European Journal of Pediatrics Mild form of 3- methylglutaconic aciduria type IV and mutation in the genes TMEM 70 --Manuscript Draft-Manuscript Number: Full Title:
Mild form of 3- methylglutaconic aciduria type IV and mutation in the genes TMEM 70
Article Type:
Case Report
Keywords:
3- methylglutaconic aciduria type IV; TMEM 70; child
Corresponding Author:
Vesna Stojanovic SERBIA AND MONTENEGRO
Corresponding Author Secondary Information: Corresponding Author's Institution: Corresponding Author's Secondary Institution: First Author:
Vesna Stojanovic
First Author Secondary Information: Order of Authors:
Vesna Stojanovic Aleksandra Doronjski
Order of Authors Secondary Information: Abstract:
The case study concerns a 3 year-old boy diagnosed with a mild form of 3-MGA-uria. Since his birth, the clinical picture was dominated by lactic acidosis, dilated cardiomyopathy and delayed phychomotor development. A genetic analysis discovered a mutated gene TMEM70.
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Vesna Stojanović1 Aleksandra Doronjski1
Mild form of 3- methylglutaconic aciduria type IV and mutation in the genes TMEM 70
Corresponding author: Vesna Stojanović, E-mail:
[email protected], Tel. +381-641806387, Fax. +381-420581.
Abstract The case study concerns a 3 year-old boy diagnosed with a mild form of 3-MGA-uria. Since his birth, the clinical picture was dominated by lactic acidosis, dilated cardiomyopathy and delayed phychomotor development. A genetic analysis discovered a mutated gene TMEM70.
Keywords: 3- methylglutaconic aciduria type IV; TMEM 70; child
1
School of Medicine, Universitiy of Novi Sad, Intensive Care Unit, Institute for Child and Youth Health Care of Vojvodina, Hajduk Veljkova 10, 21000 Novi Sad, Serbia
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Introduction
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Within the scope of 3-methylglutaconic aciduria (3-MGA-uria) we recongnise 5 different disorders,
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which damage the function of mitochondria. The damage to the mitochondria leads to increased quantities of 3-
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methylglutaconic and 3-methylglutaric acids found in urine. Types I-III and V are caused by mutations of 4
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different genes (AUH, DNAJC19, OPA3, TAZ) and have characteristic symptoms. The genetic cause of type IV
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is still unknown, although there are hints that they include mutations of TMEM70 and ANT1 genes [4].
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Type IV (incidence unknown) may include symptoms found in first 3 types (delayed speech
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development, delayed physchomotor development, metabolic adicosis, dystonia and spastic quadriplegia, dilated
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cardiomyophaty, recurrent infections caused by neutropenia, skeletal myopathy and constitutional growth delay,
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optic nerve atrophy, hypotonia, choreiform movements and cognitive impairment) [4, 1, 5].
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The case study concerns a 3 year-old boy diagnosed with a mild form of 3-MGA-uria. Since his birth,
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the clinical picture was dominated by lactic acidosis, dilated cardiomyopathy and delayed phychomotor
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development. A genetic analysis discovered a mutated gene TMEM70.
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Case report
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The boy feelt fatigue on the day of admission, refusing to accept food and vomiting several times. Other
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symptoms were not registered. He was admitted to our clinic.
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First child from second controlled pregnancy (1 artificial abortion). Pregnancy and delivery saw no
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complications. After the birth, mild axial hypotonia and facial dysmorphism – antimongoloid eye shape, flat
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philtrum, lowered earlobes, microretrognathia, were registered. He was hospitalised on several occasions for a
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short time – each time he was vomiting and had a severe metabolic-lactic acidosis. His phychomotor
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development was delayed. The parents are Romanian Roma.
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On the day of admission, the 3 year-old boy was conscious, afebrile, heart rate 100/min, sat.O2 98%,
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respiration 36/min, blood pressure 85/55mmHg. Body weight 9,200g (under 3 percentile), height 90 cm (under 3
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percentile), head circumference 46 cm (under 3 percentile). Facial dysmorphism (Fig. 1). Adynamic. Comma
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Glasgow score 7. Skin pale-yellow. Tongue and lips dry. Lung exam findings normal. Heart action rhythmic,
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tones clear, systolic murmur over left sternal border. Soft abdomen, liver and spleen cannot be palpated. Typical
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male genitals, testicles in the scrotum. Neurological exam results unremarkable.
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Laboratory and other results: C reactive protein negative. Complete blood count- mild anemia.
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Cappilary blood gas exam results – severe metabolic acidosis. Serum lactates 9.7 mmol/l (up to 2.2). Anion gap
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25. Glycaemia 1.4 mmol/l. Biochemical indicators of liver and kindey functions, as well as serum ionogram
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normal. Creatine kinase, ammonia in blood – normal values. Ketonuria - 3+. Echocardiography - left ventricular
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hypertrophy, systolic and diastolic functions preserved.
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Ultrasonography of abdomen, brain computed tomography – normal, endocranium magnetic resonance
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imaging – extracerebral liquor spaces and the chamber system were moderately dilated without pathological
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collections. Diffuse cortex edema supratentorial bilaterally. Lumbar puncture – lactates in the liquor 9 mmol/l
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(1.1-2.8). Ophthalmological exam results normal. Electromyoneurography: normal results.
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Antiedema therapy was given - mannitol, furosemide and fluid intake restriction. Thiamine deficiency
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or pyruvate metabolism disorder were suspected, hence a thiamine therapy was given (parenteral loading dose
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100 mg, followed by a maintenance dose of 50 mg/day). On the fourth day of hospitalisation the acid-base
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balance was normalised, the boy awoke and became communicative. After that, the patient was of good general
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condition, conscious, communicative, afebrile, with good appetite.
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In order to further diagnose the core illness, the following analyses were conducted – total carnitine in
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plasma 21.77 µmol/l (34.6-83.6), free carnitine 6.15 µmol/l (24.3-62.5). Organic acids in the urine: moderately
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increased excretion of 3-methylglutaconic acid and 3-methylglutaric acid, accompanied by the presence of
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massive ketonuria. Presence of borderline increased excretion of lactates, pyruvates and fumaric acid. Orotic
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acid level elevated to the upper border. Aminoacidemia test results: elevated alanine values 1,591.7 µmol/l (137-
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305), lysine (978.2 µmol/l (71-151) and proline 695.5 µmol/l (68-148) in the serum. Increased excretion of
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alanine in the urine.
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Sequencing and restriction fragment length polymorphism analysis of the mutation c.317-2A>G in the TMEM70 gene showed this mutation as the only detectable form.
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The patient was released after one month with a therapy including thiamine and carnitine. He started
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eating more frequently, food richer in fat with a lower sugar intake. A psychological evaluation was conducted:
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moderate phychomotor deficiency, general quotient 65. The boy is of good general conditions, has a good
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appetite and has started gaining weight. He is physically active, he started running.
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Discussion
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The diagnosis of 3-MGA-uria type IV is based on the exclusion of the other, well-defined clinical
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subtypes. Wortmann et al. analysed 18 children with type IV 3-MGA-uria and three were with TMEM70
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mutation. All three with TMEM70 mutation had cardiomyopahty or heart rhythm disorders - Wolf-Parkinson-
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White syndrome, extrasystoles. No patient was hypotonic. They all had normal psychomotor development, but
2
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constitutional growth delayed. They all suffered from facial dysmorphism – high forehead, curved eyebrows, flat
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midface, long philtrum, low implanted ears and thin lips and were all of Roma origin [8].
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TMEM 70 is a new gene, which plays a part in ATP synthesis. It could be significant in molecular
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diagnosis of severe mitochondrial encephalocardiomyopathy with Complex V deficit. Cizkowa et al. identified a
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new gene, whose variations correlate with the degree of severity of mitochondrial phenotype observed in 23
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subjects of Roma origin (2). The mutation c.317-2A>G is prevalent, particularly in the Roma population. The
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most significant diagnostic method is a molecular genetic analysis which would confirm the presence of a
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pathogenic mutation in the TMEM70 gene [7, 6, 3].
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Analyising patients with 3-MGA-uria is of utmost importance and the aim is to classify them correctly,
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depending on typical symptoms, thus facilitating a targeted genetic analysis from the blood, without having to
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conduct muscle or skin biopsy. Also, it enables a more adequate monitoring of patients and more precise
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prognosis of the outcome.
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Decreased sugar tolerance and good fat tolerance are characteristic of the patients. Giving fat as the
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primary source of energy, in order to avoid catabolism, can normalise severe metabolic acidosis and decrease
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hyperlactacidemia [1, 2, 9].
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Our patient suffered from a mild form of the illness, undiagnosed until he was 3 years old. From birth,
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the clinical picture had been dominated by lactic acidosis, dilated cardiomyopathy, psychomotor growth delay,
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typical facial dysmorphism and the boy is of the Roma ethnic origin. This illness should be taken into account,
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since a large number of cases may result in death as a result of a metabolic acidosis crisis.
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Each newborn with unexplained lactic acidosis and cardiomyopathy should be tested using laboratory and genetic tests for 3-MGA-uria, among other illnesses.
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3
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Acknowledgment: We’d like to thank Dr. Johannes Mayr, Department of Paediatrics, Paracelsus Medical
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University Salzburg, Muellner Hauptstrasse 48, A-5020 Salzburg, Austria, for outstanding contribution to the
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development of this work (genetic analysis).
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4
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References:
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1.
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Cizkova A, Stranecky V, Mayr JA. (2008). TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy. Nat Genet 40(11):1288-90.
90
2.
Di Rosa G, Deodato F, Loupatty FJ. (2006) Hypertrophic cardiomyopathy, cataract, developmental
91
delay, lactic acidosis:a novel subtype of 3-methylglutaconic aciduria. J Inherit Metab Dis 29(4)546-
92
50.
93
3.
94
Honzik T, Tesarova M, Mayr JA. (2010) Mitochondrial encephalocardio-myopathy with early neonatal onset due to TMEM70 mutation. Arch Dis Child 95:296-301.
95
4.
96
Houstek J, Pickova A, Vojtiskova A. (2006) Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta1757:1400-5.
97
5.
98
Mayr JA, Merkel O, Kohlwein SD.(2007) Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. Am J Hum Genet 80:478-84.
99
6.
100
Shchelochkov OA, Li FY, Wang J. (2010) Milder clinical course of Type IV 3-methylglutaconic aciduria due to a novel mutation in TMEM70. Mol Genet Metabol 101(2-3)282-5.
101
7.
Spiegel R, Khayat M, Shalev SA. (2011) TMEM70 mutations are a common cause of nuclear
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encoded ATP synthase assembly defect:further delineation of a new syndrome. J Med Genet
103
48(3):177-82.
104
8.
105
Wortmann SB, Rodenburg RJ, Jonckheere A. (2009) Biochemical and genetic analysis of 3methylglutaconic aciduria type IV:a diagnostic strategy. Brain 132(1):136-46.
106
9.
107
Zeharia A, Elpeleg ON, Mukamel M. (1992)
3-methylglutaconic aciduria:A new variant.
Pediatrics 89(6):1080-2.
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Fig. 1
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implanted ears and thin lips, microretrognathia.
Facial dysmorphism - high forehead, curved eyebrows, antimongoloid eye shape, long philtrum, low
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