Transcobalamin receptor defect: Identification of two new cases through positive newborn screening for propionic/methylmalonic aciduria and long‐term outcome

Abstract

Likely pathogenic variants in CD320 cause transcobalamin receptor defect, a recently discovered inborn errors of cobalamin metabolism. Only 12 cases have been reported to date. There are no long-term clinical and biochemical outcome reports since its first description. In this report, we present two new cases and report their long-term treatment outcome. Two asymptomatic cases were identified through a positive newborn screening for propionic/methylmalonic aciduria. Biochemical abnormalities were normalized on a short course of oral cyanocobalamin (1 mg/day). Direct sequencing of CD320 identified a known pathogenic variant (c.262_264GAG; p.Glu88del) confirming the diagnosis of transcobalamin receptor defect. To date, both patients remain asymptomatic with normal neurodevelopment more than 6 years. Our two new cases with transcobalamin receptor defect due to pathogenic variants in CD320 further expand our knowledge and provide a reassuring long-term good neurodevelopmental outcome. Identification of additional cases requires the consideration of transcobalamin receptor defect in the differential diagnosis of newborns with confirmed positive newborn screening for methylmalonic acidurias.

Knock-Out of Retrovirus Receptor Gene Tva in the Chicken Confers Resistance to Avian Leukosis Virus Subgroups A and K and Affects Cobalamin (Vitamin B12)-Dependent Level of Methylmalonic Acid

“…We, however, cannot exclude compensatory genetic changes in this case. The absence of distinct phenotype is consistent with the mouse model, where CD320 knock-out does not completely abrogate the cbl import, and clinically asymptomatic human cases with CD320 defect [49,50], implying a parallel transport mechanism [23,24]. An alternative cbl uptake pathway is also visible in the tva chicken cells, where the uptake of cbl-transcobalamin remains significantly above the background level [21].…”

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

“…Several asymptomatic individuals with CD320 mutations have been identified by elevation of C3 in extended newborn screening. Long‐term follow‐up of these individuals revealed that they remained asymptomatic.…”

“…However, some received Cbl treatment, which may have masked the natural course. Alternative Cbl transportation into cells may explain this favorable clinical outcome and the mild elevation of tHcy and MMA but based on the small number of published cases and missing information on clinical background and treatment in some, final conclusions on the morbidity associated with the TCR defect cannot yet be drawn.…”

Monitoring Methylmalonic Aciduria by NMR Urinomics

“…Usually, the appearance of first clinical symptoms ranges from hours to weeks after birth, although in about 25% of cases the first symptoms appear after one year or even in adolescence or adulthood [ 9 ]. Moreover, some completely asymptomatic MMA cases have been also reported [ 29 , 30 ]. The effects of MMA vary from mild to life-threatening and its treatment is complex, requiring regular monitoring and frequent therapeutic and dietary adjustments [ 19 ].…”