HOMOCYSTINURIA-I
DEFINITION:
An inborn error of methionine metabolism characterized by the
accumulation of homocysteine resulting in ocular, musculoskeletal,
central nervous system, and vascular manifestations.
EPIDEMIOLOGY:
- incidence: 0.5-1/100,000
- age of onset:
- after age 3 (with ectopia lentis)
- risk factors:
- familial - autosomal recessive
- chrom.#: 21q22.3
- gene: cystathionine beta-synthase
- M = F
PATHOGENESIS:
- cystathionine beta-synthase catalyzes the conversion of
homocysteine and serine to cystathionine
- this disorder was initially described in 1962 in screening
programmes of mentally retarded patients
2. Genetic Defect
- genetic defect -> deficiency of cystathionine beta-synthase
activity -> accumulation of homocysteine and methionine in the
blood and tissues
- the gene has been cloned
CLINICAL FEATURES:
- found in 55% of Vit B6-responders by age 10
- found in 82% of Vit B6-nonresponders
- may be the first clinical manifestation and often presents
between 3-5 years of age
- poor visual acuity
- blurred vison due to myopia, astigmatism, or aphakic
hyperopia
- diplopia
- displacement of the lens down and in
- displacement of a lens into the anterior chamber is
highly suggestive of homocystinuria and may produce a sudden
and painful secondary glaucoma
- iridodenesis - tremulousness of the iris
- phacodenesis - tremulousness of the lens
- complications - glaucoma
2. Others
- staphyloma, cataracts, glaucoma, retinal detachment, optic
atrophy
2. Musculoskeletal Manifestations
- resemble Marfan Syndrome
- dolichostenomelia (tall stature and thin)
- arachnodactyly
- others - pectus carinatum or excavatum, genu valgum, pes
cavus, high-arched palate, crowded teeth, kypho-scoliosis
3. Central Nervous System Manifestations
- 50% - progressive mental retardation
- 50% - psychiatric disorders, i.e., psychoses
- 20% - seizures - focal or general
- failure to thrive and developmental delay during the first 3
years of life
4. Vascular Manifestations
- occurs in 12-27% of untreated patients by age 15 yrs
- involve large or small vessels, arteries or veins, in any
part of the body but especially the brain
- CNS - optic atrophy, paralysis, seizures, stroke, CVA
- REN - severe hypertension, cor pulmonale
- GI - abdominal angina
- INT - malar flush, livedo reticularis
- increased risk after surgical procedures
- heterozygotes may have an increased risk of thrombotic
disease
INVESTIGATIONS:
- serum amino acid chromatography
- elevated methionine and homocyst(e)ine
- low or absent cyst(e)ine
- increased platelet adhesiveness
2. Urine
- screening test for homocystinuria
- positive cyanide-nitroprusside test on freshly-voided
urine (for disulfides)
- urinary amino acid chromatography
- elevated homocystine only
3. Diagnosis
- low cystathionine beta-synthase activity on liver biopsy,
cultured fibroblasts, or PHA-stimulated lymphocytes - prenatal
diagnosis on cultured amniotic cells or chorionic villi cells
4. Imaging Studies
- osteoporosis
- biconcave vertebrae
MANAGEMENT:
- diet low in methionine
- cysteine supplements
2. Medications
- cofactor for cystathionine beta-synthetase
- 200-1000 mg po od
- 50% of cases are vit B6-responders
- dramatic improvement in 40%
- mental potential significantly improves with early
treatment
- decreases the incidence of thrombotic complications
- use with Folate (1-5 mg po od) also because some patients
are folate deplete
2. Betaine
- a methyl group donar which lowers homocysteine levels by
remethylating homocysteine to methionine
- use in patients who are vit B6-nonresponders
3. Supportive
- control thrombotic events with anticoagulants - coumadin,
low dose ASA, oral birth control pill
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