Comorbidity of Chronic Fatigue Syndrome, Postural Tachycardia Syndrome, and Narcolepsy with MTHFR Mutation in an Adolescent: A Case Report

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Comorbidity of Chronic Fatigue Syndrome, Postural Tachycardia Syndrome, and Narcolepsy with MTHFR Mutation in an Adolescent: A Case Report

Abstract

This case report presents a 16-year-old male adolescent with a complex combination of chronic fatigue syndrome (CFS), postural tachycardia syndrome (POTS), narcolepsy, and hyperhomocysteinemia due to a 5,10-methylenetetrahydrofolate reductase (MTHFR) mutation. The patient’s symptoms and diagnostic journey are detailed, along with the treatment approach and outcomes. This case highlights the importance of comprehensive evaluation and multidisciplinary management in such complex cases.

Introduction

Chronic fatigue syndrome (CFS) is a debilitating condition that can significantly impact an individual’s quality of life. It is often accompanied by other comorbidities, making diagnosis and treatment challenging. In this case, we report on an adolescent with a unique combination of CFS, POTS, narcolepsy, and a genetic mutation in the MTHFR gene.

Case Presentation

Patient History

A 16-year-old male was hospitalized with intermittent dizziness, drowsiness, and fatigue for approximately 2 years. Prior to the onset of these symptoms, he had a 2-week episode of fever and pharyngalgia and underwent appendectomy for acute appendicitis. His dizziness was most severe when transitioning from a supine to an upright position in the morning, lasting minutes to hours and partially relieved by recumbency. Despite sleeping 14-15 hours a day, he felt drowsy and fatigued all day. Symptoms improved with bed rest but relapsed when he returned to school. Fatigue worsened after exertion or infection, leading to academic decline. He had no prior history of cardiovascular or nervous system disease, and no family history of such conditions.

Physical Examination and Investigations

  • Physical Examination: Overweight (BMI 25.6 kg/m²) with a surgical scar on the right lower abdomen.
  • Laboratory Tests: Normal routine blood count, liver and renal function, serum electrolytes, cortisol circadian rhythm, and thyroid function. Serum homocysteine increased to 86.14 mmol/L (max) and decreased to 31.28 mmol/L after treatment. Serum folate, vitamin B12, blood amino acid, and urinary organic acid analyses were normal. Family wide exome sequencing showed complex heterozygous mutations in the MTHFR gene. Serum immunoglobulin assay revealed elevated Epstein-Barr virus (EBV) capsid antigen IgG and nuclear antigen IgG, but normal EBV capsid antigen IgM and EBV nucleic acid. Immune function tests were normal.
  • Cardiovascular Tests: Holter monitoring, echocardiography, and ambulatory blood pressure monitoring were normal. Standing test showed heart rate increase from 61 bpm (supine) to 118 bpm (upright) with lightheadedness, suggesting POTS. 24-h urine sodium concentration and flow-mediated vasodilation (FMD) reaction showed intensive FMD.
  • Neurological Tests: Brain MRI and routine electroencephalogram were normal. Multiple sleep latency test showed short sleep latency (56 s – 3 min 45 s) and three sleep-onset rapid eye movement periods in five naps, with an Epworth Sleepiness Scale score of 19, indicating sleep disorder. Otorhinolaryngologic and ophthalmic examinations were normal.

Diagnosis

Based on the patient’s history and investigations, diagnoses of CFS, narcolepsy, POTS, and hyperhomocysteinemia (due to MTHFR mutation) were made.

Treatment and Outcomes

Initial Treatment

  • For Hyperhomocysteinemia: Oral folate (5 mg/day), vitamin B6 (10 mg/day), vitamin B12 (0.5 mg/day), and L-carnitine (1 g/day).
  • For POTS: Oral midodrine hydrochloride (7.5 mg/day).

After 1 month, dizziness improved slightly, but drowsiness and fatigue persisted.

Addition of Methylphenidate

Based on pediatric neurology expertise, methylphenidate hydrochloride tablets (18 mg/day) were added for narcoleptiform sleep disorder. After another month, daytime drowsiness decreased, sleep duration shortened to 9-10 hours/day, and he gradually resumed school life with a normal sleep rhythm.

Discussion

Chronic Fatigue Syndrome (CFS)

CFS can occur at any age, with peak incidence in school-age and adolescent children. Symptoms include significant fatigue, sleep disorders, cognitive problems, and pain. This patient’s history of EBV infection (suggested by elevated EBV IgG) may be related to CFS etiology.

Postural Tachycardia Syndrome (POTS)

POTS is more common in pediatric CFS patients. The patient’s FMD impairment suggests endothelial dysfunction as a pathogenic factor.

Narcolepsy

Narcolepsy is a common complication in CFS. Methylphenidate was effective in improving the patient’s narcoleptic symptoms.

Hyperhomocysteinemia and MTHFR Mutation

MTHFR deficiency is a common cause of hyperhomocysteinemia. The patient’s compound heterozygous mutations in the MTHFR gene likely contributed to his hyperhomocysteinemia. Studies suggest a link between MTHFR gene polymorphisms and CFS treatment response, highlighting the importance of considering homocysteine metabolism disorders in treatment.

Multidisciplinary Management

This case emphasizes the need for multidisciplinary care in CFS patients. Controlling comorbid symptoms comprehensively is crucial. Methylphenidate was effective for narcolepsy and may have broader implications for certain CFS subgroups.

Conclusion

This case report showcases the complexity of CFS and its comorbidities. The combination of CFS, POTS, narcolepsy, and MTHFR mutation required a tailored, multidisciplinary treatment approach. Early diagnosis and comprehensive management are essential for improving outcomes in pediatric CFS patients. Further research is needed to understand the role of MTHFR gene polymorphisms in CFS and optimize treatment strategies.

References

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doi: 10.1097/CM9.0000000000001387

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