Hypoventilation and progressive encephalopathy in a neonate with MTHFR deficiency

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive inherited inborn error of metabolism, which presents with various severity depending on the level of residual enzyme activity. In neonates, it can present with recurrent hypoventilation episodes, persistent encephalopathy with or without microcephaly. MTHFR deficiency also results in hyperhomocysteinemia, homocystinuria and hypomethionemia. We report a male neonate with severe MTHFR deficiency presenting to us on third week of life with progressive encephalopathy, microcephaly, seizures, central hypoventilation. There was similar history in the previous sibling. The patient’s blood lactate, ammonia, tandem mass spectrometry for amino acids and acyl carnitine were normal. He remained encephalopathic with progressive increase in need of respiratory support in spite of supportive treatment and metabolic cocktail consisting of riboflavin, pyridoxine, coenzyme Q and carnitine. This neonate had novel homozygous mutation, which results in MTHFR deficiency. In newborn with hypoventilation or recurrent apnoea with encephalopathy and microcephaly, MTHFR deficiency should be considered as a differential diagnosis. Mutation study helps in confirming diagnosis; however, extended newborn metabolic screening with homocysteine level could help in early diagnosis of these cases.

Adolescent Congenital Central Hypoventilation Syndrome: An Easily Overlooked Diagnosis

Congenital central hypoventilation syndrome (CCHS), also known as Ondine’s curse, is a rare, potentially fatal genetic disease, manifesting as a lack of respiratory drive. Most diagnoses are made in pediatric patients, however late-onset cases have been rarely reported. Due to the milder symptoms at presentation that might easily go overlooked, these late-onset cases can result in serious health consequences later in life. Here, we present a case report of late-onset CCHS in an adolescent female patient. In this review we summarize the current knowledge about symptoms, as well as clinical management of CCHS, and describe in detail the molecular mechanism responsible for this disorder.

Central Hypoventilation Is a Key Risk Factor for Mechanical Ventilation During the Acute Phase of Anti-N-Methyl-D-Aspartate Receptor Encephalitis

Objective: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an acute form of encephalitis of autoimmune etiology. We aimed to evaluate the risk factors that predicted the need for mechanical ventilation during the acute phase of anti-NMDAR encephalitis through an analysis of the clinical characteristics and biochemical test results of the patients with anti-NMDAR encephalitis.Methods: In this retrospective study, patients who primarily presented with anti-NMDAR encephalitis and exhibited anti-NMDAR antibody positivity in the cerebrospinal fluid (CSF) between November 2015 and February 2020 were included. Data on the clinical characteristics, biochemical test results, and treatment methods selected for the patients were collected for the analysis of factors predicting the need for mechanical ventilation.Results: Thirty-one patients with a median age of onset of 31 years (inter-quartile range: 21–48 years) were included in this study, of which 15 were male (48.4%). Psychosis (23, 74.2%), seizures (20, 64.5%), and memory deficit (20, 64.5%) were the most common clinical manifestations. At admission, 17 patients (54.8%) presented with pyrexia, of which 12 (38.7%) had a body temperature ≥38°C, and six patients (19.4%) presented with central hypoventilation. All patients received first-line therapy (glucocorticoids, intravenous immunoglobulin, or plasmapheresis alone or combined), whereas two patients (6.5%) received rituximab, a second-line agent, as well. Seven patents required mechanical ventilation. Results of univariate logistic regression analysis revealed that body temperature ≥38°C [odds ratio (OR) = 18, 95% confidence interval (CI): 1.79–181.31, P < 0.05] and central hypoventilation at admission (OR = 57.50, 95% CI: 4.32–764.89, P < 0.05) were the risk factors for mechanical ventilation. Multivariate logistic regression analysis showed that central hypoventilation at admission was the only risk factor predicting the need for mechanical ventilation.Conclusion: Central hypoventilation at admission is a key risk factor for mechanical ventilation during hospitalization in patients with anti-NMDAR encephalitis.

It Takes a Village: The Importance of Neuropsychological Findings in a Collaborative Approach for a Patient with Congenital Central Hypoventilation Syndrome and Specific Phobia

Congenital central hypoventilation syndrome (CCHS) is a life-threatening disorder characterized by respiratory symptoms such as hypoventilation during sleep, significantly reduced ventilatory and arousal responses, and sustained hypoxia. Patients with CCHS exhibit neurocognitive deficits due to structural abnormalities in the brainstem, cerebellum, and forebrain. Due to the potential for repeated hypoxemia and hypercarbia among patients with CCHS, neurocognitive functioning is often impaired. This is the first described report in which a patient with CCHS and specific phobia has been reported and highlights the importance of neuropsychological testing in directing treatment approaches. We report a case of a 26-year-old male, diagnosed with CCHS and specific phobia. This patient was overdue for a needed bronchoscopy to check his airway for abnormalities (recommended every 12-24 months). The patient had developed a specific phobia to procedures involving anesthesia. It was determined in the initial phase of treatment that the patient’s neurocognitive status was impacting his ability to engage in psychiatric and psychosocial treatment. This patient’s care consisted of neuropsychological testing, with medication consultation, and cognitive behavioral psychotherapy. Treatment involved consistent collaboration among the patient’s treating clinicians as well as collaboration with the patient’s family and team of nurses. At the conclusion of treatment, the patient had successfully completed his bronchoscopy and future treatment goals were identified. This case emphasizes the importance of a neuropsychological evaluation when there is a disconnect in a patient’s information processing, as the results may be highly informative in directing treatment for patients with CCHS and specific phobia. The collaborative care we provided offers insights which may direct future interventions for patients with CCHS and improve their quality of life. Our case adds support to the recommendation that patients with CCHS and impaired psychosocial functioning should receive neuropsychological testing to best direct treatment.

Mutations of PHOX2B Gene in Patients of Obesity Hypoventilation Syndrome in Central India

Background Paired-like homeobox 2B (PHOX2B) gene on chromosome 4p12 codes for a transcription factor having a role in the formation of noradrenergic neuronal circuits. Its mutations have been linked to congenital central hypoventilation syndrome (CCHS). The clinical presentation of both, obesity hypoventilation syndrome (OHS) and CCHS in adults (named late-onset central hypoventilation syndrome), is quite similar. Because of this symptomatic similarity, multifactorial causation of OHS, the mutation of PHOX2B gene was studied in patients with OHS in this study. Methods A hospital-based cross-sectional study was performed on patients diagnosed with OHS. The deoxyribonucleic acid was extracted from 2 mL of venous blood and was further amplified, specific to exon 3. The amplified products were cast and run in 2% agarose gel and then subjected to Sanger sequencing. Results Thirty patients of OHS (21 male; 9 female) were enrolled in the present study, average age being 51.7 years. The Sanger sequencing of the samples revealed no apparent areas of deletions and no apparent mutations. Conclusion Primers for exon 3 were used for amplification in thermocycler, as exon 3 is the most frequently mutated exon for PHOX2B gene, as per existing literature. The entire gene needs to be studied for mutations and the sample size needs to be increased.