A case report of methylmalonic acidemia associated with CYBT gene mutation

Rumana Islam; Mizanur Rahman; Kanij Fatema

doi:10.4103/pnjb.pnjb_12_22

CASE REPORT

Year : 2022 | Volume : 7 | Issue : 2 | Page : 81-83

A case report of methylmalonic acidemia associated with CYBT gene mutation

Rumana Islam¹, Mizanur Rahman², Kanij Fatema¹
¹ Department of Pediatric Neurology, Institute of Pediatric Neurodisorder and Autism (IPNA), Dhaka, Bangladesh
² Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh

Date of Submission	22-Mar-2022
Date of Acceptance	13-Jul-2022
Date of Web Publication	22-Nov-2022

Correspondence Address:
Dr. Kanij Fatema
Department of Pediatric Neurology, IPNA, Bangabandhu Sheikh Mujib Medical University, Dhaka
Bangladesh

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pnjb.pnjb_12_22

Abstract

Mutation in mitochondrial cytochrome b (CYTB) gene is associated with severely impaired complex III activity and oxidative phosphorylation and commonly presents with mitochondrial myopathy, exercise intolerance, and often multisystem involvement. We report a rare case of Methylmalonic acidemia who was finally found to have a pathogenic novel missense mutation (m.14766C>T, p.Thr7IIe) in the CYTB gene.

Keywords: CYTB, cytochrome b, methylmalonic academia, mitochondrial disease

How to cite this article:
Islam R, Rahman M, Fatema K. A case report of methylmalonic acidemia associated with CYBT gene mutation. Paediatr Nephrol J Bangladesh 2022;7:81-3

How to cite this URL:
Islam R, Rahman M, Fatema K. A case report of methylmalonic acidemia associated with CYBT gene mutation. Paediatr Nephrol J Bangladesh [serial online] 2022 [cited 2023 Mar 30];7:81-3. Available from: http://www.pnjb-online.org/text.asp?2022/7/2/81/361613

Introduction

Methylmalonic acidemia is a group of inherited disorder of certain aminoacid metabolism, caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase, a defect in the transport or synthesis of its cofactor- adenosyl-cobalamin, or deficiency of the enzyme methylmalonyl-CoA epimerase.^[1] Cytochrome b (CYTB) is the only mitochondrial DNA (mtDNA) encoded subunit of respiratory Complex lll. Cytochrome b alterations impair the formation of complex lll, severely reducing the complex’s activity and oxidative phosphorylation.^[2] Here we report a case of a 6 and ½-year-old boy, presented with developmental delay and episodes of vomiting. He was diagnosed as a case of Methylmalonic Acidemia on the basis of specific organic acids found on urine analysis but on Next-generation sequencing pathogenic mutation on the CYTB gene was detected [Figure 1].

Figure 1: The boy at 6 and ½-year-old in developmentally improved condition (right), MRI of brain FLAIR image showing bilateral basal ganglia hyperintensity (left)

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Case Report

A 6 and ½-year-old boy presented to a pediatric neurology OPD complaining of repeated episodes of vomiting since his 20 months of life and developmental delay. Vomiting was often intractable but not associated with lethargy and he had to be hospitalized for this event at 20 months of age. He had no seizure and no specific urine or body odor suggestive of metabolic disorder. He had no skin lesions, features of cardiac involvement, no visual or hearing impairment, no microcephaly, or involuntary movement. He was hypotonic, deep tendon reflexes were normal and planters were bilaterally flexor. He was the 2^nd child of consanguineous mating parents and his one sib died at 1.5 years of age due to an undiagnosed multisystem disease, who was developmentally age-appropriate but had a history of repeated respiratory tract infection since his 9 months of age. Before death, he was found to have Diabetes Mellitus and kidney disease. His mother also had a history of spontaneous abortion at 3 months of gestation and she had no alive child other than this reported boy till now. One of his paternal cousins had also been suffering from developmental delay. At the age of 20 months, he was evaluated with basic metabolic screening, CPK, Neuroimaging, TMS, and GCMS. Plasma Ammonia (126 micromol/l, Ref: 11–32 micromol/l) and Lactate (3.8 mmol/l, Ref: 0.6–2.1 mmol/l) were raised, no ketone body was found on urine examination. CPK, RBS, and Thyroid function tests were normal and there were no findings suggestive of megaloblastic anemia. A neurophysiological study with Electromyography (EMG) was also done for the evaluation of hypotonia, but there were no features of myopathy. On MRI of the brain, there was bilateral symmetrical T2 and FLAIR Basal Ganglia hyperintensity. On TMS there was a significant elevation of C3 and mild elevation of C5OH/C4DC. C3/C2 ratio = 2.89 (cut off>=0.22) and C3/C16 ratio = 41.18 (cut off= 2.22) and elevation of glycine. Urine organogram showed significant elevation of 3-OH propionic acid (7.68 fold), Methylmalonic acid (688.80 fold), and Methylcitric acid (19.85 fold). On Next-generation sequencing- pathogenic mutation (m.14766C>T, p.Thr7IIe) was found on the CYTB gene in ChrM: 14766. Since his 2 years of age, he was on supplementation with a mitochondrial cocktail including- Thiamin, Riboflavin, Co Enzyme Q, Levocarnitine, Pyridoxine, Biotin, Cyanocobalamin, Biotin, and Vitamin C and he showed significant clinical improvement. His development also progressed and now can stand with support, can say 3-word sentences, and can communicate with his family members.

Discussion

The isolated form of Methylmalonic academia may be caused by a complete or partial deficiency of the enzyme methylmalonyl-coenzyme A (CoA) mutase (mut; mut⁰ enzymatic subtype or mut⁻ enzymatic subtype, a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, cblD-MMA, cblH), or by a deficiency of the enzyme methylmalonyl-CoA epimerase.^[1] Onset of the manifestations of methylmalonic acidemia ranges from the neonatal period to adulthood. All phenotypes are characterized by periods of relative health and intermittent metabolic decompensation, usually associated with intercurrent infections and stress. The CYTB gene, Synonyms are- MT-CYB, COB, UQCR3 encodes for a protein called cytochrome b, which is one of the 11 components of a group of proteins called complex III. In mitochondria, complex III is involved in oxidative phosphorylation, in which oxygen and simple sugars are used to create adenosine triphosphate (ATP), the cell’s main energy source. Complex III (ubiquinol-cytochrome c reductase) catalyzes the electron transfer from ubiquinol to cytochrome c and consists of 11 subunits, only 1 of which, cytochrome b (Cyt b), is encoded by mitochondrial DNA. The cytochrome b protein is 380 amino acids long and the CYTB gene encompasses nucleotide positions 14747 to 15887 of mitochondrial DNA.^[3] Most CYTB gene mutations that cause mitochondrial complex III deficiency cause a change in single amino acids in the cytochrome b protein or lead to an abnormally short protein. These cytochrome b alterations severely impair the function of complex III and oxidative phosphorylation.

Mutations in the CYTB gene can cause mitochondrial complex III deficiency. When caused by mutations in this gene, the condition is usually characterized by muscle weakness (myopathy) and pain, especially during exercise (exercise intolerance). The percentage of mutated mitochondrial DNA is highest in the skeletal muscles, which explains the finding of myopathy in these individuals.^[4] It is unclear why the mutation is most prevalent in muscle tissue. More severely affected individuals can have problems with other body systems, including the liver, kidneys, heart, and brain. A novel missense heteroplasmic mutation (m.14864T>C) in MTCYB was found in a 15-year-old girl with a 5-year history of migraine, epilepsy, strokelike episodes, and chronic sensorimotor axonal polyneuropathy, a clinical presentation consistent with MELAS.^[2]MTCYB gene mutation was also found to play a pathogenetic role in the development of primary dilated cardiomyopathy.^[5] In another case report a 15-year-old boy presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency found to have complex III deficiency.^[6]

Mitochondrial disorders can present with non-specific symptoms and considerable phenotypic overlap also exists among mitochondrial disorders. This mutation has been described in the literature to be associated with a variety of disorders other than the mitochondrial disease: Congenital heart disease (CHD) - In an Iranian study, this variant was detected as homoplasmic in 12 children with CHD such as VSD, TOF, and ASD, and not detected in controls.^[7] Normal-tension Glucoma (NTG) - In a Korean study, this variant was detected to be present in 6 NTG patients with complete absence in control.^[8] In this current reported case the boy was found to have specific urine organic acids suggestive of Methylmalonic Acidemia, which is caused by the deficiency of enzyme- Methylmalonic Co a mutase. But on Next-generation sequence analysis he was found to have CYTB pathogenic mutation (m.14766C>T, p.Thr7IIe). Because this position has to be functional for proton transfer to occur, the C14766T mutation is likely to inhibit proton transfer and result in a partial block of the respiratory chain at complex lll.

Though methylmalonic acidemia is caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology, mitochondrial dysfunction could be a feature of this organic acidemia, evidenced by study on a background-modified Mut-knockout mouse model and liver from a patient with MMA to examine mitochondrial ultrastructure and respiratory chain dysfunction.^[9]

In conclusion, this is the first-ever reported case in world where a boy presented with features of Methylemalonic academia finally found CYTB Mitochondrial gene mutation on Next-generation sequencing.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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