A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment

Metabolic Brain Disease - Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic...     

Plasma lipid alterations in leukemia and lymphoma

Plasma lipids and lipoproteins were studied at presentation in 25 patients with acute leukemia and non-Hodgkin's lymphoma. All patients demonstrated an abnormality in at least one plasma lipid fraction, and most exhibited a predictable pattern of lipid alterations that consisted of extremely low levels of high-density lipoprotein cholesterol (median [Xm] = 23), elevated triglyceride (Xm =165) and elevated very-low-density lipoprotein (Xm = 26). Patients restudied during remission demonstrated a return to normal values. The degree of lipid abnormality was directly related to the underlying tumor burden and particularly to the presence of bone marrow involvement. However, even patients with minimal tumor bulk demonstrated plasma lipid abnormalities. The results suggest that an abnormality in systemic lipid metabolism, possibly in triglyceride clearance, is present in these patients and that its incidence in this population is high.     

Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function.

The extracellular Ca2+-sensing receptor is a member of the G-protein-coupled receptor family 3 in which agonists bind to a dimeric Venus-flytrap domain in the extracellular portion of the receptor. How agonist binding to this domain leads to activation of the seven-transmembrane domain is a major unresolved question. Information derived from the three-dimensional structure of the Venus-flytrap domain of the related metabotropic glutamate type 1 receptor, and from naturally occurring mutations of the Ca2+-sensing receptor identified in subjects with familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia offers new insights into the mechanism of receptor activation, and into the mechanism of action of allosteric modulators of the receptor.     

Percutaneous transluminal renal angioplasty in management of atherosclerotic renovascular hypertension: results in 100 patients

The long-term effect of percutaneous transluminal renal angioplasty (PTRA) on blood pressure and renal function was assessed in 100 consecutive patients with atherosclerotic renovascular hypertension. Technical success rates (complete plus partial) of a first PTRA averaged 76.2%, 74.1%, and 67.7% for the unilateral (n = 42), bilateral (n = 27), and solitary (n = 31) groups, respectively. Of the technical successes, 59% (43/73) experienced sustained blood pressure benefit (mostly amelioration) during a mean follow-up period of 29 months. Rates of blood pressure benefit were similar in the three groups. Ostial lesions comprised the majority of blood pressure benefit failures. Repeat angioplasty in 14 patients resulted in a 71% technical success rate and a 50% blood pressure benefit rate during a mean follow-up period of 22 months. Long-term stability of mean serum creatinine level was observed after technically successful angioplasty in all three groups. Acute renal insufficiency, which was reversible in all but one patient, complicated 26% of the procedures. Mechanical complications occurred in 14% (20/145) of the arteries acted on; surgical intervention was required in five patients. The mortality rate was 2%. These results suggest that angioplasty is effective in both the long-term management of renovascular hypertension and the preservation of renal function in a large fraction of patients with atherosclerotic renovascular hypertension.     

Functional interactions between the extracellular domain and the seven-transmembrane domain in Ca2+ receptor activation

We studied the activity of mutants involving the aminoterminal extracellular, seven-transmembrane (7TM) and carboxy-terminal tail domains of the human Ca²⁺ receptor to gain insight into the functional interactions between these domains during receptor activation. Missense mutations of highly conserved residues, D190 and E297, in the extracellular domain (ECD), and a mutation within part of the proximal carboxy-terminal tail, A877-880E, resulted in receptors with severely reduced response to Ca²⁺ despite adequate cell surface expression. Coexpression of either D190A or E297K mutants with A877-880E led to significant reconstitution of function. No such reconstitution occurred when D190A or E297K mutants were coexpressed with a truncation mutant possessing an intact amino-terminal extracellular and first transmembrane domain, despite evidence for heterodimerization and cell surface expression of the respective mutant receptors. In addition, no reconstitution of function was observed when D190A was coexpressed with a deletion Ca²⁺ receptor mutant lacking only a cysteine-rich region located in the ECD of the Ca²⁺ receptor (Ca-//-Ca). Moreover, coexpression of this Ca-//-Ca with A877-880E did not recover function. The results show that Ca2⁺ receptor extracellular and 7TM domains are discrete entities that can communicate within the context of a heterodimer composed of complementary mutant receptors. Two intact 7TM domains and two intact cysteine-rich regions appear to be required for such communication to occur. The results are discussed in the context of a speculative model of receptor structure and function. O. M. Hauache was supported by a grant (#10848-2) from FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil).     

Activity of the stimulatory guanine nucleotide-binding protein is reduced in erythrocytes from patients with pseudohypoparathyroidism and pseudopseudohypoparathyroidism: biochemical, endocrine, and genetic analysis of Albright's hereditary osteodystrophy in six kindreds

Multiple hormone resistance in many patients with pseudohypoparathyroidism (PHP) type Ia and Albright's hereditary osteodystrophy (AHO) is associated with deficient activity of the stimulatory guanine nucleotide-binding protein (Gs) of adenylate cyclase. To study further the relationship of deficient Gs activity to hormone resistance, we evaluated endocrine function and measured Gs activity of erythrocyte membranes from AHO patients with clinical hormone resistance (PHP type Ia) and from family members with AHO alone (pseudopseudohypoparathyroidism). The results of erythrocyte membrane Gs determinations were compared to those of unaffected relatives and normal subjects. Patients with pseudopseudohypoparathyroidism (pseudoPHP) had reductions in erythrocyte membrane Gs activity comparable to those in patients with PHP type Ia [43.4 +/- 11.9% (+/- SD) for PHP type Ia vs. 47.8 +/- 9.5% for pseudoPHP]. However, in contradistinction to patients with PHP type Ia, individuals with pseudoPHP did not have obvious endocrine dysfunction. Although deficient Gs activity appears to play an important role in the pathogenesis of these disorders, it is possible that Gs deficiency must be combined with other factors that limit cAMP production to cause clinically overt endocrine disease.