Académique Documents
Professionnel Documents
Culture Documents
95 95
75 75
25 25
5 5
0
Homocystinuria: Challenges in 0
J Garland, A Prasad, C Vardy, C Prasad. Homocystinuria: Chal- Des défis en matière de diagnostic et
lenges in diagnosis and management. Paediatr Child Health de traitement
1999;4(8):557-562.
Deux patients atteints d’homocystinurie sont présentés. Tous deux af-
Two patients with homocystinuria are discussed. Both patients presented
fichaient des anomalies de comportement et un déficit de l’attention,
with behavioural abnormalities and deficits in attention – symptoms that
des symptômes souvent observés dans le cabinet des pédiatres. Dans
are frequently encountered in paediatric office practice. In both cases, the
les deux cas, le diagnostic d’homocystinurie n’a pas été posé à la pre-
diagnosis of homocystinuria was not made at initial presentation. Subtle
mière visite. Des traits phénotypiques subtils mais établis ont fini par
but definite phenotypic features eventually provided the first indication of
fournir la première indication d’homocystinurie entre l’âge de cinq et
homocystinuria between the ages of five to seven years. Laboratory
sept ans. Des examens de laboratoire ont confirmé la présence d’ho-
screening confirmed homocystine in the urine, and elevated methionine
mocystine dans l’urine, ainsi qu’une élévation du taux de méthionine
and homocysteine plasma levels in both patients. Patients with inborn er-
et d’homocystine plasmatique chez les deux patients. Les patients atte-
rors of metabolism such as homocystinuria are treated first by family phy-
ints d’une erreur innée du métabolisme comme l’homocystinurie sont
sicians and paediatricians. Without a high index of suspicion, physicians
d’abord traités par des médecins de famille ou des pédiatres. Sans un
can easily overlook a diagnosis of homocystinuria. The management of
indice de suspicion élevé, il est facile pour les médecins d’omettre la
patients with homocystinuria continues to pose a challenge to physicians
possibilité d’homocystinurie. Le traitement des patients atteints d’ho-
and care givers.
mocystinurie continue de représenter un défi pour les médecins et les
soignants.
Key Words: Attention deficit hyperactivity disorder; Cystathionine beta-
synthase deficiency; Developmental delay; Homocystinuria; Lens disloca-
tion
overlooked. Metabolic disorders, although rare, should weight of 4.2 kg to a Gravida II, Para I mother following an
25 25
5
Correspondence and reprints: Dr Chitra Prasad, Section of Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s Hospital, 5
FE 229-820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9. Telephone 204-787-1317, fax 204-787-1419, e-mail cprasad@hsc.mb.ca
0 0
G:\PAEDS\1999\Vol4No8\Prasad.vp
Tue Dec 07 18:19:50 1999
Color profile: _DEFAULT.CCM - Generic CMYK
Composite Default screen
Garland et al
100 100
95 95
75 75
25 25
5 5
0 0
Figure 1) The metabolism of methionine, homocysteine and cystathionine. The principal pathway for the metabolism of dietary methionine is through
conversion of homocysteine to cysteine. Folate and vitamin B6 (pyridoxine) are important cofactors in the metabolism of homocysteine, while introduc-
tion of betaine leads to remethylation of homocysteine to methionine and degradation of pathways other than trans-sulfuration
mia. Her developmental milestones were normal in the formal ophthalmologic examination showed bilateral lens
5 5
first year, but subsequently she was noted to be clumsy. subluxation. The combination of ocular findings and phe-
0 0
G:\PAEDS\1999\Vol4No8\Prasad.vp
Tue Dec 07 18:20:06 1999
Color profile: _DEFAULT.CCM - Generic CMYK
Composite Default screen
100 100
G:\PAEDS\1999\Vol4No8\Prasad.vp
Tue Dec 07 18:20:15 1999
Color profile: _DEFAULT.CCM - Generic CMYK
Composite Default screen
Garland et al
100 100
95 TABLE 2: Clinical features of homocystinuria TABLE 3: Suggested metabolic investigations for a patient 95
25
Myopia Glaucoma Malar flush Plasma and urine Aminoacidopathies 25
Thin, long bones: Seizures Livedo reticularis aminoacids Phenylketonuria
5 dolichostenomelia Homocystinuria 5
Osteoporosis Psychiatric Brittle, thin hair Branched chain
0 disturbances aminoacidopathies 0
Urea cycle defects
Mental retardation Genu valgum Inguinal hernia
Serum uric acid levels Lesch-Nyhan syndrome
Arterial and venous Scoliosis High arched palate
thromboembolism Plasma ammonia levels Urea cycle defects
Organic acidemias
Plasma lactate levels Mitochondrial cytopathies
Urinary mucopolysaccharides Lysosomal storage disorders
and oligosaccharides
ics program. The diagnosis of homocystinuria was made Skeletal survey Dysostosis multiplex in
mucopolysaccharidoses
at seven years of age. The patient is a third cousin to the
Ophthalmic slit-lamp Lens dislocation in homocystinuria
first case, and one of her first cousins has two children
examination Corneal clouding in
with homocystinuria (Figure 2). She was born at term
mucopolysaccharidoses
with a weight of 4 kg following a normal pregnancy and la-
bour. At three weeks of age, she developed seizures that
remitted spontaneously. Developmental milestones were
delayed. The patient sat without support at one year of age,
and walked independently at two years of age. She re- nitive abilities, she was performing at a five to six year
quired orthopedic intervention for her flat feet and varus level. An analysis of the patient’s most recent quantitative
deformity of her hips. At seven years of age, she under- plasma amino acids revealed normal cysteine value of
went investigations for developmental delay and attention 26 mmol/L (normal five to 45 mmol/L), elevated methio-
problems. Plasma amino acid analysis demonstrated ele- nine levels of 555 mmol/L (normal 7 to 47 mmol/L) and ho-
vated methionine and homocysteine levels, and a skeletal mocysteine levels of 231 mmol/L (normal 0 to 17 mmol/L).
survey revealed osteoporosis. Ophthalmologic evaluation Serum vitamin B12 and red cell folate levels were normal.
revealed dislocated lenses bilaterally. The diagnosis of ho- The patient remains severely affected by homocys-
mocystinuria was, thus, established. Pyridoxine and folate tinuria, and requires constant supervision to perform
therapies were initiated. Compliance to treatment was activities of daily living and infant care tasks. As with
not strict, and she was lost to follow-up. the previous case, compliance with diet and medica-
The patient completed a grade one education. At tions is poor.
21 years of age, she was re-evaluated for mental retarda-
tion, psychiatric problems with multiple suicide attempts, DISCUSSION
aggressive behaviour and problems with the law. She re- Homocystinuria due to cystathionine beta-synthase de-
quired management with antipsychotic medication. Other ficiency is an inborn error of metabolism with phenotypic
medical issues included headaches, asthma, chest pain features that for the most part are readily identified (2,3).
and deep vein thrombosis in her legs. For the most part, The principal clinical features of homocystinuria are sum-
the patient remained in a group home, and treatment marized in Table 2. Because of numerous complications,
compliance was a major problem. At 29 years of age, she such as increased tendency to strokes, ocular symptoms
delivered a normal male infant after an unremarkable and neuropsychiatric abnormalities, regular medical fol-
pregnancy. At 30 years of age, she was re-evaluated to op- low-up is imperative. Recently, there has been renewed in-
timize metabolic control. On examination, she appeared terest in the relationship between elevated homocysteine
obese, her weight was 90 kg (above the 95th percentile) levels and the occurrence of vascular complications (4,5).
100 100
and her height was 175 cm (above the 95th percentile). The inheritance pattern of homocystinuria is autoso-
95 She did not have a Marfanoid habitus. She was strongly mal recessive, and the reported incidence varies from 95
myopic. Facial dysmorphism was not present. The patient 1/67,000 to 1/200,000, with a higher risk in individuals
75
had long and slender fingers without hypermobile joints. A who are of Irish descent or from New South Wales, Aus- 75
scar from the surgical removal of a clot was present on tralia (1,6). The gene for cystathionine beta-synthase is lo-
her left ankle. A formal psychological assessment was not cated on the long arm of chromosome 21 band 22.3.
25 done. Neurological evaluation was significant for poor Sixty-four mutations affecting this gene have been de- 25
comprehension, limited reading and writing skills, and a scribed (7); the most frequent are 1278T (24%) and
5
marked inability to perform fine motor skills. In her cog- G3075 (31%). The importance of molecular analysis lies 5
0 0
G:\PAEDS\1999\Vol4No8\Prasad.vp
Tue Dec 07 18:20:16 1999
Color profile: _DEFAULT.CCM - Generic CMYK
Composite Default screen
100 100
95
in establishing a genotype-phenotype correlation that is with a better prognosis (16), thus providing evidence for 95
helpful in predicting a patient’s response to pyridoxine, including the detection of homocystinuria in the newborn
75 which in turn may have implications for long term out- screening programs (2). More studies to examine the inci- 75
come. Vitamin B6 responsive patients are likely to have a dence of this disorder and to confirm the effectiveness of
lower incidence of complications, while mental retarda- early intervention are necessary.
25
tion occurs more often in patients who are nonrespon- Dietary methionine restriction and vitamin supple- 25
sive to vitamin B6. Aggressive behaviour and conduct ments have been ineffective in both patients described.
5 disorders are also seen more commonly in this sub- There are, in addition, a number of social and behav- 5
Delayed diagnosis of homocystinuria decreases the 1. Mudd S, Levy H, Skovby F. Disorders of transsulfuration.
In: Scriver CR, Beaudet AL, Sly WS, Vale D, eds. The Metabolic and
likelihood of optimal developmental outcome, and leads Molecular Bases of Inherited Disease, 7th edn, vol 1. New York:
25 to an increased risk of systemic consequences. Earlier McGraw-Hill Inc, 1995:1279-327. 25
2. Mudd SH, Skovby F, Levy HL, et al. The natural history of
case detection, along with the introduction of a low me- homocystinuria due to cystathionine beta-synthase deficiency.
5 thionine diet and pyridoxine supplements, is associated Am J Hum Genet 1985;37:1-31. 5
0 0
G:\PAEDS\1999\Vol4No8\Prasad.vp
Tue Dec 07 18:20:16 1999
Color profile: _DEFAULT.CCM - Generic CMYK
Composite Default screen
Garland et al
100 100
3. De Franchis R, Sperandeo MP, Sebastio G, Andria G. Clinical treatment of cystathionine beta-synthase deficiency: the experience
95 aspects of cystathionine beta-synthase deficiency: how wide is the of the Willink Biochemical Genetics Unit over the past 30 years. 95
spectrum? The Italian Collaborative Study Group on Eur J Pediatr 1998; 157(Suppl 2):S71-6.
75 Homocystinuria. Eur J Pediatr 1998;157(Suppl 2):S67-70. 11. Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria – 75
4. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: the effects of betaine in the treatment of patients not responsive to
an independent risk factor for vascular disease. N Engl J Med pyridoxine. N Engl J Med 1983; 309:448-53.
1991;324:1149-55. 12. Wilcken DE, Dudman NP, Tyrrell PA. Homocystinuria due to
5. Robinson K, Mayer E, Jacobsen DW. Homocysteine and coronary cystathionine beta-synthase deficiency – the effects of betaine
25 artery disease. Cleve Clin J Med 1994;61:438-50. treatment in pyridoxine-responsive patients. Metabolism 25
6. Naughten ER, Yap S, Mayne PD. Newborn screening for 1985;34:1115-21.
homocystinuria: Irish and world experience. Eur J Pediatr 13. Wilcken DE, Wilcken B. The natural history of vascular disease in
5 1998;157(Suppl 2):S84-7. homocystinuria and the effects of treatment. J Inherit Metab Dis 5
7. Kraus JP. Biochemistry and molecular genetics of cystathionine 1997;20:295-300.
0 beta-synthase deficiency. Eur J Pediatr 1998;157(Suppl 2):S50-3. 14. Swanson JM, Sergeant JA, Taylor E, Sonuga-Barke EJ, Jensen PS, 0
8. Abbott MH, Folstein SE, Abbey H, Pyeritz RE. Psychiatric Cantwell DP. Attention-deficit hyperactivity disorder and
manifestations of homocystinuria due to cystathionine hyperkinetic disorder. Lancet 1998;351:429-33.
beta-synthase deficiency: prevalence, natural history, and 15. Greenhill LL. Diagnosing attention-deficit/hyperactivity disorder in
relationship to neurologic impairment and vitamin children. J Clin Psychiatry 1998;59(Suppl 7):31-41.
B6-responsiveness. Am J Med Genet 1987;26:959-69. 16. Schimke RN. Low methionine diet treatment of homocystinuria.
9. Longhi RC, Fleisher LD, Tallan HH, Gaull GE. Cystathionine Ann Intern Med 1969;70:642-3.
beta-synthase deficiency: a qualitative abnormality of the deficient 17. Newman G, Mitchell JR. Homocystinuria presenting as multiple
enzyme modified by vitamin B6 therapy. Pediatr Res 1977;11:100-3. arterial occlusions. Q J Med 1984;53:251-8.
10. Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the
100
95
75
25
5 5
0 0
G:\PAEDS\1999\Vol4No8\Prasad.vp
Tue Dec 07 18:20:24 1999