Dolichol kinase deficiency (DOLK-CDG): Two new cases and expansion of phenotype.

Congenital disorders of glycosylation (CDGs) are a group of genetic diseases caused by mutations in genes that are necessary for the addition of oligosaccharides to acceptor proteins or lipids. An early step in this process requires dolichol kinase (DK) to catalyze the formation of dolichyl phosphate, which acts as a membrane anchor for initial attachment of sugar residues that are subsequently built up to oligosaccharides and transferred to acceptor proteins and lipids for further processing. Biallelic mutations in DOLK, the gene for DK, result in human in a CDG with variable symptoms, ranging from nonsyndromic dilated cardiomypopathy to severe multiorgan involvement. We report two female siblings with novel compound heterozygous mutations in DOLK: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Both patients presented in the neonatal period with severe ichthyosis, unusual distal digital constrictions and dilated cardiomyopathy which resulted in death. Histology of the skin showed lipid droplet accumulation in the stratum corneum and keratinocytes, which suggests defective epidermal lipid metabolism. These patients represent an earlier and more severe form of DOLK-CDG (CDG-1m) with a striking presentation at birth that expands the known phenotypic spectrum.

Newborn Screening for X-Linked Adrenoleukodystrophy in Nebraska: Initial Experiences and Challenges.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by pathogenic variants in ABCD1 resulting in defective peroxisomal oxidation of very long-chain fatty acids. Most male patients develop adrenal insufficiency and one of two neurologic phenotypes: a rapidly progressive demyelinating disease in mid-childhood (childhood cerebral X-ALD, ccALD) or an adult-onset spastic paraparesis (adrenomyeloneuropathy, AMN). The neurodegenerative course of ccALD can be halted if patients are treated with hematopoietic stem cell transplantation at the earliest onset of white matter disease. Newborn screening for X-ALD can be accomplished by measuring C26:0-lysophosphatidylcholine in dried blood spots. In Nebraska, X-ALD newborn screening was instituted in July 2018. Over a period of 3.3 years, 82,920 newborns were screened with 13 positive infants detected (4 males, 9 females), giving a birth prevalence of 1:10,583 in males and 1:4510 in females. All positive newborns had DNA variants in ABCD1. Lack of genotype-phenotype correlations, absence of predictive biomarkers for ccALD or AMN, and a high proportion of ABCD1 variants of uncertain significance are unique challenges in counseling families. Surveillance testing for adrenal and neurologic disease in presymptomatic X-ALD males will improve survival and overall quality of life.