Rare cause of post-squalene disorder of cholesterol biosynthesis

Errors of cholesterol biosynthesis represent a heterogeneous group of metabolic disorders. The aim of the authors of this article is to present a case of a patient with typical symptoms of a rare post-squalene disorder of cholesterol biosynthesis, its diagnostics and progress in neonatal period. The differential diagnosis of a typical findings on the skin with spontaneous regression ichtyosiform erythroderma, craniofacial dysmorphic features, anomalies of organs or skeletal abnormalities in a newborn may also be the result of a disorder of cholesterol biosynthesis. The final diagnosis is definitely confirmed by  DNA analysis. Prognosis depends on the different enzyme defects of cholesterol biosynthesis pathway, but typically on the post-squalene pathway.     Cholesterol is an important substance that plays a significant role in membrane structure, as well as being the precursor for the synthesis of the steroid hormones and bile acids. Cholesterol synthesis occurs in the cytoplasm and microsomes from the two-carbon acetate group of acetyl coenzyme A (acetyl-CoA). The biosynthesis of cholesterol consists of several reactions. Acetyl-CoA units are converted to mevalonate by a series of reactions. Mevalonate is formed on squalene and then lanosterol.  Lanosterol is converted by two different pathways, either with the creation of 7-dehydrocholesterol, or desmosterol with the creation of cholesterol. Errors of cholesterol biosynthesis represent a heterogeneous group of metabolic disorders that is characterized by multiple dysmorphic features underlining an important role for cholesterol in human embryogenesis and development. The differential diagnosis of atypical findings on the skin in newborn may be the result of disorder of cholesterol biosynthesis. It may be also associated with various dysmorphic features or anomalies including multiple anomalies of congenital and internal organs and skeletal abnormalities. Some of the post-squalene disorders may point to atypical findings on the skin in the form of psoriatic eruptions, psychomotoric delay or laboratory findings as hypocholesterolemia. Key words: newborn; hypocholesterolemia; stigma; chondrodysplasia punctata; ichthyosiform erythroderm

TMEM70 deficiency: long-term outcome of 48 patients

OBJECTIVES: TMEM70 deficiency is the most common nuclear-encoded defect affecting the ATP synthase. In this multicentre retrospective study we characterise the natural history of the disease, treatment and outcome in 48 patients with mutations in TMEM70. Eleven centers from eight European countries, Turkey and Israel participated. RESULTS: All 27 Roma and eight non-Roma patients were homozygous for the common mutation c.317-2A > G. Five patients were compound heterozygotes for the common mutation and mutations c.470 T > A, c.628A > C, c.118_119insGT or c.251delC. Six Arab Muslims and two Turkish patients were homozygous for mutations c.238C > T, c.316 + 1G > T, c.336 T > A, c.578_579delCA, c.535C > T, c.359delC. Age of onset was neonatal in 41 patients, infantile in six cases and two years in one child. The most frequent symptoms at onset were poor feeding, hypotonia, lethargy, respiratory and heart failure, accompanied by lactic acidosis, 3-methylglutaconic aciduria and hyperammonaemia. Symptoms further included: developmental delay (98%), hypotonia (95%), faltering growth (94%), short stature (89%), non-progressive cardiomyopathy (89%), microcephaly (71%), facial dysmorphism (66%), hypospadias (50% of the males), persistent pulmonary hypertension of the newborn (22%) and Wolff-Parkinson-White syndrome (13%). One or more acute metabolic crises occurred in 24 surviving children, frequently followed by developmental regression. Hyperammonaemic episodes responded well to infusion with glucose and lipid emulsion, and ammonia scavengers or haemodiafiltration. Ten-year survival was 63%, importantly for prognostication, no child died after the age of five years. CONCLUSION: TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood.status: publishe

TMEM70 deficiency: long-term outcome of 48 patients

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