Case report of a child with Homocystinuria- An Inborn Error of Metabolism

 

Mrs. Anna Hima Thomas

Tutor, MGM New Bombay College of Nursing, 5th Floor, MGM Educational Campus,

Plot No: 1 and 2, Sector 1, Kamothe, Navi Mumbai- 410209, Maharashtra, India.

 

ABSTRACT:

A 14 year old male child got admitted in the pediatric ward with the complaints of Convulsion since 5 years and inability to use left hand since 10 years. He was referred from a local hospital for the further investigations and management.  Since birth, the child had a progressive developmental delay as reported by father. Later the child got diagnosed with Homocystinuria. Homocystinuria is a disorder of methionine metabolism leading to abnormal accumulation of homocysteine and its metabolites in the urine. It is an autosomal recessive inherited defect in the methylation pathway. This defect leads to a multi-systemic disorder of the connective tissue, muscles, central nervous system (CNS), and cardiovascular system. The signs and symptoms of homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood. Early diagnosis and intervention can help in preventing the complications include ectopia lentis, Mental retardation and thromboembolic events.

 

 

INTRODUCTION:

It is just over 50 years since classical homocystinuria was first described independently in 1962 by Carson and Neill in Northern Ireland and Gerritsen and colleagues in Madison, Wisconsin. Homocystinuria is defined as an autosomal recessive disorder of methionine (sulfur- amino acid) metabolism that results from the Cystathionine beta synthase (CBS) deficiency. This defect leads to high accumulation of homocystine and methionine in blood and urine. Mutations in the CBS gene lead to a substantial reduction of cystathionine beta-synthase activity.

 

This may be due to dietary deficiencies in vitamin B6, vitamin B12, and folic acid. The most common form of homocystinuria affects at least 1 in 200,000 to 335,000 people worldwide. The disorder appears to be more common in some countries, such as Ireland (1 in 65,000), Germany (1 in 17,800), Norway (1 in 6,400), and Qatar (1 in 1,800). The rarer forms of homocystinuria each have a small number of cases reported in the scientific literature.

 

Inheritance Pattern:

Homocystinuria is inherited in an autosomal recessive pattern. As an autosomal recessive disorder, the parents of a child with Homocystinuria are unaffected, healthy carriers of the condition, and have one normal gene and one abnormal gene. With each pregnancy, carrier parents have a 25 percent chance of having a child with two copies of the abnormal gene, resulting in homocystinuria. Carrier parents have a 50 percent chance of having a child who is an unaffected carrier, and a 25 percent chance of having an unaffected, non-carrier child. These risks hold true for each pregnancy

 

Biochemistry:

Methionine is converted to Homocystine via S-adenosylmethionine (SAM) and S-adenosylhomocystine (SAH), releasing a methyl group which is used in numerous methylation reactions. Glycine N-methyltransferase acts on any excess SAM that is not used in these reactions. Hcy can be converted back to Met by the remethylation pathway. The methyl-group donor can either be 5-methyltetrahydrofolate (catalysed by methionine synthase, with methylcobalamin as a cofactor) or betaine (especially in patients treated with this drug). Alternatively, Homocysteine is irreversibly metabolised to cysteine by the transsulfuration pathway. This starts with condensation of Homocystine and serine to form cystathionine, catalysed by CBS. Cystathionine is subsequently cleaved by cystathionine γ-lyase to form cysteine and 2-oxobutyrate. Cysteine can be further converted to taurine or to inorganic sulfate via hydrogen sulfide.

 

Figure 1. Path ways of methionine metabolism. SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; THF, tetrahydrofolate; MeCbl, methylcobalamin. 1, cystathionine beta-synthase; 2, methionine adenosyltransferase I/III; 3, methionine adenosyltransferase II; 4, glycine N-methyltransferase; 5, numerous methyltransferases; 6, S-adenosylhomocysteine hydrolase; 7, methionine synthase; 8, betaine-homocysteine methyltransferase; 9, Serine hydroxymethyltransferase; 10, methylenetetrahydrofolate reductase; 11, cystathionine gamma-lyase

 

Clinical features:

Patients with Cystathionine beta synthase deficiency show a wide spectrum of severity and age at presentation. Some patients have a severe childhood-onset multisystem disease, whilst others are asymptomatic into adulthood

 

The usual of presentation of clinical features are 4-5 years.

 

Ophthalmological features:

·       Ectopia lentis ( displacement or malposition of the eye's crystalline lens from its normal location)

·       Microcystic peripheral retinal degeneration

·       Secondary pupillary block

·       Glaucoma

·       Retinal detachment

·       Myopia, strabismus and cataract

·       Uveitis and keratitis

 

Skeletal abnormalities:

·       Marfanoid habitus constellation of symptoms resembling those of Marfan syndrome, including long limbs, with an arm span that exceeds the height of the individual, and a crowded oral maxilla, sometimes with a high arch in the palate, arachnodactyly, and hyperlaxity.

·       Kyphoscoliosis

·       Pectus excavatum

·       Osteoporosis

·       Knee valgum

 

Neurological features:

·       Mental retardation

·       Stroke

·       Seizures

 

Vascular features:

·       Peripheral vein thrombosis

·       Atherosclerosis

·       Deep vein thrombosis

·       Myocardial infarction

 

Diagnostic evaluation:

If homocystinuria is suspected on the basis of history, physical examination, and family history, the patient may be transferred to a tertiary care center, where expertise in a variety of relevant fields is more likely to be available.

 

Plasma homocystine levels - The level above 15µmol/L is considered to be high

 

Cyanide Nitroprusside test- The sodium cyanide–nitroprusside test is a rapid, simple, and qualitative determination of cystine concentrations. Cyanide converts cystine to cysteine. Nitroprusside then binds, causing a purple hue in 2-10 minutes. The test detects cystine levels of higher than 75 mg/g of creatinine.

 

Guthrie test- A neonatal screening test, called the Guthrie test, detects high levels of methionine in heel-stick blood.

A liver biopsy and enzyme assay to check enzymatic activity

 

CT and MRI - To rule out bony abnormalities, neurological and vascular changes

EEG- To detect the seizure activity

 

Treatment:

Pyridoxine, at a dose of 100-500mg/d, is the drug of choice.

 

Measuring homocystine levels can be used to monitor the effectiveness of treatment. If pyridoxine alone is not effective, folic acid and vitamin B-12 can be added to the regimen.

 

Oral treatment with betaine is conventionally used for patients with inherited homocystinurias. The aim of betaine therapy is to reduce level of total plasma homocysteine. Daily dosages and rhythm of administration vary between 100 to 250mg/kg/d in 2 to 4 doses

 

Diet therapy with low protein or methionine free diet:

Limit animal-protein to one serving per day. These foods are generally high in methionine.

 

Encourage protein from plant-foods, such as soy, beans, and nuts.

 

Be sure to include two servings of dairy or calcium-rich foods in the diet each day

 

Processed meats such as bacon, sausage, pepperoni, and prepackaged deli meats are high in both methionine and sodium, which can worsen cystinuria.

 

Consume low methionine fruits like apple, berries, watermelon, banana, grapes. Low methionine vegetables are cucumber, peas, green beans, mushrooms, potato and sweet potato. Soy milk can be consumed. These mentioned foods are having ˂ 100gms of methionine per serving.

 

Case overview:

A 14year old male child of non consanguineous marriage got admitted in the pediatric ward with the chief complaints of convulsions since 5 years and inability to use the left hand since 10 years. The child was referred from the local hospital for the further diagnosis and management. Birth history showed that the child was born as full term normal vaginal delivery at home. Developmental history showed that the child had progressive developmental delay. He has immature pincer grasp. He sat with support at 4 years and walked with support at 5 years. As informed by his father there is no significant genetic disorders in the family. On examination, the child had poor body bulit, fair complexion,abnormal gait, pigeon chest, Microcephaly, low set ears, arachnodactyly, micrognathia,flexion of left hand, genu valgum, Anterior bowing of legs, Double malleolus, rachitic rosary, presence of contractures on the hands, rough and scaly skin, light coloured body hairs, lusterless hairs and presence of squint eyes. He presented high anthropometric parameters corresponding to the 90th percentile, an increase in the knees and their valgus installation, and incorrect posture.

 

EEG revealed right parietal interictal epileptogenic discharges. Audiometry was normal. MRI showed sequale of ischemic changes. Serum homocystine levels was 16 which showed titre positive. The drug regimen includes syrup bevon, Inj fosphenytoin 70 mg iv BD, Tablet folic acid 5 mg OD and Tablet pyridoxine 50 mg QID. The child got discharged from the hospital after one week of treatment.

 

CONCLUSION:

Classical homocystinuria is an autosomal recessive disorder of methionine metabolism due to cystathionine beta synthase deficiency. As it is not a curable disease, proper dietary supplementation with pyridoxine and folic acid along with low methionine diet, can increase the life expectancy of the patients to a great extent. Frequent monitoring of methionine and homocystine in the blood and urine can reduce the ocular, skeletal, neurological and thromboembolic complications.

 

REFERENCES:

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Received on 03.07.2019          Modified on 08.09.2019

Accepted on 14.10.2019     © AandV Publications all right reserved