Abstract
Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the MTTP gene encoding the microsomal triglyceride transfer protein large subunit. ABL is characterized by absence of apolipoprotein B–containing lipoproteins and deficiencies in fat-soluble vitamins leading to multisystem involvement of which neurological complications are the most serious. We present 3 siblings with ABL who were born to non-consanguineous parents of Filipino and Chinese background. Identical twin boys with long-standing failure to thrive and malabsorption were diagnosed at age 2 years. ABL therapy with vitamins and a specialized diet was initiated, replacing total parenteral nutrition at age 3 years. Their younger sister was diagnosed from a blood sample taken at birth; treatment was instituted shortly thereafter. We observed in the twins reversal and in their sister prevention of ABL systemic features following early implementation of fat restriction and high doses of oral fat-soluble vitamins. A targeted sequencing panel found that each affected sibling is homozygous for a novel MTTP intron 13 -2A>G splice acceptor site mutation, predicted to abolish splicing of intron 13. This variant brings to more than 60 the number of reported pathogenic mutations, which are summarized in this article. The twin boys and their sister are now doing well at 11 and 4 years of age, respectively. This experience underscores the importance of early initiation of targeted specialized dietary and fat-soluble vitamin replacements in ABL.
Highlights
Abetalipoproteinemia (ABL; OMIM 200100) is an autosomal recessive disorder whose core biochemical defect is impaired absorption of dietary lipids with impaired assembly and secretion of apolipoprotein B–containing lipoprotein particles.[1]
A female full sibling was born when the twin boys were 7 years old (Figure 2A). She was diagnosed with ABL via molecular analysis of cord blood at 3 weeks of age. She was exclusively breast fed for the first month of life, and she gradually transitioned to a fat-restricted diet with high-dose medium-chain fatty acids (MCFA) and fat-soluble vitamin supplementation by 4 months
Despite no known relationship between the parents, each child was homozygous for the identical rare unreported MTTP c.1990 -2A>G pathogenic variant, which is predicted to have compromised function in RNA splicing occurring within a splice acceptor sequence in intron 13
Summary
Abetalipoproteinemia (ABL; OMIM 200100) is an autosomal recessive disorder whose core biochemical defect is impaired absorption of dietary lipids with impaired assembly and secretion of apolipoprotein (apo) B–containing lipoprotein particles.[1] Biallelic pathogenic mutations have been reported in all functional domains of the MTTP gene that encodes the microsomal triglyceride (TG) transfer protein large subunit (MTP) in ABL patients.[2] MTP plays a critical role in the assembly of lipoproteins. The differential diagnosis of ABL includes homozygous hypobetalipoproteinemia[1,5] and chylomicron retention disease[7] due to biallelic rare mutations in the APOB and SAR1B genes, respectively. These conditions can be differentiated from ABL using both biochemical analyses and diagnostic DNA sequencing.[8]. Treatment for the boys was started at age 3 years and for their younger sister was started shortly after birth, with successful long-term outcomes to date
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