Brief communicationCerebral folate deficiency: life-changing supplementation with folinic acid
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.
References (9)
- et al.
Cerebral folate deficiency
Dev. Med. Child Neurol.
(2004) - et al.
Disorders of tetrahydrobiopterin and related biogenic amines
Molecular genetics of methylenetetrahydrofolate reductase deficiency
J. Inherit Metab. Dis.
(1996)- et al.
Beneficial effect of l-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency
Ann. Neurol.
(1998)
Cited by (55)
Cerebral folate deficiency: A report of two affected siblings
2023, Molecular Genetics and Metabolism ReportsClinical characteristics and diagnostic clues to Neurometabolic causes of dystonia
2020, Journal of the Neurological SciencesCitation Excerpt :The commonest cause is serum autoantibodies directed against folate receptor-α attached to the choroid plexus epithelial cells inhibiting 5-MTHF transport across choroid plexus [105]. Infants present early around 4 to 6 months of age with insomnia and agitation, followed by stunted growth, hypotonia, ataxia, and in one-third of cases dyskinesias (choreoathetosis, hemiballismus), spasticity, speech difficulties, and epilepsy [106]. Dystonia tends to develop later during adolescence [105].
Cerebral folate deficiency in adults: A heterogeneous potentially treatable condition
2019, Journal of the Neurological SciencesCitation Excerpt :The exact cause of CFD remains unclear in numerous children with neurologic manifestations. Treatment of CFD is the oral administration of high doses of folinic acid and has resulted in previous studies in normalization of 5MTHF in the CSF, and occasionally in a clinical and radiological improvement [13,15,23,24]. So far, CFD has only been reported as a pediatric condition, except for one case with an onset of symptoms at age 58 characterized by progressive memory loss and myoclonus, who was successfully treated with folinic acid [25].
Methods for assessment of folate (vitamin B<inf>9</inf>)
2018, Laboratory Assessment of Vitamin StatusThe basis for folinic acid treatment in neuro-psychiatric disorders
2016, BiochimieCitation Excerpt :Compared to healthy controls, serum and red blood cell folate, vitamin B12 and homocysteine values are normal, but CSF MTHF levels are significantly lowered [14,15] (see Table 1). The age at which FRα antibodies emerge, determines the specific clinical phenotype varying from infantile-onset CFD syndrome [14,15], infantile autism with neurological deficits [36], Rett syndrome, other autism spectrum disorders [25,26,37,38], a spastic-ataxic syndrome [39], intractable epilepsy among young children [40–42], to intractable schizophrenia among adolescents [27,28], and finally treatment-resistant major depression in adults [see section below] (Fig. 1). The finding of increased serum TSH concentrations among individuals with autism who test positive for high blocking FRα antibodies [28] cannot be explained by these antibodies affecting thyroid function since FRα expression in the young and adult thyroid is extremely low to nonexistent.