Inborn Errors of Metabolism: Diagnosis and Treatment
Submitting InstitutionUniversity College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Technology: Medical Biotechnology
Medical and Health Sciences: Clinical Sciences, Neurosciences
Summary of the impact
Investigators at UCL have developed new diagnostic tests, new treatments
and new methods for monitoring treatment of inborn errors of metabolism.
Certain of these tests are now used to screen all newborns in the UK, all
infants with liver disease and all infants with drug-resistant epilepsy.
This is improving outcome for >120 UK children per year. For
untreatable disorders, prenatal tests prevent the birth of a second
affected child in the family.
Inborn errors of metabolism are genetic disorders characterised by a
defective protein that disturbs an important metabolic pathway. Inborn
errors of metabolism are individually rare but collectively common
diseases, and can cause a very wide range of symptoms and signs from liver
disease to convulsions to movement disorders to loss of consciousness on
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare genetic
condition in which a person has problems breaking down fatty acids for
energy. It affects around 1 in 10,000 babies born in the UK each year, and
is life-threatening if not discovered early, as any drop in an affected
baby's blood sugar levels can result in severe illness or death. In 1998,
working with Micromass UK Ltd, we showed that electrospray ionisation
tandem mass spectrometry could be used to measure octanoylcarnitine in
blood spots thus providing the basis for an automatable method for
screening for MCADD . We showed that once MCADD had been
diagnosed and appropriately managed, the prognosis was excellent (whereas
in undiagnosed patients the mortality was 20-25% and a further 20% of
children were left disabled) .
Fabry disease is a rare lysosomal storage disorder, affecting around 1 in
58,000 individuals. The condition has serious complications including
severe neuropathic pain, renal failure, cardiomyopathy and coronary artery
disease, and strokes. Patients often die prematurely as a result of these
complications. In 2002 we published a new method for determination of
ceramide trihexoside (CTH) in plasma and urine of patients with Fabry
disease . Such measurements have proved useful in monitoring
enzyme replacement therapy. This method is now the gold standard test for
the screening and monitoring of enzyme replacement throughout the UK and
We were the first to show, in 1993, that parkinsonism in infants can be
caused by a disorder affecting the synthesis of dopamine (aromatic amino
acid decarboxylase [AADC] deficiency); some affected patients have shown a
good response to dopamine agonists and monoamine oxidase inhibitors, and
new treatments have been developed by ourselves and others which build on
our early work . We have also shown that dystonia in older
children can be caused by a disorder leading to the build-up of manganese
in the brain . This disorder can be effectively treated with a
manganese chelator and iron supplementation. We developed tests for
dopamine and serotonin metabolites in cerebrospinal fluid (CSF) (for
diagnosis of AADC) and we found the gene responsible for the manganese
disorder, thereby providing a genetic test. Overall, this work has led to
the development of useful diagnostic tests and new treatments for children
and adults with movement disorders.
In 2005 we identified the genetic defect responsible for a severe seizure
disorder in infancy which we had previously shown could be treated
effectively with pyridoxal phosphate (the active form of vitamin B6). In
2006 we showed that severe seizures in the newborn that respond to
treatment with pyridoxine (another form of vitamin B6) could be due to
another genetic defect (antiquitin deficiency) .
Progressive liver disease
We have shown that liver disease in infancy and neurological disease in
older children and adults can be caused by disorders of bile acid
synthesis and these disorders can respond extremely well to bile acid
replacement therapy. Without treatment children can progress to cirrhosis
and liver failure .
References to the research
 Clayton PT, Doig M, Ghafari S, Meaney C, Taylor C, Leonard JV, Morris
M, Johnson AW. Screening for medium chain acyl-CoA dehydrogenase
deficiency using electrospray ionisation tandem mass spectrometry. Arch
Dis Child. 1998 Aug;79(2):109-15.
 Wilson CJ, Champion MP, Collins JE, Clayton PT, Leonard JV. Outcome
of medium chain acyl-CoA dehydrogenase deficiency after diagnosis. Arch
Dis Child. 1999 May;80(5):459-62.
 Mills K, Johnson A, Winchester B. Synthesis of novel internal
standards for the quantitative determination of plasma ceramide
trihexoside in Fabry disease by tandem mass spectrometry. FEBS Lett. 2002
Mar 27;515(1-3):171-6. http://dx.doi.org/10.1016/S0014-5793(02)02491-2
 Pons R, Ford B, Chiriboga CA, Clayton PT, Hinton V, Hyland K, Sharma
R, De Vivo DC. Aromatic L-amino acid decarboxylase deficiency: clinical
features, treatment, and prognosis. Neurology. 2004 Apr 13;62(7):1058-65.
 Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz
M, Clayton PT. Hepatic cirrhosis, dystonia, polycythaemia and
hypermanganesaemia--a new metabolic disorder. J Inherit Metab Dis. 2008
 Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M,
Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT.
Mutations in antiquitin in individuals with pyridoxine-dependent seizures.
Nat Med. 2006 Mar;12(3):307-9
Details of the impact
Our demonstration of an automatable method for MCADD screening and the
resulting benefits to patients contributed to a decision to undertake a
pilot study of MCADD screening (UKCSNS-MCADD) which was co-ordinated by
the MRC Centre of Epidemiology for Child Health at the UCL Institute of
Child Health, London [a]. This pilot study showed good results,
and so MCADD screening was adopted in England in 2009 and Wales in 2012
using our methods [b]. Since screening began, we can estimate
(based on epidemiology in ref 2 above) that around 60 lives have been
saved and around 60 cases of long-term disability prevented. One such
example was recently highlighted on the Great Ormond Street Hospital
website — the parents of a child identified by screening could be given
specialist dietary advice and training on what to do in an emergency [c].
Our CTH method has been adapted for screening programmes. For example,
screening of 172,000 newborns in Taiwan identified 89 infants with low
activity of the Fabry enzyme; these infants were further assessed using
our urine CTH method [d]. Enzyme replacement therapy (ERT) has
been approved by for the treatment of Fabry disease, and early treatment
can help to avoid complications. As well as contributing to early
diagnosis, our tests provide early evidence of the success of ERT by
falling levels of CTH in the urine. We are commissioned to test urine
samples from patients receiving enzyme replacement therapy by one of the
companies producing the enzyme (Genzyme). Between 2008 and 2013 we
analysed 760 samples per year. Income from the CTH tests (£37,000 p.a.)
and other tests undertaken in our laboratories (£41,000 p.a.) contributes
to maintenance of equipment and funds further method development [e].
Our diagnostic tests and new treatments for movement disorders are now in
use in clinical practice. The treatment we devised for genetically
determined manganese build-up dramatically alleviated symptoms of
parkinsonism or dystonia in four sufferers during the period 2008-13 [f].
This work was featured on the website of the European Parkinson's Disease
As a result of our work on Aromatic Amino Acid Decarboxylase Deficiency
(AADC), diagnostic tests are now available [h]. Without our
research all the families on this website would have no diagnosis for
their child's extremely debilitating disorder. Now those that have not
responded to drugs are likely to be able to have gene therapy in a joint
UK/US venture. Our work on diagnosis of AADC is featured on the AADC
Research Trust website [i].
Our research on epilepsy has resulted in new diagnostic tests and better
treatment for infants and children now in use. We perform diagnostic tests
on 230 urine samples and 46 DNA samples per year, sent to us from
paediatricians looking after infants and children with severe epilepsy
around the country. Between 2008 and 2013, we identified the genetic
biochemical defect in 35 children (14 with pyridoxine 5'-phosphate oxidase
(PNPO) deficiency; 21 with antiquitin deficiency). These are potentially
fatal disorders. They respond poorly to antiepileptic drugs but respond
very well to high doses of vitamin B6 as pyridoxine or pyridoxal
phosphate. Our diagnostic test thus enables more successful treatment to
be given. [e]
Our research was quoted in a recent guideline on treatment of neonatal
seizures [j]. Referencing  above, along with another
publication from our group, the guidelines recommend: "Most cases of
pyridoxine-dependent epilepsy are due to alpha-aminoadipic semialdehyde
dehydrogenase (also known as antiquitin, or ATQ) deficiency, an
autosomal recessive inborn error of metabolism caused by defects in the
ALDH7A1 gene that lead to accumulation of alpha-AASA. Mutation analysis
of the ALDH7A1 gene is recommended in patients with abnormal biochemical
screening and/or clear evidence of pyridoxine or folinic acid
Progressive liver disease
Our research on progressive liver disease means that children can now be
given bile acid replacement therapy for an increasing number of bile acid
synthesis disorders, preventing death from liver disease or the need for a
liver transplant [k]. We analyse samples from patients presenting
with cholestatic liver disease in the UK and overseas (280 samples, 4
treatable positives per year). For the period 2008-13, this equates to 24
lives saved / transplants avoided. In 2011, a bile acid preparation,
Orphacol, was licensed by the European Medicines Agency for the treatment
of inborn errors in primary bile acid synthesis. In the submission, they
state that: "The literature provided by the applicant showed that, where
available to investigators, the clinical use of cholic acid has been
documented since at least the mid-1990s through the work primarily
conducted by the Jacquemin, Clayton and Setchell groups". The document
references 10 of our papers [l].
Sources to corroborate the impact
[a] Oerton J, Khalid JM, Besley G et al. 2011. Newborn screening for
medium chain acyl-CoA dehydrogenase deficiency in England: prevalence,
predictive value and test validity based on 1.5 million screened babies.
Journal of Medical Screening 18:173-181
[b] Details of MCADD screening: http://newbornbloodspot.screening.nhs.uk/mcadd
and see also laboratory guide referencing our publication:
[d] Chien YH, Olivova P, Zhang XK, Chiang SC, Lee NC, Keutzer J, Hwu WL.
Elevation of urinary globotriaosylceramide (GL3) in infants with Fabry
disease. Mol Genet Metab. 2011 Jan;102(1):57-60. http://dx.doi.org/10.1016/j.ymgme.2010.08.023
[e] For confirmation please contact Biochemistry Research Group, UCL
Institute of Child Health. Contact details provided.
[f] The following three papers (two from our group, one from elsewhere)
demonstrate how this work has impacted on patients:
- Stamelou M, Tuschl K, Chong WK, Burroughs AK, Mills PB, Bhatia KP,
Clayton PT. Dystonia with brain manganese accumulation resulting
from SLC30A10 mutations: a new treatable disorder. Mov Disord.
2012 Sep 1;27(10):1317-2211
- Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P,
Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S,
Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB. Syndrome
of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia
caused by mutations in SLC30A10, a manganese transporter in man.
Am J Hum Genet. 2012 Mar 9;90(3):457-66
- Quadri M, Federico A, Zhao T, Breedveld GJ, Battisti C, Delnooz C,
Severijnen LA, Di Toro Mammarella L, Mignarri A, Monti L, Sanna A, Lu P,
Punzo F, Cossu G, Willemsen R, Rasi F, Oostra BA, van de Warrenburg BP,
Bonifati V. Mutations in SLC30A10 cause parkinsonism and dystonia
with hypermanganesemia, polycythemia, and chronic liver disease.
Am J Hum Genet. 2012 Mar 9;90(3):467-77
[k] Hartley JL, Gissen P, Kelly DA. Alagille syndrome and other
hereditary causes of cholestasis. Clin Liver Dis. 2013 May;17(2):279-300.