Hall, Patricia L

ABSTRACTMetachromatic leukodystrophy (MLD) is a rare neurodegenerative lysosomal storage disease resulting from bi‐allelic pathogenic variants in the ARSA gene. MLD is distinguished clinically based on the age of onset into late‐infantile, juvenile, and adult. The late‐infantile type is the most severe phenotype presenting with hypotonia, weakness, gait abnormalities, which progresses to mental and physical decline leading to early death. MLD is considered to be pan‐ethnic and no founder variants have previously been described in the Ashkenazi Jewish population. We identified three unrelated individuals of Ashkenazi Jewish descent with homozygosity or compound heterozygosity for the c.178C>T (p.Arg60Trp) variant in the ARSA gene, with a phenotype consistent with late‐infantile MLD. The carrier frequency was calculated among 93,293 individuals of Ashkenazi Jewish descent through the Dor Yeshorim screening program and found to have a carrier frequency on 1 in 1554 or 0.06%, which may be representative of a founder variant. Molecular protein modeling showed that the variant affects regional folding. Late‐infantile MLD should be considered when the c.178C>T (p.Arg60Trp) variant in the ARSA gene is present in either the homozygous or the compound heterozygous states.

AbstractMedium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency is a rare but important component of the differential diagnosis for adults with a history of premortem mental status changes and the postmortem finding of hepatic steatosis. This case report describes a 30‐year‐old white man who, following a period of nausea and vomiting, was admitted to the hospital with sudden mental status deterioration followed rapidly by clinical deterioration and death. Treating physicians in this case suspected acute illicit drug toxicity with synthetic cathinones based on social history. Clinicians and medical examiners should be aware that the presentation, signs, and symptoms described may indicate an underlying inborn error of metabolism such as MCAD deficiency and take action accordingly.