Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

Background

Adenosine kinase deficiency is a recently described defect affecting methionine metabolism with a severe clinical phenotype comprising mainly neurological and hepatic impairment and dysmorphism.

Methods

Clinical data of 11 additional patients from eight families with adenosine kinase deficiency were gathered through a retrospective questionnaire. Two liver biopsies of one patient were systematically evaluated.

Results

The main clinical symptoms are mild to severe liver dysfunction with neonatal onset, muscular hypotonia, global developmental retardation and dysmorphism (especially frontal bossing). Hepatic involvement is not a constant finding. Most patients have epilepsy and recurrent hypoglycemia due to hyperinsulinism. Major biochemical findings are intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine. S-adenosylmethionine and S-adenosylhomocysteine are the most reliable biochemical markers. The major histological finding was pronounced microvesicular hepatic steatosis. Therapeutic trials with a methionine restricted diet indicate a potential beneficial effect on biochemical and clinical parameters in four patients and hyperinsulinism was responsive to diazoxide in two patients.

Conclusion

Adenosine kinase deficiency is a severe inborn error at the cross-road of methionine and adenosine metabolism that mainly causes dysmorphism, brain and liver symptoms, but also recurrent hypoglycemia. The clinical phenotype varies from an exclusively neurological to a multi-organ manifestation. Methionine-restricted diet should be considered as a therapeutic option.

     

Minireview: RET: normal and abnormal functions

The RET gene encodes a single-pass transmembrane receptor tyrosine kinase. RET is the oncogene that causes papillary thyroid carcinoma and medullary thyroid carcinoma. The latter may arise as a component of multiple endocrine neoplasia type 2 syndromes; germline mutations in RET are responsible for multiple endocrine neoplasia type 2 inheritance. In this report we review data on the mechanisms leading to RET oncogenic conversion and on RET targeting as a strategy in thyroid cancer treatment.     

Persistent truncus arteriosus: A study of 66 autopsy cases with special reference to definition and morphogenesis

Sixty-six hearts were examined in which a single arterial trunk, leaving the base of the heart through a single semilunar valve, supplied the aorta, pulmonary artery and coronary arteries. Careful attention was paid to the infundibular morphologic features in these hearts, and these were compared with findings in 24 hearts with single aortic trunk, pulmonary atresia and ventricular septal defect. It was concluded that the two anomalies represented morphologically discrete conditions. This was particularly true with regard to the disposition of the infundibular septum, the ventriculo-infundibular fold and the relation of the coronary arteries to the semilunar sinuses. Although it is theoretically possible for a heart with true persistent truncus arteriosus to have absence of the pulmonary trunk and right and left pulmonary arteries, it is argued that such hearts (“truncus type IV”) are best classified as pulmonary atresia with ventricular septal defect. It is also argued that hearts with a common arterial trunk supplied through discrete ventricular outflow tracts and two semilunar valves are best considered examples of aorticopulmonary window. It is suggested that persistent truncus arteriosus is best defined as that condition in which a single arterial trunk leaves the heart through a single semilunar valve and supplies the aorta, one or both pulmonary arteries and the coronary arteries.     

Liver frailty and all-cause mortality in the older participants of the Salus in Apulia Study

The liver contribution to the biological network underlying physical frailty in aging is underestimated. How best to measure this contribution magnitude and impact on health risk trajectories in frail individuals is not yet entirely clear. We analyzed the association of a novel liver frailty phenotype with the risk of death in older participants of the Salus in Apulia Study cohort. Clinical and physical examination, routine biomarkers, medical history, and anthropometry were analyzed in 1929 older adults (65?+). Physical frailty was classified by Cardiovascular Health Study criteria, and liver fibrosis risk by fibrosis-4 (FIB-4). The liver frailty phenotype was defined as physical frailty plus high-risk liver fibrosis (score?>?2.67). Physical frailty, high-risk liver fibrosis, and liver frailty subjects were compared to subjects without these conditions (non-frail). Proportional Cox regression tested the adjusted association between liver frailty and all-cause mortality for each category. The liver frailty prevalence was relatively low (3.8%), but higher in men (58.1%). Compared to non-frail older subjects, liver frailty subjects were significantly older (effect size (ES)???1.11, 95% confidence interval (CI)???1.35 to???0.87), with a lower education (ES 0.48, 95%CI 0.24 to 0.71) and higher multimorbidity (ES 15.81, 95%CI 4.20 to 27.41). Cox multivariate analyses showed a two-fold increased risk of overall mortality (hazard ratio 2.09, 95%CI 1.16–3.74) even after the adjustment for age, sex, education, and alcohol consumption. The liver frailty phenotype runs twice the risk of overall mortality compared with the non-frail population. This clinical tool, validated in a Southern Italian population, is based on simple sets of measures that can conveniently be assessed also in the primary care setting.

     

Osteitis condensans ilii: prevalence and characteristics of a neglected mimic of sacroiliitis

Clinical Rheumatology - Osteitis condensans ilii (OCI) is a benign condition characterised by triangular sclerosis of the iliac bone which may mimic radiographic sacroiliitis. Prevalence is...