From discrete dilated cardiomyopathy to successful cardiac transplantation in congenital disorders of glycosylation due to dolichol kinase deficiency (DK1-CDG)

Abstract

Congenital disorders of glycosylation are a growing group of inborn errors of protein glycosylation. Cardiac involvement is frequently observed in the most common form, PMM2-CDG, especially hypertrophic cardiomyopathy. Dilated cardiomyopathy, however, has been only observed in a few CDG subtypes, usually with a lethal outcome. We report on cardiac pathology in nine patients from three unrelated Israeli families, diagnosed with dolichol kinase deficiency, due to novel, homozygous DK1 gene mutations. The cardiac symptoms varied from discrete, mild dilation to overt heart failure with death. Two children died unexpectedly with acute symptoms of heart failure before the diagnosis of DK1-CDG and heart transplantation could take place. Three other affected children with mild dilated cardiomyopathy at the time of the diagnosis deteriorated rapidly, two of them within days after an acute infection. They all went through successful heart transplantation; one died unexpectedly and 2 others are currently (after 1–5 years) clinically stable. The other 4 children diagnosed with mild dilated cardiomyopathy are doing well on supportive heart failure therapy. In most cases, the cardiac findings dominated the clinical picture, without central nervous system or multisystem involvement, which is unique in CDG syndrome. We suggest to test for DK1-CDG in patients with dilated cardiomyopathy. Patients with discrete cardiomyopathy may remain stable on supportive treatment while others deteriorate rapidly. Our paper is the first comprehensive study on the phenotype of DK1-CDG and the first successful organ transplantation in CDG syndrome.

Successful Liver Transplantation and Long-Term Follow-up in a Patient With MPI-CDG

“…11 Hepatic cell and stem cell transplantation have not yet been reported in patients who have CDG. Based on the positive outcome in our patient, one might expect similar beneficial effects by using these cells in MPI-CDG.…”

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

“…The CTP-dependent dolichol kinase (DK) in yeast is encoded by sec59 (Heller et al, 1992) which, through complementation studies, led to the cloning of human DK (Fernandez et al, 2002;Shridas & Waechter, 2006). Recently, mutations in DK have been associated with autosomal recessive forms of dilated cardiomyopathy in paediatric patients, extending the genes in dolichol biosynthesis associated with CDGs (Denecke & Kranz, 2009;Kapusta et al, 2013;Kranz et al, 2007;Lefeber et al, 2011). (Larkin & Imperiali, 2011).…”

“…S3B) resulted in an astonishing 81 % and 78 % identity, respectively. Although mutations in DK have been associated with autosomal recessive forms of dilated cardiomyopathy (Denecke & Kranz, 2009;Kapusta et al, 2013;Kranz et al, 2007;Lefeber et al, 2011), to date no documented mutations in humans have been found in DOLPP1. Also included on the alignment of DOLPP1 (Fig.…”

Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

“…Several case reports in the literature suggest that CDGs should be considered in infants with cardiomyopathy and multisystem disorders. Infants with CDG Ⅰa (phosphomannomutase 2 deficiency) are have been most often been reported to have hypertrophic cardiomyopathy [12][13][14][15][16] and infants with dolichol kinase deficiency have been reported to have dilated cardiomyopathy [17,18] . Case reports exist for cardiomyopa- Byers SL et al .…”

“…Additional metabolic evaluations were unremarkable, including acylcarnitine profile, urine and plasma amino acids, ammonia, cholesterol, urine and plasma carnitine and creatine kinase. Although the lactate level was normal, pyruvate was slightly low, which caused the lactate/pyruvate ratio to be elevated at 53 (normal [10][11][12][13][14][15][16][17][18][19][20]. Pompe disease was ruled out based on normal enzyme activity.…”