Tyrosinemia & NTBC: 168 patients

Posted by & filed under Part 08: AMINO ACIDS, Treatment.

Mayorandan et al. performed a cross-sectional study on Hepatorenal tyrosinaemia. Questionnaires were used to collect retrospective data about 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel). The results of this study highlight the importance of NTBC accompanied by natural protein restriction (supplemented with essential amino acids) in the prevention of complications such as liver failure, hepatocellular carcinoma and renal disease. The main points brought forward by Mayorandan et al. are summarized below:

  • NTBC dosage should be reduced to the minimal dose allowing metabolic control (defined as succinylacetone below detection limit, plasma tyrosine <400 ?M, and NTBC-levels in the therapeutic range 20–40 ?M).
  • Side effects of NTBC are mild and often transient.
  • Indications for liver transplantation: (1) hepatocellular carcinoma or (2) failure to respond to NTBC
  • Follow-up should include, on top of therapeutic monitoring (succinylacetone, tyrosine, NTBC in blood): liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Mayorandan et al. Orphanet J Rare Dis. 2014 Aug 1;9(1):107. PMID: 25081276

Posted by Yannis Trakadis, MD

MSUD and BCKD expression

Posted by & filed under Part 08: AMINO ACIDS, _.

During a recent literature review on maple syrup urine disease, I came across an older article from 1998 (Suryawan et al. Am J Clin Nutr. 1998;68:72–81.) in which the authors examined branch chain amino acid metabolism (BCAT and BCKD) in various tissues. They found that most of the oxidative capacity was in skeletal muscle and liver (with muscle  representing the greatest proportion of activity)  and that  brain (10-20%) and kidney (8-13%)  also contribute significantly to  BCAA metabolism.

Since the muscle quantitatively has the strongest role in BCAA metabolism, “domino” transplants, in which individuals with MSUD receive liver transplants, and then are able to donate their livers to recipients with other diseases, have been successful (Braz J Med Biol Res. 2014 Jun;47(6):522-6. Epub 2014 Apr 25.)

Individuals receiving livers from MSUD donors do not appear to develop MSUD because their other tissues can successfully metabolize BCAAs.

Hilary Vernon, MD PhD

Sir Archibald Garrod: A historical perspective

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I was recently reading the 1923 second edition of Sir Archibold Garrod’s seminal work entitled “Inborn Error of Metabolism” (Archibold E Garrod, “Inborn errors of metabolism” Oxford university press, London England 2nd edition, 1923) for a review article I am working on, and came across the following passage:

“regards (to) the chemical composition of the tissues of living organisms and the metabolic processes by which those tissues are built up and broken down… the progress of biochemistry is teaching is that behind a superficial uniformity there exists a diversity which is no less real than that of structure although far less obvious”.

It stuck me to which the depth to which these words still hold true today, and is exemplified in the vast diversity of disorders considered to be inborn errors of metabolism.

Hilary Vernon, MD PhD

FOXG1 related disorders and outcome

Posted by & filed under Part 28: NEUROGENETICS.

Patients with FOXG1-related disorders have severe intellectual disability, absent speech, autistic features, and epilepsy.

Children with deletions or intragenic mutations of FOXG1 also have postnatal microcephaly and structural corpus callosum abnormalities.

Seltzer et al. reported on the epilepsy characteristics and developmental outcome of 30 patients with FOXG1 mutations (23 with deletions or intragenic mutations of FOXG1, and 7 subjects with duplications).

Epilepsy was diagnosed in 87% of the patients. Patients with duplications had earlier mean age for epilepsy but most of them did not require long-term antiepileptic medication. All children with infantile spasms and FOXG1 duplication responded to hormonal therapy and only one required long-term antiepileptic therapy.

All patients had neurodevelopmental disabilities after 3 years of age, regardless of the epilepsy type or severity of seizures. All had impaired speech and social skills (3 patients with FOXG1 duplication had autism). The motor skills of subjects with deletion/intragenic mutations were significantly more affected.

Epilepsy and outcome in FOXG1-related disorders. Seltzer LE, Ma M, Ahmed S, Bertrand M, Dobyns WB, Wheless J, Paciorkowski AR. Epilepsia. 2014 Aug;55(8):1292-300.

Posted by Yannis Trakadis, MD

Liver transplantation in CDG

Posted by & filed under Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT, Treatment.

Janssen et al. recently reported the first successful liver transplantation in a Congenital Disorders of Glycosylation (CDG), and specifically in  phosphomannose isomerase deficiency (MPI-CDG). MPI-CDG has been considered a treatable disorder usually presenting with hepato-intestinal pathology. Treatment with mannose can improve the life-threatening protein-losing enteropathy and coagulation disorder but patients ultimately develop progressive liver insufficiency.

Janssen et al. report on a patient with MPI-CDG who developed progressive liver fibrosis, despite oral mannose therapy. The proband developed hemolytic jaundice associated to mannose supplementation and secondary pulmonary involvement necessitating liver transplant. Physical exercise tolerance, pulmonary functions, and metabolic parameters were fully restored after transplantation and the patient is reportedly still doing well 2 years after transplantation.

Successful liver transplantation and long-term follow-up in a patient with MPI-CDG. Janssen et al. Pediatrics. 2014 Jul;134(1):e279-83. PMID: 24982104

Posted by Yannis Trakadis, MD

FGF21 is an endocrine signal of protein restriction

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

Several studies have proposed serum fibroblast growth factor 21 (FGF21) levels as a sensitive biomarker of mitochondrial diseases. Serum FGF21 are the best predictor of these disorders when compared to serum levels of classical indicators: creatine kinase, lactate, pyruvate, and the lactate to pyruvate ratio.

Enhanced FGF21 production and circulation has been linked to the metabolic adaptation to starvation. Laeger and colleagues have shown in the Journal of Clinical Investigation that hepatic FGF21 expression is induced by dietary protein restriction, but not energy restriction. Circulating FGF21 was increased 10-fold in mice and rats fed a low-protein (LP) diet. In these animals, liver Fgf21 expression was increased within 24 hours of reduced protein intake. In humans, circulating FGF21 levels increased dramatically following 28 days on a LP diet. The authors showed that reduced protein intake underlies the increase in circulating FGF21 in response to starvation and a ketogenic diet and that FGF21 is required for behavioral and metabolic responses to protein restriction. FGF21 therefore represents an endocrine signal of protein restriction, which acts to coordinate metabolism and growth during periods of reduced protein intake. These novel data have to be considered when using FGF21 as a biomarker for diagnosis of patients with suspected mitochondrial diseases who might often be under protein restriction giving their feeding difficulties or under ketogenic diet.


Posted  by Nicola Brunetti-Pierri

Fresh Frozen plasma as a cholesterol source in Smith Lemli Opitz Syndrome

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Boctor and Wilkerson (Ann Clin Lab Sci. 2014 Summer;44(3):332-3., reported a case of Smith Lemli Opitz Syndrome in which low cholesterol levels were increased using fresh frozen plasma (FFP) in a situation where enteral replacement of cholesterol was not possible.

To my knowledge, the practice of using FFP for cholesterol replacement in SLO has been employed previously as a perioperative measure and in situations of critical illness, though publications on exact dosing and response are scarce.  This current report carefully outlines the dosing of FFP used in this patient’s situation and the plasma cholesterol response. It is a helpful addition to the clinical approaches available for SLOS.

Hilary Vernon, MD PhD

SAM and SAH measurements in renal transplantation

Posted by & filed under Part 08: AMINO ACIDS.

Klepacki et al. (Clin Chim Acta. 2013 Jun 5;421:91-7. doi: 10.1016/j.cca.2013.03.003) developed reliable methodology to measure adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels via LC-MS/MS. The found SAH concentrations to be elevated in kidney transplant patients associated with acute rejection and nephrotoxicity events  compared to healthy controls and transplant patients without  transplant dysfunction.

This brings up interesting questions about the role of metabolism of sulfur containing amino acids and methyl donors in kidney failure. Additionally, since SAH is converted into homocysteine, it seems logical for homocysteine to be regularly measured in kidney transplant patients, and to consider MTHFR genotyping and folate supplementation in abnormal genotypes to avoid further overloading this pathway.

Hilary Vernon, MD PhD


Creation of a fully intact and functional organ

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

Bredenkamp et al. recently described how cellular reprogramming can be used to generate an entire organ for transplantation, using cells manipulated in the lab. The novelty of this study compared to past studies demonstrating the production of defined cell types in vitro, is that Bredenkamp et al. describe for the first time the creation of a fully intact and functional organ.

FOXN1 is a critical transcription factor ? for the development of thymic epithelial cells (TECs). Bredenkamp et al. showed that enforced ?Foxn1 expression is sufficient to reprogramme fibroblasts into functional TECs, which supported efficient development of both ?CD4+ and CD8+ T cells in vitro. On transplantation, these TECs established a complete, fully organized and functional thymus containing all of the TEC subtypes required to support T-cell differentiation.

These results are very promising for the future of “regenerative medicine”, the goal of which is to generate transplantable organs from cells derived or expanded in vitro.

Bredenkamp N., et al. An organized and functional thymus generated from ?FOXN1-reprogrammed fibroblasts Nature Cell Biology (2014) doi:10.1038/ncb3023, http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3023.html

posted by Yannis Trakadis, MD

Deoxypyrimidine monophosphate therapy for thymidine kinase 2 deficiency

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

Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion and/or multiple deletions due to loss of TK2 enzyme activity and unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, Dr. Michio Hirano’s group administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2?/? knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Treated mice showed raised dTTP concentrations, increased levels of mtDNA, amelioration of mitochondrial respiratory chain enzyme activities, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency.


Posted by Nicola Brunetti-Pierri, MD