Propionic acidemia in mice: Liver acyl-CoA levels and clinical course.

Propionic acidemia (PA) is a severe autosomal recessive metabolic disease caused by deficiency of propionyl-CoA carboxylase (PCC). We studied PA transgenic (Pat) mice that lack endogenous PCC but express a hypoactive human PCCA cDNA, permitting their survival. Pat cohorts followed from 3 to 20 weeks of age showed growth failure and lethal crises of lethargy and hyperammonemia, commoner in males (27/50, 54%) than in females (11/52, 21%) and occurring mainly in Pat mice with the most severe growth deficiency. Groups of Pat mice were studied under basal conditions (P-Ba mice) and during acute crises (P-Ac). Plasma acylcarnitines in P-Ba mice, compared to controls, showed markedly elevated C3- and low C2-carnitine, with a further decrease in C2-carnitine in P-Ac mice. These clinical and biochemical findings resemble those of human PA patients. Liver acyl-CoA measurements showed that propionyl-CoA was a minor species in controls (propionyl-CoA/acetyl-CoA ratio, 0.09). In contrast, in P-Ba liver the ratio was 1.4 and in P-Ac liver, 13, with concurrent reductions of the levels of acetyl-CoA and other acyl-CoAs. Plasma ammonia levels in control, P-Ba and P-Ac mice were 109 ± 10, 311 ± 48 and 551 ± 61 µmol/L respectively. Four-week administration to Pat mice, of carglumate (N-carbamyl-L-glutamic acid), an analogue of N-carbamylglutamate, the product of the only acyl-CoA-requiring reaction directly related to the urea cycle, was associated with increased food consumption, improved growth and absence of fatal crises. Pat mice showed many similarities to human PA patients and provide a useful model for studying tissue pathophysiology and treatment outcomes.

Gene-targeted deletion of OPCML and Neurotrimin in mice does not yield congenital heart defects.

Jacobsen syndrome (11q-) is a rare chromosomal disorder caused by deletions in distal11q. Many of the most common and severe congenital heart defects that occur in the general population occur in 11q-. Previous studies have demonstrated that gene-targeted deletion in mice of ETS-1, a cardiac transcription factor in distal 11q, causes ventricular septal defects with 100% penetrance. It is unclear whether deletion of other genes in distal 11q contributes to the full spectrum of congenital heart defects that occur in 11q-. Three patients with congenital heart defects have been identified that carry a translocation or paracentric inversion with a breakpoint in distal 11q disrupting one of two functionally related genes, OPCML and Neurotrimin. OPCML and Neurotrimin are two members of the IgLON subfamily of cell adhesion molecules. In this study, we report the generation and cardiac phenotype of single and double heterozygous gene-targeted OPCML and Neurotrimin knockout mice. No cardiac phenotype was detected, consistent with a single gene model as the cause of the congenital heart defects in 11q-.

Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis.

An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency. She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed. Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved. We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia.

Diagnostic Yield of Intellectual Disability Gene Panels.

BACKGROUND: Recent technological advances have improved the understanding and identification of the genetic basis of intellectual disability (ID) and global developmental delay (GDD). Next-generation sequencing panels of ID genes are now available for clinical testing; however, their overall yield in clinical practice has not yet been investigated. AIM: We determined the diagnostic yield of ID gene panels in a clinical setting and explored whether any clinical features are associated with an increased diagnostic yield. METHODS: We performed a systematic retrospective chart review of all patients with ID/GDD who underwent an ID gene panel between April 2014 and July 2017 at our institution. Chi-square analysis assessed whether any specific clinical features were significantly associated with a positive diagnostic yield. RESULTS: Forty-eight subjects (18 females, 30 males; median age: 7.5 years) were included. Consanguinity was present in 17%, autism in 38%, seizures in 42%, nonspecific dysmorphic features in 67%, and abnormalities on neurological examination in 56%; furthermore, 29% of the cohort was nonverbal and 4% was nonambulatory. Four different gene panels were used. The diagnostic yield was 21% (10/48) overall, and 38% with the more recent trio-based panel. Eight of 10 patients had de novo pathogenic dominant mutations, one had an inherited pathogenic autosomal dominant mutation, and one had compound heterozygous pathogenic recessive mutations. No clinical feature was significantly associated with an increased diagnostic yield. CONCLUSIONS: Our study suggests that ID gene panels have a high yield and are a valuable diagnostic tool in the evaluation of children with ID/GDD.

An unusual cause of Achilles tendon xanthoma.

Tendinous xanthomas are often thought to be pathognomonic for familial hypercholesterolemia. In this report, we present the case of a young man with a normal lipid profile and Achilles tendon xanthoma. Biochemical and genetic studies confirmed the diagnosis of cerebrotendinous xanthomatosis in this patient. Cerebrotendinous xanthomatosis is a rare autosomal recessive disease associated with xanthoma in tendons and the brain as well as progressive neurologic deficits. Unfortunately, this rare form of reversible dementia is thought to be underdiagnosed. Early diagnosis and treatment of this disease with chenodeoxycholic acid is essential and has been shown to greatly improve the patient's symptoms and prognosis.

[Mass spectrometry and inherited metabolic diseases diagnosis]. / Spectrométrie de masse et diagnostic des maladies héréditaires du métabolisme.

Tandem mass spectrometry is used for the diagnosis and following of metabolic disorders for acylcarnitine profiling and with liquide chromatography to explore creatin metabolism and amino and bile acids disorders. The analysis of organic acids by GC-MS is still the reference method for the diagnosis of inherited disorders of organiques acides and sterols. These techniques are also used to perform "in vitro" functional tests.

A new capillary zone electrophoresis method for the screening of congenital disorders of glycosylation (CDG).

BACKGROUND: The Congenital Disorders of Glycosylation (CDG) are an expanding group of metabolic diseases with a broad clinical presentation. We sought to validate a new Capillary Zone Electrophoresis (CZE) method (Sebia Capillarys CDT) to screen for CDG. METHODS: We analyzed 119 serum samples from children of varying ages and of both sexes to establish a reference range of transferrin glycoforms including CDT (Carbohydrate Deficient Transferrin). We then studied serums from 8 known CDG patients and compared the CZE results to the Isoelectric Focusing (IEF) profiles. We also analyzed serums after extraction from spotted Guthrie cards. RESULTS: The mean (SD) percentages of transferrin glycoforms are 18.5 (4.4), 78.5 (4.2), 2.5 (1.3) and 0.6 (0.3) for penta-, tetra-, trisialotransferrin and CDT, respectively. There is no statistically significant difference between the different age groups analyzed (0-5, 6-11, 12-15, 16-18, and >18 y) or between sexes. We observed a good correlation between the CZE and IEF profiles with both fresh serum and serum extracted from Guthrie cards. CONCLUSIONS: The Sebia Capillarys CDT system is a simple and reliable method to screen for CDG in pediatric and adult patients with an unexplained clinical syndrome, particularly when the nervous system is involved.

Olho seco em pessoas com idade superior a 40 anos selecionadas em 3 cidades brasileiras / Frequency of dry eyes in 3 different Brazilian cities

Foram estudados 300 pacientes (100 em Brasília, 100 em Säo Paulo e 100 em Teresina), de 40 a 89 anos, 50 por cento das mulheres, nos meses de junho a agosto de 1993, com o objetivo de determinar a frequência de olho seco e avaliar a influência de fatores ambientais: temperatura e umidade relativa do ar. Foram coletados dados de identificaçäo, fatores ambientais, sintomatologia e realizada avaliaçäo biomicroscópica, testes de Schrimer I, Rosa Bengala e break up time (BUT). Dos 200 olhos examinados em cada cidade, foram encontrados 38 olhos em Brasília, 37 em Säo Paulo e 2 em Teresina com teste de Schirmer I positivo; 2 olhos em Brasília, 37 em Säo Paulo e 10 em Teresina com BUT positivo. A temperatura média em Brasília foi de 21oC, variando de 14oC a 29oC; em Säo Paulo foi de 17,5 por cento, variando de 28oC a 32oC. A umidade relativa do ar média em Brasília foi de 49,5, variando de 12 por cento a 87 por cento; a média em Säo Paulo foi de 70,5 por cento, variando de 43 por cento a 98 por cento; a média em Teresina foi de 58 por cento, variando de 46 a 70 por cento. Foram determinados como olhos secos em Brasília, 42 em Säo Paulo e 5 em Teresina. Os resultados näo mostram a influência da temperatura e umidade relativa do ar na síndrome do olho seco. Os casos positivos foram mais frequentes em mulheres, em média de 60 por cento. Pacientes mais jovens em Säo Paulo apresentaram uma incidência maior de olhos secos, fato atribuído talvez a fatores do meio ambiente näo avaliados, possivelmente a poluiçäo do ar. O número de pacientes com sintomas visuais foi maior em Brasília, fato atribuído à baixa umidade relativa do ar