Analysis of ocular clinical features in 13 children with methylmalonic acidemia_Chinese Journal of Ocular Fundus Diseases

Authors：

Shi Liying ¹ , Sun Xiantao ¹ , Lu Yuebing ¹ , Sun Shuang ¹ , Huang Yunyun ¹ , Xu Lihui ¹ ,  Yu Jifeng ^1,2

1. Department of Ophthalmology, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou 450018, China;
2. Department of Ophthalmology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing 100045, China;

Corresponding author：

Yu Jifeng, Email: jeffernyu@126.com

Keywords：

Infant; Methylmalonic acidemia; Maculopathy; Nystagmus; MMACHC gene mutation

DOI：

10.3760/cma.j.cn511434-20220808-00440

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To observe the clinical features of eyes in children with methylmalonic acidemia (MMA). Methods A retrospective clinical case study. From June 2019 to June 2022, 13 children with MMA visited on the Department of Ophthalmology of Henan Children's Hospital were included in the study. The anterior segment and fundus were examined under surface or general anesthesia. Best corrected visual acuity (BCVA) and refraction were performed in 9 cases; fluorescein fundus angiography (FFA) was performed in 3 cases; flash electroretinogram (FERG) was performed in 6 cases; flash visual evoked potential (FVEP) was detected in 6 cases; optical coherence tomography (OCT) was performed in 3 cases. Results Among the 13 pediatric patients with methylmalonic acidemia, 6 cases were male and 7 cases were female. The average age at first visit was 45 months. All cases suffered from hyperhomocysteinemia; 9 cases were with epilepsy; 2 cases were with infantile spasms; 11 cases were with stunting, 13 cases were with repeated pulmonary infection during growth period; 4 cases were with hydrocephalus; 1 cases was with hypertension and renal insufficiency. Genetic dectection results of 8 cases were recorded, MMACHC:c.609G>A:p.W203* mutation site was found in all cases. One case was accompanied by corneal ulcer. There were 10 cases with nystagmus, 4 cases with macular degeneration, 3 cases with hyperopic refractive error and esotropia. Nine cases underwent BCVA examination, BCVA was light perception-0.6. In OCT, 2 cases of 3 cases showed retinal thinning and photoreceptor cell layer atrophy in the macular area. In FFA, 2 cases of 3 cases showed circular transparent fluorescence in the macular area. Five cases of 6 cases who with FVEP had different degrees of P100 peak time delay and decreased amplitude, and 4 cases of 6 cases with FERG had decrease of a and b wave in light and dark adaptation. Conclusions The clinical phenotypes of eyes in children with MMA are various and the severity was different; most of them are accompanied by nystagmus, and the fundus lesions are common in the characteristic bovine eye like macular region. Those with macular disease have severe visual impairment.

Citation： Shi Liying, Sun Xiantao, Lu Yuebing, Sun Shuang, Huang Yunyun, Xu Lihui, Yu Jifeng. Analysis of ocular clinical features in 13 children with methylmalonic acidemia. Chinese Journal of Ocular Fundus Diseases, 2023, 39(1): 28-33. doi: 10.3760/cma.j.cn511434-20220808-00440 Copy

1.	Brooks BP, Thompson AH, Sloan JL, et al. Ophthalmic manifestations and long-term visual outcomes in patients with cobalamin C deficiency[J]. Ophthalmology, 2016, 123(3): 571-582. DOI: 10.1016/j.ophtha.2015.10.041.
2.	Fuchs LR, Robert M, Ingster-Moati I, et al. Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria[J]. J AAPOS, 2012, 16(4): 370-375. DOI: 10.1016/j.jaapos.2012.02.019.
3.	Ku CA, Ng JK, Karr DJ, et al. Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia[J]. Ophthalmic Genet, 2016, 37(4): 404-414. DOI: 10.3109/13816810.2015.1121500.
4.	宇亚芬, 黎芳, 麻宏伟. cbIC型甲基丙二酸血症基因型与临床表型及疗效的关系[J]. 中国当代儿科杂志, 2015, 17(8): 769-774. DOI: 10.7499/j.issn.1008-8830.2015.08.002.Yu YF, Li F, Ma HW. Relationship of genotypes with clinical phenotypes and outcomes in children with cobalamin C type combined methylmalonic aciduria and homocystinuria[J]. Chin J Contemp Pediatr, 2015, 17(8): 769-774. DOI: 10.7499/j.issn.1008-8830.2015.08.002.
5.	Wang C, Li D, Cai F, et al. Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: a case series and literature review[J/OL]. Eur J Med Genet, 2019, 62(10): 103713[2019-07-04]. https://pubmed.ncbi.nlm.nih.gov/31279840/. DOI: 10.1016/j.ejmg.2019.103713.
6.	Kiessling E, Notzli S, Todorova V, et al. Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice[J/OL]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(10): 166201[2021-10-01]. https://pubmed.ncbi.nlm.nih.gov/34147638/. DOI: 10.1016/j.bbadis.2021.166201.
7.	Tsina EK, Marsden DL, Hansen RM, et al. Maculopathy and retinal degeneration in cobalamin C methylmalonic aciduria and homocystinuria[J]. Arch Ophthalmol, 2005, 123(8): 1143-1146. DOI: 10.1001/archopht.123.8.1143.
8.	Collison FT, Xie YA, Gambin T, et al. Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic Bull's eye maculopathy[J]. Ophthalmic Genet, 2015, 36(3): 270-275. DOI: 10.3109/13816810.2015.1010736.
9.	Gerth C, Morel CF, Feigenbaum A, et al. Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type[J]. J AAPOS, 2008, 12(6): 591-596. DOI: 10.1016/j.jaapos.2008.06.008.
10.	Matmat K, Gueant-Rodriguez RM, Oussalah A, et al. Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review[J]. Hum Genet, 2021, 141(7): 1239-1251. DOI: 10.1007/s00439-021-02350-8.
11.	杨秀芬, 刘宁朴. 牛眼样黄斑病变[J]. 国际眼科纵览, 2007, 31(5): 343-347. DOI: 10.3760/cma.j.issn.1673-5803.2007.05.013.Yang XF, Liu NP. Bull's eye maculopathy[J]. Int Rev Ophthalmol, 2007, 31(5): 343-347. DOI: 10.3760/cma.j.issn.1673-5803.2007.05.013.
12.	Francis JH, Rao L, Rosen RB. Methylmalonic aciduria and homocystinuria-associated maculopathy[J]. Eye (Lond), 2010, 24(11): 1731-1732. DOI: 10.1038/eye.2010.115.
13.	Carrillo-Carrasco N, Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type. Ⅱ. complications, pathophysiology, and outcomes[J]. J Inherit Metab Dis, 2012, 35(1): 103-114. DOI: 10.1007/s10545-011-9365-x.
14.	Martinez Alvarez L, Jameson E, Parry NR, et al. Optic neuropathy in methylmalonic acidemia and propionic acidemia[J]. Br J Ophthalmol, 2016, 100(1): 98-104. DOI: 10.1136/bjophthalmol-2015-306798.
15.	Williams ZR, Hurley PE, Altiparmak UE, et al. Late onset optic neuropathy in methylmalonic and propionic acidemia[J]. Am J Ophthalmol, 2009, 147(5): 929-933. DOI: 10.1016/j.ajo.2008.12.024.
16.	Patton N, Beatty S, Lloyd IC, et al. Optic atrophy in association with cobalamin C (cblC) disease[J]. Ophthalmic Genet, 2000, 21(3): 151-154. DOI: 10.1076/1381-6810(200009)2131-ZFT151.
17.	Pinar-Sueiro S, Martinez-Fernandez R, Lage-Medina S, et al. Optic neuropathy in methylmalonic acidemia: the role of neuroprotection[J]. J Inherit Metab Dis, 2010, 33(Suppl 3): S199-203. DOI: 10.1007/s10545-010-9084-8.

1. Brooks BP, Thompson AH, Sloan JL, et al. Ophthalmic manifestations and long-term visual outcomes in patients with cobalamin C deficiency[J]. Ophthalmology, 2016, 123(3): 571-582. DOI: 10.1016/j.ophtha.2015.10.041.
2. Fuchs LR, Robert M, Ingster-Moati I, et al. Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria[J]. J AAPOS, 2012, 16(4): 370-375. DOI: 10.1016/j.jaapos.2012.02.019.
3. Ku CA, Ng JK, Karr DJ, et al. Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia[J]. Ophthalmic Genet, 2016, 37(4): 404-414. DOI: 10.3109/13816810.2015.1121500.
4. 宇亚芬, 黎芳, 麻宏伟. cbIC型甲基丙二酸血症基因型与临床表型及疗效的关系[J]. 中国当代儿科杂志, 2015, 17(8): 769-774. DOI: 10.7499/j.issn.1008-8830.2015.08.002.Yu YF, Li F, Ma HW. Relationship of genotypes with clinical phenotypes and outcomes in children with cobalamin C type combined methylmalonic aciduria and homocystinuria[J]. Chin J Contemp Pediatr, 2015, 17(8): 769-774. DOI: 10.7499/j.issn.1008-8830.2015.08.002.
5. Wang C, Li D, Cai F, et al. Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: a case series and literature review[J/OL]. Eur J Med Genet, 2019, 62(10): 103713[2019-07-04]. https://pubmed.ncbi.nlm.nih.gov/31279840/. DOI: 10.1016/j.ejmg.2019.103713.
6. Kiessling E, Notzli S, Todorova V, et al. Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice[J/OL]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867(10): 166201[2021-10-01]. https://pubmed.ncbi.nlm.nih.gov/34147638/. DOI: 10.1016/j.bbadis.2021.166201.
7. Tsina EK, Marsden DL, Hansen RM, et al. Maculopathy and retinal degeneration in cobalamin C methylmalonic aciduria and homocystinuria[J]. Arch Ophthalmol, 2005, 123(8): 1143-1146. DOI: 10.1001/archopht.123.8.1143.
8. Collison FT, Xie YA, Gambin T, et al. Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic Bull's eye maculopathy[J]. Ophthalmic Genet, 2015, 36(3): 270-275. DOI: 10.3109/13816810.2015.1010736.
9. Gerth C, Morel CF, Feigenbaum A, et al. Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type[J]. J AAPOS, 2008, 12(6): 591-596. DOI: 10.1016/j.jaapos.2008.06.008.
10. Matmat K, Gueant-Rodriguez RM, Oussalah A, et al. Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review[J]. Hum Genet, 2021, 141(7): 1239-1251. DOI: 10.1007/s00439-021-02350-8.
11. 杨秀芬, 刘宁朴. 牛眼样黄斑病变[J]. 国际眼科纵览, 2007, 31(5): 343-347. DOI: 10.3760/cma.j.issn.1673-5803.2007.05.013.Yang XF, Liu NP. Bull's eye maculopathy[J]. Int Rev Ophthalmol, 2007, 31(5): 343-347. DOI: 10.3760/cma.j.issn.1673-5803.2007.05.013.
12. Francis JH, Rao L, Rosen RB. Methylmalonic aciduria and homocystinuria-associated maculopathy[J]. Eye (Lond), 2010, 24(11): 1731-1732. DOI: 10.1038/eye.2010.115.
13. Carrillo-Carrasco N, Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type. Ⅱ. complications, pathophysiology, and outcomes[J]. J Inherit Metab Dis, 2012, 35(1): 103-114. DOI: 10.1007/s10545-011-9365-x.
14. Martinez Alvarez L, Jameson E, Parry NR, et al. Optic neuropathy in methylmalonic acidemia and propionic acidemia[J]. Br J Ophthalmol, 2016, 100(1): 98-104. DOI: 10.1136/bjophthalmol-2015-306798.
15. Williams ZR, Hurley PE, Altiparmak UE, et al. Late onset optic neuropathy in methylmalonic and propionic acidemia[J]. Am J Ophthalmol, 2009, 147(5): 929-933. DOI: 10.1016/j.ajo.2008.12.024.
16. Patton N, Beatty S, Lloyd IC, et al. Optic atrophy in association with cobalamin C (cblC) disease[J]. Ophthalmic Genet, 2000, 21(3): 151-154. DOI: 10.1076/1381-6810(200009)2131-ZFT151.
17. Pinar-Sueiro S, Martinez-Fernandez R, Lage-Medina S, et al. Optic neuropathy in methylmalonic acidemia: the role of neuroprotection[J]. J Inherit Metab Dis, 2010, 33(Suppl 3): S199-203. DOI: 10.1007/s10545-010-9084-8.

Previous Article
Changes of microvascular structure in the macular region of pediatric uveitis
Next Article
Anti-vascular endothelial growth factor treatment in X-linked retinoschisis with vitreous hemorrhage

Chinese Journal of Ocular Fundus Diseases

Analysis of ocular clinical features in 13 children with methylmalonic acidemia

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content