Rare disorders presenting in the diabetic clinic: an example using audit of the NSCT adult Alström clinics

Paisey, RB; Barrett, Timothy; Carey, Catherine; Cramb, Robert; White, Alison; Seymour, Richard J.; Bunce, S.; Waterson, Michael; Rockett, Carol B.; Vogler, K; Williams, Kathleen A.; Parkinson, Kay; Kenny, Thomas J.

doi:10.1002/pdi.1631

Cited by 6 publications

(5 citation statements)

References 19 publications

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“…The prevalence of ALMS is difficult to estimate as some individuals with attenuated forms of this syndrome may be underdiagnosed [ 2 ]. There is a higher frequency of some specific ALMS1 pathogenic variants in certain ethnic populations, for example, c.10534_10535ins in French Acadians, and c.10775delC in up to 20% of patients of English descent [ 3 , 4 ].…”

Section: Definition and Epidemiologymentioning

confidence: 99%

Consensus clinical management guidelines for Alström syndrome

Tahani

Maffei

Dollfus

et al. 2020

Orphanet J Rare Dis

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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.

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Section: Definition and Epidemiologymentioning

confidence: 99%

Consensus clinical management guidelines for Alström syndrome

Tahani

Maffei

Dollfus

et al. 2020

Orphanet J Rare Dis

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“…Coronary artery disease has been described in the syndrome ( 19 ). Greater awareness of genetic causes of type 2 diabetes has led to identification of older subjects with Alström syndrome ( 20 ). There is therefore a clinical need to monitor vascular function in Alström subjects with appropriate risk factor intervention.…”

mentioning

confidence: 99%

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

Paisey

Smith

Carey

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

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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.

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“…In patients with AS‐related traits, such as nephronophthisis‐related ciliopathies 27 and inherited retinal dystrophy patients, 28 ALMS1 variants are identified. Similarly, some adult AS patients without a typical syndrome phenotype were diagnosed in diabetes clinics 29 . Recent studies have reported that patients carrying syndromic genetic variants manifest isolated diabetes features.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, some adult AS patients without a typical syndrome phenotype were diagnosed in diabetes clinics. 29 Recent studies have reported that patients carrying syndromic genetic variants manifest isolated diabetes features. Specifically, certain patients with HNF1B or WFS1 pathogenic mutations do not present with typical extrapancreatic features; instead, they only exhibit glycaemic impairment.…”

Section: Totalmentioning

confidence: 99%

Overburden of rare ALMS1 deleterious variants in Chinese early‐onset type 2 diabetes with severe insulin resistance

Zhang,

Gong,

et al. 2024

Diabetes Metabolism Res

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AimsAlström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early‐onset type 2 diabetes (age at diagnosis ≤40 years; EOD).Materials and MethodsALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre‐diabetes and fasting IR. In‐silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants.ResultsSixty‐two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C‐peptide, postprandial C‐peptide, and HOMA2‐IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin‐resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre‐diabetes with fasting IR.ConclusionsALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function.

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Rare disorders presenting in the diabetic clinic: an example using audit of the NSCT adult Alström clinics

Cited by 6 publications

References 19 publications

Consensus clinical management guidelines for Alström syndrome

Consensus clinical management guidelines for Alström syndrome

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

Overburden of rare ALMS1 deleterious variants in Chinese early‐onset type 2 diabetes with severe insulin resistance

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