Posts By: pcampeau

Adenosine Kinase Deficiency

Posted by & filed under Exome sequencing, New IEM.

Two siblings with developmental delay, liver dysfunction and hypermethioninemia were investigated by exome sequencing. A homozygous missense mutation was identified in adenosine kinase, which could explain the block in the methionine cycle. Additional families were identified, and the mutations affected enzymatic function. The mouse deficient in adenosine kinase, described previously, displays phenotypic similarities, and to […]

Molecular basis of a combined malonic and methylmalonic aciduria solved by exome sequencing

Posted by & filed under Exome sequencing.

In the article below, Alfares et al. used exome sequencing to solve the molecular basis of combined malonic and methylmalonic aciduria. Two individuals with a benign course identified by the Quebec urine screening program did not have mutations in the gene encoding Malonyl-CoA decarboxylase. Exome sequencing revealed mutations in ACSF3, which encode a mitochondrial acyl-CoA synthase. The authors […]

New disorder of the methionine cycle

Posted by & filed under Part 08: AMINO ACIDS.

Bjursell MK, Blom HJ, Cayuela JA, Engvall ML, Lesko N, Balasubramaniam S,Brandberg G, Halldin M, Falkenberg M, Jakobs C, Smith D, Struys E, von Döbeln U, Gustafsson CM, Lundeberg J, Wedell A. Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function. Am J Hum Genet. 2011 Sep 28. PubMed PMID:21963049. Phenotype […]

Lysosomal Storage Disorders and calcium handling

Posted by & filed under Part 16: LYSOSOMAL DISORDERS.

Several lysosomal storage disorders are characterized by aberrant calcium handling in affected cells (reviewed in Kiselyov et al, 2010, Cell Calcium 47:103-11). Increasing ER calcium stabilizes several lysosomal enzymes. It was shown that the chaperone calnexin significantly contributes to this phenomenon for glucocerebrosidase (Ong et al, 2010, Nat Chem Biol 6:424-32).   For more info […]

FAOD and oxidative stress

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

Mice models of VLCAD develop oxidative stress in the liver upon fasting, suggesting reactive oxygen species are important culprits in the hepatopathy of affected patients (Tucci et al, 2010, FEBS J 277:4699-708). Increased oxidative stress was also seen when over-expressing a mutant SCAD in cultured cells (Schmidt et al, 2010, Mol Genet Metab 100:155-62), while […]

Niemann–Pick disease: recombinant HSP70 +/- recombinant acid sphingomyelinase

Posted by & filed under _.

Niemann–Pick disease is caused by acid sphingomyelinase deficiency. It has be shown that HSP70 binds to an endolysosomal anionic phospholipid, bis(monoacylglycero)phosphate (BMP). This facilitates the activity of activity of acid sphingomyelinase, and thus stabilizes lysosomes. It is hypothesized that recombinant HSP70 could be beneficial alone or in combination with recombinant  acid sphingomyelinase to treat Niemann–Pick […]

Lafora disease and mTOR

Posted by & filed under Part 28: NEUROGENETICS.

Lafora disease, a progressive myoclonus epilepsy, is caused by mutations in Laforin. Now, laforin has been shown to regulate autophagy through the mTOR pathway (Aguado et al., 2010, Am J Hum Genet 19:2867-76). In Lafora disease, it is thought that inhibition of mTOR is decreased and results in impaired autophagy.   Posted by Philippe Campeau […]

Immune deficiency in abetalipoproteinemia

Posted by & filed under Part 20: IMMUNE AND DEFENSE SYSTEMS.

Abetalipoproteinemia, caused by mutations in the gene encoding microsomal triglyceride transfer protein, causes fat malabsorption, pigmentary degeneration of the retina, progressive ataxic neuropathy, and acanthocytosis. Many of the features are caused by secondary vitamin E deficiency. It has now been recognized that patients also have immune defects with altered presentation of self and microbial lipid […]

Mevalonate kinase deficiency

Posted by & filed under Part 20: IMMUNE AND DEFENSE SYSTEMS.

Immune and inflammatory reactions are increasingly being linked to inborn errors of metabolism. It is well known that mevalonate kinase deficiency causes an auto-inflammatory syndrome. It has now been shown that the NALP3 inflammasome, which acts as an intracellular sensor for the innate immunity, is the missing link between a lack of geranylgeranyl pyrophosphate (downstream […]

New Channelopathies

Posted by & filed under New IEM.

Three metabolic disorders caused by channel mutations have been described: a renal Fanconi syndrome with mutations in NaPi-IIa causing impaired renal phosphate reabsorption (Magen et al., 2010, N Engl J Med 362:1102-09). ATP7A, encoding a copper transporter causing Menkes disease and occipital horn syndrome, can also be the cause of X-Linked Distal Hereditary Motor Neuropathy […]