Clinical research
Multiple congenital anomalies in two boys with mutation in HCFC1 and cobalamin disorder

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Abstract

The cobalamin type C deficiency is a rare condition that results from impaired biosynthesis of both methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Hemizygous mutations of the HCFC1 gene explain the majority of clinically and biologically compatible cblC patients without MMACHC mutations (OMIM 309541). We report a family with two maternal half-brothers with multiple congenital anomalies and HCFC1 gene mutation in the second Kelch domain. Both presented with dysmorphic features (flat profile, cleft lip for one), increased nuchal translucency, prenatal onset microcephaly and hypospadias. Additionally to early onset intractable epilepsy and profound neurocognitive impairment, this familial observation suggests that HCFC1 gene should be considered in boys with midline malformations, even without proven cobalamin C deficiency.

Introduction

Inborn errors of metabolism can be responsible for multiple congenital malformations such as Smith–Lemli–Opitz syndrome, a deficiency in cholesterol biosynthesis. The metabolic pathway of vitamin B12 (cobalamin) is fundamental to cell metabolism through the production of two essential cofactors: methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Clinical studies on patients with inborn errors of cobalamin metabolism have led to their division into nine complementation groups (cobalamin A to G, J and mut). The cobalamin type C deficiency (cblC, OMIM 277400) is a rare condition that results from impaired biosynthesis of both MeCbl and AdoCbl. The consequent functional deficiencies of methylmalonyl-CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria with decreased methionine synthesis. The mutations responsible for cblC deficiency affect the MMACHC gene and are transmitted in an autosomal recessive mode [Lerner-Ellis et al., 2009]. Clinical features in cblC deficiency are multisystemic with neurological (lethargy, progressive neurological deterioration), hematological (pancytopenia, non-regenerative anemia), and ocular (retinopathy) symptoms as well as renal failure (Hemolytic and Uremic Syndrome [HUS]), hepatic dysfunction, cardiomyopathy, interstitial pneumonia, and thromboembolic events. Many patients are acutely ill in the first month of life and most are diagnosed within the first year. The classic clinical neonatal phenotype associates lethargy, seizures, megaloblastic anemia, and a susceptibility to HUS. A new gene, HCFC1, responsible for X-linked cobalamin deficiency, was recently reported in 14 boys [Yu et al., 2013]. Hemizygous mutations of the HCFC1 explain the majority of clinically and biologically compatible cblC patients without MMACHC mutations (OMIM 309541 [Lerner-Ellis et al., 2006, Lerner-Ellis et al., 2009], thus identifying a cblX, X-linked, sub-group. The HCFC1 gene, as Host Cell Factor 1, encodes a chromatin-associated transcriptional regulator, and is located in the Xq28 region. In a murine model, the high expression of the HCFC1 gene during brain development is consistent with a role in proliferative cells. Expression decreased during embryogenesis, but was still present during postnatal development, suggesting a role in post-mitotic cells [Huang et al., 2012]. Mutations of HCFC1 had been previously found in affected members of a family with X-linked mental retardation, originally reported by Gedeon et al. [1991], and by exome sequencing in a second family in which X-linked mental retardation was present [Huang et al., 2012]. These results had determined a new X-linked locus for mental retardation named MRX3 (OMIM 300019). We report here two brothers with dysmorphic features and complex malformations resulting from an X-linked inherited cobalamin deficiency due to HCFC1 gene mutation.

Section snippets

Patients data

Patient 1 is the first boy born to healthy and non-consanguineous parents. Abnormal nuchal translucency was discovered at the 12th week of gestation (WG). The antenatal karyotyping performed on chorionic villi cells was normal. The morphological ultrasonography at 22 WG revealed a right cleft lip, a short femur (3rd centile), and a mitral calcification. At the 24th WG, a small inter-ventricular communication that closed spontaneously was noted. An excess of amniotic fluid was present around the

Materials and methods

Urine samples, blood samples and fibroblasts were collected for biochemical and DNA analyses for patient 1. Blood sample was collected for DNA analyses for patient 2 and an autopsy was performed. Informed consents were obtained from parents according to the French law.

Results

Cytogenetic and molecular analysis: CGH analysis was normal. The entire coding sequence of MMACHC, MMADHC (cblD) and LMBRD1 (cblF) genes, including exon–intron boundaries, were sequenced from genomic DNA (primers available upon request) and were found normal. We identified a novel single nucleotide substitution in exon 2 of gene HCFC1. It consists of a T → C transition at position 307 in the cDNA (c.307T > C). Patient 1 and patient 2 were hemizygous for this transition and their mother was

Discussion

Classic cobalamin C deficiency (cblC) results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl-CoA mutase and methionine synthase produce methylmalonic aciduria, homocystinuria, and hypomethioninemia. Clinical descriptions of cblC patients have been reviewed [Ogier de Baulny et al., 1998, Rosenblatt et al., 1997, Saudubray et al., 2012]. Within the first weeks of life, most cblC patients present with progressive feeding

Acknowledgments

We thank the family for their participation. The authors declare no conflict of interest.

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