Journal of Research in Medical and Dental Science 2020, Volume 8, Issue 3, Page No: 153-156 Copyright CC BY-NC 4.0 Available Online at: www.jrmds.in eISSN No. 2347-2367: pISSN No. 2347-2545

A Child with Dihydrolipoamide (DLD) Deficiency with a Rare Variant-A Case Report

Ahmed Bin Gaith Al-Mehmadi, Helal Helal Almalki, Aalia Akhtar Hayat* Department of Pediatrics, Maternity and Children Hospital, Makkah Al Mukarmah, Saudi Arabia

ABSTRACT DLD c.685G>T, P. (Gly22gcys) is categorized as pathogenic and has the entrenched role as a disease- causing variant. Diseases caused by DLD variants are inherited in an autosomal recessive fashion. The patient is typically homozygous for the variant. Typically, both parents are carriers of the variant. Each offspring of an affected individual has a 25% probability of being homozygous for the variant, a 50% chance of being an asymptomatic carrier, and a 25% chance of being an unaffected non-carrier. Mutations in DLD are associated with a severe disorder of infancy with failure to thrive, hypotonia, and metabolic acidosis. We presented the case of a 6-year-old child with homozygous splice region missense variant c.685G>T, p. (Gly229Cys) in DLD, her presentation, course of the illness, diagnosis and management in detail. Genetic counseling and family member testing are recommended, and early diagnosis and intervention may prevent the precipitation of an acute episode in such cases. Key words:

Pyruvate dehydrogenase E3 deficiency, DLD deficiency, E3-deficient maple syrup urine disease, E3 deficiency, Maple syrup urine disease type III, Autosomal recessive disease, Rare gene variant, DLDD, DLDH, E3, GCSL, LAD, PHE3, Genetic diseases,Abbreviations: Metabolic disorders, Lipoic acid biosynthesis defects, Pyruvate dehydrogenase complex deficiency DLD: Dihydrolipoamide Dehydrogenase, PDH: Pyruvate Dehydrogenase, BCAA: Branched Chain Amino Acids, BCKDH: Branched Chain Alpha- Ketoacid Dehydrogenase, OKGDH: O-Ketoglutarate Dehydrogenase HOW TO CITE THIS ARTICLE

: Ahmed Bin Gaith Al-Mehmadi, Helal Helal Almalki, Aalia Akhtar Hayat, A Child with Dihydrolipoamide Dehydrogenase (DLD) Deficiency with a Rare Variant- A Case Report, J Res Med Dent Sci, 2020, 8 (3):153-156.

Corresponding author: Aalia Akhtar Hayat e-mail: [email protected] very rare however if present it is concomitant with Received: 23/04/2020 aDeficiency severe disorder of DLD asof ainfancy result ofwith genetic failure mutations to thrive, is Accepted: 18/05/2020 hypotonia, and metabolic acidosis. It displays itself with an unlimited degree of unpredictability, INTRODUCTION ranging from the neurodegenerative and cardiac disease to Friedreich's ataxia and ischemic Prevalence of genetic disorders is high in Saudi Arabia accounted by an ominously elevated rate Many variants of DLD have been reported of consanguineous and intertribal marriages along reperfusion injury [4, 5]. nevertheless we want to account the case of a disease burden is pitched in by autosomal recessive 6-year-old girl with homozygous splice region diseaseswith large and family genetic sizes [1]. studies A significant on this share populace of this have not only played an instrumental role in the DLD and to converse her presentation, course of themissense illness, variant diagnosis c.685G>T, and management p. (Gly229Cys) in detail. in but also in addition of substantial information in CASE HISTORY theidentification international of genetic various database novel causal [2]. mutations Dihydrolipoamide dehydrogenase (DLD), is emergency department at the age of 3 years and 10The months child presented(2017) with for fever the and first vomiting. time to ourOn constituentalso identified of asmore E3 (Dihydrolipoamide:than one mitochondrial NAD+ the physical examination she was oriented but complex., It is vital EC for 1.8.1.4), the process and is of a catalysis. common In humans, it is encoded by the DLD gene [3]. was slightly tender w lethargic and slightly jaundiced. The abdomen ithout ascites. The liver was Journal of Research in Medical and Dental Science | Vol. 8 | Issue 3 | May 2020 153 Ahmed Bin Gaith Al-Mehmadi et al J Res Med Dent Sci, 2020, 8 (3):153-156

died at the age of 2 years with status epilepticus followed by stroke while her other sister, temperaturepalpable. Her was weight 37.2F was and 13.4 she kg had whereas tachycardia height (21 years) underwent recurrent admissions (100was 93beats cm. per Her minute). blood pressure was 109/51, with acute liver failure sans any neurological Laboratory data at admission demonstrated manifestation. Consent to report secondary prothrombin time. Ultrasonography revealed was unremarkable: she sat at 6 months, walked mildderanged to moderate liver profile, hepatomegaly bone profile(Figure and1) findings was not received. The perinatal history diagnosis of acute liver failure was made, and she delay.at 9 months, MRI brain and was controlled found to be sphincters normal. at 14 months. There was no history of social or speech waswith managed no other conservatively significant finding. by giving A provisional vitamin A sample was sent for genetic testing to look out for any genetic abnormality which failed to yield metronidazole and omeprazole. She was moved toK, ursodeoxycholicinpatient ward till acid, she cefotaxime, stabilized lactulose,and then similar lines and discharged after being stable discharged on recovery after one week. howeverany positive a sample finding. was She taken was again managed and sent along for the axon test out of Saudi Arabia. It was not until with similar symptoms and was managed along theShe samewas admitted lines with second additional time administrationafter five months of the presence of an underlying abnormal and rare ondansetron intravenously. She became better geneOctober variant. 2018 that the result came and confirmed and was discharged. However, a subsequent Whole-exome sequence analysis and the additional laboratory tests were Whole axon test consists of sequence analysis performedsimilar episode to exclude followed all possible another causes five monthsof liver of all coding genes in the genome for turned out to be negative. Autoantibodies were axons, exon intron boundaries and selected absent;injury. Hepatitis iron studies A, B, C,and and ceruloplasminE, CMV, and HIV levels tests the proband. The test targets all protein coding were normal. Abdominal ultrasound revealed used to detect single nucleotide variants and hepatomegaly with ascites. Portal and hepatic smallnoncoding, insertions deep and intronic deletions. variants. It may This not testdetect is veins were unremarkable. After ruling out all the low level mosaicism. possible underlying causes, degenerative liver disease secondary to abnormal genetic variation RESULTS was considered the most plausible diagnosis. Whole-exome sequence analysis of variants Family, birth and developmental history in previously established disease genes test revealed that patient was homozygous for DLD

There was a history of strong consanguinity in the family. Two of her sisters were affected; one c.685G>T, p(Gly229Cys) which is pathogenic

Figure 1: Hepatomegaly on ultrasonography at initial presentation.

Journal of Research in Medical and Dental Science | Vol. 8 | Issue 3 | May 2020 154 Ahmed Bin Gaith Al-Mehmadi et al J Res Med Dent Sci, 2020, 8 (3):153-156

Table 1: Variant table: Genetic alterations in established disease genes.

Gene Inheritance Nomenclature Consequence Genotype Phenotype AR (Autosomal c.685G>T, p missense splice_region_variant, gnomAD HOM Dihydrolipoyl dehydrogenase DLD recessive) (Gly229Cys) 77/276964 (homozygous) deficiency

ketoacid dehydrogenase (B supportive therapy at each presentation, o-ketoglutarate dehydroge nutritional(Table 1). support, Management and intravenous plan consisted for of complex, and pyruvate dehydrogenaseCKDH) complex, (PDH) hypoglycemia, treatment of metabolic acidosis nase (oKGDH) and correction of coagulopathy. She was booked glycine cleavage system and in addition may for regular follow ups to monitor growth and complex [8]. lt is also a component of the development and plasma amino acid levels complexes are an essential component in three (to guide dietary management). Family was majorfunction metabolic as serine pathways: protease. the The conversion counselled and advised to take precautions in order to avoid circumstances precipitating the acute episodes such as fasting, catabolic stressors degradationof pyruvate [11]. to acetyl-CoA, the Krebs cycle and liver-toxic medications. She was found to be and the branched chain amino acid (BCAA) faring well till her last follow up 6 months ago. early-onset typically manifests as a hypotonic DISCUSSION In inherited mutations type of DLD deficiency, infants do not survive their initial metabolic infant in contrast to our findings. Affected

Pyruvate Dehydrogenase (PDH) Complex decompensation and usually die within the first Deficiency and related deficiencies have a growth and neurodevelopmental abnormalities. few years of life. Those who survive, endure both homozygouspathological significanmutation cein the[4, 6].interface With this domain report of have a varied age range of presentation that DLD.we described Her predominantly a DLD-deficient liver childfailure with symptoms a novel mayConversely, extend casesfrom ofbirth sole till hepatic late thirties involvement [10]. and no neurological, developmental or muscular Involvement of numerous metabolic pathways symptoms as opposed to the other variants extend the spectrum of clinical features of this inmakes DLD managementhave been reported of DLD deficiencyin the literature. challenging. It has Patients with homozygous variant generally deficiency [7)]. beenTo date, suggested 14 missense that the and phenotypic 7 truncating heterogeneity mutations present in early childhood or later as was evident in this case, which is different as compared to residual DLD activity but rather with the impact typical disease in those who are compound ofin DLDthe mutationdeficiency on is notthe directly multi enzymatic correlated complexwith the heterozygous and present with very early activity [12].

RECOMMENDATIONS patientsonset severe with Dihydrolipoamide disease [6]. The DLDdehydrogenase c.685G>T, p.(Gly229cys) variant has been identified in 27 Screening of family members at risk state like our patient, four in a compound If the DLD pathogenic variants in an affected heterozygous(DLD) deficiency, state, includingand one in 22 a heterozygous in a homozygous state proband are known, at-risk siblings should undergo molecular genetic testing prenatally or Isolated liver disease is found usually in late onset after birth so that they can receive appropriate typein whom and amay second vary variant between was raised not identified liver [8, 9]. interventions to get management and avoid alone to fulminant hepatic failure, cirrhosis and precipitation of an acute event. death [10]. In this case however, the child presented Prenatal and premarital genetic counseling early with warning signs of acute liver failure and recovered with supportive treatment. Dihydrolipoamide dehydrogenase functions relativesDLD deficiency and prenatal is inherited testing for in pregnancies an autosomal at increasedrecessive risk manner. are possible Carrier if the testing DLD pathogenic for at-risk enzyme complexes: branched chain alpha- variants in the family are known. as the E3 subunit of three mitochondrial Journal of Research in Medical and Dental Science | Vol. 8 | Issue 3 | May 2020 155 Ahmed Bin Gaith Al-Mehmadi et al J Res Med Dent Sci, 2020, 8 (3):153-156

CONCLUSION 4. Shaag A, Saada A, Berger I, et al. Molecular basis of

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