Pasi I. Salmela

Epidemiology of A3243G, the Mutation for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes: Prevalence of the Mutation in an Adult Population

Mitochondrial diseases are characterized by considerable clinical variability and are most often caused by mutations in mtDNA. Because of the phenotypic variability, epidemiological studies of the frequency of these disorders have been difficult to perform. We studied the prevalence of the mtDNA mutation at nucleotide 3243 in an adult population of 245,201 individuals. This mutation is the most common molecular etiology of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), one of the clinical entities among the mitochondrial disorders. Patients with diabetes mellitus, sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia were ascertained on the basis of defined clinical criteria and family-history data. A total of 615 patients were identified, and 480 samples were examined for the mutation. The mutation was found in 11 pedigrees, and its frequency was calculated to be >=16. 3/100,000 in the adult population (95% confidence interval 11.3-21. 4/100,000). The mutation had arisen in the population at least nine times, as determined by mtDNA haplotyping. Clinical evaluation of the probands revealed a syndrome that most frequently consisted of hearing impairment, cognitive decline, and short stature. The high prevalence of the common MELAS mutation in the adult population suggests that mitochondrial disorders constitute one of the largest diagnostic categories of neurogenetic diseases.

Clinical characteristics and therapeutic responses in patients with Germ-line AIP mutations and pituitary adenomas : An international collaborative study

CONTEXT AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN This study was an international, multicenter, retrospective case collection/database analysis. SETTING The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.

Thymic carcinoids in multiple endocrine neoplasia type 1

Thymic carcinoid is a rare malignancy with about 150 cases reported to date. It is associated with multiple endocrine neoplasia type 1 (MEN-1), but compared with other MEN-1-related neoplasia little is known about it. We have recently described and studied 20 MEN-1-related cases and found that up to 25% of all reported thymic carcinoids are MEN-1 related. It is an insidious tumour not associated with Cushings syndrome or carcinoid syndrome. Local invasion, recurrence and distant metastasis are common with no known effective treatment. Its male predominance, the absence of loss of heterozygosity (LOH) in the MEN1 region, clustering in some MEN-1 families and the findings of different MEN1 mutations in these clustered families suggest the involvement of additional aetiological factors. We propose that computed tomography (CT) or magnetic resonance imaging (MRI) of the chest should be included as part of the clinical workup for all MEN-1 patients. Prophylactic thymectomy should be considered during subtotal or total parathyroidectomy on MEN-1 patients to reduce the risk of this malignancy.

Apolipoprotein E phenotype is related to macro- and microangiopathy in patients with non-insulin-dependent diabetes mellitus.

The role of apoliprotein E (apo E) in modulating the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 143 male and 128 female patients with NIDDM. The data show that the apolipoprotein phenotype E2 somehow protects from macrovascular complications in NIDDM both in men and women. E2 also tends to protect from microvascular complications. In contrast, apo E phenotypes E4/4 and E4/3 tend to increase the risk for macroangiopathy in NIDDM patients. The lower prevalence of macroangiopathy in the subjects with E2 was associated with lower plasma total and LDL cholesterol concentrations and low plasma lipoprotein(a) levels. Overall, this study demonstrates the role of the apo E phenotype to modulate the risk for diabetic complications in patients with NIDDM. The confirmation of the association of apo E polymorphism with diabetic complications warrants, however, long-term follow-up studies.

Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP)

Familial forms of primary hyperparathyroidism (PHPT) constitute a broad group of disorders in which PHPT is either a main or an associated feature. With the advances in disease gene identification, some of the genetic abnormalities underlying familial PHPT have been clarified.1,2 In hyperparathyroidism–jaw tumour syndrome (HPT-JT; OMIM #145001) the affected family members frequently develop PHPT, ossifying jaw fibromas, and cystic and neoplastic renal lesions.3–6 A typical feature of HPT-JT is adenomas and carcinomas of the parathyroid glands, which often have cystic features.1 This is in contrast to the other forms of familial PHPT in which the parathyroid tumours are generally benign. The disease locus was first mapped to chromosomal region 1q25–q32 by linkage in affected families3,5–7 and recently the causal HRPT2 gene was isolated through a positional cloning approach.3 The HRPT2 gene consists of 17 exons encoding an evolutionarily well conserved, 531 amino acid protein named parafibromin. The inactivating mutations demonstrated in the germline of HPT-JT kindreds and as somatic events in some sporadic parathyroid adenomas3 are in agreement with the observations of somatic loss of the wild type alleles,6 suggesting that parafibromin has a tumour suppressor function.3,6 The importance of the multiple endocrine neoplasia type 1 gene ( MEN1 ) in familial PHPT has been well established. MEN1 is a tumour suppressor gene located in 11q13,8–10 and its encoded protein menin has been shown to interact with several proteins involved in transcriptional regulation.11,12 The MEN1 syndrome (OMIM #131100) is clinically characterised by the frequent development of tumours in the parathyroids, the endocrine pancreas and duodenum, and the anterior pituitary gland. MEN1, which is the most common form of hereditary PHPT, is caused by germline mutations of MEN1 , both in the form of inherited …

Hypophyseal hemorrhage and panhypopituitarism during Puumala Virus Infection: Magnetic Resonance Imaging and detection of viral antigen in the hypophysis.

We describe 3 cases of nephropathia epidemica (NE) that confirm that Puumala virus infection may cause hypophyseal injury. Autopsy revealed a hemorrhagic hypophysis positive for Puumala virus antigen in both neuroendocrine stromal and vascular endothelial cells in 1 patient, and 2 patients developed hypophyseal hemorrhage (diagnosed with magnetic resonance imaging) during or shortly after acute NE, both of whom developed panhypopituitarism.

Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes

Aims/hypothesisNocturnal hypoglycaemia may contribute to sudden death in diabetic patients. However, it is not well known why hypoglycaemia makes these patients prone to death.MethodsWe assessed the effects of controlled hypoglycaemia on cardiac repolarisation using novel electrocardiographic descriptors of T-wave and QRS complex morphology in 16 type 1 diabetic patients and eight healthy counterparts. Several electrocardiographic variables characterising repolarisation were analysed from digitised 12-lead electrocardiograms during a euglycaemic and a hypoglycaemic clamp.ResultsHypoglycaemia did not result in significant changes either in the QT interval corrected for heart rate by the nomogram method or in QT dispersion. However, the morphology of the T-wave changed significantly during hypoglycaemia. The T-wave amplitude and area in precordial leads decreased significantly in both groups (p < 0.05 to p < 0.001). The spatial QRS-T angle (total cosine R to T) (p < 0.05) and the height and the width of the T-wave loop (p < 0.05 and p < 0.01, respectively) were also reduced in the diabetic patients. The changes in the repolarisation parameters did not exhibit any significant association with changes in catecholamine levels or in heart rate variability in either group.Conclusions/interpretationHypoglycaemia results in distinct alterations in cardiac repolarisation, which may increase the vulnerability to arrhythmic events.

Adrenal steroidogenesis is related to insulin in hyperandrogenic women

OBJECTIVE To evaluate ovarian and adrenal steroid secretion in women with severe hyperandrogenism. DESIGN A prospective study. SETTING The Gynecological Endocrine Research Unit of the University Central Hospital, Oulu, Finland. PATIENTS Thirteen obese, hirsute women with severe hyperandrogenism. INTERVENTIONS Adrenocorticotropin hormone stimulation and dexamethasone suppression tests and selective catheterizations of the left ovarian and adrenal veins were performed. MAIN OUTCOME MEASURES The concentrations of insulin, P, 17-hydroxyprogesterone (17-OHP), androstenedione (A), T, DHEA, DHEAS, and cortisol were measured. RESULTS The secretory gradients of T and its precursors, P, 17-OHP, A, and DHEA in the selective catheterizations showed the adrenal to be the main source of excessive steroid production in these patients. The concentrations of P (r = 0.82), 17-OHP (r = 0.89), A (r = 0.84), T (r = 0.86), and cortisol (r = 0.87) in the adrenal vein showed a strong correlation with insulin measured from the same samples. CONCLUSIONS Excessive androgens were secreted mainly by the adrenals in these obese hyperinsulinemic women. Correlation analyses suggested that insulin stimulates adrenal androgen and cortisol secretion, which may constitute an important component of the pathogenetic mechanisms of hyperandrogenism and the polycystic ovary syndrome.

Apolipoprotein B gene DNA polymorphisms are associated with macro‐ and microangiopathy in non‐insulin‐dependent diabetes mellitus

Ukkola O, Savolainen MJ, Salmela PI, von Dickhoff K, Kesäniemi YA. Apolipoprotein B gene DNA polymorphisms are associated with macro‐and microangiopathy in non‐insulin‐dependent diabetes mellitus.

DNA polymorphisms at the locus for human cholesteryl ester transfer protein (CETP) are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus.

The effect of variation at the cholesteryl ester transfer protein (CETP) gene locus and in the apolipoprotein (apo) AI‐CIII‐AIV gene cluster on the susceptibility of individuals with non‐insulin‐dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 136 male and 122 female patients with NIDDM. The prevalence of myocardial infarction was high (38%) in patients with the EcoNI genotype 2–2 of the CETP gene locus (= 2‐2; subjects homozygous for the absence of the restriction site) compared with patients with the genotype 1–1 (=1–1; subjects homozygous for the presence of the restriction site) (18%, p < 0.02). The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was high in 2–2 (73%) compared with the genotype 1–2 (= 1–2; heterozygous for the presence of the restriction site) (52%, p < 0.02) and genotype 1–1 (p = 0.06). CHD was more prevalent in men with 2–2 (70%) than in those with 1–1 (42%, p < 0.05), but in women no significant differences were found in the prevalences of CHD between the EcoNI genotypes. Neuropathy was more often present in the patients with 2–2 (31%) than in those with 1–1 (12%, p < 0.02) or 1–2 (14%, p < 0.01). Plasma total cholesterol and total‐ and VLDL‐triglycerides were higher in women with the EcoNI genotype 1–1 than in those with the genotype 1–2. In men no significant differences in plasma lipids were found. In addition, the prevalence of cerebrovascular disease was high (21%) in the patients with the genotype 1–1 of the TaqlB polymorphism compared with the genotype 2–2 (6%, p < 0.0–2). None of the alleles defined by four polymorphisms in the apo AI‐CIII‐AIV gene region were associated with an increased risk for macroangiopathy. The PstI polymorphism had an effect on plasma triglyceride levels. At the CETP locus one pair of loci (TaqlB and EcoNI) and three pairs of loci at the apo AI‐CIII‐AIV gene cluster (SacI and MspI, SapI and PvuII and MspI and PvuII) showed significant allelic association. In conclusion, the variation of CETP locus modulates the risk for diabetic complications in patients with NIDDM and the effect seems to be different between men and women. In contrast, the AI‐CIII‐AIV gene cluster polymorphisms seem not to be related to the risk of CHD in NIDDM. Long‐term follow‐up studies are needed to confirm the association of CETP gene polymorphism with diabetic complications.