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Cerebral folate deficiency: life-changing supplementation with folinic acid

https://doi.org/10.1016/j.ymgme.2004.12.001Get rights and content

Abstract

Cerebral folate deficiency is characterized by low cerebrospinal fluid (CSF) concentrations of 5-methyltetrahydrofolate and a broad spectrum of clinical signs and symptoms. A patient with progressive spasticity, gait disturbance, speech difficulties, initially diagnosed as a recessive spastic paraplegia recovered on folinic acid (15–30 mg/day) and her 5-methyltetrahydrofolate in CSF normalized. This report demonstrates the importance of CSF investigation in the diagnosis of cerebral folate deficiency and efficiency of folinic acid (5-formyltetrahydrofolate) supplementation.

Introduction

Cerebral folate deficiency (CFD) is defined by low cerebrospinal fluid (CSF) folates [1]. Particularly the active metabolite and C1-donor 5-methyltetrahydrofolate (5MTHF) is significantly reduced in CSF. A number of well characterized inherited neurometabolic disorders may present with CFD, including dihydropteridine reductase deficiency (OMIM 261630; hyperphenylalaninemia due to tetrahydrobiopterin deficiency with progressive mental and physical retardation, hypotonia/hypertonia, swallowing difficulties, hypersalivation, chorea/athetosis, temperature instability, and basal ganglia calcifications) [2], 5,10-methylene-tetrahydrofolate reductase deficiency (OMIM 236250; mental retardation, microcephaly, gait disturbance, psychiatric disturbances, seizures, abnormal EEG, occlusions, and limb weakness) [3], and 3-phosphoglycerate dehydrogenase deficiency (OMIM 601815; microcephaly, megaloblastic anemia, thrombocytopenia, seizures, spastic tetraplegia, nystagmus, cataract, and hypogonadism) [4]. Disturbed folate transport across the blood-CSF barrier was proposed in 31 patients with CFD characterized by psychomotor retardation, spastic paraplegia, cerebral ataxia, and dyskinesia [5], in eight girls with Rett syndrome [6], and in three patients with a variant of the Aicardi–Goutières syndrome [7]. With the exception of patients with 5,10-methylene-tetrahydrofolate reductase deficiency, they all potentially may benefit from folinic acid substitution. This report documents a girl with CFD who recovered on folinic acid (Isovorin) supplementation, a life-changing treatment.

Section snippets

Case report

Pregnancy, birth, and early development were normal. At the age of 3.5 years the girl presented with spasticity, gait problems, and speech difficulties. She was referred to a school for physically handicapped children. Repeated videos from the school reveal disease progression and stagnation of her mental development. At the age of 9.5 years her leg spasticity was so pronounced that i.t. Baclofen was considered. She was drooling. No polyneuropathy was evident. Visual evoked potential suggested

Results and discussion

The analysis of folate metabolites in CSF is part of the basic investigations for the diagnosis of pediatric neurotransmitter disorders and should be considered in patients presenting with hypo-/hyperkinesia, distal chorea, myoclonic epilepsy, dystonia, oculogyric crises, hypersalivation, temperature instability, aggressive behavior, or mental retardation. We found very low folates (5MTHF) in a girl initially diagnosed with recessive spastic paraplegia. This investigation requires only a small

Acknowledgment

This work was supported by the Swiss National Science Foundation Grant No. 3100-066953.01.

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