2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Masked by Chronic Substance Abuse, and Blindsided by a Multi-Enzyme Complex Deficiency: An Intriguing Case Report

Pdf Summary

Dihydrolipoamide dehydrogenase deficiency (DLDD) is an autosomal recessive disorder caused by biallelic pathogenic variants within the DLD gene. The DLD gene encodes an enzymatic component (dihydrolipoamide dehydrogenase) used by several mitochondrial multicomplex α-ketoacid dehydrogenases and the glycine cleavage system. DLDD is characterized by a range of biochemical abnormalities, particularly during episodes of decompensation. The severity of these abnormalities does not correlate with residual enzyme activity, but rather with different phenotypical presentations.<br /><br />DLDD can present with various clinical manifestations. The predominant hepatic phenotype is characterized by symptoms such as nausea, vomiting, hepatomegaly, liver failure, encephalopathy, coagulopathy, and other Reye syndrome-like symptoms. Some cases may also include vision impairment, muscle cramps, and behavioral disturbances. However, the non-specific nature of these clinical manifestations and the potential for unremarkable metabolic results after resolution of acute decompensation episodes often lead to DLDD being overlooked and diagnosed late.<br /><br />The case presented in the document describes a 41-year-old male with a complex medical history who initially attributed his ophthalmological manifestations to chronic substance abuse. However, molecular genetic analyses revealed compound heterozygous variants within the DLD gene, confirming DLDD. The pathogenicity of these variants included a premature stop codon and a missense variant affecting protein stability and function.<br /><br />Treatment and management of DLDD involve abstaining from hepatic and neurotoxic substances, following a branched-chain amino acid (BCAA)-restricted diet, and receiving vitamin supplementation. In the case described, the patient's ophthalmologic abnormalities temporarily improved but worsened due to non-adherence to dietary treatment regimens.<br /><br />Overall, this case highlights the complexity and variability of DLDD and emphasizes the importance of considering this disorder in patients with clinical manifestations that may be masked by more common factors.

Asset Subtitle

Presenting Author - Zinandré Stander, PhD; Co-Author - Jessica A. Kraker, MD, MS; Co-Author - Silvia Tortorelli, MD,PhD; Co-Author - Devin Oglesbee, PhD; Co-Author - John J. Chen, MD, PhD; Co-Author - Lisa A. Schimmenti, MD, FAAP, FACMG;

Meta Tag

Biochemical genetics

Genetic Testing

Metabolic Disorder

Co-Author Jessica A. Kraker, MD, MS

Co-Author Silvia Tortorelli, MD,PhD

Co-Author Devin Oglesbee, PhD

Co-Author John J. Chen, MD, PhD

Co-Author Lisa A. Schimmenti, MD, FAAP, FACMG

Presenting Author Zinandré Stander, PhD

Keywords

Dihydrolipoamide dehydrogenase deficiency

DLDD

autosomal recessive disorder

DLD gene

enzymatic component

mitochondrial multicomplex α-ketoacid dehydrogenases

glycine cleavage system

biochemical abnormalities

hepatic phenotype

ophthalmological manifestations