 6–43; 10 females). Results Among AS patients, 11/32 (34%) had total empty sella and 6/32 (19%) partial empty sella, while 3/21 (14%) of controls had partial empty sella and none presented with total empty sella (P Conclusions Total or partial empty sella appears commonly during the course of AS. Pituitary gland flattening might represent the morphological underpinning of subtle endocrinologic dysfunctions and raises the need to further investigate the pituitary function in this rare ciliopathy.
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Alstrom Syndrome is associated with short stature and reduced gh reserve
Clinical Endocrinology, 2013Co-Authors: Sara Romano, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Vera Bettini, Francesca Favaretto, Marina Paola Gardiman, Nella Augusta Greggio, G B Pozzan, Gayle B. CollinAbstract:SummaryIntroduction Alstrom Syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called ‘ciliopathies’ and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population. Material and Methods Twenty-three patients with ALMS (age, 1–52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone–releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic–pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. Results The length-for-age measurements from birth to 36 months showed normal growth with most values falling within −0·67 SDS to +1·28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16–20 years; mean SDS, −2·22 ± 1·16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154·7 ± 10·6 cm vs 162·9 ± 4·8 cm, P = 0·009) and a mild increase in BMI (Kg/m2) (27·8 ± 4·8 vs 24·1 ± 2·5, P = 0·007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11·9 ± 6·9 μg/l vs 86·1 ± 33·2 μg/l, P < 0·0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149·7 ± 6·2 cm vs 161·9 ± 9·2 cm, P = 0·04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. Conclusions Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.
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extreme clinical variability of dilated cardiomyopathy in two siblings with Alstrom Syndrome
Pediatric Cardiology, 2013Co-Authors: Jamal Mahamid, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Avraham Lorber, Yoseph Horovitz, Stavit A Shalev, Ronen SpiegelAbstract:Alstrom Syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report two brothers, 3 and 4 years of age and diagnosed with ALMS, who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intrafamilial variability. Although cardiomyopathy in the older sibling has mainly resolved thus 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 intrafamilial variability of ALMS, mainly during the natural course of cardiac disease.
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the Alstrom Syndrome protein alms1 interacts with α actinin and components of the endosome recycling pathway
PLOS ONE, 2012Co-Authors: Gayle B. Collin, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Daniel J Jagger, Benjamin L King, Jurgen K NaggertAbstract:Alstrom 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 Alstrom 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.
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arrayed primer extension technology simplifies mutation detection in bardet biedl and Alstrom Syndrome
European Journal of Human Genetics, 2011Co-Authors: Ines Pereiro, Gayle B. Collin, Jan D. Marshall, Jurgen K Naggert, Bethan E Hoskins, Teresa Pineirogallego, Eneli Oitmaa, Nicholas Katsanis, Diana Valverde, Philip L BealesAbstract:Bardet–Biedl Syndrome (BBS; OMIM no. 209 900) and Alstrom 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.
Juergen K Naggert - One of the best experts on this subject based on the ideXlab platform.
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comprehensive endocrine metabolic evaluation of patients with Alstrom Syndrome compared with bmi matched controls
The Journal of Clinical Endocrinology and Metabolism, 2018Co-Authors: Jan D. Marshall, Joan C Han, Daniela P Reyescapo, Joy Bryant, Chiaying Liu, James C Reynolds, Evrim B Turkbey, Ismail B Turkbey, Juergen K NaggertAbstract:Background Alstrom Syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body-associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. Objective We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)-matched controls. Methods We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. Results Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic Syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). Conclusion Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.
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characteristics of cardiomyopathy in Alstrom Syndrome prospective single center data on 38 patients
Molecular Genetics and Metabolism, 2017Co-Authors: Alessandra Brofferio, Juergen K Naggert, Jan D. Marshall, Joy Bryant, Vandana Sachdev, Hwaida Hannoush, Stanislav Sidenko, Anna Noreuil, Arlene Sirajuddin, Joan C HanAbstract:Abstract Background Alstrom 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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auditory and otologic profile of Alstrom Syndrome comprehensive single center data on 38 patients
American Journal of Medical Genetics Part A, 2017Co-Authors: Spencer Lindsey, Juergen K Naggert, Joy Bryant, Carmen C Brewer, Olga Stakhovskaya, Hung Jeffrey Kim, Chris Zalewski, Kelly A King, William A GahlAbstract:Alstrom Syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7–37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5–15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10–15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation.
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pituitary morphovolumetric changes in Alstrom Syndrome
Journal of Neuroradiology, 2016Co-Authors: Valentina Citton, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Alessandro Baglione, Roberto Vettor, Renzo ManaraAbstract:Summary Purpose Alstrom Syndrome (AS) is a rare monogenic ciliopathy characterized by cone-code dystrophy, leading to early blindness, and obesity. Early endocrinological dysfunctions, especially growth hormone deficiency and hypogonadism, are detected in about half of AS patients. This MRI study investigates the presence of pituitary gland abnormalities in a large cohort of AS patients. Methods Pituitary morphological changes (gland flattening with partial or total empty sella) were evaluated on midsagittal high-resolution T1-weighted images of 32 AS patients (mean-age 23.2 ± 9.4 years; range: 6–45, 15 females) and 21 unrelated healthy subjects (mean age 23.2 ± 11.2 years; range: 6–43; 10 females). Results Among AS patients, 11/32 (34%) had total empty sella and 6/32 (19%) partial empty sella, while 3/21 (14%) of controls had partial empty sella and none presented with total empty sella (P Conclusions Total or partial empty sella appears commonly during the course of AS. Pituitary gland flattening might represent the morphological underpinning of subtle endocrinologic dysfunctions and raises the need to further investigate the pituitary function in this rare ciliopathy.
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Alstrom Syndrome cardiac magnetic resonance findings
International Journal of Cardiology, 2013Co-Authors: Francesco Corbetti, Juergen K Naggert, Jan D. Marshall, Gabriella Milan, Renato Razzolini, Vera Bettini, Francesco Tona, Pietro MaffeiAbstract:Abstract Background Alstrom Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1 . Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR). Methods Eight genetically proven ALMS patients (ages 11–41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group. Results In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5min: 152±12 vs 186±16, p 0.0002; 10min: 175±8 vs 204±18, p 0.0012; 15min: 193±9 vs 224±16, p 0.0002). Conclusions Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.
Pietro Maffei - One of the best experts on this subject based on the ideXlab platform.
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defining renal phenotype in Alstrom Syndrome
Nephrology Dialysis Transplantation, 2020Co-Authors: Shanat Baig, Pietro Maffei, Timothy Barrett, R B Paisey, Charlotte Dawson, James Hodson, Srinivasa Bhargav Rambhatla, Priyesh Chauhan, Shaun Bolton, Francesca DassieAbstract:BACKGROUND Alstrom Syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the Syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD Prospective observational cohort study. SETTING AND PARTICIPANTS Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.
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pituitary morphovolumetric changes in Alstrom Syndrome
Journal of Neuroradiology, 2016Co-Authors: Valentina Citton, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Alessandro Baglione, Roberto Vettor, Renzo ManaraAbstract:Summary Purpose Alstrom Syndrome (AS) is a rare monogenic ciliopathy characterized by cone-code dystrophy, leading to early blindness, and obesity. Early endocrinological dysfunctions, especially growth hormone deficiency and hypogonadism, are detected in about half of AS patients. This MRI study investigates the presence of pituitary gland abnormalities in a large cohort of AS patients. Methods Pituitary morphological changes (gland flattening with partial or total empty sella) were evaluated on midsagittal high-resolution T1-weighted images of 32 AS patients (mean-age 23.2 ± 9.4 years; range: 6–45, 15 females) and 21 unrelated healthy subjects (mean age 23.2 ± 11.2 years; range: 6–43; 10 females). Results Among AS patients, 11/32 (34%) had total empty sella and 6/32 (19%) partial empty sella, while 3/21 (14%) of controls had partial empty sella and none presented with total empty sella (P Conclusions Total or partial empty sella appears commonly during the course of AS. Pituitary gland flattening might represent the morphological underpinning of subtle endocrinologic dysfunctions and raises the need to further investigate the pituitary function in this rare ciliopathy.
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Degeneration and plasticity of the optic pathway in Alström Syndrome.
AJNR. American journal of neuroradiology, 2014Co-Authors: Renzo Manara, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Valentina Citton, Alessandro Baglione, Roberto Vettor, Jurgen K Naggert, A. Vitale, Chiara BrianiAbstract:BACKGROUND AND PURPOSE: Alstrom Syndrome is a rare inherited ciliopathy in which early progressive cone-rod dystrophy leads to childhood blindness. We investigated functional and structural changes of the optic pathway in Alstrom Syndrome by using MR imaging to provide insight into the underlying pathogenic mechanisms. MATERIALS AND METHODS: Eleven patients with genetically proved Alstrom Syndrome (mean age, 23 years; range, 6–45 years; 5 females) and 19 age- and sex-matched controls underwent brain MR imaging. The study protocol included conventional sequences, resting-state functional MR imaging, and diffusion tensor imaging. RESULTS: In patients with Alstrom Syndrome, the evaluation of the occipital regions showed the following: 1) diffuse white matter volume decrease while gray matter volume decrease spared the occipital poles (voxel-based morphometry), 2) diffuse fractional anisotropy decrease and radial diffusivity increase while mean and axial diffusivities were normal (tract-based spatial statistics), and 3) reduced connectivity in the medial visual network strikingly sparing the occipital poles (independent component analysis). After we placed seeds in both occipital poles, the seed-based analysis revealed significantly increased connectivity in patients with Alstrom Syndrome toward the left frontal operculum, inferior and middle frontal gyri, and the medial portion of both thalami (left seed) and toward the anterior portion of the left insula (right and left seeds). CONCLUSIONS: The protean occipital brain changes in patients with Alstrom Syndrome likely reflect the coexistence of diffuse primary myelin derangement, anterograde trans-synaptic degeneration, and complex cortical reorganization affecting the anterior and posterior visual cortex to different degrees.
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Alstrom Syndrome is associated with short stature and reduced gh reserve
Clinical Endocrinology, 2013Co-Authors: Sara Romano, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Vera Bettini, Francesca Favaretto, Marina Paola Gardiman, Nella Augusta Greggio, G B Pozzan, Gayle B. CollinAbstract:SummaryIntroduction Alstrom Syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called ‘ciliopathies’ and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population. Material and Methods Twenty-three patients with ALMS (age, 1–52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone–releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic–pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. Results The length-for-age measurements from birth to 36 months showed normal growth with most values falling within −0·67 SDS to +1·28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16–20 years; mean SDS, −2·22 ± 1·16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154·7 ± 10·6 cm vs 162·9 ± 4·8 cm, P = 0·009) and a mild increase in BMI (Kg/m2) (27·8 ± 4·8 vs 24·1 ± 2·5, P = 0·007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11·9 ± 6·9 μg/l vs 86·1 ± 33·2 μg/l, P < 0·0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149·7 ± 6·2 cm vs 161·9 ± 9·2 cm, P = 0·04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. Conclusions Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.
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Alstrom Syndrome cardiac magnetic resonance findings
International Journal of Cardiology, 2013Co-Authors: Francesco Corbetti, Juergen K Naggert, Jan D. Marshall, Gabriella Milan, Renato Razzolini, Vera Bettini, Francesco Tona, Pietro MaffeiAbstract:Abstract Background Alstrom Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1 . Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR). Methods Eight genetically proven ALMS patients (ages 11–41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group. Results In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5min: 152±12 vs 186±16, p 0.0002; 10min: 175±8 vs 204±18, p 0.0012; 15min: 193±9 vs 224±16, p 0.0002). Conclusions Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.
Gabriella Milan - One of the best experts on this subject based on the ideXlab platform.
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pituitary morphovolumetric changes in Alstrom Syndrome
Journal of Neuroradiology, 2016Co-Authors: Valentina Citton, Gayle B. Collin, Juergen K Naggert, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Alessandro Baglione, Roberto Vettor, Renzo ManaraAbstract:Summary Purpose Alstrom Syndrome (AS) is a rare monogenic ciliopathy characterized by cone-code dystrophy, leading to early blindness, and obesity. Early endocrinological dysfunctions, especially growth hormone deficiency and hypogonadism, are detected in about half of AS patients. This MRI study investigates the presence of pituitary gland abnormalities in a large cohort of AS patients. Methods Pituitary morphological changes (gland flattening with partial or total empty sella) were evaluated on midsagittal high-resolution T1-weighted images of 32 AS patients (mean-age 23.2 ± 9.4 years; range: 6–45, 15 females) and 21 unrelated healthy subjects (mean age 23.2 ± 11.2 years; range: 6–43; 10 females). Results Among AS patients, 11/32 (34%) had total empty sella and 6/32 (19%) partial empty sella, while 3/21 (14%) of controls had partial empty sella and none presented with total empty sella (P Conclusions Total or partial empty sella appears commonly during the course of AS. Pituitary gland flattening might represent the morphological underpinning of subtle endocrinologic dysfunctions and raises the need to further investigate the pituitary function in this rare ciliopathy.
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Degeneration and plasticity of the optic pathway in Alström Syndrome.
AJNR. American journal of neuroradiology, 2014Co-Authors: Renzo Manara, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Valentina Citton, Alessandro Baglione, Roberto Vettor, Jurgen K Naggert, A. Vitale, Chiara BrianiAbstract:BACKGROUND AND PURPOSE: Alstrom Syndrome is a rare inherited ciliopathy in which early progressive cone-rod dystrophy leads to childhood blindness. We investigated functional and structural changes of the optic pathway in Alstrom Syndrome by using MR imaging to provide insight into the underlying pathogenic mechanisms. MATERIALS AND METHODS: Eleven patients with genetically proved Alstrom Syndrome (mean age, 23 years; range, 6–45 years; 5 females) and 19 age- and sex-matched controls underwent brain MR imaging. The study protocol included conventional sequences, resting-state functional MR imaging, and diffusion tensor imaging. RESULTS: In patients with Alstrom Syndrome, the evaluation of the occipital regions showed the following: 1) diffuse white matter volume decrease while gray matter volume decrease spared the occipital poles (voxel-based morphometry), 2) diffuse fractional anisotropy decrease and radial diffusivity increase while mean and axial diffusivities were normal (tract-based spatial statistics), and 3) reduced connectivity in the medial visual network strikingly sparing the occipital poles (independent component analysis). After we placed seeds in both occipital poles, the seed-based analysis revealed significantly increased connectivity in patients with Alstrom Syndrome toward the left frontal operculum, inferior and middle frontal gyri, and the medial portion of both thalami (left seed) and toward the anterior portion of the left insula (right and left seeds). CONCLUSIONS: The protean occipital brain changes in patients with Alstrom Syndrome likely reflect the coexistence of diffuse primary myelin derangement, anterograde trans-synaptic degeneration, and complex cortical reorganization affecting the anterior and posterior visual cortex to different degrees.
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Alstrom Syndrome is associated with short stature and reduced gh reserve
Clinical Endocrinology, 2013Co-Authors: Sara Romano, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Vera Bettini, Francesca Favaretto, Marina Paola Gardiman, Nella Augusta Greggio, G B Pozzan, Gayle B. CollinAbstract:SummaryIntroduction Alstrom Syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called ‘ciliopathies’ and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population. Material and Methods Twenty-three patients with ALMS (age, 1–52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone–releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic–pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. Results The length-for-age measurements from birth to 36 months showed normal growth with most values falling within −0·67 SDS to +1·28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16–20 years; mean SDS, −2·22 ± 1·16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154·7 ± 10·6 cm vs 162·9 ± 4·8 cm, P = 0·009) and a mild increase in BMI (Kg/m2) (27·8 ± 4·8 vs 24·1 ± 2·5, P = 0·007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11·9 ± 6·9 μg/l vs 86·1 ± 33·2 μg/l, P < 0·0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149·7 ± 6·2 cm vs 161·9 ± 9·2 cm, P = 0·04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. Conclusions Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.
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Alstrom Syndrome cardiac magnetic resonance findings
International Journal of Cardiology, 2013Co-Authors: Francesco Corbetti, Juergen K Naggert, Jan D. Marshall, Gabriella Milan, Renato Razzolini, Vera Bettini, Francesco Tona, Pietro MaffeiAbstract:Abstract Background Alstrom Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1 . Dilated cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR). Methods Eight genetically proven ALMS patients (ages 11–41) underwent CMR performed by standard cine steady state, T1, T2 and late gadolinium enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group. Results In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5min: 152±12 vs 186±16, p 0.0002; 10min: 175±8 vs 204±18, p 0.0012; 15min: 193±9 vs 224±16, p 0.0002). Conclusions Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.
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the Alstrom Syndrome protein alms1 interacts with α actinin and components of the endosome recycling pathway
PLOS ONE, 2012Co-Authors: Gayle B. Collin, Jan D. Marshall, Pietro Maffei, Gabriella Milan, Daniel J Jagger, Benjamin L King, Jurgen K NaggertAbstract:Alstrom 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 Alstrom 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.
