Identification of MMACHC and ZEB2 mutations causing coexistent cobalamin C disease and Mowat-Wilson syndrome in a 2-year-old girl

Cobalamin C (cblC) disease and Mowat-Wilson syndrome (MWS) are rare hereditary diseases. To date, there have been no reports of people suffering from these two genetic diseases, or whether there is any correlation between the two diseases. We reported a 2-year-old girl with both cblC disease and MWS. The patient initially manifested as slow weight gain, hypotonia, broad nasal bridge, high forehead, high palate arch, ear crease, patent ductus arteriosus, atrial and ventricular septal defect and bilateral mild ventriculomegaly in the neonatal period. However, as the baby grew older, the typical facial features became more prominent, and overall developmental delays were noted at the subsequent follow-up, with the motor and cognitive development significantly lagging behind that of other children of the same age. At 26 days old, laboratory tests revealed remarkably elevated levels of serum homocysteine, C3/C2 and urine organic acid. Whole-exome sequencing detected compound heterozygous variants in MMACHC, including one previously reported mutation [c.609G > A (p.W203X) and a novel missense mutation[ c.643 T > C (p.Y215H)]. The computer simulations of the protein structure analysis of the novel missense mutation showed the variant p.Y215H replaced a neutral amino acid with a strongly basic lysine, which broken the local structure by changing the carbon chain skeleton and decreasing the interaction with adjacent amino acid. This is expected to damage the utilization of vitamin B12 and influence the synthesis of AdoCbl and MeCbl, contributing to its pathogenicity. Thus, clinical and genetic examinations confirmed the cblC disease. Another heterozygous variant in ZEB2 [NM_014795; loss1(exon:2-10)(all); 127901 bp] was detected by whole-exome sequencing. The heterozygous 3.04 Mb deletion in EB2 [GRCH37]del(2)(q22.2q22.3) (chr2:142237964-145274917) was also confirmed by genome-wide copy number variations (CNVs) scan, which was pathogenic and led to the diagnosis of Mowat-Wilson syndrome. The biochemical indicators associated with cblC disease in the patient were well controlled after treatment with vitamin B12 and betaine. Here, a patient with coexisting cblC disease and MWS caused by different pathogenic genes was reported, which enriched the clinical research on these two rare genetic diseases.