Term Neonate Presenting with the Combined Occurrence of Mucolipidosis Type II and Leigh Syndrome

Abstract

Mucolipidosis II α/beta (MLII) is an autosomal recessive disease in which a gene mutation leads to improper targeting of lysosomal enzymes with an end result of accumulation of lysosomes in the mitochondria resulting in a dysfunctional mitochondria.[1] Leigh syndrome (LS) is a rare progressive neurodegenerative disorder associated with dysfunctional mitochondria and oxidative phosphorylation.[4] Both disease processes typically present in infancy.[3] [7] Herein, we present a case of an infant diagnosed with both mucolipidosis II and Leigh syndrome. Genetic analysis in this case revealed two mutations (NDUFA12 c.178C > T p.Arg60* and GNPTAB c.732_733delAA) on the long arm of chromosome 12 as the etiology of MLII and LS in this neonate, respectively. We are unaware of any previously published cases of the presence of these two diseases occurring in the same patient. The complex clinical presentation of this case led to a delay in the diagnosis, and we believe that the clinical phenotypes of these two conditions were likely worsened. The genetic alterations presented in this case occurred as a result of mutations on chromosome 12. We suggest further investigation into the potential overlap in the pathophysiology, specifically the inheritance pattern, linkage disequilibrium, mitochondrial–lysosomal interaction, or crosstalk contributing to both diseases.

Keywords

mucolipidosis II - I cell disease - Leigh syndrome

Authors' Contributions

R.R.S. and U.C.E. drafted the initial and reviewed the final version of the manuscript. C.N.O.-M., S.J.B., and K.M.G. reviewed and edited the final manuscript. All the authors reviewed and accepted the final manuscript for publication.

• References

• 1 Cury GK, Matte U, Artigalás O. , et al. Mucolipidosis II and III alpha/beta in Brazil: analysis of the GNPTAB gene. Gene 2013; 524 (01) 59-64
• 2 Wraith JE. Mucopolysaccharidoses and mucolipidoses. In: Dulac O, Lassonde M, Sarnat HB. , eds. Handbook of Clinical Neurology Vol 133. Amsterdam, Netherlands: Elsevier Health Sciences; 2013: 1723-1729
• 3 Genetics Home Reference: Mucolipidosis II alpha/beta. U.S. National Library of Medicine, National Institutes of Health. Available at: https://ghr.nlm.nih.gov/condition/mucolipidosis-ii-alpha-beta . Accessed December 11, 2018
• 4 Pincus JH. Subacute necrotizing encephalomyelopathy (Leigh's disease): a consideration of clinical features and etiology. Dev Med Child Neurol 1972; 14 (01) 87-101
• 5 Leigh D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry 1951; 14 (03) 216-221
• 6 McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S. Late-adult onset Leigh syndrome. J Clin Neurosci 2012; 19 (02) 195-202
• 7 Genetics Home Reference: Leigh Syndrome. U.S. National Library of Medicine, National Institutes of Health. Available at: https://ghr.nlm.nih.gov/condition/leigh-syndrome . Accessed December 11, 2018
• 8 Lake NJ, Bird MJ, Isohanni P, Paetau A. Leigh syndrome: neuropathology and pathogenesis. J Neuropathol Exp Neurol 2015; 74 (06) 482-492
• 9 Cathey SS, Leroy JG, Wood T. , et al. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet 2010; 47 (01) 38-48
• 10 Ostergaard E, Rodenburg RJT, van den Brand M. , et al. Respiratory chain complex I deficiency due to NDUFA12 mutations as a new cause of Leigh syndrome. J Med Genet 2011; 48 (11) 737-740
• 11 Chinnery PF. Mitochondrial disorder overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington; 2000. [Updated 2014]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1224/#mt-overview . Accessed May 7, 2019
• 12 Pazzaglia UE, Beluffi G, Bianchi E, Castello A, Coci A, Marchi A. Study of the bone pathology in early mucolipidosis II (I-cell disease). Eur J Pediatr 1989; 148 (06) 553-557
• 13 Leroy JG, Cathey S, Friez MJ. Mucolipidosis II. In: Adam MP, Ardinger HH, Pagon RA. , et al., eds. GeneReviews [Internet]. Seattle, WA: University of Washington; 2008. [Updated 2012]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1828/ . Accessed April 7, 2019
• 14 Kurobane I, Inoue S, Gotoh Y. , et al. Biochemical improvement after treatment by bone marrow transplantation in I-cell disease. Tohoku J Exp Med 1986; 150 (01) 63-68
• 15 Lund TC, Cathey SS, Miller WP. , et al. Outcomes after hematopoietic stem cell transplantation for children with I-cell disease. Biol Blood Marrow Transplant 2014; 20 (11) 1847-1851
• 16 Inclusion-Cell (I-Cell) Disease. (Mucolipidosis Type II) Follow-Up: Complications, Prognosis, Patient Education. Inclusion-Cell (I-Cell) Disease (Mucolipidosis Type II) Follow-Up: Complications, Prognosis, Patient Education. Available at: https://emedicine.medscape.com/article/945460-followup . Published January 4, 2019. Accessed April 5, 2019
• 17 Leigh's Disease Information Page. National Institute of Neurological Disorders and Stroke. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Leighs-Disease-Information-Page . Accessed April 5, 2019
• 18 Plotegher N, Duchen MR. Mitochondrial dysfunction and neurodegeneration in lysosomal storage disorders. Trends Mol Med 2017; 23 (02) 116-134
• 19 de Pablo-Latorre R, Saide A, Polishhuck EV, Nusco E, Fraldi A, Ballabio A. Impaired parkin-mediated mitochondrial targeting to autophagosomes differentially contributes to tissue pathology in lysosomal storage diseases. Hum Mol Genet 2012; 21 (08) 1770-1781
• 20 Audano M, Schneider A, Mitro N. Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration. J Neurochem 2018; 147 (03) 291-309