J Inherit Metab Dis DOI 10.1007/s10545-010-9084-8
CASE REPORT
Optic neuropathy in methylmalonic acidemia: the role of neuroprotection Sergio Pinar-Sueiro & Ricardo Martínez-Fernández & Sergio Lage-Medina & Luis Aldamiz-Echevarria & Elena Vecino
Received: 3 August 2009 / Revised: 10 March 2010 / Accepted: 11 March 2010 # SSIEM and Springer 2010
Abstract We report the case of a patient with an optic neuropathy induced by neurotoxicity in the setting of methylmalonic acidemia. The patient responded with a significant and long-term improvement in visual acuity, perimetry, and chromatic function after a neuroprotective treatment with vitamin E and coenzyme Q10 was started. Coenzyme Q10 levels had been proven to be normal before Communicated by: Matthias Baumgartner References to electronic database: Methylmalonic aciduria: OMIN 251000; Methylmalonyl-CoA mutase: EC 5.4.99.2 Competing interest: None declared. S. Pinar-Sueiro (*) Department of Ophthalmology, Hospital de Cruces, Plaza de Cruces s/n, 48903 Barakaldo, Vizcaya, Spain e-mail:
[email protected] S. Pinar-Sueiro Department of Cell Biology and Histology, University of the Basque Country, Lejona, Biscay, Spain R. Martínez-Fernández Department of Ophthalmology, Hospital de Cruces, Barakaldo, Spain S. Lage-Medina Department of Pediatric Metabolism, Hospital de Cruces, Barakaldo, Spain L. Aldamiz-Echevarria Department of Pediatric Metabolism, Hospital de Cruces, Barakaldo, Spain E. Vecino Department of Cell Biology and Histology, University of the Basque Country, Lejona, Biscay, Spain
starting treatment. This case report is particularly important because it describes a possible treatment for optic neuropathy in methylmalonic patients. Although the response might be, in part, specific to the individual, it suggests the existence of a cause–effect relationship between the treatment undergone by our patient and the improvement in her visual acuity. To date, no other treatments with beneficial effects have been reported for the few optic neuropathies caused by methylmalonic acidemia. Further studies should determine the applicability of coenzyme Q10 and vitamin E for the treatment of optic neuropathies in methylmalonic acidemia. Abbreviations MMA Methylmalonic acidemia MM CoA M Methylmalonic–CoA mutase CoQ10 Coenzyme Q10
Introduction Methylmalonic acidemia (MMA) is the most common form of branched-chain organic aciduria. This rare metabolic disease is inherited as an autosomal recessive trait, and it is thought to occur in 1:50000–1:80000 newborns. The disease arises from impaired catabolism of branched-chain amino acids isoleucine, methionine, threonine, and valine, and various other propionic substances, such as odd-chain fatty acids and cholesterol. The enzyme involved in the catalysis is methylmalonyl-CoA mutase (MCM, EC 5.4.99.2), which is adenosylcobalamin dependent. The disease may result from defects in the structure/function of the enzyme itself or in the enzyme’s cobalamin cofactor (Deodato et al. 2006). Management of these patients is
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based on careful dietary protein control to maintain low concentrations of branched-chain amino acids, and the use of special dietary products free of the offending amino acids and propionic substrates. They are also supplemented with vitamins, trace elements, and carnitine (Yannicelli 2006). Although uncommon, cases of optic neuropathy secondary to organic acidemias have been reported, and optic atrophy typically presents early. An association between neurological dysfunction, optic atrophy, and increased urinary excretion of 3-methylglutaconic acid in infants with Behr syndrome has been described in the literature (Costeff et al. 1993). In addition, bilateral optic atrophy has been observed in three patients with cobalamin C MMA with homocystinuria (cblC disease) (Patton et al. 2000). In these cases, optic neuropathy was diagnosed at 6 months, 1 year, and 3 years of age. To the best of our knowledge, very few cases of optic neuropathy have been reported in the setting of MMA (Williams et al. 2009). Two men (16 and 21 years old, respectively) developed optic atrophy and visual dysfunction despite good metabolic control (restriction of propionic amino acids and dietary supplementation). These two cases represent the latest onsets of optic atrophy described in organic acidemias. To date, no clinically effective treatments have been reported for this type of neuropathy in the setting of MMA, and it is not known whether therapies should target neuroprotection, mitochondria, nutrition, or a combination of all of these approaches. Research has been focused on therapies that aim to achieve adequate regulation of mitochondrial metabolism, for example, using diazoxide, (Kowaltowski et al 2006), but their effect has only been demonstrated in MMA cells. However, experimental studies suggest the potential of some neuroprotective treatments for this condition. In particular, several studies evaluating the topical administration of coenzyme Q10 (CoQ10) and Fig. 1 a Baseline funduscopic image, with a normal appearance. b An incipient pallor is seen in the right optic nerve head before initiating treatment with coenzyme Q10 and vitamine E
vitamin E have highlighted the potential neuroprotective role of these antioxidants (Nucci et al. 2007; Russo et al. 2008). Under in vivo and in vitro conditions of oxidative stress, these substances proved to be effective to prevent cell damage in retinal ganglion cells (RGCs). We report the case of a female patient with optic neuropathy secondary to MMA who experienced a clear clinical improvement after administration of two wellknown antioxidant and neuroprotective products: CoQ10 and vitamin E.
Case report A 15-year-old female patient reported a decrease in visual acuity in her right eye over the previous month, as well as fluctuating episodes of blurred vision in both eyes during the past 5 months. Symptoms were more severe at nearworking distances. The patient’s medical history was significant for a severe neonatal presentation of MMA with hyperammonemia, requiring peritoneal dialysis and feedingtube insertion. Genetic studies revealed that this patient suffered from mut0 MMA (OMIM 251000), which was not responsive to vitamin B12 supplements due to a defect in the protein of the enzyme. Two mutations in the MUT gene were identified: NM_000255.2 c.1105C>T (p. R369C) and NM_000255.2 c.671–678dup (p. V227N fsX16). Studies of [14C]propionate incorporation into cultured fibroblasts revealed a mutase activity of 2.1 nmol/h per milligram of protein [control fibroblast enzyme activity: 11.9±2.4 (7.1– 16.8))]in basal medium and 2.4 nmol/h milligram protein [control fibroblast enzyme activity: 10.5±1.9 (6.8–14.3)]in hydroxocobalamin-enriched medium. The management of the patient was carried out through the Department of Metabolism at our hospital. She was on a restrictive low-
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protein, high-energy diet supplemented with a specific formula free of propionic substrates and including vitamins and trace elements. She was also supplemented with Lcarnitine (100 mg/kg/day). At the first examination (28 July 2008), the patient’s visual acuity (on the decimal scale) was 0.2 in her right eye (RE) and 0.6 in her left eye (LE). The patient’s right eye showed a marked relative afferent pupillary defect. Biomicroscopy and funduscopy results were normal (Fig. 1). The Ishihara color test revealed bilateral impairment, with results of 5/17 in RE and 12/17 in LE. Campimetry (Humphrey) using a Swedish Interactive Thresholding Algorithm (SITA) standard strategy showed a generalized decrease in sensitivity as well as centrocecal and upper temporal scotoma in both eyes [mean deviation (MD): –16.84 dB RE, –18.81 dB LE) (Fig. 2). An electroretinogram and optical coherence tomography (OCT) of the optic nerve and macula revealed no changes, but visual evoked potentials were altered in both eyes, especially the RE, with an increased P100 latency. No changes were found in magnetic resonance imaging of the central nervous system (CNS) and orbits after administration of gadolinium contrast or analysis of cerebrospinal fluid [lactic dehydrogenase(LDH) 37; adenosine desaminase (ADA) 6; glucose 64; protein 29; outflow pressure 200 mmH2O; pressure using the Valsalva maneuver 300 mmH2O]. A study of mitochondrial DNA was negative for mutations 3460, 11778, and 14484 of Leber’s hereditary optic neuropathy (LHON). Laboratory testing revealed elevated MMA, vitamin A, and glycine levels. Vitamins B1, B6, and D, and selenium, zinc, ammonium, and lactate levels were normal. Her fatty acid profile was also analyzed, and we found decreased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. Given this, our patient was given supplements of these essential fatty acids. Table 1 shows the patient’s metabolic control as measured by blood levels of amino acids and urine levels of methylmalonic acid corresponding to the dates on which perimetric examinations were carried out. However, the clinical condition of our patient notably worsened (4 August 2008) in both visual acuity (RE 0.05, LE 0.5) and perimetry values (MD –19.08 dB RE; –15.67 dB LE) (Fig. 2) as well as progressive pallor of the right disc (Fig. 1). CoQ10 activity on fibroblasts was normal before the treatment (4.2 nmol/min). Levels ranging from 3.4 to 12.7 nmol/min are considered normal. Despite this normal CoQ10 activity, treatment was started (20 November 2008) with 200 mg/day of CoQ10 (Decorene®) and 200 mg/day of vitamin E due to reports in the literature of their beneficial effects as potential neuroprotective agents against neurological damage caused by increased levels of MMA. A stable and clear subjective clinical improvement was observed from 2 weeks after establishing treatment. On 5 December 2008,
Fig. 2 Humphrey perimetry using Swedish Interactive Thresholding Algorithm (SITA) standard strategy and stimulus III. 28 July 2008: MD –16.84 dB, FN 17%, FP 0%, FL 5/13 (RE); MD –18.81 dB, FN 8%, FP 0%, FL 4/12 (LE). 4 August 2008: MD –19.09 dB, FN 0%, FP 0%, FL 0/13 (RE); MD –15.67 dB, FN 16%, FP 0%, FL 0/12 (LE). 5 December 2008: MD –10.52 dB, FN 33%, FP 23%, FL 0/0 (RE); MD –7.20 dB, FN 25%, FP 17%, FL 5/11 (LE). 7 October 2009: MD –14.44 dB, FN 18%, FP 21%, FL 0/0 (RE); MD –8.85 dB, FN 0%, FP 0%, FL 10/11 (LE). RE right eye, LE left eye, MD mean deviation, dB decibels, FN false negative, FP false positive, FL fixation losses
J Inherit Metab Dis Table 1 Metabolic control as measured by blood levels of amino acids and urinary levels of methylmalonic acid Date
Valinea
Methioninea
Isoleucinea
Threoninea
Glycinea
Methylmalonic acidb
29/07/2008 05/12/2008 07/10/2009 Reference values
51 78 96 (74–321)
17 26 28 (7–47)
18 25 40 (34–106)
144 185 199 (102–246)
728 873 1050 (166–330)
2671 4980 7064 (0.2–8.5)
a
Expressed as μmol/L.
b
Expressed as mmol/mol creatinine.
visual acuity was of 0.3 in the RE and 0.8 in the LE, and perimetric examination revealed an MD of –10.52 dB in the RE and –7.20 dB in the LE (Fig. 4). Her Ishihara scores also improved (12/17 RE; 16/17 LE). Treatment was continued, and this clinical improvement remained stable until the patient was last seen 12 months after beginning treatment. On last examination (7 October 2009), visual acuity was 03 In the RE and 08 in the LE, MD was –14.44 dB in the RE and –8.85 dB in the LE (Fig. 2); Ishihara test results remained as 12/17 and 16/17 in RE and LE, respectively, and the visual evoked potential did not change with respect to the previous measurements.
Discussion Although the pathophysiology of optic atrophy in MMA is not well understood, it is suspected to be due to an accumulation of neurotoxic byproducts resulting from the blocking of enzyme activity, which in turn impairs mitochondrial metabolism as well as causing an increase in oxidative stress. These physiological presentations are common characteristics of secondary degeneration in other optic neuropathies of different origin, such as glaucoma and Leber’s optic neuropathy (Williams et al. 2009; Kanaumi et al. 2006). A recent study in patients with organic acidurias found mitochondrial oxidative phosphorylation (OXPHOS) deficiency in both patients with propionic aciduria and MMA (de Keyzer et al. 2009). The impairment of mitochondrial OXPHOS in MMA enhances methylmalonic acid accumulation, which induces lipid peroxidation and a decrease in brain tissue antioxidant reserve. Therefore, free radical formation may be involved in the development of the pathogenesis (Fontella et al. 2000) by altering the polyunsaturated fatty acids that constitute mitochondrial and plasma membranes. CoQ10 is a mobile lipophilic electron carrier of the respiratory chain in the internal membrane of mitochondria. It has an antioxidant role similar to that played by vitamin E. Although a previous attempt to treat an optic neuropathy in a 16-year-old MMA patient with CoQ10 (Williams et al. 2009) failed to improve his visual acuity, this antioxidant,
along with vitamin E, has proved useful to ameliorate optic neuropathies caused by oxidative stress due to the presence of high levels of glutamate or N-methyl-D-aspartate (Nucci et al. 2007; Russo et al. 2008). As described above, our 15-year-old patient suffered from unexplained and sudden bilateral vision loss (Figs. 1, 2) despite having no recent dietary changes to precipitate metabolic decompensation. Moreover, there was no clear trend showing any correlation between the levels of biochemical variables and the loss of visual acuity (Table 1). This clinical presentation is similar to those described by Williams et al. in two MMA patients (Williams et al. 2009). The authors suggested that the clinical symptoms referred to by their patients bore striking resemblance to LHON, in which— despite the presence of the genetic defect—it may be many years before sudden visual loss appears. In addition, our patient’s ocular findings include many characteristics of mitochondrial optic neuropathies (Sadun 2009). It has been suggested that both impairment of oxidative phosphorylation and increased production of free radicals contribute to the opening of the mitochondrial permeability transition pores switching on the apoptotic cascade and inducing cell death. Vitamin deficiency was ruled out as a predisposing factor leading to vision loss because their levels were normal when the patient was referred for neuro-ophthalmic evaluation for the first time. We also considered the possibility of our patient’s optic neuropathy being caused by other conditions, but they were ruled out based on adequate testing and patient’s clinical features. A DNA study revealed absence of point mutations at nucleotide positions 3460, 11778, and 14484, which are generally related to LHON. Based upon these considerations, we decided to start treating our patient with CoQ10 and vitamin E. Although previous studies have found decreased levels of CoQ10 in MMA patients (Haas et al. 2009), the activity of this coenzyme on fibroblasts was within the normal range for healthy individuals. In our case, both substances may have played a neuroprotective role against cell damage caused by free radicals. As previously described, there was a clear visual acuity gain from the time the treatment started. Although spontaneous recovery of optic neuropathies is possible, this phenom-
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enon occurs in cases related to an idiopathic inflammatory etiology, such as demyelination in multiple sclerosis or after a viral infection. Therefore, the results seem to suggest the existence of a relationship between CoQ10 and vitamin E intake and our patient’s visual improvement. Both antioxidants may reduce levels of free radicals, thereby inhibiting activation of the apoptotic cascade and avoiding subsequent cell death. However, we must point out that the improvement showed by our patient may be, at least in part, specific to the individual, bearing in mind a previous case report (Williams et al. 2009) in which the authors did not find such an improvement after treatment with CoQ10 alone. In conclusion, our patient demonstrated a temporal relationship between improvement in vision and administration of CoQ10 and vitamin E. As one prior case report (Williams et al. 2009) did not demonstrate such an improvement after treatment with CoQ10 alone, we suggest that the response may be, to some degree, specific to the individual but also be helped by the addition of vitamin E. Given this, we would recommend additional trials in the setting of optic neuropathies secondary to MMA to clarify the possible beneficial role of these vitamin and coenzyme supplements as neuroprotective agents for optic neuropathies in patients with organic acidemia. Acknowledgement We acknowledge support from O+IKER (Basque Institute for Healthcare Research, Basque Foundation for Healthcare Innovation and Research), Red SAMID (Red de Salud Materno-Infantil y del Desarrollo RD08/0072/0036—Spanish Research Network for Maternal and Child HealtVEPmh and Development).
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