Glucagon-like peptide-1 analogues in monogenic syndromic obesity: Real-world data from a large cohort of Alström syndrome patients.

AIM: To examine the real-world efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in monogenic obesity in patients with Alström syndrome (ALMS). METHODS: We screened 72 UK adult patients with ALMS and offered treatment to 34 patients meeting one of the following criteria: body mass index of 25 kg/m2 or higher, insulin resistance, suboptimal glycaemic control on antihyperglycaemic medications or non-alcoholic fatty liver disease. RESULTS: In total, 30 patients, with a mean age of 31 ± 11 years and a male to-female ratio of 2:1, completed 6 months of treatment with GLP-1 RAs either in the form of semaglutide or exenatide. On average, treatment with GLP-1 RAs reduced body weight by 5.4 ± 1.7 (95% confidence interval [CI] 3.6-7) kg and HbA1c by 12 ± 3.3 (95% CI 8.7-15.3) mmol/mol, equating to 6% weight loss (P < .01) and 1.1% absolute reduction in HbA1c (P < .01). Significant improvements were also observed in serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and alanine aminotransferase. The improvement of metabolic variables in our cohort of monogenic syndromic obesity was comparable with data for polygenic obesity, irrespective of weight loss. CONCLUSIONS: Data from our centre highlight the non-inferiority of GLP-1 RAs in monogenic syndromic obesity to the available GLP-1 RA-use data in polygenic obesity, therefore, these agents can be considered as a treatment option in patients with ALMS, as well as other forms of monogenic obesity.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström 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.

Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and Thiamine-responsive megaloblastic anemia.

We developed a variant database for diabetes syndrome genes, using the Leiden Open Variation Database platform, containing observed phenotypes matched to the genetic variations. We populated it with 628 published disease-associated variants (December 2016) for: WFS1 (n = 309), CISD2 (n = 3), ALMS1 (n = 268), and SLC19A2 (n = 48) for Wolfram type 1, Wolfram type 2, Alström, and Thiamine-responsive megaloblastic anemia syndromes, respectively; and included 23 previously unpublished novel germline variants in WFS1 and 17 variants in ALMS1. We then investigated genotype-phenotype relations for the WFS1 gene. The presence of biallelic loss-of-function variants predicted Wolfram syndrome defined by insulin-dependent diabetes and optic atrophy, with a sensitivity of 79% (95% CI 75%-83%) and specificity of 92% (83%-97%). The presence of minor loss-of-function variants in WFS1 predicted isolated diabetes, isolated deafness, or isolated congenital cataracts without development of the full syndrome (sensitivity 100% [93%-100%]; specificity 78% [73%-82%]). The ability to provide a prognostic prediction based on genotype will lead to improvements in patient care and counseling. The development of the database as a repository for monogenic diabetes gene variants will allow prognostic predictions for other diabetes syndromes as next-generation sequencing expands the repertoire of genotypes and phenotypes. The database is publicly available online at https://lovd.euro-wabb.org.

Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.

BACKGROUND AND AIMS: Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi-organ fibrosis. Despite phenotypically being high risk of non-alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS. METHODS: Observational cohort study with comprehensive assessment of metabolic liver phenotype including liver elastography (Fibroscan® ), serum Enhanced Liver Fibrosis (ELF) Panel and liver histology. In addition, abdominal adipose histology and gene expression was assessed. We recruited 30 patients from the UK national AS clinic. A subset of six patients underwent adipose biopsies which was compared with control tissue from nine healthy participants. RESULTS: Patients were overweight/obese (BMI 29.3 (25.95-34.05) kg/m2 ). A total of 80% (24/30) were diabetic; 74% (20/27) had liver ultrasound scanning suggestive of NAFLD. As judged by the ELF panel, 96% (24/25) were categorized as having fibrosis and 10/21 (48%) had liver elastography consistent with advanced liver fibrosis/cirrhosis. In 7/8 selected cases, there was evidence of advanced NAFLD on liver histology. Adipose tissue histology showed marked fibrosis as well as disordered pro-inflammatory and fibrotic gene expression profiles. CONCLUSIONS: NAFLD and adipose dysfunction are common in patients with AS. The severity of liver disease in our cohort supports the need for screening of liver fibrosis in AS.

The progression from obesity to type 2 diabetes in Alström syndrome.

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 at a young age. OBJECTIVE: To study the relationship between weight and metabolism in a group of ALMS patients and matched controls. RESEARCH DESIGN AND METHODS: Fifteen ALMS patients (eight males, seven females; aged 3-51) 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 oral glucose tolerance test (OGTT) conditions were measured. Furthermore, anthropometric and body composition data were obtained from an international group of 27 ALMS patients (13 males, 14 females, age range: 4-29 yr). RESULTS: In ALMS we observed an inverse correlation between age and standard deviation scores for height, weight, and body mass index. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, whereas insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index, HOMA%ß-cell and insulinogenic index in ALMS, but unlike the insulin-resistance indices, the ß-cell function indices showed a significant reduction with age. CONCLUSIONS: In ALMS the progression from the early onset obesity toward the impaired fasting glucose or impaired glucose tolerance and overt diabetes is mostly because of a progressive failure of ß-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.

Body weight, diabetes incidence vascular events and survival 15 years after very low calorie diet in community medical clinics in the UK.

Objective: To assess weight loss maintenance, diabetes status, mortality and morbidity 15 years after a very low calorie diet programme (VLCD) in patients with obesity. Design: General practice data bases were interrogated for subjects coded for group therapy with VLCD in the 1990s. Causes of death, occurrence of vascular disease and remission or development of diabetes were ascertained from patient records and national stroke and cardiovascular disease data bases. Results: 325 subjects engaged in the programme and had sufficient data for analysis. Baseline characteristics were: age 47.8±12. 8 years; body mass index (BMI) 36.1±6.8 kg/m2; 79.1% female/20.9% male; 13.5% had type 2 diabetes. After 15±4 years weight had changed from 97.9±19 kg at baseline to 100±20.8 kg. 10 with diabetes at baseline were in remission at 3 months, but only two remained in remission at 5 years. 50 new cases of type 2 diabetes and 11 of impaired fasting glucose developed during follow-up. Only 5.9% who remained healthy at follow-up had maintained >10% body weight reduction. Neither diabetes incidence nor diabetes free survival were related to percentage body weight lost during VLCD. Only baseline BMI was related to development of new impaired fasting glucose or diabetes by 15 years (p=0.007). 37 subjects had a cardiovascular event. Age (p=0.000002) and degree of weight loss after VLCD (p=0.03) were significantly associated with subsequent vascular events. Conclusion: Long-term maintenance of weight loss after VLCD was rare in this single centre retrospective study 15 years later. Glucose intolerance developed in 21.4%. Lasting remission of type 2 diabetes or prevention of later glucose intolerance were not achieved. Vascular events were more frequent in those who lost most weight. Risk management during weight regain should be studied in future to assess potential for reduction in adverse cardiovascular outcomes.

Service user and community clinician design of a partially virtual diabetic service improves access to care and education and reduces amputation incidence.

INTRODUCTION: Design of an integrated diabetes service based on needs of service users (persons living with diabetes) and community clinicians in a semirural low-income health district of the UK. RESEARCH DESIGN AND METHODS: One hundred and eighty-five service users engaged through public meetings, questionnaires and focus groups. General practice staff contributed views through workshops and questionnaires. Analysis of feedback indicated service user needs for better access to education, dietary advice and foot care. General practice staff endorsed these views and requested regular access to secondary care in the community. Seven hundred persons registered with diabetes attended eight well-being events in the community. From 2017 virtual practice multidisciplinary patient reviews, virtual referral of foot cases and non-face-to-face helplines were developed. A National Health Service (NHS) approved 'App' and web-based personalized education support for those recently diagnosed with diabetes was introduced. RESULTS: Engagement in education for those recently diagnosed with diabetes increased from 5% to 71%. Weight and hemoglobin A1c (HbA1c) levels before and 6 months after starting the program were 99.4±25 and 95.5±24.2 kg and 59.3±16 and 54.8±12.9 mmol/mol, respectively, p=0.00003 and 0.003. Of those engaging at well-being events, 44 had missed regular follow-up. One hundred and seventy-five cases were reviewed virtually with practice staff by the secondary care team avoiding referral to the hospital diabetic clinic. One hundred and seventy-six referrals were made to the virtual multidisciplinary diabetic foot team clinic. Major amputation incidence declined from 13 to 3 major procedures/10 000 per annum and minor amputation from 26 to 18/10 000. Percentage bed day occupancy by persons with diabetes fell significantly in the district general hospital. CONCLUSIONS: Integrated community-based diabetes care delivery has been achieved with partially virtual reviews. Patient education, secondary care in the community, access to dietetic advice and foot care outcomes have all improved.

New insights and therapies for the metabolic consequences of Alström syndrome.

PURPOSE OF REVIEW: Recent studies have begun to evaluate the heterogeneity of insulin resistance in syndromes associated with type 2 diabetes, dyslipidaemia and associated cardiac, renal and hepatic consequences. These insights are of particular importance in Alström syndrome in which all of these conditions coexist from a young age with considerable morbidity and reduction in life expectancy. Clear definition of the phenotype in the syndrome may clarify biochemical pathways of crucial importance in propensity to diabetic complications and heart disease in the general population. This review will focus on ways in which more effective treatments can be put in place for Alström families from childhood and adolescence. RECENT FINDINGS: Studies of body fat distribution, insulin resistance, glucose metabolism and dyslipidaemia in Alström syndrome will be discussed as well as genotypic and phenotypic variation in the syndrome in the context of recent metabolic studies in insulin resistance. Potential therapies including low-carbohydrate diet, niaspan and incretins will be considered. SUMMARY: These new insights will encourage early introduction of protective nutrition, exercise and drug therapies in Alström syndrome and suggest novel approaches to understanding diabetes mellitus, hyperlipidaemias and heart disease in the general population.

Consensus clinical management guidelines for Alström syndrome.

Alström Syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive variants in the ALMS1 gene, which is located on chromosome 2p13. ALMS is a multisystem, progressive disease characterised by visual disturbance, hearing impairment, cardiomyopathy, childhood obesity, extreme insulin resistance, accelerated non-alcoholic fatty liver disease (NAFLD), renal dysfunction, respiratory disease, endocrine and urologic disorders. Clinical symptoms first appear in infancy with great variability in age of onset and severity. ALMS has an estimated incidence of 1 case per 1,000,000 live births and ethnically or geographically isolated populations have a higher-than-average frequency. The rarity and complexity of the syndrome and the lack of expertise can lead to delayed diagnosis, misdiagnosis and inadequate care. Multidisciplinary and multiprofessional teams of experts are essential for the management of patients with ALMS, as early diagnosis and intervention can slow the progression of multi-organ dysfunctions and improve patient quality of life.These guidelines are intended to define standard of care for patients suspected or diagnosed with ALMS of any age. All information contained in this document has originated from a systematic review of the literature and the experiences of the authors in their care of patients with ALMS. The Appraisal of Guidelines for Research & Evaluation (AGREE II) system was adopted for the development of the guidelines and for defining the related levels of evidence and strengths of recommendations.These guidelines are addressed to: a) specialist centres, other hospital-based medical teams and staffs involved with the care of ALMS patients, b) family physicians and other primary caregivers and c) patients and their families.

Alström syndrome and cecal volvulus in 2 siblings.

Alström syndrome (ALMS1, MIM 203800) is a rare, autosomal recessively inherited monogenic condition caused by mutations in the ALMS1 gene located on the short arm of chromosome 2. ALMS1 is a multisystem condition characterized by childhood onset of blindness, dilated cardiomyopathy, sensorineural hearing loss, renal failure, fibrotic lung disease, and metabolic abnormalities, including hypertriglyceridemia, liver steatosis, insulin resistance, type 2 diabetes mellitus, and obesity. We describe 2 siblings with ALMS who presented with the potentially life-threatening condition of acute cecal volvulus, an association not previously reported. Cecal volvulus may, therefore, represent a significant new feature of the Alström syndrome.

Refining genotype-phenotype correlation in Alström syndrome through study of primary human fibroblasts.

BACKGROUND: Alström syndrome (AS), featuring retinal dystrophy, neuronal deafness, cardiomyopathy, metabolic syndrome, and diffuse fibrosis, is caused by biallelic mutations in the centrosomal protein ALMS1. Genotype-phenotype correlation has been suggested without assessment of ALMS1 expression. METHODS: ALMS1 expression (real-time PCR and immunocytochemistry) and cilia formation (immunocytochemistry) were assessed in fibroblasts from deeply phenotyped volunteers diagnosed with AS recruited from a dedicated AS Service. Exome sequencing was used in two participants without convincing biallelic ALMS1 mutations, and BBS2 (Bardet-Biedl syndrome 2) protein expression was assessed in one patient with biallelic BBS2 mutations. Hedgehog-induced GLI1 expression and PDGFA signaling was assessed using quantitative real-time PCR, immunoblotting, or immunostaining of fixed cells after stimulation. RESULTS: In 16 of the patient cell lines examined, ALMS1 protein was undetectable (14 with biallelic loss-of-function (LoF) mutations), and in two, ALMS1 staining was equivocal (one with biallelic LoF mutations). In five lines, ALMS1 expression was normal using at least one fixation method (one with biallelic LoF mutations). These differences were not accounted for by major differences in ALMS1 mRNA expression. Exome sequencing of two participants with normal ALMS1 expression identified biallelic LoF BBS2 mutations in one. No second, known ciliopathy mutation was found in the other patient, who had one LoF ALMS1 mutation. Phenotypes were milder or atypical in participants with preserved ALMS1 immunostaining, even when two with likely alternative genetic diagnoses were excluded. All cells studied developed normal cilia, ALMS1 and BBS2 mutant cells showed normal Hedgehog-induced upregulation of GLI1 expression, and PDGFA signaling was normal in ALMS1-deficient cells. CONCLUSION: Milder or atypical presentations of AS should prompt genetic evaluation for alternative, clinically overlapping ciliopathies. A subgroup of patients with bona fide ALMS1 defects have milder phenotypes due to residual ALMS1 expression, which may be more important than mutation site.

New Alström syndrome phenotypes based on the evaluation of 182 cases.

BACKGROUND: Alström syndrome is a recessively inherited genetic disorder characterized by congenital retinal dystrophy that leads to blindness, hearing impairment, childhood obesity, insulin resistance, and type 2 diabetes mellitus. We provide new details on cardiologic, hepatic, gastrointestinal, urologic, pulmonary, and neurobehavioral phenotypes in Alström syndrome and describe the histopathologic findings in 5 individuals. METHODS: We obtained data on 182 patients from clinical examinations, medical record reviews, standardized questionnaires, and personal interviews with physicians and parents. RESULTS: Dilated cardiomyopathy occurred in 60% of patients. Age at onset was either during infancy, often before vision disturbances were noted, or in adolescence or adulthood. There is a risk of recurrence of infantile cardiomyopathy. Hyperinsulinemia (92%) developed in early childhood and progressed to type 2 diabetes mellitus in 82% of those older than 16 years. Hypertriglyceridemia (54%) precipitated pancreatitis in 8 patients. Urologic dysfunction and gastrointestinal disturbances occurred in 48% and 35% of patients, respectively. Fifty-three percent of patients had persistent pulmonary symptoms. Neurologic symptoms in 20% of patients included clonic tic and absence seizures. Developmental motor or language delays were observed in 46% of patients. Fibrotic infiltrations of multiple organs, that is, kidney, heart, liver, lung, urinary bladder, gonads, and pancreas, were observed. CONCLUSIONS: The wide-ranging and complex spectrum of phenotypes reported herein broadens those previously described for Alström syndrome. These findings will aid physicians in making an early and accurate diagnosis and will help effect appropriate monitoring and treatment.

Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57).

OBJECTIVE: To evaluate the efficacy of the addition of insulin when maximal sulfonylurea therapy is inadequate in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of 23 U.K. Prospective Diabetes Study (UKPDS) centers that used a modified protocol. Patients were randomly allocated to a conventional glucose control policy, primarily with diet (n = 242) or an intensive policy with insulin alone (n = 245), as in the main study. However, for patients randomized to an intensive policy with sulfonylurea (n = 339), insulin was added automatically if the fasting plasma glucose remained >108 mg/dl (6.0 mmol/l) despite maximal sulfonylurea doses. RESULTS: Over 6 years, approximately 53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA(1c) in the sulfonylurea +/- insulin group was significantly lower (6.6%, interquartile range [IQR] 6.0-7.6) than in the group taking insulin alone (7.1%, IQR 6.2-8.0; P = 0.0066), and significantly more patients in the sulfonylurea +/- insulin group had an HbA(1c) <7% (47 vs. 35%, respectively; P = 0.011). Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea (+/- insulin) group compared with the insulin alone group (1.6 vs. 3.2% per annum, respectively; P = 0.017). CONCLUSIONS: Early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain.

Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome: an observational study.

BACKGROUND: Alström syndrome is a rare inherited ciliopathy with progressive multisystem involvement. Dilated cardiomyopathy is common in infancy and recurs or presents de novo in adults with high rates of premature cardiovascular death. Although Alström syndrome is characterised by fibrosis in solid organs such as the liver, the pathogenesis of related cardiomyopathy are not clear. To date it is not known whether diffuse interstitial myocardial fibrosis is present before the onset of heart failure symptoms or changes in conventional parameters of left ventricular function. METHODS: In this observational study, 26 patients with Alström syndrome (mean age 27 ± 9 years, 65 % male, 24 h ABPM 130 ± 14 / 77 ± 9 mmHg) without symptomatic cardiovascular disease were recruited from a single centre and compared to matched healthy controls. All subjects underwent cardiac MRI (1.5 T) to assess ventricular function, diffuse interstitial myocardial fibrosis by measurement of extracellular volume on T1-mapping (MOLLI) and coarse replacement fibrosis using standard late gadolinium enhancement imaging. RESULTS: Global extracellular volume was increased in Alström syndrome with wider variation compared to controls (0.30 ± 0.05 vs. 0.25 ± 0.01, p < 0.05). Left ventricular long axis function and global longitudinal strain were impaired in Alström syndrome without change in ejection fraction, ventricular size or atrial stress (NT-proBNP) (p < 0.05). Global extracellular volume was associated with reduced peak systolic longitudinal strain (r = -0.73, p < 0.01) and strain rate (r = -0.57, p < 0.01), increased QTc interval (r = 0.49, p < 0.05) and serum triglycerides (r = 0.66, p < 0.01). Nine (35 %) patients had diffuse mid-wall late gadolinium enhancement in a non-coronary artery distribution. CONCLUSION: Diffuse interstitial myocardial fibrosis is common in Alström syndrome and is associated with impaired left ventricular systolic function. Serial studies are required to determine whether global extracellular volume may be an independent imaging biomarker of vulnerability to dilated cardiomyopathy and heart failure.

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.

Modification of severe insulin resistant diabetes in response to lifestyle changes in Alström syndrome.

BACKGROUND: Alström syndrome is a recessively inherited condition characterised by severe insulin resistance and metabolic syndrome with progression to type 2 diabetes, hepatic dysfunction and coronary artery disease. The metabolic responses to lifestyle changes in the syndrome have not been reported. CASE REPORTS: We describe the effects on glycaemia of intense cycling in two insulin treated Alström patients with diabetes, and the effects of opposite lifestyle changes over one year in two others. METHODS: After practise and clinical assessment two patients aged 21 and 39 years undertook a 380 km cycle ride over 4 days by tandem. The effects of planned reductions in insulin therapies and increased regular carbohydrate ingestion were monitored by frequent capillary blood glucose measurements. Two siblings aged 22 and 25 years underwent assessment of glycaemia, C-peptide/glucose ratio serum lipids, hepatic function and ultrasound, Enhanced Liver Fibrosis test and measures of insulin resistance. Measurements were repeated one year later after profound lifestyle changes. RESULTS: Aerobic exercise strikingly improved blood glucose control despite reduction in insulin dose and increased carbohydrate intake. Increase in exercise and exclusion of fast foods improved all aspects of the metabolic syndrome and induced remission of diabetes in one sibling. Reduction in exercise and consumption of high energy foods in the other resulted in development of type 2 diabetes, severe metabolic syndrome and fatty liver in the other. CONCLUSIONS: Despite dual sensory loss and genetic basis for insulin resistance, Alström patients can successfully ameliorate the metabolic syndrome with lifestyle changes.

Coronary artery disease in Alström syndrome.

Alström syndrome (ALMS) is a rare autosomal recessive condition, caused by mutations in the ALMS1 gene located on the short arm of chromosome 2. This gene codes for a protein linked with the centrosome, whose precise function is unknown. This condition was first described by Alström in 1959. ALMS is a multisystem condition that is characterised by childhood onset of blindness secondary to rod-cone retinal degeneration and dilated cardiomyopathy with heart failure, which often presents in infanthood and may recur later in life. Metabolic abnormalities including hypertriglyceridemia, liver steatosis, insulin resistance and type 2 diabetes mellitus are common, often occurring in association with obesity. Other abnormalities include endocrinological disturbances, such as thyroid disorder, growth hormone deficiency, hypogonadism and, in women, hyperandrogenism. This syndrome is also associated with sensorineural hearing loss, renal failure secondary to glomerulo-fibrosis, and fibrotic lung disease. Multiorgan fibrotic infiltration is the common feature in all cases. Considering the history of diabetes, hypertension, dyslipidemia, obesity and renal dysfunction in ALMS, it would be expected that this group of patients could develop coronary artery disease (CAD). But such cases have not been reported so far. We report a case of premature onset of CAD in one of the longest surviving patient with ALMS.

Cardiac magnetic resonance imaging in Alström syndrome.

BACKGROUND: A case series of the cardiac magnetic resonance imaging findings in seven adult Alström patients. METHODS: Seven patients from the National Specialist Commissioning Group Centre for Alström Disease, Torbay, England, UK, completed the cardiac magnetic resonance imaging protocol to assess cardiac structure and function in Alström cardiomyopathy. RESULTS: All patients had some degree of left and right ventricular dysfunction. Patchy mid wall gadolinium delayed enhancement was demonstrated, suggesting an underlying fibrotic process. Some degree of cardiomyopathy was universal. No evidence of myocardial infarction or fatty infiltration was demonstrated, but coronary artery disease cannot be completely excluded. Repeat scanning after 18 months in one subject showed progression of fibrosis and decreased left ventricular function. CONCLUSION: Adult Alström cardiomyopathy appears to be a fibrotic process causing impairment of both ventricles. Serial cardiac magnetic resonance scanning has helped clarify the underlying disease progression and responses to treatment. Confirmation of significant mutations in the ALMS1 gene should lead to advice to screen the subject for cardiomyopathy, and metabolic disorders.

Protection from clinical peripheral sensory neuropathy in Alström syndrome in contrast to early-onset type 2 diabetes.

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.

Threshold for detection of diabetic peripheral sensory neuropathy using a range of research grade monofilaments in persons with Type 2 diabetes mellitus.

AIMS: To identify the threshold of reduced sensory perception in Type 2 diabetes mellitus (Type 2 DM) using a range of research grade monofilaments. METHODS: Three groups of participants were recruited into a between subject, cross-sectional study. Group 1(NEW), persons with Type 2 DM diagnosed for less than 2 years (n = 80); Group 2 (EST) persons with Type 2 DM diagnosed for more than 2 years (n = 91), and Group 3, a Comparison group without Type 2 DM (n = 73), resulted in a total study population, n = 244. Research grade monofilaments (2, 4, 6, 8 and 10-gram) were employed using standardised protocol, at 6 sites on the plantar aspect of both feet. The demographic and anthropometric measures of gender, age, height, weight, body mass index (BMI), blood pressure and duration of Type 2 DM since diagnosis (if applicable) of the participants were analysed. RESULTS: Perception of the research grade monofilaments differed significantly between the 3 groups (p < 0.05). The 6-gram monofilament was found to be the threshold of normal perception, based on 90% of the Comparison group perceiving the 6-gram monofilament at all sites in contrast to 64% of NEW and 48% of EST groups. CONCLUSION: The 6-gram monofilament was identified as the threshold of normal sensory perception. Inability to perceive the 6-gram monofilament indicates, when using the method described in this study, that diminution of sensory perception is evident. Employing a range of monofilaments, 6, 8 and 10-grams in Type 2 DM foot screening would allow the clinical detection of deteriorating sensory perception and enable implementation of foot protection strategies at an earlier stage than is currently practised.