Intranasal ERT in LSDs may bypass BBB

• May 13th, 2012

According to the study by Wolf et al. intranasal administration of α-l-iduronidase (IDUA) enzyme may be able to bypass the blood-brain barrier. This appears to be the case in IDUA-deficient mice after a single intranasal treatment with concentrated Aldurazyme®. Promising results in mice were also noted after intranasal treatment with an adeno-associated virus (AAV) vector expressing human IDUA. These experiments raise the possibility of non-invasive treatments for lysosomal storage disorders.

Lysosomal enzyme can bypass the blood-brain barrier and reach the CNS following intranasal administration. Wolf et al. Mol Genet Metab. 2012 May;106(1):131-4. PMID: 22420937 http://dx.doi.org/10.1016/j.ymgme.2012.02.006

posted by Yannis Trakadis MD, MSc

Liver-targeted gene therapy in PKU mice: neurogenic amines & neuropsych function

• March 20th, 2012

Aminergic deficit is one of the abnormalities found in the brain of hyperphenylalaninemic patients and a mouse model of PKU. Liver-targeted gene therapy has been previously reported to correct hyperphenylalaninemia and concomitant behavioral recovery in PKU mice. In this study Yagi et al. provide evidence that the functional recovery is mediated by reversal of the aminergic deficit (improved amine metabolism: dopamine, norepinephrine, and serotonin levels) in the brain of PKU mice along with the systemic improvement of phenylalanine levels.

Recovery of neurogenic amines in phenylketonuria mice after liver-targeted gene therapy. Yagi et al. Neuroreport. 2012 Jan 4;23(1):30-4. PMID: 22107842

posted by Yannis Trakadis MD, MSc

Intellectual impairment after long-term NTBC treatment?

• March 20th, 2012

Treatment of hypertyrosinemia (HT) type I with NTBC can prevent acute liver failure and hepatocellular carcinoma thus improving survival of patients. However, there is some evidence of cognitive impairment in patients with secondary elevated plasma tyrosine levels. Thimm et al. used standardized psychometric test batteries to evaluate the neurocognitive development (cognition, motor abilities and speech) in nine early-treated patients under long-term NTBC treatment. The 12-month median plasma tyrosine concentration was elevated in seven out of nine patients despite NTBC concentrations generally being in the lower therapeutic range.

• Total IQ score was below average in 5 out of 7 patients
• Motor abilities were subnormal in 4 out of 7 patients
• Cerebral MRI revealed no abnormalities
• Logopedic evaluation demonstrated problems in language development in all but one of the tested patients (80%)

The authors conclude that intellectual impairment may be a long-term complication in HT type I with elevated plasma tyrosine under NTBC treatment as observed in other hypertyrosinemias.  

Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC. Thimm  et  al. J Inherit Metab Dis. 2012 Mar;35(2):263-8. PMID: 22069142

posted by Yannis Trakadis MD, MSc

ERT and adult Pompe disease outcome

• February 24th, 2012

Regnery et al (2012) performed an open-label observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 38 adult patients with GSD2. The patients first presented with the disease at a mean age of 36.2 ± 10.5 years but ERT treatment was only started after  14.5 ± 7.2 years (mean delay). This study demonstrates a variable course of neuromuscular deficits during the 36 months of this observational study (36 months of ERT treatment).

36 months observational clinical study of 38 adult Pompe disease patients under alglucosidase alfa enzyme replacement therapy. Regnery et al. J Inherit Metab Dis. 2012 Jan 31. [Epub ahead of print] PMID: 22290025

posted by Yannis Trakadis MD, MSc

Treatable IEM causing intellectual disability

• February 16th, 2012

Dr. van Karnebeek and Dr. Stockler performed a systematic literature review for treatable inborn errors of metabolism causing intellectual disability. Recommendations for investigation of genetic causes of intellectual disability are usually based on the frequencies of single conditions and the yield of diagnostic methods. The objective of this manuscript was to identify all currently treatable inborn errors of metabolism presenting with predominantly intellectual disability so that availability of treatment is also factored in the recommendations. The authors applied Cochrane Collaboration guidelines in formulation of PICO and definitions, and searched in Pubmed (1960-2011) and relevant (online) textbooks to identify ‘all inborn errors of metabolism presenting with intellectual disability as major feature’. 81 ‘treatable inborn errors of metabolism’ presenting with intellectual disability as a major feature were identified. 62% (n=50) of all disorders are identified by metabolic screening tests in blood (plasma amino acids, homocysteine) and urine (creatine metabolites, glycosaminoglycans, oligosaccharides, organic acids, pyrimidines). For the remaining disorders (n=31) a ‘single test per single disease’ approach is required. The levels of available evidence for the various treatments ranged from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=45), Level 4-5 (n=27). The results of this work were translated into digital information tools for the clinician (www.treatable-id.org).  

Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review. van Karnebeek CD, Stockler S. Mol Genet Metab. 2011 Nov 30. [Epub ahead of print] PMID: 22212131

posted by Yannis Trakadis MD, MSc

Sapropterin and stability of blood phenylalanine in PKU

• October 10th, 2010

Variability in blood phenylalanine levels is inversely correlated with IQ and was recently shown to be a better predictor of IQ in early and continuously treated patients with PKU than mean blood phenylalanine levels. This study concludes that sapropterin results in increased stability of blood phenylalanine levels in BH4-responsive PKU.

Sapropterin therapy increases stability of blood phenylalanine levels in patients with BH4-responsive phenylketonuria (PKU). Burton et al. Mol Genet Metab. 2010 Oct-Nov;101(2-3):110-4. Epub 2010 Jun 27.

posted by Yannis Trakadis

Treatment of Wilson disease with NaPB

• January 5th, 2010

Chaperones such as phenylbutyrate and curcumin can be used to treat conditions with misfolded proteins such as ATP7 in Wilson Disease.

Hepatology. 2009 Dec;50(6):1783-95.
Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin.
van den Berghe PV, Stapelbroek JM, Krieger E, de Bie P, van de Graaf SF, de Groot RE, van Beurden E, Spijker E, Houwen RH, Berger R, Klomp LW.

Phenylbutyrate also has other pharmacological effects, such as HDAC inhibition,  ↓ stability of HSC70 mRNA leading to ↓ degradation of ΔF508 CFTR, ↑ PPARG activation, isoprenylation inhibition, and ↓ methylation. These properties render it an attractive compound for the treatment of other genetic conditions such as cystic fibrosis and thalassemias.

Philippe Campeau

MPS VI gene therapy pre-clinical model

• June 7th, 2009

Mol Genet Metab. 2009 Jun;97(2):102-8. Epub 2009 Feb 27.
Lentiviral-mediated correction of MPS VI cells and gene transfer to joint tissues.
Byers S, Rothe M, Lalic J, Koldej R, Anson DS.

In this publication, the authors use a lentivirus to tranduce human fibroblasts and chondrocytes, as well as the synovial membrane and the fascia in injected rat joints.

Click this link to see the most recent online abstracts of major genetics journals.

Philippe Campeau

Mefolinate (5-methyltetrahydrofolate) as a treatment of severe MTHFR deficiency

• June 29th, 2008

Li, D. et al. Mefolinate (5-methyltetrahydrofolate), but not folic acid, decreases mortality in an animal model of severe methylenetetrahydrofolate reductase deficiency. Journal of Inherited Metabolic Disease Volume 31, Number 3 / June, 2008
In a mouse model of severe MTHFR deficiency, Mefolinate administration to the mother improved survival and cerebellar morphology in the pups. This agent could potentially be used eventually in clinical trials for the rare patients with severe MTHFR deficiency.
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Click this link to see the most recent online abstracts of major genetics journals.

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

Reversion of white matter changes with treatment of HMG-CoA lyase deficiency.

• December 19th, 2007

Pediatr Neurol. 2007 Jul;37(1):47-50.

3-Hydroxy-3-methylglutaryl coenzyme a lyase deficiency with reversible white
matter changes after treatment.

Zafeiriou DI, Vargiami E, Mayapetek E, Augoustidou-Savvopoulou P, Mitchell GA.

Click this link to see the most recent online abstracts of major genetics journals.
Philippe Campeau, MD
Resident in Medical Genetics at McGill University
OMMBID Blog Administrator