Folic acid inhibits 5-methyltetrahydrofolate transport across the blood-cerebrospinal fluid barrier: Clinical biochemical data from two cases.

Objective: The use of folic acid (FA) has been discouraged in cerebral folate deficiency (CFD) because, theoretically, it could inhibit the transport of 5-methyltetrahydrofolic acid (5MTHF) across the blood-cerebrospinal fluid (CSF) barrier. We present the clinical biochemical data of two cases with CFD to support this hypothesis. Methods: We measured CSF and serum 5MTHF concentrations in a patient with Kearns-Sayre syndrome (KSS) and a patient homozygous for MTHFR C677T polymorphism before and during folate supplementation therapy. To evaluate these 5MTHF concentrations, we also analyzed CSF and serum samples in pediatric patients without folate supplementation. Results: Both patients had low CSF 5MTHF before treatment and high-dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF-to-serum 5MTHF ratio. Conclusions: Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood-CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

Preliminary report for Epilepsia Open A case of West syndrome with severe global developmental delay and confirmed KIF5A gene variant.

Objective: Kinesin family member 5A (KIF5A) is a molecular motor protein responsible for intracellular transport, specifically in neurons. While abnormalities in the KIF5A gene have been reported in the onset of various neurological diseases, there are no studies demonstrating an association between this gene and West syndrome. Methods: In the case presented here, epileptic spasms appeared at 7 months; electroencephalogram (EEG) investigation confirmed hypsarrhythmia, resulting in a diagnosis of West syndrome. The patient exhibited peculiar facies, hypotonia, failure to thrive, and severe global developmental delay. Results: Cranial magnetic resonance imaging (MRI) revealed severe delayed myelination. 123I-iomazenil SPECT image at 7 months demonstrated decreased accumulation in bilateral areas, including the primary somatosensory and motor cortices, and the primary and association visual areas compared to an age-matched control. Whole exome sequencing analysis demonstrated a novel de novo heterozygous missense variant in KIF5A, (NM_004984.4:c.710A>T: p. Glu237Val). Significance: It was concluded that the KIF5A variant impaired the transport of GABAA receptors to the cell membrane surface, thus leading to an imbalance of these receptors between regions of the cerebrum and resulting in the onset of epilepsy.

Chronological dynamic changes in cortico-subcortical imbalance of cerebral blood flow in a boy with CAPOS syndrome.

BACKGROUND: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy and Sensorineural hearing loss (CAPOS) syndrome is a known ATP1A3-related disorder, but little has been elucidated regarding its pathophysiology. We now report two new patients, a Japanese boy and his mother with a pathogenic mutation (c.2452G>A) in ATP1A3, who were diagnosed with CAPOS syndrome. METHODS: After febrile illnesses at 7 months of age, and again at 22 months of age, the boy had a reduced level of consciousness, truncal ataxia and eye movement-disorders. The patient's 32-year-old mother may have experienced an episode of acute encephalopathy in her childhood and sustained sensorineural hearing loss. In the present study, we demonstrated chronological dynamic changes in cerebral blood flow (CBF) in the son, using serial single-photon emission computed tomography (SPECT). RESULTS: The serial CBF-SPECT findings using statistical methods showed progressive hyperperfusion in the frontal lobes, basal ganglia and thalamus, and hypoperfusion in the occipital and temporal lobes during the acute and subacute phases. Thereafter, the dynamic changes of CBF improved in the chronic but hypoperfusion in thalamus appeared to the chronic phase. CONCLUSION: The abnormal cortico-subcortical CBF may contribute to an acute encephalopathy-like condition in the acute stage of CAPOS syndrome. CAPOS syndrome is not often reported, and is possibly an under-recognized syndrome in clinically mild cases.

An unusual manifestation of Sjögren syndrome encephalitis.

Sjögren syndrome (SS) is a systemic inflammatory and autoimmune disease characterized by systemic disorders of the exocrine glands, predominantly the salivary and lacrimal glands. Here, we report a 4-year-old boy who presented with the repetition of generalized tonic-clonic seizures for 1-2 min. Initially, he was diagnosed with idiopathic autoimmune encephalitis and was treated with steroids. He was eventually diagnosed with SS based on the examination results, such as inflammatory cell infiltration into the minor salivary glands and positive serum anti-SSA/Ro antibody. Although central nervous system complications are rare in pediatric SS, this condition should be considered in the differential diagnosis when a patient presents with idiopathic autoimmune encephalitis of unknown cause. Furthermore, SS can occur in relatively young children and can present without imaging abnormalities.

A child with acute transverse myelitis requiring permanent pacemaker implantation.

We diagnosed a 3-year-old girl with acute transverse myelitis (ATM). She presented with weakness of the limbs and developed urination difficulty and respiratory disturbance. Magnetic resonance imaging revealed a symmetric area of high signal intensity on T2-weighted images involving the lower end of the medulla oblongata to the level of the fourth thoracic vertebra. Anti-aquaporin-4 antibody was negative. She was treated with intravenous methylprednisolone pulse therapy, immunoglobulin therapy, and plasmapheresis; however, her clinical symptoms did not change. At 10 and 20days after symptom onset, cardiac arrest occurred on postural change, requiring cardiopulmonary resuscitation. A permanent pacemaker was implanted 23days after onset. In the presence of sympathetic nerve hypofunction, relative hyperactivity of the parasympathetic nerves may have led to severe bradycardia and cardiac arrest in the presence of an inducer, such as a postural change. This is the first reported case of pacemaker implantation for management of ATM.

A pediatric patient of hemorrhagic acute transverse myelitis.

An 11-year-old boy presented with progressive leg hypesthesia but no history of trauma. Dysuria and constipation appeared subsequent to gait difficulty. He was admitted 8days after onset. Spinal magnetic resonance imaging (MRI) revealed longitudinal hyperintensity with cord swelling and hypointensity on T2-weighted images, suggesting severe inflammation and microbleeding change, respectively. Gadolinium contrast-enhanced MRI demonstrated mild enhancement in the lesions. Platelet count and coagulation findings were normal, and cerebrospinal fluid analysis showed no pleocytosis. He was diagnosed with idiopathic acute transverse myelitis (ATM), and intravenous methylprednisolone pulse therapy and plasmapheresis were initiated. On day 14, motor dysfunction aggravated suddenly, accompanied by expanding hemorrhagic lesions. Thereafter, administration of intravenous immunoglobulin, repeated intravenous methylprednisolone pulse therapy and prednisolone for one month resulted in complete recovery four months later. Both anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative. We presented the first pediatric case showing hemorrhagic spinal lesions in the clinical course of ATM. This severe complication should be recognized in the management of ATM.

Quinidine therapy for West syndrome with KCNTI mutation: A case report.

The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2years and 6months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.