Alström syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center.

Alström 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 < 60 mL/min/1.73 m2 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 Alström syndrome, identification of novel targeted therapies is needed.

Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls.

Background: Alström 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.

Auditory and otologic profile of Alström syndrome: Comprehensive single center data on 38 patients.

Alström 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.

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

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 37.9years; 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.

Spectral-domain optical coherence tomography findings in Alström syndrome.

BACKGROUND: Alström syndrome is a multi-system recessive disorder caused by mutations in ALMS1 gene. The aim of this study was to characterize morphological retinal changes in Alström patients using spectral-domain optical coherence tomography. METHODS: We studied volunteer patients attending the conference of Alström Syndrome International, a support group for affected families, using hand-held spectral-domain optical coherence tomography (SD-OCT) in an office setting. Patients had a clinical dilated retinal examination. Past medical records were reviewed. RESULTS: Twenty-two Alström patients (mean age 17 years, range 2-38 years, 12 males) were studied. OCT imaging demonstrated that central macular OCT changes are often mild during the first decade of life and gradually progress, demonstrating disruption of normal retinal architecture, and progressive loss of photoreceptors and retinal pigment epithelium. Other changes found included hyperreflectivities in all retinal layers, severe retinal wrinkling, optic nerve drusen, and vitreoretinal separation. Vision correlated with severity of OCT macular changes (r = 0.89, p = 0.002). CONCLUSIONS: This study reports on OCT findings in a large group of patients with Alström syndrome. We document a panretinal gradual progression of retinal changes, which are often mild during the first years of life. Previously unreported observations include intraretinal opacities, optic nerve drusen, and foveal contour abnormalities. Morphological retinal changes demonstrated by SD-OCT may help in understanding the pathophysiology of the disease and defining strategies for treatment such as gene therapy.

Respiratory manifestations in 38 patients with Alström syndrome.

OBJECTIVES: Alström 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.

Long-term clinical follow-up and molecular testing for diagnosis of the first Tunisian family with Alström syndrome.

Alström 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 Alström 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 Alström 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.

Pituitary morphovolumetric changes in Alström syndrome.

PURPOSE: Alström 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<0.005). AS patients harboring a total or partial empty sella did not differ from those with normal pituitary gland for gender (P=0.98), BMI (P=0.10) or visual impairment (P=0.21), while the presence of empty sella was associated with an older age (P=0.007) being especially frequent above the age of 30. 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.

Theory-of-mind in individuals with Alström syndrome is related to executive functions, and verbal ability.

OBJECTIVE: This study focuses on cognitive prerequisites for the development of theory-of-mind (ToM), the ability to impute mental states to self and others in young adults with Alström syndrome (AS). AS is a rare and quite recently described recessively inherited ciliopathic disorder which causes progressive sensorineural hearing loss and juvenile blindness, as well as many other organ dysfunctions. Two cognitive abilities were considered; Phonological working memory (WM) and executive functions (EF), both of importance in speech development. METHODS: Ten individuals (18-37 years) diagnosed with AS, and 20 individuals with no known impairment matched for age, gender, and educational level participated. Sensory functions were measured. Information about motor functions and communicative skills was obtained from responses to a questionnaire. ToM was assessed using Happés strange stories, verbal ability by a vocabulary test, phonological WM by means of an auditory presented non-word serial recall task and EF by tests of updating and inhibition. RESULTS: The AS group performed at a significantly lower level than the control group in both the ToM task and the EF tasks. A significant correlation was observed between recall of non-words and EF in the AS group. Updating, but not inhibition, correlated significantly with verbal ability, whereas both updating and inhibition were significantly related to the ability to initiate and sustain communication. Poorer performance in the ToM and EF tasks were related to language perseverance and motor mannerisms. CONCLUSION: The AS group displayed a delayed ToM as well as reduced phonological WM, EF, and verbal ability. A significant association between ToM and EF, suggests a compensatory role of EF. This association may reflect the importance of EF to perceive and process input from the social environment when the social interaction is challenged by dual sensory loss. We argue that limitations in EF capacity in individuals with AS, to some extent, may be related to early blindness and progressive hearing loss, but maybe also to gene specific abnormalities.

Histopathology of the human inner ear in Alström's syndrome.

Alström's syndrome is an autosomal recessive syndromic genetic disorder caused by mutations in the ALMS1 gene. Sensorineural hearing loss occurs in greater than 85% of patients. Histopathology of the inner ear abnormalities in the human has not previously been fully described. Histopathology of the inner ear in Alström's syndrome is presented in 2 genetically confirmed cases. The predominant histopathologic correlates of the sensorineural loss were degeneration of the organ of Corti, both inner and outer hair cells, degeneration of spiral ganglion cells, and atrophy of the stria vascularis and spiral ligament.

Duration of Diabetes Predicts Aortic Pulse Wave Velocity and Vascular Events in Alström Syndrome.

CONTEXT: Alström syndrome is characterized by increased risk of cardiovascular disease from childhood. OBJECTIVE: To explore the association between risk factors for cardiovascular disease, aortic pulse wave velocity, and vascular events in Alström syndrome. DESIGN: Cross-sectional analyses with 5-year follow-up. SETTING: The UK NHS nationally commissioned specialist clinics for Alström syndrome. PATIENTS: Thirty-one Alström patients undertook vascular risk assessment, cardiac studies, and aortic pulse wave velocity measurement. Subsequent clinical outcomes were recorded. INTERVENTIONS: Insulin resistance was treated with lifestyle intervention and metformin, and diabetes with the addition of glitazones, glucagon-like peptide 1 agonists, and/or insulin. Thyroid and T deficiencies were corrected. Dyslipidemia was treated with statins and nicotinic acid derivatives. Cardiomyopathy was treated with standard therapy as required. MAIN OUTCOME MEASURES: The associations of age, gender, and risk factors for cardiovascular disease with aortic pulse wave velocity were assessed and correlated with the effects of reduction in left ventricular function. Vascular events were monitored for 5 years. RESULTS: Aortic pulse wave velocity was positively associated with the duration of diabetes (P = .001) and inversely with left ventricular ejection fraction (P = .036). Five of the cohort with cardiovascular events had higher aortic pulse wave velocity (P = .0247), and all had long duration of diabetes. CONCLUSIONS: Duration of diabetes predicted aortic pulse wave velocity in Alström syndrome, which in turn predicted cardiovascular events. This offers hope of secondary prevention because type 2 diabetes can be delayed or reversed by lifestyle interventions.

Alström Syndrome: Mutation Spectrum of ALMS1.

Alström Syndrome (ALMS), a recessive, monogenic ciliopathy caused by mutations in ALMS1, is typically characterized by multisystem involvement including early cone-rod retinal dystrophy and blindness, hearing loss, childhood obesity, type 2 diabetes mellitus, cardiomyopathy, fibrosis, and multiple organ failure. The precise function of ALMS1 remains elusive, but roles in endosomal and ciliary transport and cell cycle regulation have been shown. The aim of our study was to further define the spectrum of ALMS1 mutations in patients with clinical features of ALMS. Mutational analysis in a world-wide cohort of 204 families identified 109 novel mutations, extending the number of known ALMS1 mutations to 239 and highlighting the allelic heterogeneity of this disorder. This study represents the most comprehensive mutation analysis in patients with ALMS, identifying the largest number of novel mutations in a single study worldwide. Here, we also provide an overview of all ALMS1 mutations identified to date.

Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader-Willi and Alström syndromes.

Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader-Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process.

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

GLUT4 defects in adipose tissue are early signs of metabolic alterations in Alms1GT/GT, a mouse model for obesity and insulin resistance.

Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alström Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of Alms1 disruption in AT expansion and insulin responsiveness in a murine model for Alström Syndrome. A gene trap insertion in Alms1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alström mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alström mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.

Theory-of-mind in adolescents and young adults with Alström syndrome.

OBJECTIVE: The study focuses on theory-of-mind in adolescents and young adults with Alström syndrome (ALMS). ALMS, an autosomal recessive syndrome causes juvenile blindness, sensorineural hearing loss, cardiomyopathy, endocrinological disorders and metabolic dysfunction. Theory-of-mind (ToM) refers to the ability to impute mental states to one self and to others. Clinical observations have revealed an increased occurrence of deviances in mental state understanding in ALMS. In the present study ToM will be examined and related to working memory (WM), verbal ability and sensory loss. METHODS: Twelve young individuals (16-37 years) with ALMS and 24 nondisabled individuals matched on age, gender and educational level participated. ToM was assessed by means of a multiple task that taxes the ability to understand thoughts and feelings of story characters'. WM was examined by means of a reading span task and verbal ability by means of a vocabulary test. RESULTS: The ALMS group performed at significantly lower levels in ToM tasks and displayed a higher variability in performance than the control group. Individuals with ALMS and a relatively poor level performance provided fewer correct mental state inferences in ToM tasks than ALMS individuals with relatively higher performance levels. ALMS individuals with relatively high performance levels made as many correct inferences in ToM tasks as the control group, but their inferences were more often incomplete. Vocabulary skills and educational level, but not WM-capacity predicted ToM performance. Degree of deafblindness did not have an impact on ToM. Age of onset of visual loss but not hearing loss related to ToM. CONCLUSIONS: The individuals with ALMS display a high degree of heterogeneity in terms of ToM, where some individuals reached performance levels comparable to nondisabled individuals. The results are discussed with respect to how cognitive and verbal abilities and factors related to the disability affect ToM.

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.

Extreme clinical variability of dilated cardiomyopathy in two siblings with Alström syndrome.

Alström 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.