Two Siblings with D-Bifunctional Protein Deficiency and Unusual Clinical Course

Background: D-Bifunctional protein deficiency (DBP) is an autosomal recessive disorder of peroxisomal fatty oxidation. Virtually all patients have a severe phenotype with craniofacial dysmorphism, profound hypotonia and seizures from the first days of life, very poor development and death by age two. Elevated VLCFA, phytanic and MRI changes suggestive of peroxisomal disorder are typical.

Methods and Results: Our patient presented with profound hypotonia, difficult to control seizures from day 1of life. MRIs, VLCFA, phytanic acid were normal. Seizures stopped at age 3 months. She remained very hypotonic, but learnt to crawl. Between ages 3 and 4, she lost all her milestones; at age 5, her flaccid paraparesis began to improve some. Her brother was hypotonic from birth hypotonia and develops seizures in the first week of life. Whole-exome sequencing revealing two variants in HSD17B4: c.46G>A; p.Gly16Ser and c.742C>T; p.Arg248Cys in both children. Segregation analysis showed each parent to be carrier of one variant. These mutations have previously been reported as cause for DBP deficiency.¹ In vitro studies have shown that the variant p.Gly16Ser leads to loss of function of 3-hydroxyacyl-CoA-dehydrogenase.² p.Arg248Cys is associated with some remaining protein function.³

Conclusion: We propose that the DBP phenotype seen in this family, results from reduced dehydrogenase activity. In cases of negative results in biochemical testing and MRI, it is likely that milder forms of DBP deficiency are underdiagnosed. We recommend the use whole-exome sequencing to prove diagnosis in suspected cases.

• References

• 1 Ferdinandusse S, Denis S, Mooyer PA. , et al. Clinical and biochemical spectrum of D-bifunctional protein deficiency. Ann Neurol 2006; 59 (01) 92-104
• 2 van Grunsven EG, van Berkel E, Ijlst L. , et al. Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect and its molecular basis in bifunctional protein deficiency. Proc Natl Acad Sci U S A 1998; 95 (05) 2128-2133
• 3 Mehtälä ML, Lensink MF, Pietikäinen LP, Hiltunen JK, Glumoff T. On the molecular basis of D-bifunctional protein deficiency type III. PLoS One 2013; 8 (01) e53688