Homocystinuria is an inborn error of aminoacid
metabolism in which homocystine, the disulphide of homocysteine, is
excreted in the urine as a consequence of elevated homocysteine levels
in the blood(1). Homocystinuria type I, due to deficiency of the enzyme
cystathionine synthase, is the most common inborn error of methionine
metabolism. It is characterized by mental retardation, lens dislocation,
skeletal abnor-malities and thrombotic vascular disease. Homocystinuria
may also be due to defects in methyl cobalamin formation, i.e.,
homo-cystinuria type II, characterized by the triad of megaloblastic
anemia, homo-cystinuria and hypomethioninemia. Deficiency of the enzyme
methyltetra-hydrofolate reductase, results in homo cystinuria type III,
which is characterized by homocystinuria and homocystinemia with low or
normal blood methionine levels(2).
We encountered a patient with macro-cytosis with
bicytopenia and megaloblastic changes in the marrow, treated with folate
and vitamin B12 at this hospital. After the initial improvement in
anemia, the patient reported back after two years with pallor and pain
in his right eye when we made a diagnosis of homocystinuria and
instituted specific treatment.
An 8-year-old boy, born of non-consanguineous
marriage, first presented with pallor to the out-patient department of
this hospital. The child had a history of progressively increasing
pallor for the past two years and of receiving one blood transfusion at
the age of 6 year. On examination, the child was pale; there was no
pedal edema, jaundice, petechiae, ecchymosis, hepatosplenomegaly,
lymphadenopathy and sternal tenderness. Investigations showed hemoglobin
level of 7.15 g/dL, total leukocyte count 5700 cells/mm3 and a normal
differential count, platelet count 80,000/mm3 and reticulocyte count
1.8%. Peripheral smear revealed normo-chromic RBCs with few macrocytes
and reduced platelets. The mean corpuscular volume was 128 fL, mean
corpuscular hemoglobin was 37 pg and the mean corpuscular hemoglobin
concentration was 29 g/dL. Bone marrow examination showed megaloblastic
changes. The patient was started on treatment for megaloblastic anemia
with 5 mg of folic acid and 100 µg of vitamin B12 per day orally.
After one month of treatment the hemoglobin improved to 10.4 g/dL and
mean corpuscular volume reduced to 98 fL while the reticulocyte count
increased to 4%.
After an initial improvement in anemia the patient
was lost to follow-up. After two years the patient again came with
pallor, and redness and pain in his right eye. On examination the
intraocular pressure of his right eye was increased and bilateral
inferonasal subluxation of lens was found. The right lens showed
cataract and atrophic patches on the iris while the left lens was clear.
The blood pressure was within normal limits.
The hemoglobin was 4.5 g/dL, total leukocyte count
was 7500 cells/mm3 and the platelet count was 69000/mm3. The mean
corpuscular volume was 112 fL and the mean corpuscular hemoglobin was
36.9 pg. Peripheral smear showed anisopoikilocytosis with macrocytes,
ovalocytes, tear drop cells, polychromatic cells with coarse basophilic
stippling, cabot rings and few microcytic hypochromic cells. Sodium
nitroprusside test in urine was positive. The serum homocysteine level
was 72.4 µmol/L (normal range 5-15 µmol/L) and vitamin B12
was 364 pg/mL (normal range 200-800 pg/mL). Stool examination for
malabsorption for fat and reducing substance was negative; urinalysis
was also normal. Doppler studies were normal. There was no evidence of
osteoporosis in the radiographs of long bones of the patient.
Qualitative estimation of fasting serum and urinary amino acids, using
paper chromato-graphy technique, showed raised fasting urinary
methionine and homocysteine level and raised fasting plasma methionine
level. On the basis of these investigations the patient was diagnosed as
homocystinuria type I and started on oral pyridoxine (200 mg/day) and
oral folic acid (5 mg/day). The intelligence quotient was 61-65 on
Malin’s intelligence scale. The response to treatment was further
assessed by a repeat plasma and urinary amino-acidogram(3,4). There was
a disappearance of fasting plasma methionine and urinary homocysteine
and methonine after 8 weeks of treatment. After 12 weeks of treatment,
hemoglobin level was 13.3 g/dL, mean corpuscular volume was 84.7 fL,
mean corpuscular hemoglobin was 27.8 pg and mean corpuscular hemoglobin
concentration was 32.8 g/dL.
Methionine is normally activated and converted to
homocysteine. Homocysteine is further converted to either cysteine or
methionine. The conversion of homocysteine to cysteine requires
pyridoxal phosphate as a coenzyme while the methylation of homocysteine
to methionine requires N5-methyltetrahydrofolate as methyl donor as well
as methyl-B12 as coenzyme(2,3). Normally homocysteine is an
intracellular intermediate and is not detectable in plasma or urine.
However, when the reconversion pathway of homocysteine to methionine or
to cysteine is blocked, it accumulates extracellularly resulting in
Classically megaloblastic anemia has been known to be
associated with homocystinuria type II(2). In homocystinuria type II
there is a deficiency of methyl B12 as a result of which DNA synthesis
is impaired due to interference with folate metabolism by trapping
folate as methyltetrahydrofolate(1). Not many cases of megaloblastic
anemia have been seen with homocystinuria type I(1). The pathogenesis
implicated for megaloblastic anemia seen in homocystinuria type I is the
development of folate deficiency due to the excessive consumption of
N5-methyltetrahydrofolate in the methylation of homocysteine to form
methionine(1,3). Thrombocytopenia seen in our patient can be attributed
to folate deficiency which improved subsequently on treatment with
The megaloblastic anemia seen in homocytinuria type
II responds to treatment with vitamin B12. However, treatment in
homocystinuria type I constitutes administra-tion of pyridoxine.
Pyridoxine acts as a coenzyme for the enzyme cystathionine synthase and
its administration results in greater binding of enzyme with substrate
by simple mass action(5,6). However, due to associated folate
deficiency, the response to pyridoxine may not be seen unless folate is
also given concurrently. It has been observed that serum folate levels
may fall further when homocystinurics are treated with pyridoxine due to
increased remethylation of homo-cysteine to methionine(3,6).
We conclude that homocystinuria must be remembered as
a rare but treatable cause of megaloblastic anemia. All patients with
homocystinuria treated with pyridoxine should receive folate
supplementation. The treatment of homocystinuria assumes greater
significance because institution of specific treatment can prevent
progression of this disease and associated complications.
Contributors: SG diagnosed and managed the cases,
PD drafted the manuscript and collected the data, TD helped in
management of the case. SG will act as guarantor.
Competing interests: None stated.