PEDIATRICS Vol. 116 No. 5 November 2005, pp. 1170-1177 (doi:10.1542/10.1542/peds.2004-2407)
Long-term Follow-up of Neonatal Mitochondrial Cytopathies: A Study of 57 Patients
* Metabolic Diseases Unit, Department of Pediatrics, Centre Hospitalier Universitaire Necker Enfants-Malades, Paris, France
Institut National de la Santé et de la Recherche Médicale, Research Units U375 and 30, Paris, France
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objectives. We sought to determine the long-term clinical and biochemical outcome of newborns with mitochondrial cytopathies (MCs) and to identify possible prognostic factors that may modify the course of these diseases.
Material and Methods. Fifty-seven newborns with MCs were identified in a retrospective review (1983–2002). We defined 2 different outcome categories: clinical (neurologic, hepatic, myopathic, and multiorganic) and biochemical (lactate level normalization or initially normal remaining unchanged, decreased but not normalized, and persistently high). We used 2 different statistical approaches: (1) survival studies depending on the initial symptoms and lactate and enzymatic deficiencies using the Kaplan-Meier method; and (2) the same variables compared with different survival age groups and clinical and biochemical outcome categories using the 
2 test.
Results. Thirty-three patients died (57.8%), 12 remain alive (21%), and 12 were lost in the follow-up; 6 of them are currently older than 4 years. Most of the patients manifested multiorganic disease (64.8%) and high lactate level (77.1%) over time. Children surviving to 2.5 to 3 years of age were more likely to survive for a long period of time. Initial neurologic and hepatic presentation increased the risk to develop neurologic disease and severe persistent hyperlactacidemia, respectively. Initial severe hyperlactacidemia and combined enzyme deficiencies were significant risk factors for higher mortality and multiorganic disorders. Two patients with exclusively myopathic outcome are alive and cognitively normal at 12 years of life.
Conclusions. Children with neonatal-onset MCs have very high mortality and poor prospects. However, some with life-threatening presentations may gradually improve, giving rise to less severe diseases. Those with exclusively myopathic symptoms have a better prognosis.
Key Words: long-term follow up • mitochondrial disorders • neonatal morbidity • neonatal mortality • hyperlactacidemia
Abbreviations: C, electron transport chain complex • CPK, creatine phosphokinase • MC, mitochondrial cytopathy
Mitochondrial disorders are considered to be among the most prevalent metabolic diseases. The clinical presentation of these disorders has been widely reported in pediatrics.1–3 The great variety of symptomatology and, in most of the cases, rapidly progressive course are well known because of the major involvement of high-rate aerobic metabolism in most organs. Furthermore, neonatal presentation is quiet common because of the high energy requirements of the growing newborn. Clinical unspecific features such as hypotonia, feeding difficulties, failure to thrive, and seizures are very frequent early-onset presentation symptoms.4
Biochemically, markers such as high levels of plasmatic lactate, pyruvate, and some amino acids such as alanine, proline, and glutamine, as well as raised urinary lactate and other Krebs-cycle organic acid levels, are also well-recognized impaired redox-function features.5
By contrast, relatively little is known about the long-term clinical and biological outcome. A rapid and fatal course is normally suspected in neonatal presentations of these diseases. Nevertheless, no long-term studies have been reported in the literature.
Here we report the clinical and biochemical outcome over a long period of time of a group of patients diagnosed and managed in our hospital. We examined the long-term outcome and its relation with the clinical presentation, with enzymatic deficiency and initial plasmatic lactate level as possible contributing prognosis factors.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients' Characteristics
Fifty-seven patients (30 males and 27 females) with respiratory chain disorders of neonatal onset (age range: 0–30 days; mean: 6.35 days; SD: 8.5 days) were diagnosed at the metabolic unit of the Hôpital Necker Enfants Malades from 1983 to 2002. A suggestive clinical picture associated with high plasmatic lactate level in the majority of cases (50 of 57 [87.7%]; mean: 9.7 mmol/L), abnormal plasma amino acids (44 of 57 [77.1%]) consisting of increased alanine (46 of 57 [80.7%]), proline (23 of 57 [40.3%]), and glutamine (17 of 57 [29.8%]), and abnormal urine organic acids (43 of 57 [75.4%]; consisting of increased lactate level in 43 of 57 [75.4%] and other Krebs-cycle metabolites in 40 of 57 [70.1%]) led us to suspect the diagnosis.
Concerning the clinical symptoms, we mostly found multiorganic presentations. Hypotonia, tachypnea, and feeding difficulties formed the most common pattern of association, followed by neurologic and hepatodigestive symptoms.
Depending on these different presentation types, we established the following clinical categories: multiorganic (53 of 57 [92.9%]); association of hypotonia, tachypnea, and feeding difficulties (25 of 57 [43.8%]); neurologic (21 of 57 [36.8%]); hepatodigestive (15 of 57 [26.3%]); failure to thrive (8 of 57 [14%]); and cardiac (3 of 57 [5.2%]). Most of the patients presenting with cardiac disorders are evaluated and followed in the cardiology unit; therefore, there is a very low proportion of them in our series.
Methods
Lactate level was measured in 1- to 1.5-mL blood samples obtained by venipuncture, avoiding hand exercise before the sampling, and collected in heparinized tubes. From these tubes, 0.5 mL of whole blood that was accurately pipetted was immediately deproteinized and transferred into 1-mL ice-cold perchloric acid (1 mmol/L) tubes. After thorough mixing, samples could be stored at –20°C and thawed immediately before analysis by enzymatic semiautomated methods.
Initial blood lactate level ranged from 1.7 to 25.5 mmol/L (mean: 9.7 mmol/L; SD: 6.65 mmol/L). The following lactate-level categories were defined: normal lactate level (<2.4 mmol/L), 7 patients (12.2%); mild hyperlactacidemia (2.5–2.9 mmol/L), 1 patient (1.7%); moderate hyperlactacidemia (3–5.9 mmol/L), 11 patients (19.2%); and severe hyperlactacidemia (>6 mmol/L), 38 cases (66.6%).
The diagnosis was confirmed by measurements of respiratory chain enzymes in muscle, fibroblasts, lymphocytes, or liver by spectroscopy and polarography. Twenty-four electron transport chain complex (C)I, 12 CI+CIV, 7 CIV, 7 generalized (6 of which were associated with DNA mitochondrial depletion), 3 CII, 1 CIII, 1 CV, 1 CIII+CIV deficiencies, and 1 patient diagnosed on muscle morphology criteria, were observed. We defined 5 enzymatic categories: CI; CI + CIV; CIV; generalized; and others (CII, CIII, CV, CIII+IV, muscle morphology).
Other than mitochondrial DNA depletions, genetic studies only found a mutation in the ATP synthase gene (p8993) in 1 patient. Mitochondrial DNA depletions (depletion range in our patients: 20–75%) were detected by using Southern blot analysis in muscle (4 patients who presented with neurologic and hepatic symptoms), liver (1 patient with liver failure), and heart (1 patient with dilated cardiomyopathy).
Treatment and Clinical Follow-up
All the patients were initially treated with different cofactors (thiamin, riboflavin, carnitine), most of them with bicarbonate (40 of 57 [70.1%]), some of them with a ketogenic diet (3 of 57 [5.2%]), and some others more recently with coenzyme Q10 (3 of 57 [5.2%]). They were visited every 3 months during the first year and every 6 months thereafter. Clinical examination and general biochemical studies (hemogram, glucose, hepatic and muscle enzymes, and renal function), plasma lactate, amino acids, and urinary organic acids were performed systematically in every visit. Ophthalmologic and audiologic evaluations and heart ultrasonography were performed every 6 months during the first year and every 6 to 12 months thereafter. Brain imaging was conducted initially and on clinical demand.
We established the following outcome categories.
Clinical Outcome Categories
- Progression toward neurologic disease.
- Progression toward hepatodigestive disease.
- Progression toward myopathic disease.
- Progression toward multisystem disease.
Biochemical Outcome Categories
- Plasma lactate-level normalization or initially normal lactate level that remained unchanged.
- A decrease but no normalization in plasma lactate level.
- Persistent hyperlactacidemia.
The clinical, biochemical, enzymatic, and outcome characteristics of the patients are shown in Table 1.
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Statistical Analysis
We used 2 different statistical approaches:
- The probabilities of survival depending on the presentation symptoms, the enzymatic deficiency, and the initial lactate-level category were estimated by using the Kaplan-Meier method for univariate analysis, with the difference calculated by using a log-rank test.6 The survival probability as a function of the initial total amount of lactate (mmol/L) was analyzed by using the Cox regression method.
- We described 4 main groups of patients depending on their survival time: (1) those who died during the first 3 months of life; (2) those who died between 4 and 12 months of life; (3) those who died between 1 and 3.9 years of life; and (4) those who survived beyond 4 years of life. We compared these groups as a function of the initial lactate level and clinical presentation, enzymatic defect, and clinical and biochemical outcomes. This analysis was performed by using the 2 test.
Finally, we attempted to relate the clinical and biochemical outcomes of these patients with the presentation symptoms initial lactate and enzymatic deficiency. Comparison between groups was performed by using the 2 test.
We did not perform statistical analysis in function of the different treatments because of a great heterogeneity in therapeutic trials and a short, irregular follow-up in those treated with coenzyme Q10.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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At the time of data collection, 33 patients had died (18 males and 15 females), 12 remained alive (6 males and 6 females), and 12 had been lost in the follow-up. Concerning the 12 patients who were lost, the minimum follow-up from the beginning of symptoms was 30 days (maximum: 3 years; median: 180 days). Regarding the 33 patients who died, the age of death ranged from 2 days to 3 years (median: 90 days). Most of the patients died during the first 3 months (16 of 33), 12 patients from 3 to 12 months, and 7 patients beyond 1 year of life. The 15 patients who were alive at the time of this writing had follow-up ranging from 30 days to 18 years (median: 3.2 years; mean: 5.4 years; SD: 5.4 years): 2 patients younger than 2 months, 4 patients from 1 to 3 years of age, 6 patients older than 4 years whose ages are 4, 5, and 6 years, respectively, 2 patients who are 12 years of age, and 1 who is 18 years (Fig 1).
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Clinical outcome mostly tended toward a multisystem disorder (39 of 57 [68.4%]) followed by neurologic (9 of 57 [15.8%]), hepatodigestive (6 of 57 [10.5%]), or myopathic (3 of 57 [5.2%]) disease (see Table 2 for details).
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Biochemical progression regarding blood lactate level showed persistent hyperlactacidemia in the majority of patients (31 of 57 [54.4%]). Plasma lactate-level normalization and consistently normal lactate levels were found in 13 of 57 (22.8%) patients. The same number of patients had a lactate-level decrease, but it was not normalized.
Survival Studies Using the Kaplan-Meier Method
We found no statistical differences in survival probability depending on the diverse clinical presentation forms (combined, neurologic, hepatic, failure to thrive, cardiac, or multiorganic), the different initial lactate-level categories (normal, mild, moderate, or severe), or the diverse enzymatic deficiencies. We also did not find differences in survival probability depending on the blood lactate-level presentation values (significance of P = .6241) after the Cox regression test. However, we observed a common tendency in all the survival figures (Fig 2): patients who survived beyond 2.5 to 3 years were more likely to remain alive for a long period of time regardless of the initial symptoms, lactate level, or enzymatic deficiency.
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Relation of Clinical and Biochemical Outcome With the Initial Clinical and Biochemical Characteristics Using
2 TestSurvival-Time Category
We found statistical significance when comparing survival-time categories with lactate-level outcome (P < .0005; 2-sided) (Table 3 and Fig 3A). In fact, 21 (87.5%) of 24 patients with persistent hyperlactacidemia died during the first 3 months of life. On the other hand, we also found a positive correlation (P = .0019; 2-sided) with enzymatic deficiency: those patients with CI+CIV deficit and those with generalized deficiency had a clearly shorter survival time (most of them [11 of 12 and 4 of 7 patients, respectively] died during the first 3 months of life).
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Initial Presentation
Initial Symptoms and Clinical Outcome (Comparison Between the Specific Type of Initial Symptoms and the Categories of Clinical Outcome as Described in "Patients and Methods")
Although most of the patients developed a multisystem disorder as they evolved, we could find statistical significance (P = .0017; 2-sided) because of patients later progressing toward a neurologic disease: most of these patients presented initially with symptoms of nervous system involvement (7 of 9).
Initial Symptoms and Lactate Outcome
In general, a notable proportion of the patients had persistent hyperlactacidemia, but we only found clear statistical significance in those who presented with hepatic symptoms (P = .028;2-sided). These newborns always had hyperlactacidemia that was severe and persistent in the majority of the cases (80%) (Fig 3B).
Initial Lactate Level and Clinical Outcome
We found a high proportion of patients (73.6%) presenting with severe hyperlactacidemia and later developing a multiorganic disorder. This finding has a positive statistical significance (P = .0048; 2-sided) (Fig 3C).
Initial Lactate Level and Lactate Outcome
An important statistical significance (P < .0005; 2-sided) was found. In fact, we observed that the lower the initial lactate level, the more the chances of normalizing or decreasing it. On the contrary, severe hyperlactacidemias were more likely to remain at these very high levels.
Enzymatic Deficiency and Clinical Outcome
Patients affected with CI deficiency (82.61%) and CI+IV (83.33%) were inclined to develop multisystem involvement. These results have statistical significance (P = .0006; 2-sided) (Fig 3D).
Enzymatic Deficiency and Lactate Outcome
We did not find statistical significance between these 2 variables (P = .0290; 2-sided).
Description of the Patients Surviving >4 Years
Among patients with evolution to neurologic disease (4, 6, and 18 years of age at the time of this writing), 2 patients (Table 1, patients 3 and 6) presented with severe liver failure, but hepatic function normalized over time (at 9 months and 2 years, respectively) (Table 4). In patient 6 the diagnosis was possible at 17 years of age after a liver biopsy despite the absence of hepatic involvement over a period of 15 years. In this case, a muscle biopsy performed at 2 years of life was normal.
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Regarding patients with evolution to myopathic disease (each 12 years of age, patients 4 and 5), the presentation was severe and life threatening in patient 4 (CI [14 mU/units of citrate synthase; range: 70–250]+CIV [200 mU/units of citrate synthase; range: 810–3120]); furthermore, multiorganic involvement was present during the first 2 years of life, but it gradually normalized, giving rise to myopathic dysfunction only at 3 years of age. At 9 years, electromyography and nerve-conduction studies disclosed signs of anterior horn involvement. This patient now has mild proximal limb weakness (3 of 5) with autonomous motor function and exercise intolerance, slightly elevated muscle enzymes (creatine phosphokinase [CPK]: 245 IU/L; lactate dehydrogenase: 1272 U/L), and growth retardation (height and weight are at –2.5 SD), but brain MRI and cognitive function are normal. Patient 5 presented with feeding difficulties, tachypnea, and hypotonia. Marked limb hypotonia with weak deep reflexes were present from the first months of life. From the first years of life, limb weakness as well as mild bilateral ptosis were present. At 5 years, muscular power was +3/5 in proximal limb muscles. Now, the boy is 12 years old, he has normal intelligence and myopathic face with persistent muscle weakness (+3–4/5) but autonomous gait, Gower's sign, and generalized slowness in physical activities. Delayed bone age and growth-hormone deficiency have also been found.
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This is the first study showing data on the long-term outcome of various types of neonatal-onset mitochondrial cytopathies (MCs). Some reports have described the outcome of isolated cases,7–10 but we have not come across studies of large series in the medical literature, nor have we found a systematic study concerning survival or potential risk factors that could modify the natural course of this type of metabolic disorder starting in infancy. By contrast, data dealing with clinical presentation have been widely reported.1–3,11–13 There are several factors that could explain this lack of information. The high early mortality and the important number of patients that are lost in follow-up are probably the most relevant limiting conditions.
In this series we analyzed different outcome aspects of these patients by using diverse approaches: general description, statistical methods, and detailed medical reports of the oldest surviving patients.
A global overview of this work would highlight some main points. First, found a remarkable mortality rate (33 of 57 [57.8%]) that is especially high in the first 3 months of life (16 of 33 [48.4%]). This finding supports the widespread perception of such disorders as being fatal in the newborn.4 Of our 57 patients, 12 (21%) were lost in follow-up; this fact implies that some censored cases (incomplete observations; the final situation of the patient cannot be evaluated) will constantly appear in our survival statistical analysis. Despite this limitation, most of these patients had been followed for a relatively long period of time, and their information is useful to the results of our study. The other 21% corresponds to the surviving children. Half of them (10.5%) are now older than 4 years (mean: 9.5 years), and 3 are in their second decade of life; among them, only 2 are cognitively normal.
Second, we observed a clear tendency for developing multiple health handicaps in a notable proportion of the patients (68%). Therefore, not only is survival expectance low, but the chances of good outcome are very poor.
Finally, the third general trait that is worth of consideration is the great proportion of patients with persistent high lactate level over time (31 patients with persistent unchanged hyperlactacidemia + 13 patients with a decrease but not normalization in plasma lactate level: 44 of 57 [77.1%]). This fact makes a remarkable difference compared with late-onset mitochondrial disorders, in which lactate level is lower and tends to normalize in a high proportion of patients.14,15
We analyzed these general main features by using different statistical methods to establish possible prognostic factors contributing to the natural course of these disorders.
Survival studies did not disclose significant differences with any selected variable (clinical presentation form, initial lactate level, or enzymatic deficiency). By contrast, we could demonstrate statistical significance when comparing survival-time categories with different variables. This apparent contradiction is a result of the difficulties in analyzing a population with a great age dispersion (from 0 to 18 years at the time of data collection) and 12% of censored cases (patients who were lost in follow-up) by using survival Kaplan-Meier curves. Therefore, this test was not useful for identifying risk factors in our study; however, we could observe that all the survival curves marked a break point around 2.5 to 3 years. In general, children who survived this "critical" age had more probability of surviving for a long period of time. This finding may reflect the strong sensitivity of very young children to an impaired ATP production in a period of time at which energy demands are very high.
We identified different prognostic factors relating initial and follow-up variables. Concerning clinical presentation, we identified neurologic and hepatic symptoms as potential prognostic outcome factors. In fact, in newborns with initial neurologic signs we detected a strong risk to develop an established neurologic illness over time. No other presentation type could statistically predict the clinical outcome. This finding is logical if we consider that many other neonatal symptoms are more likely to regress, because they represent an age-linked manifestation rather than features exclusively caused by the disease. Furthermore, the higher division rate of heteroplasmic cells in other organs can minimize the clinical expression as time passes.16 Obviously, this cannot be the case for the nervous system. On the other hand, initial hepatic symptoms represented a risk factor of persistent severe hyperlactacidemia. Reduced activity of respiratory chain complexes has been associated with liver disease of varying severity; however, neonatal presentation predominates, and one of the key features to be noted is severe lactic acidemia.17–19 CI, CIII, and CIV as well as mitochondrial DNA-depletion syndrome are related to neonatal liver failure presenting with severe hyperlactacidemia.17–25 In our series, CI deficiency and mitochondrial DNA depletion were the most frequent deficiencies.
Regarding initial lactate level, the group of children who did not survive the first 3 months of life had a clear, more persistent and severe hyperlactacidemia with significant differences in relation to the other survival age groups. It is interesting to note that more than one third of patients who die between 4 and 12 months die despite normalizing their blood lactate levels. On the other hand, initial severe hyperlactacidemia indicated a significantly high propensity to develop a multiorganic disease. Therefore, initial lactic acidosis in neonatal MCs resulted in a bad prognosis sign, not only because of the shorter survival expectance but also because of the severity of the disease involving several organs.
If we consider the different type of enzymatic abnormalities, a significantly higher mortality was observed in combined CI+CIV forms and generalized deficiencies in very young children (0–3 months). The severity of generalized deficiencies is well known in different reported cases, above all if they are caused by mitochondrial DNA depletion.26–28 It also has been reported that patients with CI deficiency combined with other defects tend to have a more severe illness when compared with those with isolated CI.29 A fatal infantile multisystemic form of CI deficiency has been described in different articles.30,31 Although many cases of fatal CI were present in our population, this group did not show statistical differences compared with the others.
CI and CI+IV deficiencies in the total population represented, in our study, a negative outcome factor because they evolved toward a multisystemic disease in a high proportion of patients. Nevertheless, this finding could be explained by the important prevalence of these deficiencies in our series associated with the well-known general tendency to develop multiorganic involvement in mitochondrial disorders.
Concerning the 6 oldest surviving patients, only 2 could be considered as having "benign" or "mild" forms because of their normal intellectual level and minor motor limitations without dysfunction of other organs. Other than limitation in some physical activities, these patients can lead a normal life. They are similar in some aspects to the described cases of those with benign reversible muscle cytochrome c oxidase deficiency32–34 but with some discrepancies. In our patients, different degrees of CI deficiency are associated. The great majority of benign mitochondrial myopathies have been related to cytochrome c oxidase deficiency; however, at least 1 case of combined CI and CIII has been described.35 Furthermore, in 1 of them signs of spinal anterior horn involvement are present. Mitochondrial myopathies mimicking early spinal progressive muscular atrophies, although very rare, have also been reported.36,37 Several elements, however, are atypical in our case, such as the late onset and the mild nonprogressive clinical expression.
Regarding the other 4 patients, 1 has a multiorganic disease with persistent severe lactic acidosis, despite which she has a preserved quality of life. This is exceptional, because both features (persistent severe hyperlactacidemia and multiorganic involvement) are theoretically bad prognostic factors. Two patients evolved toward a more common clinical expression in these disorders: neurologic disease manifested as slight-moderate mental retardation and different motor handicaps. Finally, our older patient has a severe encephalopathy. Some aspects of this late case are worthy of consideration. The first is the normalization of severe initial liver failure. We observed a similar phenomenon in other patients in our series. A progressive reversion of liver failure and lactic acidosis was reported previously in a child with liver and mitochondrial DNA depletion38 and in one with cytochrome c oxidase deficiency.39 Second, although liver function tended to normalize over time and the expression of the disease is now exclusively neurologic, the defect was only found in hepatic tissue.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Neonatal MCs have a high early mortality and many chances to develop complex multiorganic diseases or severe encephalopathies over time. Persistent lactic acidosis and combined enzymatic deficiencies are markers of poor prognosis. Some initial symptoms can improve gradually and later normalize, giving rise to less severe forms that, in some exceptional cases, evolve to "benign" forms. Exclusively myopathic outcome is the most frequent "benign" clinical type.
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ACKNOWLEDGMENTS |
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We thank Susana Ochoa from the Fundació Sant Joan de Déu for support with the statistical analysis.
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FOOTNOTES |
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Accepted Jan 21, 2005.
Address correspondence to A. García-Cazorla, PhD, Neurology Service, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: agarcia{at}hsjdbcn.org
No conflict of interest declared.
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