Classical Homocystinuria

CLASSICAL
HOMOCYSTINURIA
Dr. Priyanshu Mathur
Consultant Metabolic Genetics & Pediatric Rare Disorders
Assistant Professor, SMS Medical College, Jaipur
Case
Disclaimer: This case was reported by Dr. Arezoo Rezazadeh from Department of
Neurology, Valiasr Hospital, Iran
Case
9 years old female patient born to consanguineous couple presented with:

o Dystonia of right hand and abnormal gait since 4 years of age.
o She also developed blurred vision and lens dislocation at 4 years of age for that she was
operated at the age of 7 years.
o History of severe low back pain since 8 years of age.
o History of right femur fracture at the age of 8 years.
Family history of undiagnosed progressive motor disability and seizures in older brother,
who died at the age of 10 years.
Case
General physical examination:

o She had blonde and wooly hair.
o Pectus carinatum present.
Nervous system examination:

o Motor deficit on right side
o She had dystonic posture in her limbs on both side, which was more on right side
o DTR – brisk more on right side
o Gait - dystonic
Case
Investigations:
o CBC, LFT, Thyroid function, Calcium, serum ceruloplasmin, 24 hour urinary Cu, serum B12 were
normal
o Serum Homocysteine – 200 µmol/L
o MRI brain – watershed infarct in left centrum semiovale.
o MRI Lumbosacral vertebra – degenerative changes
o Carotid Doppler – Left carotid narrowing with evidence of thrombosis.
Treatment given:
1. Oral pyridoxine – 360 mg daily
2. Methionine restricted diet
Case
Follow up:
o She attained the ability of standing and walking without help.
o She showed remarkable recovery from her limb dystonia.
o After 3 months serum homocysteine :40 µmol/L
o After 9 months serum homocysteine :26.5 µmol/L
Homocysteine Metabolism
Homocystinuria
◦ Homocystinuria is a defect of methionine metabolism.

◦ Classical homocystinuria is an autosomal recessive disorder due to deficiency of
cystathionine beta-synthase enzyme.
◦ Cystathionine beta-synthase is an enzyme that converts homocysteine to
cystathionine in the transulfuration pathway of the methionine cycle and
requires pyridoxal 5-phosphate as a cofactor.
◦ The other two cofactors involved in remethylation pathway of methionine
include vitamin B12 and folic acid.
Methionine
◦ Essential amino acid

◦ It is first amino acid produced in an nascent polypeptide during m-RNA
translation. It is coded by initiation codon (AUG).
◦ Methionine contains:
Amino group
Carboxylic acid group
S-methyl thio-ester side chain
Methionine
Apart from protein synthesis methionine is used in:

1. Synthesis of other amino acids – Cysteine and Taurine
2. Synthesis of s-adenosyl methionine (SAM) – SAM is a cofactor and acts as a
methyl donor with the help of cobalamin
3. Synthesis of Glutathione (antioxidant)
4. Angiogenesis (initial part of angiogenesis)
5. Cu poisoning
Overconsumption of methionine is linked to cancer growth as it acts as a methyl

donor in DNA methylation.
Homocysteine Metabolism
Homocysteine is sulfur containing amino acid – metabolism by 2 pathways
1. Transsulfuration pathway - cystathionine, which requires pyridoxal-5'-

phosphate.
2. Remethylation pathway - remethylation to methionine, which requires
folate and vitamin B12 (or betaine in an alternative reaction).
Severe hyperhomocysteinemia is due to rare genetic defects resulting in

deficiencies in cystathionine beta synthase, methylenetetrahydrofolate
reductase, or in enzymes involved in methyl-B12 synthesis.
Homocysteine
◦ Homocysteine can be used to regenerate methionine or to form cysteine.

◦ Homocysteine to methionine regeneration occurs with the help of 2 enzymes –
1. Methionine synthase (Vit B12 acts as a cofactor)
2. Betaine homocysteine methyl transferase (BHMT) – 1.5% of total soluble
liver protein.
◦ Homocysteine to cystathionine and then to cysteine conversion occurs with the
help of Cystathionine beta synthase (Pyridoxal 5-phosphate acts as a cofactor).
◦ Betaine is also known as Trimethyl glycine.

Homocysteine level
Normal Homocysteine levels – 4-15 µmol/L
◦ Hyperhomocysteinemia (mild elevation, multiple causes) – 5-12%

◦ Homocystinuria (genetic defect) – 1/344,000 (in NBS)
◦ Homocystinuria (genetic defect) – 1/50,000 (Overall)
Note: Hypermethioninaemia used as a screening criteria in NBS.

Hypermethioninemia doesn`t occur in first few days of life when most blood
spots are taken for screening and also remember that breast fed babies have a
relatively low methionine level.
Clinical and pathological abnormalities in Classical
Homocystinuria
◦ Major involvement in 4 organ systems:
1. Eye
2. Skeleton
3. Central nervous system
4. Vascular system
Other organs such as liver, skin and hairs can also be involved.
Homocysteine nomenclature
◦ Homocysteine – sulphydryl form (reduced form)

◦ Homocystine – disulphide form (oxidized form)
80-90% of homocysteine exists in protein bound form.

10-20% of the remaining exists in free or non protein bound fraction – homocysteine-
cysteine mixed disulphide, homocystine-homocystine (Hcy-Hcy) disulphide, free
homocysteine (<2%).
Together all these moieties make up what is called total homocysteine (tHcy).
Note: to measure homocysteine, blood sample should be deproteinised immediately
within 10 minutes.
Classical Homocystinuria
◦ It`s incidence is as high as 1 in 300 to 1 in 4500 in intellectual disability patients in

different studies.
◦ It`s incidence is 5% in non traumatic ectopia lentis patients.
◦ 70% of the classical homocystinuria patients develops ectopia lentis by the age of
10 years.
Causes of raised Homocysteine level and its
consequences
Damage caused by high Homocysteine levels
Role of Newborn Screening
◦ Early diagnosis of homocystinuria is vital to prevent mental retardation,

delayed development, ocular complications and, in the long run, prevention of
thromboembolic phenomenon.
◦ The best possible option is an extended newborn screening program by tandem
mass spectrometry.
◦ Early diagnosis of homocystinuria can be made and the child can be put on a
protein and methionine-restricted diet to prevent the accumulation of toxic
intermediaries and correct the biochemical abnormality. This will prevent most
of the complications and help in near normal development of the child.
Diagnosis
Investigations
1. Urine examination
◦ Cyanide-nitroprusside test (Brand test): It is a qualitative screening test for the
presence of homocystine in urine. It is not a totally sensitive or specific test. The
test is also positive in patients with high creatinine levels, acetonuria, cystinuria
and in those taking penicillamine.
◦ Silver nitroprusside test: This test is more specific as it excludes cystinuria.
2. Blood examination: It is essential for the diagnosis of classical homocystinuria

to be confirmed by determination of amino acids in fasting blood.
Diagnosis
◦
Analyte Specimen Expected Expected control
findings in findings in
affected untreated
neonate individual
Homocystine plasma 10-100 >100 <1 micromol/litre
micromol/litre micromol/litre
Total Plasma 50-100 >100 <15
homocysteine micromol/litre micromol/litre micromol/litre
Methionine Plasma 200-1500 >50 10-40
micromol/litre micromol/litre micromol/litre
Homocystine Urine Detectable Detectable Undetectable
Diagnosis
3. Direct enzyme assays: Estimating the cystathionine beta synthase enzyme in

liver biopsy specimens or cultured skin fibroblasts or cultured lymphocytes.
4. Molecular diagnosis: Screening for cystathionine beta synthase mutations can

be done on cultured fibroblasts.
5. Antenatal diagnosis: Prenatal diagnosis of cystathionine beta synthase

deficiency has been feasible. Extracts of cells from cultured amniotic fluid activity
contains readily detectable activity of cystathionine beta synthase.
Signs and Symptoms of Classical Homocystinuria
◦ Marfanoid appearance
◦ Epilepsy
◦ Intellectual disability
◦ Progressive myopia
◦ Lens dislocation
◦ Thromboembolism
◦ Osteoporosis
◦ Narrowing and hardening of blood vessels
Management of Homocystinuria
Optimal Therapeutic Approach:

The currently available modalities of treatment include:
◦ Vitamin B6 (Pyridoxine) therapy
◦ Methionine restricted, cysteine supplemented diet
◦ Betaine, a methyl donor
◦ Folate and vitamin B12 supplementation
The best option is to diagnose the disease in the newborn by extended newborn
screening before the newborn leaves the hospital.
Treatment depends upon pyridoxine (vitamin B6) responsiveness.

◦ Pyridoxine trial to ascertain responsive status
◦ All newly diagnosed patients must be given a pyridoxine trial while remaining
on normal diet. Pyridoxine 50mg three times a day in the neonate and 100-200mg
three times a day in older children is given to asses vitamin responsiveness.
◦ Biochemically, vitamin B6 responsiveness is indicated by falling homocysteine

and methionine levels while remaining on pyridoxine, in the presence of
adequate vitamin B12 and folate. While on pyridoxine, the patient is deemed
vitamin responsive when the free homocystine is <5 mmol/L. If the free
homocystine and methionine levels remain persistently elevated or rise while on
pyridoxine then the patients is biochemically pyridoxine nonrespnsive.
◦ Pyridoxine responsive patients have a less severe disease compared to
pyridoxine non responders. The nonresponders are treated with Betaine and
put on methionine restricted diet.
Pyridoxine
◦ Approximately 50% of classical homocystinuria patients respond to
pharmacological doses of pyridoxine (30-600 mg orally once a day can be
increased to 1000-1200mg per day if necessary).
◦ There are no reported side effects from the usage of high dose of pyridoxine (up
to 500mg/day) in classical homocystinuria.
Methionine restricted, cysteine rich diet
◦ An early diet consisting of methionine restriction and cysteine supplementation
is of paramount importance.
Diet for homocystinuria patient

Forbidden foods:
(a) Meat, chicken, fish, eggs
(b) Milk, cheese, curd, ice cream, chocolates, Horlicks, Ovaltine
(c) Wheat flour, bajra, maize, barley, jowar, oatmeal, bread, cakes, biscuits,
pastries
(d) Rice and pulses
(e) Maggi and other soup cubes
(f) Peas
Foods to be consumed in moderate amounts:

(a) Beans, beet root, cauliflower, cabbage, carrot, onion, potatoes, radish, sweet
potato, brinjal, ladies finger, pumpkin, tomatoes.
(b) Banana, grapes, mango, guava, papaya, apple
Betaine
◦ Betaine is useful in pyridoxine nonresponders who cannot tolerate a methionine-
restricted diet or as an adjunct to such a diet. Treatment with betaine provides an
alternate remethylation pathway to convert excess homocysteine to methionine and
may help to prevent complications, especially thrombosis.
Dosage:
◦ Adults: 4-6gm/day orally in two divided doses
◦ In children < 3 years: 100mg/kg/day orally
◦ Side effects are few: (1) detectable body odor in some individuals (2) the increase in
methionine is usually harmless but can cause cerebral edema when the values are
very high (>1000 micromoles/litre). Cerebral edema can be resolved by stopping the
drug.
Folate and vitamin B12 supplementation

◦ Folate and vitamin B12 optimize the conversion of homocysteine to
methionine by methionine synthase, thus helping to decrease plasma
homocystine concentration. When the red blood cell folate and vitamin
B12 concentrations are reduced, supplementation is given.
◦ Folic acid is given in dose of 1 to 5 milligram orally once a day. Vitamin
B12 given as cyanocobalamin 25-250 micrograms per day or
hydroxycobalamin 1 milligram intramuscular per month.
Management of complications
◦ Ocular: management of myopia, glaucoma, surgical removal of lens in
case of ectopia lentis.
◦ Skeletal: surgical correction of deformities and management of
osteoporosis
◦ Vascular: prevention and management of thromboembolic events.
Signs and symptoms of MTHFR deficiency
◦ Infantile epileptic encephalopathy

◦ Progressive psychomotor retardation
◦ Variable progressive neurological and psychiatric presentations (posterior tract
lesion)
◦ Thromboembolism

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CLASSICAL

9 years old female patient born to consanguineous couple presented with:

General physical examination:

Nervous system examination:

◦ Homocystinuria is a defect of methionine metabolism.

◦ Essential amino acid

Apart from protein synthesis methionine is used in:

Overconsumption of methionine is linked to cancer growth as it acts as a methyl

Homocysteine is sulfur containing amino acid – metabolism by 2 pathways

1. Transsulfuration pathway - cystathionine, which requires pyridoxal-5'-

Severe hyperhomocysteinemia is due to rare genetic defects resulting in

◦ Homocysteine can be used to regenerate methionine or to form cysteine.

◦ Betaine is also known as Trimethyl glycine.

Normal Homocysteine levels – 4-15 µmol/L

◦ Hyperhomocysteinemia (mild elevation, multiple causes) – 5-12%

Note: Hypermethioninaemia used as a screening criteria in NBS.

◦ Homocysteine – sulphydryl form (reduced form)

80-90% of homocysteine exists in protein bound form.

◦ It`s incidence is as high as 1 in 300 to 1 in 4500 in intellectual disability patients in

◦ Early diagnosis of homocystinuria is vital to prevent mental retardation,

2. Blood examination: It is essential for the diagnosis of classical homocystinuria

3. Direct enzyme assays: Estimating the cystathionine beta synthase enzyme in

4. Molecular diagnosis: Screening for cystathionine beta synthase mutations can

5. Antenatal diagnosis: Prenatal diagnosis of cystathionine beta synthase

Optimal Therapeutic Approach:

Treatment depends upon pyridoxine (vitamin B6) responsiveness.

◦ Biochemically, vitamin B6 responsiveness is indicated by falling homocysteine

Diet for homocystinuria patient

Foods to be consumed in moderate amounts:

Folate and vitamin B12 supplementation

◦ Infantile epileptic encephalopathy

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