Introduction and background - HCU

Classical Homocystinuria (HCU) is an inborn error of metabolism, caused by a deficiency of the enzyme cystathionine ɞ-synthase (CBS). This defect leads to an abnormal accumulation of homocysteine and it metabolites in blood and urine, which leads to a multisystemic disorder with involvement of the eye, skeletal system, vascular system and CNS.

Infants with HCU due to CBS deficiency are clinically normal at birth, but without newborn screening and proper management they may fail to grow and gain weight at the expected rate (failure to thrive) and have developmental delays.

By approximately age three, additional and more specific symptoms and findings may become apparent. Although intelligence may be normal in some cases, many children may be affected by progressive mental retardation.

The major clinical features involve:

Eye vision problems such as partial dislocation of the lens of the eyes, severe nearsightedness, and other eye abnormalities.
Skeletal system-osteoporosis, scoliosis, elongation and thinning of the long bones, marfanoid appearance.
Vascular nervous system – developmental delay, learning difficulties, electroencephalogram changes, epilepsy, psychiatric disturbance.
In addition, and/or episodes of uncontrolled electrical activity in the brain (seizures).
Affected individuals also tend to be thin with unusually tall stature; long, slender fingers and toes; and elongated arms and legs.
In addition, affected individuals may be at risk for the development of blood clots that can become lodged within certain large and small blood vessels, potentially leading to life-threatening complications.

A low methionine and high cysteine diet must be introduced and followed through life. A less strict diet may also be necessary to achieve adequate control in the pyrodixine-responsive group.

Pharmacological treatment involves the use of a drug called betaine, which is especially helpful if patients have difficulties to be compliant to their diet. Betaine is a methyl donor which remethylates homocysteine back to methionine and subsequently reduces plasma homocysteine levels, but raises plasma concentrations of methionine^1,6.

Clinical outcome:

Good long term biochemical control is HCU can prevent the onset of complications in early diagnosed individuals and can curtail further progression, but not reversal, of the disorder in late diagnosed cases, apart from the eye disease.

The best results occur in those individuals identified by newborn screening and managed shortly after birth in which the plasma homocystine concentration is maintained below 11 µmol/L (preferably, ≤5 µmol/L) (4). It is not yet known to what extent plasma total homocysteine concentrations need to be controlled for optimal outcome.

The incidence of HCU is not yet fully determined. Even though newborn screening and clinical diagnosis are established, undetected cases are still present. Incidence has been reported as to 1:200.000 to 1:335.000, but in some geographical area’s the prevalence may be much higher, such as Ireland³ (1:65.000), Germany⁴ (1:17.800) and Norway⁵ (1:6400).

References

Baric I, Fowler B. Sulphur amino acids. In; Blau N (ed) Physician’s guide to the diagnosis, treatment and follow-up of inherited metabolic diseases, 2^nd Springer Heidelberg, 2014:33-46
Dixon M, MacDonald A, White F, Stafford J. Disorders of Amino Acid Metabolism, Organic Acidaemias and Urea Cycle Disorders. In: Clinical Paediatric Dietetics. 4^th ed: Shaw V. West Sussex: John Wiley & Sons Limited, 2014:381-525: 19914636
Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr. 1998;157 Suppl 2:S84–7
Linnebank M, Homberger A, Junker R, Nowak-Goettl U, Harms E, Koch HG. High prevalence of the I278T mutation of the human cystathionine beta-synthase detected by a novel screening application. Thromb Haemost. 2001;85:986–8
Refsum H, Fredriksen A, Meyer K, Ueland PM, Kase BF. Birth prevalence of homocystinuria. J Pediatr. 2004;144:830–2
Generosa, A., B. Fowler, and G. Sebastio, Disorders of sulfer amino acid metabolism, in Inborn Metabolic Diseases, J.-M. Saudubray, van den Berghe, G and Walter, J. H., Editor. 2012, Springer-Verlag: Berlin. p. 311-321

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