Richard B Paisey

Maternal Uniparental Disomy of Chromosome 1 with No Apparent Phenotypic Effects

URL for data in this article is as follows:Marshfield Center for Medical Genetics, http://www.marshmed.org/genetics (for marker mapping information)

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

AimsTo identify the threshold of reduced sensory perception in Type 2 diabetes mellitus (Type 2 DM) using a range of research grade monofilaments.MethodsThree 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.ResultsPerception 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.ConclusionThe 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.

Characterization of the IGF system in 15 patients with Alström syndrome

Background  Alström syndrome (ALMS) is a rare recessively inherited progressive disease (OMIM 203800). Among its diverse spectrum of clinical features are phenotypes associated with deficiencies of the GH/IGF‐I axis, including short stature, obesity, insulin resistance, hypertriglyceridaemia and heart failure.

Clinical utility gene card for: Alström Syndrome - update 2013.

Update to: European Journal of Human Genetics (2011) 19, 1108; doi:10.1038/ejhg.2011.72; published online 27 April 2011

Cardiac magnetic resonance imaging in Alström syndrome

BackgroundA case series of the cardiac magnetic resonance imaging findings in seven adult Alström patients.MethodsSeven 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.ResultsAll 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.ConclusionAdult 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.

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

Bettini V, Maffei P, Pagano C, Romano S, Milan G, Favaretto F, Marshall JD, Paisey R, Scolari F, Greggio NA, Tosetto I, Naggert JK, Sicolo N, Vettor R. The progression from obesity to type 2 diabetes in Alström syndrome.

Clinical utility gene card for: Alström syndrome

1.5 Mutational spectrum There have been 98 different disease-causing mutations described thus far including nonsense (49%), indels (43%), and rare compound frameshift, and splice site (3%).1 Two missense alterations of uncertain pathogenicity were reported by Joy et al.2 The majority of those are clustered in exon 16 (41%), exon 10 (27%), and exon 8 (25%) of ALMS1. Compound heterozygosity is common. Chromosomal translocations and large deletions are rare but have been reported.3,4

Coronary artery disease in Alstrom 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.

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.