Joumal of Mental Deficiency Research, 1989, 33, 261-265

CASE REPORT

Cystathioninuria in Down's syndromeA. HESTNES,' O. BORUD,^ H. LUNDE^ AND L. GJESSING^

'Hallsetheimen Central Institution for mentally retarded, Klaebu and Department ofNeurology, Regionsykehuset, Trondheim University Hospital, Trondheim, ^ClinicalChemical Department, University Hospital of Troms0, Troms0, and ̂ Research Laboratory,Dikemark Hospital, Asker, Norway

ABSTRACT. Secondary cystathioninuria is associated with various pathologicalconditions (Gjessing, 1963; Gjessing & Mauritzen, 1965; Endres & Wuttge, 1978). Inmany cases, cystathioninuria has been associated with mental retardation (Harris et al.,1959; Robb et al., 1984). As far as the authors know, cystathioninuria has notpreviously been described in Down's syndrome. In 1981, in the authors' institution forthe mentally retarded, all patients with Down's syndrome were screened with regard toaminoaciduria, using thin layer chromatography. In the course of this process, a case ofcystathioninuria was discovered. The results are presented in detail.

CASE R E P O R T

The patient is a female, born 1925, the second of three siblings. The father was 50years old and the mother 30 when the patient was born a couple of weeks prior toterm. Soon after birth, one suspected that a pathological development was about totake place. Feeding was difficult from the very beginning. She was unable to walkuntil 3 years old, when she also began to speak. She had German measles at 5, afterwhich she was reduced in her skills. At 31, she was hospitalized in a home for thementally retarded. On admission, she was continent and could eat and dressunassisted. At times, she was unwilling to stand, and when examined by the doctor,she was described as sitting rocking to and fro; she was drooling. She repeated somewords, but she never advanced beyond that. It seemed that her vision was reduced.Things she examined she held just in front of her eyes and she could not manage anyof the Terman-Merill tests for the 2-year stadium. When examined ophthalmologi-cally in 1962, keratitis was present bilaterally as well as spastic entropium of all foureyelids. Previously, there had been symptoms of chronic blepharo-conjunctivitis.

From approximately 1973, her vision gradually failed, and by 1979 she could justbarely sense light and darkness. In recent years, she has been regarded as totallyblind. When ophthalmologically examined in December 1984, it was concluded thather eyes had gone into phtisis on both sides; no therapeutic alternatives were left.

In 1977, the patient was operated on for an epigastric hernia. In 1982, she was

Correspondence: Amulf Hestnes, Nevrologisk Avdeling, Vestfold Sentralsykehus, 3100 T0nsberg,Norway

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262 A. Hestnes et al.

operated upon because of left-sided fracture of the humerus and in 1984 she wasoperated upon because ofa leg fracture. She also has been treated for haemorrhoidesand repeated urinary infections through the years.

The patient is short in stature, has a small head, small and deformed ears,underdeveloped maxilla, and a single palmar crease in the left hand. There is goodfunction in all extremities. She walks with short steps. Chromosomal examination inDecember 1985 verified that the patient has a trisomy 21; i.e. Down's syndrome.

When screening the patients of the institution with regard to urinary aminoacidsand peptides, thin layer of chromatography disclosed a reproducible cystathioninuria.Thereafter, urinary amino acids were quantified, using Stein & Moore technique(Perry et al., 1968). Cystathionine was excreted in a quantity of 290 fimol/g creatinine.Reference values in adults are <70, with a mean value of 7. Homocystine was notpresent.

The patient was given vitamin B^, 40 mg t.i.d. When controlled 8 months later, thecystathionine value was fully normalized, at 10 /wmol. During this period, the staff hadnot registered any particular changes in the patient's situation, but some of themclaimed that the patient looked a bit more awake, was a bit more willing to get up andwas more eager to walk.

The patient has received vitamin B6 supplementation ever since the discovery of thecystathioninuria.

D I S C U S S I O N

Cystathionin is an intermediate product in the formation of cysteine from methionine.The cleavage of cystathionine to cysteine and a-keto-butyric acid is mediated by y-cystathionase where pyridoxine (vitamin B(,) is a cofactor.

One usually classifies the cystathioninurias into eight groups (Endres, 1982):(1) Transient cystathioninuria in premature children (Mudd & Levi, 1983).(2) Primary cystathioninuria caused by an autosomal, recessively inherited defect in

the formation of cystathionase (Mudd & Levi, 1983).(3) Impaired activity of 5-methyltetrahydrofolate-homocysteine methyl-transferase

(Mudd & Levi, 1983).(4) Vitamin Bg deficiency (Mudd & Levi, 1983).(5) Thyreotoxicosis (Mudd & Levi, 1983).(6) Liver disease (Shaw et al., 1967).(7) Neuroblastoma, ganglioblastoma, hepatoblastoma (Gjessing, 1963; Gjessing &

Mauritzen, 1965).(8) Defective renal reabsorption of cystathionine in the renal tubuli (Frimpter &

Greenberg, 1967; Frimpter, 1969).The only moderate elevation of cystathionine levels in the urine combined with the

normalizing effect of vitamin Be supplementation makes it unlikely that there is a lackof y-cystathionase in this patient. In cases of genetic lack of y-cystathionase, thecystathionine in urine typically is elevated considerably more than in this case, i.e.usually in the range 400-1200 j^mol/g creatinine (Endres & Seibold, 1978).

Theoretically, cystathioninuria could be a result of overproduction ofthe substrate.

Cystathioninuria in Down's syndrome 263

homocysteine, as well. This situation occurs when 5-methyl-tetrahydrofolate-homocysteine methyl-transferase activity is impaired by lack of methylcobalamin orby lack of 5-methyl-tetrahydrofolate (Mudd & Levi, 1983). In some of these patients(Levy et al., 1970; Shih et al., 1972; Higginbottom et al., 1978), an increased excre-tion of cystathionine has been reported and the increase has been a moderate one.However, in these cases, there is also an accompanying homocystinuria, which theauthors did not find in this patient.

The possibility exists that, in the authors' patients, the increased amount ofcystathionine in urine is secondary to a lack of vitamin B^- An alternative explanationmight be that there is a vitamin B^ resistance, so that the patient needs higher dosesthan normal to metabolize cystathionine, i.e. a vitamin B(, dependency rather than adeficiency. Vitamin Be is the generic name for all 2-methyl-pyridine derivates withbiological activity, including an alcohol (pyridoxol), an amine (pyridoxamine) and analdehyde (pyridoxal). Pyridoxal-5-phosphate (P5P) is the major co-enzyme metaboliteof this group of compounds and is involved in a large number of transaminations,decarboxy la tions, deaminations, and other reactions involving most brain amino acidsas well as lipid, nucleic acid, and glycogen metabohsm (Coleman et al., 1985).

There is considerable evidence that patients with Down's syndrome may be vitaminB6 deficient. Serotonin (5-hydroxytryptamine or 5-HT), a metabohte with neuro-transmission as one of its functions, is significantly depressed in Down's syndrome(Tu & Zellweger, 1965), and this can be corrected with vitamin Bg supplementation.Indirect studies using the deoxypyridoxine administration suggest that patients withDown's syndrome have a small body pool of vitamin B(, compared to controls (McCoy& England, 1968). The reduction of taurine metabohsm in Down's syndrome(Goodmann et al., 1964) is another possible indirect piece of evidence for vitamin B6deficiency, and dopamine-B-hydroxylase activity, which utilizes pyridoxine as acoenzyme is also relatively low in Down's syndrome.

During the last years, many biochemical deviations have been discovered inDown's syndrome (for review, see Hestnes, 1987). Many patients with Down'ssyndrome develop hypothyreosis and arthritis urica is also rather common. Defects inthe immune system (Nav & Schwartz, 1984) and ocular complications, first andforemost cataracts, may have a metabolic origin.

This article points to cystathioninuria as a metabolic derangement to the authors'knowledge not previously described in Down's syndrome. The screening procedurealso included 29 other Down's syndrome patients without this abnormality, whichmakes it clear that this derangement is uncommon also in Down's syndrome. Thispatient is, however, particular in some respects. For obscure reasons, ophthalmo-logical evaluation has not afforded any clues as to why her eyes have gone into phtisisover years. Since the authors' treatment with vitamin B6 started at an old age, anydramatic results were unlikely to occur.

On the other hand, it has been claimed that even the great excretion ofcystathionine seen in y-cystathioninase deficiency is not linked to any clinicalabnormality (Mudd & Levi, 1983).

Clinical trials in Down's syndrome with supplementation of vitamin Bg inpharmacological doses have been conducted. In a 3-year double blind trial with

264 A. Hestnes et al.

vitamin Be (25-35 mg/kg) and placebo (Coleman et al., 1985), no significant effect wasfound in mental age, height, weight, cranial circumference or tongue protriision.However, in the same study (Frimpter, 1969), significant improvement in corticalauditory evoked potentials were found.

Down's syndrome is perhaps the most important single cause of mental retardation.Research during the last years has made it clear that this condition is not a static one.Some of the associated metabolic derangements, for example, hypothyreosis andarthritis urica, can be treated to the obvious benefit of the patient. More knowledge inthis exciting field may in the future give rise to even more extensive or more effectivetreatment schedules. A putative, beneficial effect of vitamin Bg supplementation incystathioninuria in Down's syndrome is still sub judice.

R E F E R E N C E S

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Endres W. (1982) Die verschiedenen Formen von Cystathioninurie. Fortschritte der Medizin 11,460-4.

Endres W. & Seibold H. (1978) Renal excretion of cystathionine and creatinine in humans atdifferent ages. Clinica Chimica Acta 87, 425.

Endres W. & Wuttge B. (1978) Occurrence of secondary cystathioninuria in children withinherited metabolic disorders, liver diseases, neoplasms, cystic fibrosis and coeliac disease.European Joumal Pediatrics 129, 29-35.

Frager J., Barnet A., Weiss I. & Coleman M. (1985) A double blind study of vitamin B5 inDown's syndrome infants: part 2—Cortical auditory evoked potentials. Joumal of MentalDeficiency Research 29, 241-6.

Frimpter G.W. (1969) Cystathioninuria in a patient with cystinuria. American Joumal ofMedicine 46, 832.

Frimpter G.W. & Greenberg A.J. (1967) Renal clearance of cystathionine in homo-zygous andheterozygous cystathioninuria, cystinuria, and the normal state. Joumal of ClinicalInvestigation 46, 975.

Gjessing L.R. (1963) Cystathioninuria and vanil-lactic-acid-uria in neuro-blastoma andargentafinoma. Lancet ii, 1281-2.

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Levy H.L., Mudd S.H., Schulman J.D., Dreyfus P.M. & Abeles R.H. (1970) A derangementin B12 metabolism associated with homocystinemia, cystathioninuria, hypomethioninemia,and methylmalonic aciduria. American Joumal of Medicine 48, 390.

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McCoy E.E. & England J. (1968) Excretion of 4-pyridoxic acid during deoxypyridoxine andpyridoxine administration to mongoloid and non-mongoloid subjects. Joumal of Nutrition96, 525.

Mudd S.H. & Levi H.L. (1983). Disorders of Transsulfuration. In: The Metabolic Basts forInherited Disease, 5th, edn, J.B. Stanbury, J.B. Wyngaarden, D.S. Fredrickson, H.L.Goldstein & M.S. Brown (eds). McGraw-Hill Book Company s.528.

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Received 25 February 1988