Homocysteinemia

Samuel is an 8-year-old boy with significantly impaired intellectual and adaptive functioning. Although he has been receiving both physical and speech therapy, he has a history of progressive lethargy and muscular weakness. He also has myopia and currently his eyes are red.

Developmental testing was done at age 4 for language delay and hypotonia. At that time, a chromosomal microarray showed a deletion at chromosome 16p11.2, and developmental delay secondary to genomic copy number variation was diagnosed.

Today, Samuel has been brought to his pediatrician's office because of persistent vomiting and headache. He has no fever, chills, or abdominal pain. Viral causes have been investigated and no infectious agents were found…

There are many reasons that children can experience headaches with vomiting. The differential diagnosis for a child with recurrent vomiting and headache is very nonspecific. Furthermore, headache can be the primary cause, with vomiting a secondary symptom, or a cause that is primarily gastrointestinal can be accompanied by headache. Therefore, a thorough history and physical examination is necessary for appropriate diagnosis and treatment.

One common cause of headaches and vomiting in infants and young children is viral gastroenteritis. For this reason, one of the first steps in identifying the cause of these symptoms is to eliminate infectious etiologies. The main symptoms of viral gastroenteritis are watery diarrhea and vomiting. Other symptoms include headache, fever, chills, and abdominal pain. In most cases, symptoms persist for 1 to 3 days, but some viruses cause symptoms that last longer.

Most cases of viral gastroenteritis are caused by 4 types of viruses: rotavirus, caliciviruses, adenovirus, and astrovirus. Rotavirus is the leading cause of gastroenteritis among infants and young children. Adenovirus mainly infects children younger than 2 years. Astrovirus primarily infects infants and young children, but adults may also be infected. Caliciviruses and norovirus cause infection in people of all ages.

Headaches may be classified as primary or secondary. Primary headaches include migraine, tension-type, and cluster headache. Secondary headaches are those that are symptomatic of an underlying intracranial or medical condition. Nausea and vomiting frequently accompany many kinds of headache. It cannot be overemphasized that a complete history and thorough physical examination is essential and provides the clues for appropriate diagnosis and management. In 'Samuel's case, the intellectual disability and history of progressive lethargy, muscular weakness, myopia, and eye redness focuses the differential diagnosis…

Samuel is referred to a neurologist. .. In addition to the issues already described, the neurological examination reveals a previously unnoticed mild left-sided weakness.

Recurrent headaches in a child with intellectual disability should be investigated by a neurologist. Other symptoms that would signal the need for neurological expertise include altered sensation; dizziness; weakness; fatigue; memory loss; visual problems; tremor; and gait, sphincter, and speech disturbance…

Samuel's history, combined with his current symptoms, should raise the suspicion for a vascular cause of his headaches. Vascular headaches usually reflect abnormal function of the brain's blood vessels or vascular system. The most common type of vascular headache is migraine, which would be consistent with 'Samuel's symptoms of headache and vomiting. Other kinds of vascular headaches include cluster headaches and headaches caused by a rise in blood pressure.

Samuel's intellectual disability, combined with his symptoms, also warrants investigation of metabolic causes for his headaches. The metabolic investigation should include measurement of homocysteine, methionine, and methylmalonic acid (MMA)…

The neurologist orders an MRI, which shows white matter abnormality with T2 hyperintensity in periatrial and periventricular white matter, with thinning of the corpus callosum. A magnetic resonance angiography is then obtained, which shows that 'Samuel's bilateral internal carotid arteries are occluded. Metabolic screening shows high homocysteine levels, low plasma methionine, and absent methylmalonic acid on urine organic acid analysis…

Hyperhomocysteinemia due to MTHFR deficiency typically presents in infancy or early childhood. Severe cases will be identified in a neonatal intensive care unit because of the significant deficits in neurologic function. For example, neonates with severe MTHFR deficiency can be almost comatose. Patients with milder variants will not present as dramatically, but all will have intellectual disability as the hallmark. Additional presenting symptoms in neonates and young infants can include feeding difficulties, hydrocephalus, apnea, and muscular hypotonia. Seizures and cognitive impairment are often seen in older infants and children. As patients get older, peripheral neuropathy, gait abnormalities, and spasticity may develop.

Brain MRI abnormalities are common in patients with remethylation defects, including variable degrees of white matter abnormality, with thinning of the corpus callosum. In a patient with MTHFR deficiency, hydrocephalus may be seen. Epilepsy is also common in patients with remethylation disorders. In these patients, electroencephalogram and seizure patterns are nonspecific. In severe cases, the seizures are difficult to treat and patients may have recurrent status epilepticus.

Vascular issues are also common in remethylation defects, and a high homocysteine level may be a risk factor for occlusive vascular disease…

The normal level of plasma total homocysteine (tHcy) is below approximately 15 μM. The threshold of tHcy above which a metabolic disorder of homocysteine metabolism should be suspected and a specific therapy initiated is about 50 μM...

Betaine (N,N,N-trimethylglycine) is formed in the body from choline, and small amounts are found in a typical diet.  Betaine anhydrous for oral solution is a methylation agent indicated for the treatment of hyperhomocysteinemia, regardless of the cause, to decrease elevated homocysteine blood levels.[ This pharmacologic treatment provides an alternative pathway by remethylation of homocysteine to methionine.

It should be noted that patients with homocystinuria due to CBS deficiency may also have elevated plasma methionine concentrations, and betaine treatment may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Therefore, plasma methionine concentrations should be monitored in patients with CBS deficiency, and concentrations should be kept below 1000 μmol/L by means of dietary modification and betaine dose reduction if needed…

Samuel initiates treatment with betaine anhydrous for oral solution 200 mg/kg/d. Molecular analysis confirms a diagnosis of homocysteinemia due to MTHFR deficiency. 'Samuel's parents are relieved that a definitive diagnosis has been established and ask whether Samuel will now "get better."

If hyperhomocysteinemia due to MTHFR deficiency is diagnosed early and betaine treatment is started right away, affected infants may have a much better developmental outcome. Later diagnosis and treatment will not reverse preexisting neurological injury but may result in improvements in some symptoms.

In Samuel's case, it is too late to expect significant improvements in the intellectual disability, but his risk of having subsequent vascular events is reduced with betaine treatment. There is typically improvement in both lethargy and hypotonia after initiation of treatment but the response to therapy is variable.

https://www.medscape.org/viewarticle/894122