Science blogs

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 Here a few interesting blogs related to genetics:


Genetics and Health, administered by the astute Hsein-Hsein Lei

The Loom, by Carl Zimmer

Bioethics is written by the editors of the American Journal of Biotheics

Free Association (Nature Genetics Blog) 

Gene expression


The Minnesota Gene Pool Blog

Notes from the biomass, a bioinformatics blog

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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator


Heterogeneity of SCADD

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION, Part 12: LIPIDS.

JAMA. 2006 Aug 23;296(8):943-52.

Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency.
van Maldegem BT, Duran M, Wanders RJ, Niezen-Koning KE, Hogeveen M, Ijlst L, Waterham HR, Wijburg FA.

This study of 31 patients from the Netherlands is the largest study of SCADD. It highlights the clinical heterogeneity, with numerous patients being asymptomatic or having a relatively benign clinical course. They conclude that SCADD should not be included in newborn screening.

For a review of Mitochondrial Fatty Acid Oxidation Disorders, please see chapter 101 of OMMBID.

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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator


Chapter 101 : Mitochondrial Fatty Acid Oxidation Disorders

Authors: Charles R. Roe, Jiahuan Ding

Mitochondrial β-oxidation plays a major role in energy production, especially during periods of fasting. The pathway is complex and includes as many as 20 individual steps: cellular uptake of fatty acids; their activation to acyl-CoA esters; transesterification to acylcarnitines; translocation across the mitochondrial membrane; re-esterification to acyl-CoA esters; and the intramitochondrial β-oxidation spiral, generating electrons that are transferred to electron transfer flavoprotein, and acetyl-CoA, which is converted to ketone bodies in the liver. Within the spiral, each step is catalyzed by enzymes with overlapping chain-length specificities. There is also a series of enzymes specifically required for the oxidation of unsaturated fatty acids.

Inherited defects of 11 proteins directly involved in this process have been identified in humans. These include defects of plasma membrane carnitine transport (MIM 212140); carnitine palmitoyltransferase (CPT) I (MIM 255120) and CPT II (MIM 255110); carnitine/acylcarnitine translocase (MIM 212138); very long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases [VLCAD (MIM 201475), MCAD (MIM 201450), and SCAD (MIM 201470), respectively]; 2,4-dienoyl-CoA reductase (MIM 222745); and long- and short-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD (MIM 143450), SCHAD (MIM 601609)]; and mitochondrial trifunctional protein (MIM 600890).

MCAD deficiency is the most common defect in the pathway and highlights many of the features that characterize patients with disorders of β-oxidation. It has been described in patients worldwide, most of whom are of northwestern European origin. MCAD deficiency is a disease primarily of hepatic fatty acid oxidation. The most frequent presentation is episodic hypoketotic hypoglycemia provoked by fasting and beginning in the first 2 years of life. Accumulation of fatty acid intermediates results in plasma and urinary metabolites, some of which are general indicators of impaired function of the β-oxidation pathway (e.g., dicarboxylic acids), while others are unique and characteristic of MCAD deficiency (e.g., octanoylcarnitine). Although the first episode may be fatal, resembling sudden infant death syndrome (SIDS), patients with MCAD deficiency are normal between episodes. Therapy includes avoidance of fasting and treatment of acute episodes with IV glucose. Diagnosis can be made by analysis of blood acylcarnitines or, in many cases, by molecular analysis because a single MCAD missense allele accounts for nearly 90 percent of the mutant MCAD genes causing this disorder.

Other disorders of the β-oxidation pathway are characterized by skeletal and/or cardiac muscle weakness. These include deficiencies of VLCAD, LCHAD, trifunctional protein, CPT II, SCAD, and carnitine/acylcarnitine translocase deficiencies, as well as a carnitine transport defect. In some of these disorders unique metabolites can be identified in blood or urine; the exceptions are CPT I deficiency and the carnitine transport defect, in which no abnormal metabolites are excreted. In addition, hypoketotic hypoglycemia with increased blood carnitine levels occurs in CPT I deficiency.

VLCAD deficiency has two distinct clinical phenotypes: hypertrophic cardiomyopathy (VLCAD-C) and a milder form manifesting recurrent hypoglycemia (VLCAD-H). They can be distinguished biochemically by different acylcarnitine profiles following incubation of fibroblasts or amniocytes with 16-2H3-palmitate.

Carnitine deficiency is a primary manifestation of the carnitine transport defect; patients with this defect respond dramatically to carnitine therapy. Carnitine deficiency is a secondary feature of all other β-oxidation disorders, except CPT I deficiency which is characterized by increased plasma carnitine levels.

Syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by LCHAD, trifunctional protein, and CPT I deficiencies. These may require emergency delivery in the last trimester. The 1528G > C mutation observed in LCHAD deficiency can often identify a mother at risk for that disease.

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crtap sequencing

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Good morning all,

Baylor's Medical Genetics Laboratories would like to announce the addition of a new test. We are now offering diagnostic sequencing testing for Autosomal Recessive Osteogenesis Imperfecta-CRTAP gene.

The sequencing test and the KFM is found on our DNA requisition form:

Also, we will offer a Prenatal for this test.

Test code information as follows:

6310-index case (sequencing)

6315- KFM


Please check the Test Information Sheet for CPT codes. All CPT codes are listed. You can access the information sheet through the “Find Test in List” search engine or the “Search Diagnostic Test” search engine. For a quick summary read the HHMI News article, “Genetic Mutation Explains Form of Brittle Bone Disease” or use this link The journal paper title is “CRTAP Is Required for Prolyl 3-Hydroxylation and Mutations Cause Recessive Osteogenesis Imperfecta”(Cell 127, 291-304, October 20, 2006).


Alex H. Quick, B.S.

Account Representative

Medical Genetics Laboratories

Baylor College of Medicine


visit our website at


Nonsense-mediated decay of RNA occurs frequently in carbamyl phosphate synthetase I deficiency.

Posted by & filed under Part 08: AMINO ACIDS.


In this study using cells from 26 patients with CPSI deficiency, 21/52 alleles have proven to be infrequently found in the cDNA, suggesting RNA instability. In liver tissue from two patients, Northern blot proved CPSI-specific RNA degradation.
Mol Genet Metab. 2006 Sep-Oct;89(1-2):80-6. Epub 2006 Jun 5.

The frequent observation of evidence for nonsense-mediated decay in RNA from
patients with carbamyl phosphate synthetase I deficiency.

Eeds AM, Hall LD, Yadav M, Willis A, Summar S, Putnam A, Barr F, Summar ML.


For more information on urea cycle defects, please see chapter 85 of OMMBID.
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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator
Chapter 85 : Urea Cycle Enzymes

Authors: Saul W. Brusilow, Arthur L. Horwich

The urea cycle, which consists of a series of five biochemical reactions, has two roles. In order to prevent the accumulation of toxic nitrogenous compounds, the urea cycle incorporates nitrogen not used for net biosynthetic purposes into urea, which serves as the waste nitrogen product in mammals. The urea cycle also contains several of the biochemical reactions required for the de novo synthesis of arginine.

Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis (the earliest objective evidence of encephalopathy). Five well-documented diseases (each with considerable genetic and phenotypic variability) have been described, each representing a defect in the biosynthesis of one of the normally expressed enzymes of the urea cycle. Four of these five diseases—deficiencies of carbamyl phosphate synthetase (CPS) (OMIM 237300), ornithine transcarbamylase (OTC) (OMIM 311250), argininosuccinic acid synthetase (AS) (OMIM 215700), and argininosuccinate lyase (AL) (OMIM 207900)—are characterized by signs and symptoms induced by the accumulation of precursors of urea, principally ammonium and glutamine. The most dramatic clinical presentation of these four diseases occurs in full-term infants with no obstetric risk factors who appear normal for 24 to 48 hours and then exhibit progressive lethargy, hypothermia, and apnea all related to very high plasma ammonium levels.

Milder forms of these diseases occur; they may present with signs of encephalopathy at any age from infancy to adulthood. The most common of these late-onset diseases occurs in female carriers of a mutation at the OTC locus of one of their X chromosomes. The late-onset cases present with respiratory alkalosis and episodic mental status changes progressing, if not emergently treated, to cerebral edema, brainstem compression, and death. The acute encephalopathy is characterized by brain edema and swollen astrocytes, the cause of which is attributed to intraglial accumulation of glutamine resulting in osmotic shifts of water into the cell. Axons, dendrites, synapses, and oligodendroglia are normal. A fifth disease, arginase deficiency (OMIM 107830), is characterized by a clinical picture consisting of progressive spastic quadriplegia and mental retardation; symptomatic hyperammonemia, which can be life-threatening, occurs neither as severely or as commonly as in the other four diseases. Apart from OTC deficiency, which is inherited as an X-linked disorder, the other four diseases are inherited as autosomal-recessive traits. Carrier status of OTC mutations in women is determined by pedigree analysis and molecular methods. For fetuses at risk, antenatal diagnosis is available by a number of methods, particular to each disease, including enzyme analysis of fibroblasts cultured from aminocytes, as well as molecular (DNA) methods.

Molecular genetic analysis of the urea cycle enzymes has addressed their structure and expression and has permitted DNA-based diagnosis of deficiency, in many cases by direct analysis of mutations. Using the cloned complementary DNA as probes, expression in liver of RNA for all the enzymes has been observed to be increased severalfold by starvation. RNA coding for the 160-kDa subunit of the CPS I homodimer is detected almost exclusively in the liver and translates a precursor protein representing the product of fusion of two ancestral prokaryotic subunits, joined with an N-terminal mitochondrial targeting sequence. Few mutations have been identified in this large coding sequence in affected pedigrees so far, but a restriction fragment-length polymorphism (RFLP) in the human CPS locus is useful in prenatal diagnosis of deficiency. OTC is also expressed principally in the liver, and its subunit is also translated as a precursor, comprising an N-terminal mitochondrial targeting sequence that functions via an α-helical structure and net positive charge, joined with a mature portion that resembles prokaryotic transcarbamylases. Mitochondrial import requires the action of a variety of components in the cytosol to maintain an import-competent conformation, in the outer mitochondrial membrane for recognition of the precursor, in both outer and inner membrane for protein translocation, and in the matrix for proteolytic processing and folding to the active conformation. Gene deletions have been observed in approximately 15 percent of affected males. More than 100 different single base substitutions have been identified, producing amino acid substitution in many cases, involving either of the two domains of the OTC subunit. In other cases, splicing is affected, either destabilizing the messenger RNA (mRNA) or frameshifting the subunit. Prenatal diagnosis can be offered to most women who are established as heterozygous carriers by pedigree analysis, allopurinol testing, or DNA analysis, using direct DNA analysis of fetal DNA where the mutation is known, or using RFLPs. Recombinant OTC retroviruses have transduced cultured hepatocytes of mice with inherited OTC deficiency, and recombinant OTC adenoviruses have been injected into newborn mutant animals with evidence of rescue of deficiency. These gene transfer experiments aim toward achieving stable long-term OTC expression. Argininosuccinate synthetase (AS) is programmed from a single locus, but a large number of homologous processed pseudogenes are localized throughout the genome. Expression of AS mRNA has been studied in cultured cells, where the level of mRNA is greatly increased in response to canavanine treatment and repressed by the presence of arginine. The AS coding sequence has been successfully transferred into both cultured cells and mouse bone marrow cells as an approach to AS deficiency of supplying enzyme activity outside the liver. Analysis of AS mutations reveals considerable heterogeneity in the position of mutation, with most composed of codon substitutions that produce unstable protein products. Where direct mutation analysis is not possible, a number of polymorphisms at the AS locus enable linkage study of affected pedigrees. Human AL is similar to avian δ-crystallins, in which a virtually identical protein is apparently used as a structural component. Analysis of AL mutants also reveals considerable heterogeneity. Arginase in human liver and red cells is a cytosolic enzyme distinct from a second mitochondrial-localized enzyme. Deficient patients have shown heterogeneity in the site of mutation. Two RFLPs at the locus have been identified.

Treatment requires restriction of dietary protein intake and activation of other pathways of waste nitrogen synthesis and excretion. For patients deficient in CPS, OTC, and AS, treatment with sodium phenylbutyrate activates the synthesis of phenylacetylglutamine, which has a dual effect. By providing a new vehicle for waste nitrogen excretion, which suppresses residual urea synthesis in the late-onset group, a reserve urea synthetic capacity is generated that may support nitrogen homeostasis when required. In patients deficient in AS and argininosuccinase, supplementation of the diet with arginine promotes the synthesis of citrulline in the former and argininosuccinate in the latter, both of which serve as waste nitrogen products.

Outcome of treatment of neonatal-onset disease has been disappointing. Even those neonates treated prospectively prior to the onset of hyperammonemia are at high risk for neurologic deficits. Parents should be realistically counseled as to the likely outcome if the infant is rescued. Treatment of late-onset disease appears to preserve the neurologic status found at the start of therapy.




Identification of the gene encoding the enzyme deficient in mucopolysaccharidosis IIIC (Sanfilippo disease type C)

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

MPS IIIC was the only mucopolysaccharidosis for which the gene had not been cloned. This is no longer the case thanks to the recent identification of the causal gene by a group from Toronto, Canada.
Am J Hum Genet. 2006 Oct;79(4):738-44. Epub 2006 Aug 23.

Identification of the gene encoding the enzyme deficient in
mucopolysaccharidosis IIIC (Sanfilippo disease type C).

Fan X, Zhang H, Zhang S, Bagshaw RD, Tropak MB, Callahan JW, Mahuran DJ.

For more information on mucopolysaccharidoses, please see chapter 136 of OMMBID.
Thank you very much in advance for your contributions to this blog (Click on login to register and post a message).

Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator


Congenital myasthenic syndromes

Posted by & filed under Part 21: MEMBRANE TRANSPORT DISORDERS, Part 25: MUSCLE.

Science. 2006 Sep 29;313(5795):1975-8.

Dok-7 mutations underlie a neuromuscular junction synaptopathy.

Beeson D, Higuchi O, Palace J, Cossins J, Spearman H, Maxwell S, Newsom-Davis J, Burke G, Fawcett P, Motomura M, Muller JS, Lochmuller H, Slater C, Vincent A, Yamanashi Y.


A new gene involved in a congenital myasthenic syndrome, in this case with proximal muscle weakness, has been identified. It was found earlier this year that dok-7 knock-out mice could not form acetylcholine receptor clusters nor neuromuscular synapses.



Science 23 June 2006 312: 1802-1805

The Muscle Protein Dok-7 Is Essential for Neuromuscular Synaptogenesis

Kumiko Okada, Akane Inoue, Momoko Okada, Yoji Murata, Shigeru Kakuta, Takafumi Jigami, Sachiko Kubo, Hirokazu Shiraishi, Katsumi Eguchi, Masakatsu Motomura, Tetsu Akiyama, Yoichiro Iwakura, Osamu Higuchi, and Yuji Yamanashi

The next step was to screen patients with congenital mysthenic syndromes for mutations in the gene encoding dok-7.
For a review of congenital mysthenic syndromes, see this article by Andrew Engel:


Curr Opin Pharmacol. 2005 Jun;5(3):308-21.

Current understanding of congenital myasthenic syndromes.

Engel AG, Sine SM

For a review of channelopathies, please see chapter 204 of OMMBID.

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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator


Gene therapy for SCAD

Posted by & filed under Part 12: LIPIDS.

Hum Gene Ther. 2006 Jan;17(1):71-80.

Systemic correction of a fatty acid oxidation defect by intramuscular injection
of a recombinant adeno-associated virus vector.

Conlon TJ, Walter G, Owen R, Cossette T, Erger K, Gutierrez G, Goetzman E,
Matern D, Vockley J, Flotte TR.

In this article by a group from Pittsburg, proof of principle for gene therapy of a fatty acid oxidation defect (SCAD deficiency) was provided using rAAV in a murine model.
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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator

Liver transplantation for inborn errors of metabolism

Posted by & filed under Part 02: PERSPECTIVES, Part 03: GENERAL THEMES, Part 08: AMINO ACIDS, Part 09: ORGANIC ACIDS.

This articles provides an overview and discussion on an important area of the treatment of inborn errors of metabolism.
Transplantation. 2005 Sep 27;80(1 Suppl):S135-7.

Liver transplantation for inborn errors of metabolism.

Meyburg J, Hoffmann GF.


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Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator