Homocystinuria is an inborn error of methonine metabolism and was discovered in 1962 independently in Northern Ireland by Carson and Neill and in the United States by Gerritsen et al. The basic defect was defined by Mudd and his co-workers in 1964 as a deficiency of the hepatic enzyme Cystathionine ß Synthase. ( Nina A.J. Carson, The Treatment of Inherited Metabolic Disorders)
Homocystinuria (HCU), is a particular type of metabolic disorder similar to Phenylketonuria (PKU), Methylmalonic Acidemia(MMA) and Tyrosinemia. Each of these disorders require food products which are low in particular types of amino-acids. i.e. Methonine in the case of HCU, Phenylalanine in the case of PKU. .
A simple explanation of the disorders such as HCU is given below. Methonine, an amino acid, which is present in regular food protein undergoes the following steps in digestion in the body
(absent in Homocystinuria)
The conversion of Methonine to Homocyst(e)ine takes place without any problem but Homocyst(e)ine to Cyst(e)ine does not happen because of absence of the enzyme, Cystathionine b-synthase. Homocyst(e)ine is not converted to form Cyst(e)ine. This leads to accumulation of Homocyst(e)ine, which is toxic, and deficiency of Cyst(e)ine, which is an essential amino acid in Homocystinuria patients. ( In healthy individual, Cyst(e)ine is made by the body but since HCU patients do not make this amino acid in their body it needs to be supplemented). In order to reduce the toxicity of accumulated Homocyst(e)ine, only low-protein diet products which are low in Methonine are given regularly. The protein required to maintain proper growth, is given in the form of supplement which is free from Methonine.
The following highlights of HCU were taken from reference 5 below:
a. Initial studies appropriate for neurologic symptoms, developmental delay, hematologic, abnormalities.
b. Diagnostic studies: amino acid studies in blood and urine. Metabolite identification and quantitation in blood and urine. Organic acid analysis in blood and/or urine. Carnitine quantitation in blood and/or urine.
c. Definitive diagnosis by enzymatic assay and/or DNA analysis if available.
a. Medication : Adjuvant therapy with standard nutrients in pharmacologic doses : cobalamin or appropriate isoform.
b. Duration: Treatment continues for life.
a. If untreated or poorly treated: progressive neurologic disease.
b. If well treated: marked symptom improvement.
The following references give very useful details about HCU.
1. Nina A.J. Carson, Homocystinuria - Chapter 2 - 'The Treatment of Inherited Metabolic disease'
2. S.Yap and E.Naughten, Homocystinuria due to Cystathionine b-synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control,
3. D.E.L. Wilcken and B, Wilcken, The Natural history of vascular disease in Homocystinuria and the effects of treatment, J. Inherited Metabolic Disorder, 20 (1997) 295 - 300.
4. Howard, P, Irranca,M., Kellet, M., Yap, S., Thornton, P., Naughten, E., The Childrens' Hospital, Temple Street, Dublin, Ireland,Protein, Methionine and Cystine Intakes in Non- Vitamin Responsive Homocystinuria, Correspondence, Metabolic Unit, The Children's Hospital, Temple street, Dublin, Ireland.
5. S. Harvey Mudd et al, The natural History of Homocystinuria Due to Cystathionine b-Synthase Deficiency, American Journal of Human Genetics, 37:1 - 31, 1985.
6. Susan C. Winter et al, Clinical treatment guide to inborn errors of metabolism 1998, Journal of Rare Diseases, Vol 4, No 2, Mar/Apr 1998.