Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophic cardiomyopathy and bilateral cataracts. We present here a case of neonatal demise, within the first day of life, who initially presented with severe lactic acidosis, with evidence of both chorioamnionitis and cardiogenic shock. Initial metabolic labs demonstrated a severe lactic acidosis prompting genetic testing which revealed a homozygous pathogenic variant for Sengers syndrome i

Andescavage, Nickie

Beck, David B

Cusmano-Ozog, Kristina

Leon, Eyby

English

George Washington University: Health Sciences Research Commons (HSRC)

Himmelfarb Health Sciences Library, The George Washington UniversityHealth Sciences Research CommonsPathology Faculty Publications Pathology4-13-2018Extending the phenotypic spectrum of Sengerssyndrome: Congenital lactic acidosis with syntheticliver dysfunction.David B BeckKristina Cusmano-OzogGeorge Washington UniversityNickie AndescavageGeorge Washington UniversityEyby LeonGeorge Washington UniversityFollow this and additional works at: https://hsrc.himmelfarb.gwu.edu/smhs_path_facpubsPart of the Medical Pathology Commons, Pathology Commons, and the Translational MedicalResearch CommonsThis Journal Article is brought to you for free and open access by the Pathology at Health Sciences Research Commons. It has been accepted forinclusion in Pathology Faculty Publications by an authorized administrator of Health Sciences Research Commons. For more information, pleasecontact hsrc@gwu.edu.APA CitationBeck, D., Cusmano-Ozog, K., Andescavage, N., & Leon, E. (2018). Extending the phenotypic spectrum of Sengers syndrome:Congenital lactic acidosis with synthetic liver dysfunction.. Translational Science of Rare Diseases, 3 (1). http://dx.doi.org/10.3233/TRD-180020Translational Science of Rare Diseases 3 (2018) 45–48DOI 10.3233/TRD-180020IOS Press45Original ResearchExtending the phenotypic spectrumof Sengers syndrome: Congenital lacticacidosis with synthetic liver dysfunctionDavid B. Becka, Kristina Cusmano-Ozogb, Nickie Andescavagec and Eyby Leonb,∗aNational Human Genome Research Institute, National Institute of Health, Bethesda, MD, USAbChildren’s National Health System, Rare Disease Institute, Genetics and Metabolism, Washington,DC, USAcChildren’s National Health System, Pediatrics, Neonatology, Washington, DC, USAAbstract. Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophiccardiomyopathy and bilateral cataracts. We present here a case of neonatal demise, within the first day of life, who initiallypresented with severe lactic acidosis, with evidence of both chorioamnionitis and cardiogenic shock. Initial metabolic labsdemonstrated a severe lactic acidosis prompting genetic testing which revealed a homozygous pathogenic variant for Sengerssyndrome in AGK, c.979A > T; p.K327∗. In addition to the canonical features of Sengers syndrome, our patient is the firstreported case with liver dysfunction extending the phenotypic spectrum both in terms of severity and complications. Thiscase also highlights the importance of maintaining a broad differential for congenital lactic acidosis.Keywords: Congenital lactic acidosis, Sengers syndrome, AGK, acylglycerol kinase1. IntroductionSengers syndrome was first identified in 1975 by the co-occurrence of the near pathognomonictriad of congenital cataracts, lactic acidosis and cardiomyopathy [1]. This disorder was subsequentlyshown to be caused by recessively inherited mitochondrial dysfunction and was noted to presentin two distinct forms: a severe neonatal and more insidious later onset presentation [2, 3]. Sengerssyndrome is caused by loss of function variants in AGK, the gene encoding acylglycerol kinase [4].Acylglycerol kinase is a mitochondrial transmembrane enzyme that catalyzes the phosphorylation ofmonoacylglycerol and diacylglycerol to lysophosphatidic and phosphatidic acid, which are importantsecondary messengers and regulate mitochondrial ultrastructure. AGK was recently identified as acomponent of the mitochondrial TIM22 complex, and is essential for import and assembly of metabolitecarrier proteins in a kinase-independent manner [5]. These kinase dependent and independent findingshave helped elucidate the multiple functions of AGK, explaining the diverse metabolic findings presentin Sengers syndrome.To date there have been less than thirty molecularly diagnosed patients with Sengers syndrome,with the majority of these consisting of later onset disease as opposed to the neonatal form [3]. These∗Corresponding author: Eyby Leon, Children’s National Health System, Rare Disease Institute, Genetics and Metabolism,Washington, DC, USA. Tel.: +1 202 476 5033; Fax: +1 202 476 2390; E-mail: ELeon@childrensnational.org.2214-6490/18/$35.00 © 2018 – IOS Press and the authors. All rights reservedThis article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0).46 D.B. Beck et al. / Extending the phenotypic spectrum of Sengers syndromedistinct presentations differ in that neonatal forms are noted to have central nervous system involvementincluding cerebellar hypoplasia while adult onset forms are more likely to have pathogenic variantssecondary to splicing defects suggesting possible low level gene expression [6]. We report here a caseof neonatal demise within the first day of life, presenting with severe lactic acidosis and systemichypotension, in the setting of both chorioamnionitis and cardiomyopathy, found to have Sengerssyndrome.2. Materials and methodsA CMA SNP array (CytoScan® Dx) was performed showing areas of homozygosity over 5.8% ofthe array. Candidate genes within the areas of homozygosity were reviewed. A nuclear mitochondrialpanel of 35 genes was done by Massively Paralleled Sequencing using TruSight One kit (v1.0). Plasmaamino acids were run on a Biochrom 30 Amino Acid Analyzer.3. Case presentationOur case is a 1-day-old full term boy born from a G1P0 31-year-old mother who had an uneventfulpregnancy receiving routine prenatal care. He was the product of Iranian consanguineous parents,known to be second cousins, with reported history of infertility prior to this naturally conceivedpregnancy. Rupture of membranes occurred 40 hours prior to delivery and meconium stained fluidwas present. During labor, maternal fever was noted, and maternal administration of broad-spectrumantibiotics were started for clinically diagnosed chorioamnionitis. At birth, the newborn showed aweak cry and decreased tone. He was found to be tachycardic and febrile with APGAR scores of 7 and8 and was started on broad spectrum antibiotics for presumed sepsis. Physical exam was notable forbilateral opacification of the corneas and hypospadias. At 5 hours of life, he began to have progressiveencephalopathy and respiratory distress resulting in intubation. Initial laboratory findings were notablefor a severe metabolic acidosis with insufficient respiratory compensation (pH = 6.94, pCO2 = 22.8,HCO3 = 6, Anion Gap = 49, Lactate of 354.6 mg/dl). Fluid resuscitation with normal saline and admin-istration of intravenous sodium bicarbonate resulted in minimal improvement in acidosis. The infantbecame progressively hypotensive, despite initiation of continuous vasopressor infusion. A chest X-raywas notable for cardiomegaly and an echocardiogram revealed severe biventricular dysfunction andventricular trabeculations suggestive of cardiomyopathy (Fig. 1A). Further studies showed evidence ofsynthetic liver dysfunction including low albumin, total protein, and fibrinogen, and prolonged PT, PTTwith normal bilirubin and elevated transaminases. Hematologic labs were significant for leukocytosiswith a predominance of immature bands, anemia, and thrombocytopenia which in combination withcoagulation studies were concerning for disseminated intravascular coagulation. Bacterial cultures ofblood, urine and cerebrospinal fluid were drawn and ultimately resulted as normal studies. Imagingincluded a head ultrasound showing “slit-like” lateral ventricles, decreased size of the extra-axialspaces and crowded posterior cranial fossa, suggestive of generalized brain edema. Abdominal ultra-sound showed an edematous liver with increased periportal echogenicity, but no evidence of hepatitis.Initially, the combined clinical and laboratory findings were suggestive of both cardiogenic and septicshock. However, the degree of lactic acidosis seemed excessive relative to the infant’s hemodynamicstatus and was refractory to resuscitation, prompting a more detailed metabolic evaluation.Serum lactate was elevated at 354.6 mg/dl, pyruvic acid 3.81 mg/dL, and the lactate to pyruvate ratiowas 91, suggestive of mitochondrial disease. Additional genetic and metabolic testing included chro-mosomal microarray and plasma amino acids. Results from a nuclear mitochondrial gene panel revealeda homozygous pathogenic variant in AGK, c.979A > T p.K327∗. This same genotype was present in aD.B. Beck et al. / Extending the phenotypic spectrum of Sengers syndrome 47Fig. 1. A) Portable CXR showing marked cardiomegaly. B) Plasma amino acid levels represented as ratio of the upper limitof normal. Dashed line is present at the upper level of normal, equal to one, with amino acids with asterisk denoting valuesmore than double.large consanguineous family with multiple neonatal Sengers syndrome cases [7, 8]. Plasma amino acidanalysis revealed elevation of alanine, methionine, phenylalanine, and branched chain amino acids,indicating liver dysfunction and catabolism (Fig. 1B). These elevations were also consistent with invitro experiments where loss of AGK leads to an accumulation of TCA cycle intermediates [5]. Despiteaggressive medical management, the patient had a cardiac arrest likely due to worsening cardiac func-tion secondary to refractory metabolic acidosis and multi-organ system dysfunction, dying on day oflife one. An autopsy was declined per the family’s request.The clinical course and genetic tests suggest that this infant had severe manifestation of Sengerssyndrome, that may have been exacerbated by clinical chorioamnionitis and culture-negative sepsis.Although testing was unable to provide a diagnosis prior to our patient’s death, it allowed the familythe option for pre-implantation genetic testing for future pregnancies.4. ConclusionsTo our knowledge, we present the most severe case of Sengers syndrome reported to date. A novelfinding in our patient was clinically-apparent synthetic liver dysfunction. While elevated transaminasesand prolonged coagulation studies can result from septic shock, and/or disseminated intravascularcoagulation, ultimately, infectious studies were negative. Rather, this may represent an additionalmanifestation of Sengers syndrome. Although a single patient is reported in the literature with primaryliver involvement, characterized as cytosolic granules in liver cells found on autopsy, none has hadclinically-evident liver impairment [8].Alternatively, this patient may have had another autosomal recessive condition that could explainhis synthetic liver dysfunction, especially considering the multiple areas of homozygosity noted byCMA; however, given the acute situation and rapid demise, whole exome sequencing was not able tobe performed.This case highlights the importance of maintaining a wide differential diagnosis for congenital lacticacidosis despite seemingly obvious etiologies [9]. This is particularly striking in our case given theevidence for septic and cardiogenic shock, yet these etiologies were unlikely to be the sole underly-ing cause of such profound, and disproportionate metabolic decompensation. Finally, despite recentadvances in our understanding of AGK function, the phenotypic diversity attributed to other genes48 D.B. Beck et al. / Extending the phenotypic spectrum of Sengers syndromeinvolved in the TIM22 complex, such as DDP1 in Mohr-Tranebjaerg Syndrome, suggest multiplemechanisms of action that may be better elucidated through further detailed genotype-phenotypecorrelations [10].AcknowledgmentsWe thank the families for their generous contributions. The authors have no competing interests.References[1] R.C. Sengers, et al., Congenital cataract and mitochondrial myopathy of skeletal and heart muscle associated withlactic acidosis after exercise, J Pediatr 86(6) (1975), 873–880.[2] A. Haghighi, et al., Sengers syndrome: Six novel AGK mutations in seven new families and review of the phenotypicand mutational spectrum of 29 patients, Orphanet J Rare Dis 9 (2014), 119.[3] G.J. van Ekeren, et al., A retrospective study of patients with the hereditary syndrome of congenital cataract: Mito-chondrial myopathy of heart and skeletal muscle and lactic acidosis, Eur J Pediatr 152(3) (1993), 255–259.[4] J.A. Mayr, et al., Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome, Am J Hum Genet90(2) (2012), 314–320.[5] Y. Kang, et al., Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22Protein Import Complex, Mol Cell 67(3) (2017), 457–470 e5.[6] M.S. Perry and J.T. Sladky, Neuroradiologic findings in Sengers syndrome, Pediatr Neurol 39(2) (2008), 113–115.[7] S. Pitkanen, et al., Familial cardiomyopathy with cataracts and lactic acidosis: A defect in complex I (NADH-dehydrogenase) of the mitochondria respiratory chain, Pediatr Res 39(3) (1996), 513–521.[8] K. Siriwardena, et al., Mitochondrial citrate synthase crystals: Novel finding in Sengers syndrome caused by acylglyc-erol kinase (AGK) mutations, Mol Genet Metab 108(1) (2013), 40–50.[9] D.R. Johns, Seminars in medicine of the Beth Israel Hospital: Boston, Mitochondrial DNA and disease, N Engl J Med333(10) (1995), 638–644.[10] K. Roesch, et al., Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13complex, Hum Mol Genet 11(5) (2002), 477–486.

Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction.

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Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction.

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