History of Metabolic Tests. Dr Mick Henderson Biochemical Genetics Leeds and Manchester

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1 History of Metabolic Tests Dr Mick Henderson Biochemical Genetics Leeds and Manchester

2 This presentation Wont just be a history lesson But there will be some of that! Hopefully will give an impression of the timescales Some key developments, but obviously selective! Some thoughts about the where we are and where we are going in the immediate future

3 Inborn Errors of Metabolism The term IEM was coined by a British physician Archibald Garrod in 1908 Based on studies in alkaptonuria, The idea of hereditability of course started earlier and lead to the acceptance of Mendelian genetics by the 1920s In the 1950s Watson, Crick building on the work of Rosalind Franklin, demonstrated the double helix structure of DNA leading to the discovery of the genetic code

4 PKU Disease first described by Norwegian physician, Ivar Asbjørn Følling in 1934, also described the detection of phenyl pyruvic acid using ferric chloride Horst Bickel and others published a paper showing that plasma phenyalanine could be reduced by using a diet low in phe and that this lead to clinical improvement

5 Neonatal Screening Started in early 1960s for PKU Robert Guthrie, American Microbiologist Bacterial growth inhibition assays Began in UK in about 1970

6 Neonatal screening in the UK PKU 1970 Hypothyroidism 1984 Hb & Sickle disease 2000 Cystic fibrosis 2001 MCAD deficiency 2007 MSUD, IVA, GA1, hcys 2015

7 RUSP, The position in the US

8 Amino acids were amongst the earliest metabolites to be measurable in the 1950s It could take 48 hrs for one analysis Watson, I told you that this phenyalanine was urgent, I promised it by Easter, its now Christmas!

9 Automated ion exchange amino acid analysis

10 Mass spectrometry The first mass spectrometers came into use in the 1960s One of the first into the clinical field was in Sheffield operated by Rodney Pollitt

11 Modern benchtop GCMS came into clinical labs in the early 1980s This was made possible not only by Miniturisation but also by automating much of the skilled procedures, especially autotuning

12 Tandem mass spectrometry TMS for clinical use was pioneered by Don Chase, David Milligan and others in the USA foracycarnitine analysis. One of the first groups to use this in the UK was Kim Bartlett in Newcastle in a research setting in the mid 1990s. Kim demonstrated the high sensitivity of TMS for detecting MCADD in dried bloodspots

13 History of the SSIEM SSIEM The origins of the SSIEM may be traced to an informal meeting held in England at the Manchester Royal Infirmary in 1962 when an enthusiastic group of biochemists and paediatricians met to discuss phenylketonuria. In May of the following year, the same group held a symposium in Sheffield which was entitled "Neurometabolic disorders in childhood". The Society was constituted formally in October The first symposium organised by the newly formed SSIEM was held in Liverpool in 1964 on the subject of "Biochemical approaches to mental handicap in children".

14 An Explosion of Knowledge! Depth and breadth, new disorders and categories of IEM being described at SSIEM and in JIMD every year Much, but not all, due to the greater use of next generation sequencing Disease categories continue to arise e.g. Complex lipid synthesis defects We are discovering fundamental processes still e.g. Moonlighting enzymes Metabolite repair pathways

15 Congenital Disorders of Glycosylation First patient described by Jaeken in 1980, CDG 1a. Second type, CDG1b early 1990s, Now over 80 separate disorders are described

16 A Similar Story with Understanding Mitochondrial Disease

17 Categories of Disease Historically this has been by analytical technique, e.g. amino acidurias Many are grouped by organelle affected, e.g. mitochondrial disorders Many miscellaneous enzyme defects As discussed, increasingly new disorders being discovered by NGS are changing the balance OMIM and ICD 10

18 Changing World Increasing use of NGS panels or whole exome sequencing Metabolomic profiling sensitive high resolution mass spec analysis giving rise to large profile of analytes

19 Is changing Targetted: Approach to Diagnosis Metabolites enzymes and genes indicated by clinical presentation Untargetted: Gene panels, whole exome or whole gene sequencing Metabolome analysis with untargeted high spec MS analyses

20 Think big think omics JIMD May 2018 Targeted and untargeted next gen metabolomic screening, Coene et al, Nijmegen

21 Metabolomics

22 NGS and biochemical phenotype Early predictions were that NGS panels and whole exome sequencing would make biochemistry redundant How wrong could they be! Now testing biochemical phenotype is held to be critical for diagnosis and followup of unknown variants A good example was made at this years SSIEM

23 Pex Puzzle Fred Vaz, Amsterdam, Educational Session Seven unrelated patients described, all having clinical and biochemical evidence of peroxisomal biogenesis disorders; Visual impairment, liver dysfunction, adrenal insufficiency, dev delay, hypotonia, MRI abnormalities, elevated VLCFA, pristanic and phytanic acids All heterozygous for a disease causing mutation in PEX6, c2578c But with seven healthy relatives heterozygous for identical mutation

24 What does PEX6 do?

25 Multiple functional studies confirmed absent PEX6 protein e.g. immunofluorescence microscopy Assays to determine subcellular localization Of peroxisomal matrix protein catalase (gree And PEX receptor (red) plus peroxisomal membrane proteins ABCD3 and 1

26 Why this dominant expression in some family members? There is a second mutation in the non coding region of the gene that affects the transcription of that allele. its at the 3 end and it disrupts the most distal of the two known polyadenylation signals of PEX6 This second mutation was found in the alleles of all affected cases but not mutant genes in unaffected family members

27 Implications Allelic Imbalance Profound implications for other monogenic disorders and may explain unaccountable disease where only one affected allele is found

28

29

30 Biochemistry has a bright future

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