Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption

Kishimoto, Kenji; Kobayashi, Ryōji; Sano, Hirozumi; Suzuki, Daisuke; Maruoka, Hayato; Yasuda, Kazue; Chida, Natsuko; Yamada, Masafumi; Kobayashi, Kunihiko

doi:10.1016/j.clim.2014.03.014

Cited by 23 publications

(20 citation statements)

References 21 publications

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“…The immune deficiency, studied in detail in recent years, involves defects in both B and T cell function. The immune deficient state has been reported in patients from diverse ethnic backgrounds: African-American (Malatack et al, 1999), Puerto Rican (Borzutzky et al, 2009), Central American (Zhao et al, 2007), Iraqi (Erlacher et al, 2015), Japanese (Kishimoto et al, 2014), and Turkish (Corbeel et al, 1985). One interesting aspect of the pneumonia is that it can progress rapidly after the administration of folate.…”

Section: Hereditary Folate Malabsorptionmentioning

confidence: 99%

“…One interesting aspect of the pneumonia is that it can progress rapidly after the administration of folate. While the reason for this is not known, it has been proposed that the immunological defects, sometimes with leukopenia, result in a failure tomount an inflammatory response to the infection which emerges after folates become available and the immunological defects are rapidly reversed (Erlacher et al, 2015; Kishimoto et al, 2014; Malatack et al, 1999). Be that as it may, with timely folate repletion and appropriate treatment, the pneumonia usually resolves.…”

Section: Hereditary Folate Malabsorptionmentioning

confidence: 99%

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The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

Zhao

Aluri

Goldman

2017

Molecular Aspects of Medicine

130

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The proton-coupled folate transporter (PCFT) is the mechanism by which folates are absorbed across the apical brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder "hereditary folate malabsorption" (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in "cerebral folate deficiency" (CFD), the designation for this disorder. This paper reviews the current understanding of the functional and structural properties and regulation of PCFT, an electrogenic proton symporter, and contrasts PCFT properties with those of the reduced folate carrier (RFC), an organic anion antiporter, that is the major route of folate transport to systemic tissues. The clinical characteristics of HFM and its treatment, based upon the thirty-seven known cases with the clinical syndrome, of which thirty have been verified by genotype, are presented. The ways in which PCFT and FRα might interact at the level of the choroid plexus such that each is required for folate transport from blood to cerebrospinal fluid are considered along with a basis for the different clinical presentations of HFM and CFD.

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Section: Hereditary Folate Malabsorptionmentioning

confidence: 99%

Section: Hereditary Folate Malabsorptionmentioning

confidence: 99%

The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

Zhao

Aluri

Goldman

2017

Molecular Aspects of Medicine

130

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“…It presents in early infancy with megaloblastic anemia, poor growth, diarrhea, infections, stomatitis, hypotonia, and progressive neurological deterioration including severe developmental delay and seizures that could be refractory to treatment (Diop-Bove et al 1993Fernandes et al 2012;Scriver et al 1995;Zhao et al 2012). To date 31 patients have been reported in the literature (Atabay et al 2010;Borzutzky et al 2009;Corbeel et al 1985;Diop-Bove et al 2013;Geller et al 2002;Hansen and Blau 2005;Jebnoun et al 2001;Kishimoto et al 2014;Lanzkowsky et al 1969;Lasry et al 2008;Malatack et al 1999;Ponz et al 1898;Rosenblatt and Fenton 2001;Santiago-Borrero et al 1973;Shin et al 2011;Sofer et al 2007;Steinschneider et al 1990;Su 1976;Urbach et al 1987;Wang et al 2014;Zhao et al 2007). It is imperative that the patients be treated very early and effectively with 5-formyltetrahydrofolate (folinic acid) in order to prevent irreversible neurological disease (Surtees 2001;Urbach et al 1987;Wang et al 2014;Whitehead 2006).…”

Section: Introductionmentioning

confidence: 99%

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

et al. 2015

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Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease.

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“…Even though anemia, immune dysfunction, and Ponto-cerebellar hypoplasia in addition to generalized lack of cerebral volume and myelination, bilateral symmetrical mature hemorrhagic infarction of the basal ganglia, symmetrical periventricular, and deep white matter change over the frontal lobes ( Fig. 1 No progression of prominent white matter changes and ponto-cerebellar volume reduction gastrointestinal symptoms are reversible with the oral or parenteral administration of folinic acid and normalization of blood folate levels is easily achieved, it has been proven that CSF levels remain suboptimal (Zhao et al 2017;Borzutzky et al 2009;Torres et al 2015;Min et al 2008;Erlacher et al 2015;Kishimoto et al 2014;Wang et al 2015). Thus, the major challenge remains to achieve normal CSF 5-MTHF levels for treatment of neurological disease (Zhao et al 2017).…”

Section: Case Presentationmentioning

confidence: 99%

“…HFM is a (Erlacher et al 2015). Findings include poor feeding, faltering growth, megaloblastic anemia or even pancytopenia, diarrhea, immune dysfunction, and neurological manifestations with progressive deterioration (Kronn and Goldman 2008;Erlacher et al 2015;Kishimoto et al 2014). In our small cohort, Patient 1 and 2 had typical features of the disease, which in combination with low 5-MTHF led to the diagnosis of HFM.…”

Section: Case Presentationmentioning

confidence: 99%

Role of Intramuscular Levofolinate Administration in the Treatment of Hereditary Folate Malabsorption: Report of Three Cases

et al. 2017

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Hereditary folate malabsorption is a rare autosomal recessive disorder caused by impaired active folate transport across membranes and into the central nervous system due to loss-of-function mutations in proton-coupled folate transporter (PCFT). Newborns with this condition have initially normal folate stores, but as they are unable to absorb dietary folate and use rapidly their stores because of their growth demands, symptoms appear in the early infancy. Significant neurological morbidity usually follows the initial non-specific clinical presentation and delayed initiation of treatment. High dose oral and parenteral folinic acid treatment have been previously reported in literature to improve the clinical outcome without achieving optimal cerebrospinal fluid (CSF) folate levels though. The active isomer of 5-formyltetrahydrofolate, also known as levofolinic acid, is available for administration. We report our experience in achieving normal (age dependent) CSF 5-Methyltetrahydrofolate (5-MTHF) levels following daily intramuscular administration of levofolinic acid in three patients with HFM. Follow-up assessment with repeated lumbar punctures has shown a stabilization of 5-MTHF levels within normal range. Clinical features and brain MRI findings had as well either improvement or stabilization. To the best of our knowledge, we provide as well for the first time data in regard to the im levofolinate treatment dosage.

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Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption

Cited by 23 publications

References 21 publications

The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

Role of Intramuscular Levofolinate Administration in the Treatment of Hereditary Folate Malabsorption: Report of Three Cases

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