Background
Psychotic disorders are known to affect all age groups including children. It was more commonly seen in adults but has also been increasingly reported in children from 3 years and above. The prevalence has been found to be significantly higher in adolescents after the age of 14 up to the early 20s [1]. During the prepubertal years, it is commoner in males while it has equal sex predilection in adolescence [1]. In the UK, In 2012, Kelleher et al, [2] conducted a systematic review of all published literature on psychotic disorders in children and found a prevalence of 17% among children aged 9-12 years and 7.5% among 13-17 years [2].
Before arriving at a diagnosis of Schizophrenia in young children, it is important to perform a full list of investigations to rule out organic causes of psychosis in these children. These investigations include screening for infections, autoimmune disorders, tumors, toxins, drugs, and metabolic disorders [3]. Homocysteine remethylation disorders have been shown to have a causal effect on neuropsychiatric and neurodegenerative problems [4]. Some publications have emphasized the importance of considering homocysteine disorders in patients with psychiatric symptoms [5,6,7].
This case report identifies the need to consider homocysteine remethylation disorders in cases of psychosis in children.
Case Presentation
A 14-year-old young girl presents with a 2-month history of becoming more withdrawn, quiet, and poor school performance. She was accompanied by her mother who was concerned about self-neglect, poor cognition, and a week history of mutism.
On initial examination, she was noted to have occasional unexplained smiling and laughing and lack of speech, other systemic and neurological examination was normal. A prompt referral to the child psychiatry team was made while further investigations and brain magnetic resonance imaging were carried out which were all normal.
A preliminary diagnosis of the first episode of psychosis was made after a psychiatrist assessment. She was discharged with a plan for follow up by the psychiatrists.
She re-attended a week later with a deterioration of symptoms and refusal to eat. She was subsequently admitted to the pediatrics unit for further investigations. On the sixth day of admission, she developed tremors of the right hand after being started on aripiprazole based on the diagnosis of psychosis. She also developed difficulty with walking and required support for mobilization.
Investigations
On the first presentation, the initial investigations were within normal limits except for a low vitamin B12 and folate. A brain magnetic resonance imaging (MRI) also showed no abnormalities. During the second admission, another set of investigations was performed. The key tests aiding diagnosis were plasma amino acids and total homocysteine levels. Electroencephalogram showed severely abnormal brain activity, which was consistent with severe encephalopathy, but no finding consistent with Landau-Kleffner syndrome. This prompted the need for further investigations as electoencephalogram (EEG) does not show encephalopathy in acute psychosis.
Differential Diagnosis
Differential diagnoses that were considered include:
Landau-Kleffner syndrome – this was ruled out by EEG
Drugs and toxins – there was no history suggestive of drug abuse
Intracranial pathologies – ruled out by MRI
Schizophrenia
Treatment
Intramuscular vitamin B12 injections and oral folate supplements were started early on the first admission. Following a diagnosis of Homocysteine Remethylation disorder, oral betaine was commenced at 3 g twice daily, initially via nasogastric tube, as she was not accepting feeds and medications orally. Following betaine therapy, she made a significant improvement, the nasogastric tube was discontinued, and the medication was changed to oral. She was also able to communicate appropriately before discharge. However, she was still unable to weight bear or walk and required physiotherapy input to aid her physical function.
Outcome and Follow-Up
A diagnosis of Homocysteine Remethylation disorder was confirmed following input from the pediatric metabolic team. A general pediatric follow up was arranged for 3 months post-discharge alongside a follow up with the metabolic team. An outpatient follow-up with a physiotherapist and speech therapist was also organized to help her get back to baseline as the betaine treatment improved her basic function.
She made a remarkable improvement in her cognitive function and is doing well in school; however, she still required a walking frame for mobility at the time of writing the case report
Discussion
The term “psychosis” as defined by NICE guidelines includes symptoms associated with significant alternations to a person’s perception, thoughts, mood, and behavior. Its presentation ranges from positive symptoms such as delusions, hallucinations, disorganized speech, and behavior/thoughts, and negative symptoms include self-neglect, loss of motivation, reduced speech, emotional blunting, and social withdrawal [1].
Several conditions have been identified as causes of acute psychosis in children. These range from infections, [8] toxins and drugs, autoimmune disorders, [9] metabolic conditions, epilepsy, systemic diseases, and psychiatric disorders [3]. It has also been described following administration of medications such as levetiracetam in patients with epilepsy, [10] and steroids [11]. Metabolic disorders that have been linked to psychosis in children include urea cycle defects, electrolyte imbalance such as hyponatremia, hypoglycemia, Wilson disease, and acute intermittent porphyria. Recent case reports have focused on immune-mediated diseases such as antibodies to N-Methyl-D-Aspartate receptor, Leucine-rich glioma-inactivated 1 (LGI1), Contactin-associated protein-like 2 (CASPR 2), glutamic acid decarboxylase (GAD), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and Gamma-aminobutyric acid B (GABAB) presenting as new-onset psychosis in children [12].
We describe the case of a 14-year-old who presented with acute psychosis secondary to homocysteine remethylation disorder. Remethylation disorders are rare inherited metabolic disorders that occur as a result of impairment of remethylation of homocysteine into methionine. Remethylation is catalyzed by methionine synthase leading to the conversion of homocysteine to methionine. The process of homocysteine metabolism involves transmethylation, methylation, and transulfuration. The most common problems are with the gene encoding the methyl tetrahydrofolate reductase (MTHFR). This results in the accumulation of homocysteine. Also, vitamin B12 is involved in the maintenance of proper function of the MTHFR enzyme while folate is responsible for the provision of the methyl part of the reaction, Hence, folate and vitamin B12 are also involved in the reaction and should be measured while investigating these patients. A few hypotheses have been postulated for the pathophysiology of remethylation disorders. These include accumulation of homocysteine leading to toxicity (hyperhomocysteinemia), folate trapping, oxidative stress, impaired methylation capacity, and impaired nonenzymatic protein functions [5].
Recent publications have proposed that neuropsychiatric disturbances are considered as clinical features of remethylation disorder [5,13,14]. A 15-minute consultation published in 2018, on the approach to a child presenting in the emergency department with acute psychosis identifies metabolic disorders as a possible cause of psychosis; however, there was no mention of homocysteine disorder as a possible cause under the metabolic disorders [3]. Another recent publication by Huemer et al, [5] suggested that plasma homocysteine levels should be checked in patients presenting with neurological, visual, hematological, and spinal cord degeneration disorders.
| Test | Result | Reference range |
|---|---|---|
| Full blood count | Normal | - |
| Urea and electrolytes | Normal | - |
| Liver profile | Normal | - |
| Bone profile | Normal | - |
| B12 | 88 umol/l | 150 - 620 |
| Folate | 1.9 umol/l | 3.1 - 19.9 |
| Cerebrospinal fluid | Normal | - |
| Autoimmune screen | Normal | - |
| Plasma ammonia | 21 umol/l | 11 - 48 |
| Urine Toxicology | Normal | - |
| CMV & Toxoplasmosis antibody | Negative | - |
| Treponema antibodies | Not detected | - |
| Free carinitine | 22.8 umol/l | 20 - 40 |
| Very long chain fatty acids | Normal | - |
| Fixed NMDA receptor antibody | Negative | - |
| Anti VGKC antibody | <1 pmol/l | 0 - 69 |
| MRI | Normal | - |
| Plasma amino acids | ||
| Taurine | 41 umol/l | 40 - 160 |
| Aspartic acid | 7 umol/l | 5 - 30 |
| Threonine | 113 umol/l | 70 - 190 |
| Serine | 128 umol/l | 85 - 180 |
| Asparagine | 50 umol/l | 40 - 130 |
| Glutamic acid | 79 umol/l | 35 - 190 |
| Glutamine | 534 umol/l | 390 - 740 |
| Glycine | 197 umol/l | 160 - 400 |
| Alanine | 220 umol/l | 190 - 530 |
| Citrulline | 15 umol/l | 10 - 40 |
| A-Amino N-butyric acid | 25 umol/l | 10 - 30 |
| Valine | 160 umol/l | 130 - 300 |
| Cystine | 5 umol/l | 15 - 50 |
| Methionine | 7 umol/l | 15 - 40 |
| Isoleucine | 52 umol/l | 30 - 95 |
| Leucine | 114 umol/l | 65 - 170 |
| Tyrosine | 64 umol/l | 40 - 100 |
| Phenylalanine | 66 umol/l | 40 - 85 |
| Free homocysteine | 3 umol/l | - |
| Total homocysteine | >400 umol/l | 5-15 |
| Ornithine | 51 umol/l | 40 - 150 |
| Lysine | 162 umol/l | 100 - 260 |
| Histidine | 69 umol/l | 50 - 100 |
| Tryptophan | 29 umol/l | 15 - 70 |
| Arginine | 86 umol/l | 20 - 100 |
| CSF amino acids | Normal | |
| Genetic studies | MTHFR (methyl tetrahydrofolate reductase) c.584C>T p(Ala195Val) homozygous variant |
Even though our patient did not present with the schizophrenic type of psychosis, she had self-neglect, mutism, unexplained smiling and laughing. At the initial presentation, the first set of investigations were normal, hence she was discharged to be followed up by the Psychiatrist. It was during her second admission that further investigations were requested after a discussion with the Neurologists and the metabolic team. As listed above, our patient had all the investigations and was noted to have low vitamin B12, this prompted the need for further investigations as vitamin B12 is important in the metabolism of homocysteine. Although, she did not have enzyme studies, she had a genetic confirmation of the MTHFR c.584C>T p(Ala195Val) homozygous variant, alongside her twin sister, who had no symptoms at the time of testing, Also, clinical improvement was noted after commencement of betaine confirming the underlying diagnosis of remethylation defects. This was also noted in a previous case report where a child with MTHFR deficiency had a significant improvement in psychosis following regular betaine treatment [15].
Conclusion
This case report highlights the importance of thorough investigation in a child with acute psychosis.
Homocysteine remethylation disorders should be considered in patients with acute psychosis.
A multidisciplinary approach involving general pediatricians, neurologists, and psychiatrists is prudent in the management of patients with acute psychosis.
Betaine is a highly effective medication in the management of Homocysteine remethylation disorder.