Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter

Abstract

Hereditary folate malabsorption is a rare inborn error of metabolism due to mutations in the protoncoupled folate transporter (PCFT). Clinical presentation of PCFT deficiency may mimic severe combined immune deficiency (SCID). We report a 4-month-old female who presented with failure to thrive, normocytic anemia, Pneumocystis jirovecii pneumonia and systemic cytomegalovirus infection. Immunological evaluation revealed hypogammaglobulinemia, absent antibody responses, and lack of mitogen-induced lymphocyte proliferative responses. However, the absolute number and distribution of lymphocyte subsets, including naïve T cells and recent thymic emigrants, were normal, arguing against primary SCID. Serum and cerebrospinal fluid folate levels were undetectable. A homozygous 1082-1G>A mutation of the PCFT gene was found, resulting in skipping of exon 3. Parenteral folinic acid repletion resulted in normalization of anemia, humoral and cellular immunity, and full clinical recovery. PCFT mutations should be considered in infants with SCID-like phenotype, as the immunodeficiency is reversible with parenteral folinic acid repletion.

Identification and Functional Impact of Homo-oligomers of the Human Proton-coupled Folate Transporter

“…The role of hPCFT in intestinal folate absorption was established by demonstrating loss-of-function mutations in hPCFT in patients with the rare autosomal inherited disorder, hereditary folate malabsorption (HFM) (5). To date, 17 unique hPCFT mutations have been reported in ethnically varied kindreds (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Although proton-coupled, this transporter is also func-tional at more physiologic pH, at which it retains appreciable affinity for pemetrexed (16), a newer antifolate currently approved for treating mesothelioma and non-squamous, nonsmall cell lung cancer (17)(18)(19).…”

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

“…Her diagnosis, hematological, and immunological rehabilitation was the subject of a previous report (Borzutzky et al 2009). …”

“…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).…”

Random Mutagenesis of the Proton-coupled Folate Transporter (SLC46A1), Clustering of Mutations, and the Bases for Associated Losses of Function

“…Loss-of-function mutations in the pcft gene lead to the rare autosomal recessive disorder, hereditary folate malabsorption (HFM) characterized by markedly reduced folate levels in blood and cerebrospinal fluid (1)(2)(3)(4). A homozygous mutation in most cases or two compound heterozygous mutations in two cases have been identified in all subjects with the clinical diagnosis of HFM indicating that this disease is caused solely by alterations of the pcft gene (1,2,(5)(6)(7)(8)(9)(10)(11)(12).…”

“…Six result in drastic changes in predicted protein sequences (nonsense). p.Y362_G398del, occurred multiple times in unrelated families and is the result of skipping of exon 3 during RNA splicing (1,9,13). C66X introduces a stop codon at position 66 due to a two-base substitution (5).…”