2. Homocystinuria
Homocystinuria is a disorder of methionine
metabolism, leading to an abnormal
accumulation of homocysteine and its
metabolites (homocystine, homocysteine-
cysteine complex, and others) in blood and
urine.
Normally, these metabolites are not found
in appreciable quantities in blood or urine.
3. Homocystinuria
Homocystinuria is inherited as an autosomal
recessive trait.
prevalence of 1 in 200,000 to 1 in 350,000 live
births has been estimated.
The condition seems more common in New
South Wales, Australia (1 in 60,000 live births),
and Ireland.
Prenatal diagnosis is feasible by performing an
enzyme assay of cultured amniotic cells or
chorionic villi or by DNA analysis.
4. Metabolic cycle of methionine
Methionine is an essential, non-polar α-amino
acid.
Under normal conditions methionine undergoes
conversion to homocysteine. This in turn
undergoes trans- sulfuration to ultimately yield
cysteine.
This step is catalyzed by the enzyme Cystathionine
beta synthase (CBS).
People suffering from this disease are unable to
synthesize CBS, hence leading to an inability to
metabolize methionine.
5. Metabolic cycle of methionine
Due to the absence of CBS enzyme , homocysteine
accumulates in the blood serum leading to an
increased excretion of homocystine in the urine
6. Metabolic cycle of methionine
Normally, most homocysteine, an intermediate
compound of methionine degradation, is
remethylated to methionine.
This methionine sparing reaction is catalyzed
by the enzyme methionine synthase,
which requires a metabolite of folic acid (5-
methyltetrahydrofolate) as a methyl donor and a
metabolite of vitamin B12(methylcobalamin), as
well as S-adenosylcobalamin, as cofactors
7.
8. Only approximately 20% of total homocysteine
(and its dimer homocystine) is in free form in
the plasma of normal individuals.
The rest is bound to proteins as mixed
disulfides.
3 major forms of homocystinemia and
homocystinuria have been identified
9. Homocystinuria Caused by Cystathionine
β-Synthase Deficiency (Classic Homocystinuria)
Homocystinuria Caused by Defects
in Methylcobalamin Formation
Homocystinuria Caused by Deficiency of
Methylene tetrahydrofolate Reductase
10. Homocystinuria Caused by Cystathionine
β-Synthase Deficiency
((ClassicHomocystinuria
This is the most common inborn error of
methionine metabolism
is an autosomal recessive inherited disorder
Approximately 40% of affected patients
respond to high doses of vitamin B6 and usually
have milder clinical manifestations than those who
are unresponsive to vitamin B6 therapy.
These patients possess some residual enzyme
activity.
11. Clinical
Infants with this disorder are normal at birth.
Clinical manifestations during infancy are
nonspecific and may include:
failure to thrive and developmental delay.
The diagnosis is usually made after 3 yr of age,
when subluxation of the ocular lens (ectopia
lentis)occurs. retinal detachment, and optic
atrophy may develop later in life.
Progressive intellectual disabilityis common.
12. Normal intelligence has been reported.
Higher IQ scores are seen in vitamin B6
responsive patients.
Psychiatric and behavioral disorders ( 50% )
Convulsions (20%)
13.
14. skeletal abnormalities resembling those of
Marfan syndrome they are usually tall and thin,
with elongated limbs and arachnodactyly.
Scoliosis, pectus excavatum or carinatum, genu
valgum, pes cavus, high-arched palate, and
crowding of the teeth are commonly seen.
These children usually have fair hair, blue eyes,
and a peculiar malar flush.
Generalized osteoporosis, especially of the spine
15. Thromboembolic episodes
which is caused by changes in the vascular walls
and increased platelet adhesiveness secondary to
elevated homocystine levels
involving both large and small vessels, especially
those of the brain, are common and may occur at
any age.
Optic atrophy, paralysis, cor pulmonale, and severe
hypertension (from renal infarcts) .
The risk of thromboembolism increases after
surgical procedures.
Spontaneous pneumothorax and acute
pancreatitis are rare complications
19. diagnosis
Elevations of both methionine and homocystine in
body fluids are the diagnostic laboratory findings.
Freshly voided urine should be tested for
homocystine because this compound is
unstable and may disappear as the urine is
stored.
Cystine is low or absent in plasma.
20. Clotting studies are normal
The diagnosis may be established by assay of
the enzyme in liver biopsy specimens, cultured
fibroblasts, or phytohemagglutinin-stimulated
lymphocytes or by DNA analysis
21. Treatment
with high doses of vitamin B6 (200-1,000 mg/24
hr)
causes dramatic improvement in most patients who
are responsive this therapy.
The degree of response to vitamin B6 treatment may
be different in different families.
Some patients may not respond because of folate
depletion;
a patient should not be considered unresponsive
to vitamin B6 until folic acid (1-5 mg/24 hr) has
been added to the treatment regimen.
.
22. Restriction of methionine intake in conjunction
with cysteine supplementation is recommended
for patients who are unresponsive to vitamin B6
The need for dietary restriction and its extent
remains controversial in patients with vitamin
B6 responsive form.
Dislocation of the lens seemed to be prevented in
some patients.
23. Betaine (trimethylglycine, 200-250 mg/kg/day )
lowers homocysteine levels in body fluids
This treatment has produced clinical improvement
(preventing vascular events) in patients who are
unresponsive to vitaminB6 therapy.
Cerebral edema has occurred in a patient with
vitamin B6 nonresponsive homocystinuria and
dietary noncompliance during betaine therapy.
Administration of large doses of vitamin C (1 g/day)
has improved endothelial function;
long-term clinical efficacy is not known
24. Homocystinuria Caused by Defects
in Methylcobalamin Formation
Methylcobalamin is the cofactor for the enzyme
methionine synthase,
which catalyzes remethylation of homocysteine to
methionine.
There are at least 7 distinct defects in the
intracellular metabolism of cobalamin that may
interfere with the formation of
methylcobalamin.
25. The clinical manifestationsare similar in patients with
all of these defects.
Vomiting, poor feeding, failure to thrive, lethargy,
hypotonia,
seizures, and developmental delay may occur in the
first few months of life.
One patient with the cblG defect was not symptomatic
(except for mild developmental delay) until she was 21
yr old when she developed difficulty in walking and
numbness of the hands
26. Laboratory findings include
megaloblastic anemia,
homocystinuria, and hypomethioninemia. The
presence of megaloblastic anemia differentiates
these defects from homocystinuria due to
methylene tetrahydrofolate reductase deficiency .
Renal artery thrombosis, hemolytic uremic
syndrome, pulmonary hypertension and optic
nerve atrophy have been reported in some
patients with these defects
27. Diagnosis
is established by complementation studies
performed in cultured fibroblasts.
Prenatal diagnosis has been accomplished by
studies in amniotic cell cultures
Treatment with vitamin B12 in the form of
hydroxycobalamin (1-2 mg/24 hr) is used to correct
the clinical and biochemical findings.
28. Homocystinuria Caused by Deficiency of
Methylene tetrahydrofolate Reductase
This enzyme reduces 5,10-methylene
tetrahydrofolate to form 5-
methyltetrahydrofolate, which provides the methyl
group needed for remethylation of homocysteine
to methionine
The severity of the enzyme defect and the
clinical manifestations varies considerably in
different families
29. Clinical findings vary from apnea, seizure,
microcephaly, coma, and death to developmental
delay, ataxia, and motor abnormalities or even
psychiatric manifestations.
Premature vascular disease or peripheral
neuropathy has been reported as the only
manifestation of this enzyme deficiency in some
patients.
30. Adults with severe enzyme deficiency may even be
completely asymptomatic.
Exposure to the anesthetic nitrous oxide
(which inhibits methionine synthase) in
patients with methylenetetrahydrofolate
reductase (MTHFR) deficiency may result in
neurologic deterioration and death.
31. diagnosis
Laboratory findings include moderate
homocystinemia and homocystinuria.
The methionine concentration is low or low
normal.
Thromboembolism of vessels has also been
observed in these patients.
Diagnosis may be confirmed by the enzyme
assay in cultured fibroblasts or leukocytes or by
finding causal mutation in the MTHRgene
32. diagnosis
Prenatal diagnosis can be offered by measuring
MTHFR enzyme activity in cultured chorionic
villus cells or amniocytes, by linkage analysis in
informative families, or by DNA analysis of the
mutation
33. Treatment
Treatment of severe MTHFR deficiency with a
combination of folic acid, vitamin B6, vitamin B12,
methionine supplementation, and betaine has
been tried.
Of these, early treatment with betaine seems to
have the most beneficial effect
