Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome

Abstract

BackgroundKearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.MethodsPatients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1–4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.ResultsNo adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.ConclusionsFour patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.Trial registrationEudracT2007-00-6748-23Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0217-2) contains supplementary material, which is available to authorized users.

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

“…Although epilepsy appears to be a constant feature of CFD caused by mutations in FOLR1 (encoding folate receptor alpha) or DHFR (encoding dihydrofolate reductase) [33], not all patients with KSS and CFD have epilepsy. Treatment with oral folinic acid is associated with improvements in clinical and neuroimaging features [31,34], suggesting an etiological relationship between CFD and the mitochondrial phenotype in these patients.…”

The homozygous R504C mutation in MTO1 gene is responsible for ONCE syndrome

“…The patients Pt1 and Pt2 had other metabolic deficiencies that have not been reported before in patients with MTO1 gene mutations. Thus, Pt1 had cerebral folate deficiency without abnormalities in brain MRI, unlike it has been demonstrated in other mitochondrial syndromes . Supplementation with folinic acid normalized the biochemical parameters in CSF, as described in cerebral folate deficiency syndrome , but without major changes in her cognitive status.…”

Can folic acid have a role in mitochondrial disorders?

“…However, she died at 5.5 years of age. A more recent study reported CFD in eight Spanish patients with KSS [41]. Six patients were treated with 1 mg/kg/day of folinic acid, two cases received 3 mg/kg/day, and two patients refused therapy.…”