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Respiratory Chain Defects May Present Only with Hypoglycemia

Service des Maladies Métaboliques (F.M., G.T., I.D., D.R., J.-M.S., P.D.), Hôpital Necker Enfants-Malades, Paris 75015, France; Service de Biochemie, Hôpital Bicêtre (A.S., M.B.), Le Kremlin-Bicêtre, France; and Département de Génétique and Institut National de la Sante et del la Recherche Medicale U-393 (I.G., P.R.), Hôpital Necker Enfants-Malades, Paris, France

Address all correspondence and requests for reprints to: Dr. Fanny Mochel, Service des Maladies Métaboliques, Hôpital Necker Enfants-Malades, 149 rue de Sèvres, Paris 75015, France.

	Abstract

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Hypoglycemia occasionally results from oxidative phosphorylation deficiency, associated with liver failure. Conversely, in some cases of respiratory chain defect, the impairment in glucose metabolism occurs with normal hepatic function. The mechanism for this hypoglycemia remains poorly understood. We report here three unrelated children with hypoglycemia as the presenting symptom associated with oxidative phosphorylation deficiency but without liver dysfunction. Two patients had, respectively, complex III and complex IV deficiency and presented with long fast hypoglycemia. During a fasting test, the first patient showed evidence for impaired gluconeogenesis (progressive increase of plasma lactate and no decrease of alanine levels), whereas the second patient appeared to have impaired fatty acid oxidation (hypoketotic hypoglycemia with increased levels of non esterified fatty acids). The third patient presented with both long and short fast hypoglycemia related to complex IV deficiency. The mechanism of hypoglycemia for this patient may have been partly related to GH insufficiency, whereas impaired glycogen metabolism possibly accounted for short fast hypoglycemia. We suggest that hypoglycemia can be the presenting symptom for respiratory chain defects, through the possible reduction in cofactors resulting from oxidative phosphorylation deficiency, and that respiratory chain defects should therefore be considered in the differential diagnosis of hypoglycemia.

	Introduction

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HYPOGLYCEMIA OCCASIONALLY OCCURS in the context of oxidative phosphorylation defects associated with liver failure. However, in some cases of respiratory chain defect, hypoglycemia may be the presenting symptom without any obvious hepatic dysfunction (1, 2).

For the sake of comparison, the causes of hypoglycemia (blood glucose level less than 3 mmol/liter) can be clustered in two groups. The first includes diseases in which synthesis and/or release of glucose is decreased, mostly due to liver involvement, e.g. glycogen storage or glycogen synthesis diseases, impaired gluconeogenesis, or fatty acid oxidation defects. The other group includes endocrine diseases leading to the dysregulation of glucose synthesis, e.g. hyperinsulinism, GH deficiency, or cortisol deficiency. The diagnosis can be achieved after extensive and highly specific testing in a specialized department by collection of clinical parameters as well as redox data, plasma amino acids, urinary organic acids, and hormone level tests during the hypoglycemic episodes. A fasting test, performed in a specialized unit, can be very helpful for the determination of the etiology of the hypoglycemia.

We report here two unrelated children manifesting with hypoglycemia as the presenting symptom of an underlying oxidative phosphorylation defect without hepatic failure. A third patient also presented with hypoglycemia after both short (less than 4 h) and long (more than 8 h) fasts but associated with growth retardation, psychomotor impairment, and facial dysmorphy.

	Case Reports

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Patient 1

She was the first child of healthy, consanguineous, Turkish parents. Pregnancy, birth, and perinatal period were uneventful until 8 months of age when the patient was referred for hypoglycemia (1.8 mmol/liter) and lactic acidosis (bicarbonate: 6 mmol/liter, lactate: 11 mmol/liter) that occurred after a 30-h fast due to acute gastroenteritis. Hypoglycemia was quickly responsive to glucose and bicarbonate infusion. Clinical examination was normal apart from moderate hepatomegaly associated with slight elevation of the hepatic enzymes (aspartate aminotransferase, 60 IU/liter; alanine aminotransferase, 56 IU/liter) but no sign of hepatic failure. Blood glucose, bicarbonate, lactate, and ammonia were normal after glucose infusion, as were the plasma amino acids and urinary organic acids.

The girl is now 7 yr old with normal growth and psychomotor development. Liver, renal, cardiac, and ophthalmologic follow-up did not reveal any impairment. She continues to have a moderate hyperlactacidemia (2–3 mmol/liter) and occasional hypoglycemic episodes after long fasts associated with intercurrent infections. These are readily corrected by glucose infusion.

Patient 2

She was the third child of healthy and consanguineous Lebanese parents. Reduced placental perfusion was noticed during pregnancy, but birth and the neonatal period were uneventful. The first 2 yr of life were marked by recurrent kidney infections, chronic diarrhea, and progressive growth retardation (–2.5 SD) but normal psychomotor development. The first hypoglycemic episode (1.6 mmol/liter) occurred at 2.5 yr after a 15-h fast. Moderate hepatomegaly was noted, whereas standard biochemical tests were normal, including liver function tests. Metabolic investigations (plasma lactate, ammonia, amino acids, and urinary organic acids) were all normal. Because of the persistence of growth retardation and recurrent hypoglycemia after long fasts (more than 8 h), the patient was further investigated at 4 yr of age.

The girl is now 5 yr old with normal psychomotor development. Growth improved after increased caloric intake, despite the persistence of intercurrent diarrhea, likely related to pancreatic insufficiency. A moderate renal tubular problem was recently revealed by low plasma bicarbonate (but normal plasma lactate) and proteinuria. Brain magnetic resonance imaging has shown abnormal signals of the basal ganglia; however, she is asymptomatic. Ophthalmologic and cardiac evaluations remained normal.

Patient 3

He was the first child of healthy, consanguineous, Indian parents. Pregnancy and birth were uneventful. However, clinical examination at birth revealed short stature (–1.5 SD), microcephaly (head circumference at –2 SD), facial dysmorphism, and axial hypotonia. The first year of life was associated with progressive psychomotor and growth retardation (–3 SD). At 10 months of age, clinical examination confirmed facial dysmorphism as well as neurological impairment. Biochemical analyses revealed chronic metabolic acidosis (pH 7.3, bicarbonate: 15 mmol/liter) associated with high plasma lactate (8 mmol/liter) and asymptomatic but profound hypoglycemia (0.8 mmol/liter) after a 4-h fast. Plasma ammonia and amino acids were normal, but analysis of urinary organic acids showed abnormal excretion of lactate and ketone bodies. Hepatic enzymes and creatinine were normal. Elevated calcium (2.7 mmol/liter) and low phosphorus (0.65 mmol/liter) reflected renal tubular dysfunction with loss of phosphate. Skeletal x-rays evidenced poor mineralization as well as delayed bone age. Further investigations including brain magnetic resonance imaging, electroretinogram, visual evoked potentials, heart ultrasounds, and high-resolution karyotype were all normal.

The child is now 6 yr old, with stabilized renal tubular function but severe growth retardation and psychomotor impairment. Despite nocturnal enteral feeding, he has recurrent hypoglycemic episodes after short fasts and was hospitalized twice for hypoglycemic coma after a 12-h fast resulting from infection.

	Materials and Methods

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Biochemical studies

Lactate, pyruvate, ketone bodies, and nonesterified fatty acids (NEFAs) were assayed during hypoglycemia as previously described (3). Plasma amino acids were analyzed by exchange-ion chromatography (4), and urinary organic acids were determined by gas chromatography-mass spectrometry after solvent extraction (5). Plasma insulin was determined by a radioenzymatic method (insulin IMX; Abbott Diagnostic Division, Abbott Park, IL). GH, cortisol, and TSH were measured as described (6). In vitro fatty acid oxidation was tested by measuring tritiated water produced from [9,10 (n)-³H] palmitate and [9,10 (n)-³H] myristate in fibroblasts (7).

Liver (10–20 mg, patient 1) and deltoid muscle samples (120 mg, patient 2) were obtained under local anesthesia at the age of 11 and 21 months, respectively. Muscle mitochondria were prepared according to standard procedures (8). Skin fibroblasts were grown in the presence of 200 µM uridine and 2.5 mM pyruvate (8). Complex I-IV activities as described (8) as well as polarographic studies and the screening for mitochondrial DNA (mtDNA) deletions and mutations (8) were spectrophotometrically measured.

Fasting test

Fasting tests were performed, in a specialized metabolic unit as recommended, for patients 1 and 2 because they presented with long-fast hypoglycemias to determine whether gluconeogenesis or fatty acid oxidation was impaired. After their last meal at 2000 h, the patients were evaluated clinically with simultaneous determination of venous blood glucose every hour and then every 15 min at the predicted time for hypoglycemia. Samples were assayed for plasma amino acids, lactate, pyruvate, NEFAs, and ketone bodies as shown in Table 1. Organic acids were determined in urine collected 6, 12, and 24 h after the initiation of the fasting test.

	Results

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Patient 1

Determination of serum insulin, GH, and cortisol, although hypoglycemic, were normal. The fasting test (Table 1) showed significant proteolysis (progressive increase of the branched-chain amino acids) and lipolysis (increased NEFAs while fasting). However, a progressive increase of plasma lactate occurred while fasting without any significant decrease of alanine levels, indicating impaired gluconeogenesis. The increase of plasma fatty acids was associated with a significant increase of ketone bodies, with plasma NEFAs to ketone bodies ratio around 1, suggesting normal fatty acid oxidation. Urinary chromatography did not show any abnormal excretion of organic acids, and fatty acid oxidation by cultured skin fibroblasts revealed normal activity (data not shown). Therefore, a loading test with iv administration of fructose was performed and showed no abnormality (data not shown). Fructose 1,6-diphosphatase was also measured and revealed normal activity on both lymphocytes and hepatocytes (data not shown).

Because both gluconeogenesis and ß-oxidation were found normal in patient 1, respiratory chain was investigated and detected a complex III deficiency (ubiquinol-cytochrome c reductase) on cultured skin fibroblasts and liver biopsy (Table 2). A deletion in the nuclear gene encoding the human ubiquinone-cytochrome c reductase-binding protein of complex III was identified and confirmed the electron transfer chain defect (10).

Determination of serum insulin, GH, and cortisol, although hypoglycemic, were normal. The fasting test (Table 1) revealed both efficient proteolysis and lipolysis. The decrease in plasma alanine (more than 50%) and lactate levels during fasting suggested normal gluconeogenesis. Conversely, the small increase of ketone bodies, emphasized by the elevated NEFA to ketone bodies ratio, suggested impaired ß-oxidation. Urinary organic acids were normal (data not shown). Plasma acylcarnitine profile was not performed, but fatty acid oxidation by cultured skin fibroblasts was found normal (data not shown).

Therefore, respiratory chain was investigated in mitochondria isolated from patient 2 cultured skin fibroblasts. Abnormal cytochrome c oxidase (COX; respiratory chain complex IV) activity and COX/succinate cytochrome c reductase (respiratory chain complexes II+III) activity ratio indicated a COX deficiency (Table 2). Neither large-scale rearrangement nor common mtDNA mutations were identified (data not shown).

Patient 3

GH insufficiency was suspected because of severe growth retardation and delayed bone age. Insufficient secretion of GH was found on stimulation with ornithine (GH 9 ng/ml, normal > 10) and glucagon (GH 2.9 ng/ml, normal > 10). Very low levels of IGF-I were also measured (31 ng/ml, normal > 100). If the poor nutritional status of our patient partially accounted for reduced IGF-I levels, such values remained abnormally low when adjusted to the patient’s height and supported GH insufficiency. Conversely, basal TSH and cortisol levels were normal. Appropriately low levels of insulin were measured in hypoglycemia, so that hyperinsulinism was ruled out. Metabolic investigations were performed during hypoglycemia that occurred after 3 and 10 h fasting (Table 1). Despite GH insufficiency, we observed a synthesis of NEFAs. The hypoglycemic episodes were associated with significant elevation of ketone bodies correlated to a low NEFA to ketone bodies ratio (<1), consistent with normal fatty acid oxidation. Because plasma lactate levels were chronically elevated and because plasma amino acids, including alanine, were not obtained during hypoglycemia, gluconeogenesis could not be evaluated for this patient. Because patient 3 presented with short fast hypoglycemias, the fasting test was not performed.

Regarding the association of psychomotor delay, facial dysmorphism, renal tubular acidosis, and GH insufficiency, we suspected that an oxidative phosphorylation defect could account for the complex phenotype of this patient. A complex IV deficiency was identified in patient 3 skeletal muscle and cultured skin fibroblasts (Table 2), but neither large-scale rearrangement nor common mtDNA mutations were found (data not shown).

	Discussion

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Genetic defects of oxidative phosphorylation are known to account for a variety of neuromuscular and nonmuscular symptoms in childhood due to the ubiquitous nature of the mitochondrial respiratory chain (11, 12). Hypoglycemia is a symptom frequently encountered in patients with respiratory chain defect but usually associated with liver failure (13, 14, 15, 16). Conversely, impairment of glucose homeostasis, despite normal liver function, has been observed in few cases of respiratory chain defect, but its mechanism remains poorly understood so far (1, 2). Here we report respiratory chain enzyme deficiency in three unrelated children presenting with hypoglycemia as a primary symptom, unrelated to liver dysfunction, drug therapy, or gastric surgery.

In children glucose level regulation is complex because it involves several metabolic pathways, many of them taking place in the liver, and is subject to a number of hormonal regulations (17). During fasting, the maintenance of normoglycemia is primarily dependent on a functional hepatic glycogenolysis (glycogen). After about 6–8 h fasting, an adequate energy supply is provided by gluconeogenesis, using various substrates (lactate, glycerol, and amino acids, principally alanine), and fatty acid oxidation, which includes two main catalyzing steps, i.e. the acyl-CoA dehydrogenase and the 3-hydroxyacyl-CoA dehydrogenase. Lipolysis provides both glycerol for gluconeogenesis and NEFAs further oxidized into acetyl-CoA by the mitochondrial ß-oxidation pathway. Acetyl-CoA is mainly used for the synthesis of ketone bodies that are exported to peripheral tissues and used as an alternative fuel. ATP synthesis resulting from fatty acid oxidation activates gluconeogenic ATP-dependent enzymes, such as pyruvate carboxylase, mitochondrial phosphoenol-pyruvate carboxykinase, or phosphoglycerate kinase. Finally, a normal endocrine system (insulin vs. glucagon, cortisol, GH, and catecholamines) is required for integrating and modulating blood glucose levels (17). Based on the knowledge of the homeostatic mechanisms resulting in normoglycemia, a fasting test is useful to evaluate gluconeogenesis and fatty acid oxidation pathway in those patients whose hypoglycemia occurs after prolonged fasting (>8 h). Because such a test can be risky, particularly in case of a fatty acid oxidation defect, it must be performed in a specialized unit, after checking for baseline urinary organic acids, plasma cortisol, and the blood acylcarnitine profile.

Therefore, after eliminating hormonal defects, patients 1 and 2, who presented with long-fast hypoglycemia, underwent a fasting test (Table 1). The nonuse of lactate and alanine during fasting suggested an impairment of gluconeogenesis for patient 1, presumably responsible in part for the patient’s hypoglycemia. Patient 2 gluconeogenesis was normal. By contrast, fatty acid oxidation was clearly impaired (hypoketotic hypoglycemia and increased NEFAs) despite normal functional investigation on patient 2 fibroblasts.

Interactions between the fatty acid oxidation enzymes and the complexes of the respiratory chain have been largely described. Sumegi and Srere (18) hypothesized the existence of a fatty acid-catabolizing enzyme complex on the matrix surface of the inner mitochondrial membrane, colocalizing with the different complexes of the respiratory chain that would functionally link the two pathways. The binding of complex I with a number of dehydrogenases, including the 3-hydroxyacyl-CoA dehydrogenase (19), was further confirmed by the isolation and characterization of a binding protein (20), linking complex I and the 3-hydroxyacyl-CoA dehydrogenase. This could favor a kinetic compartmentation of a subpool of the matrix pyridine nucleotides with an increased redox turn-over (21).

It was therefore not surprising to observe biochemical and functional abnormalities suggestive of impaired 3-hydroxyacyl-CoA dehydrogenase activity in patients with complex I deficiency (22, 23). In addition, the reoxidation of the flavin adenine dinucleotide (FAD) prosthetic group of the acyl-CoA dehydrogenase is known to require the FAD-linked protein, electron transfer flavoprotein (ETF), which passes reducing equivalents to ETF-ubiquinone oxidoreductase and the respiratory chain at the level of the ubiquinone pool (24). In keeping with this, Parker and Engel (25) successfully purified a macromolecular assembly consisting of acyl-CoA dehydrogenase, ETF, ETF-ubiquinone oxidoreductase, ubiquinone, and complex III, suggesting another ternary complex linking the ß-oxidation and the respiratory chain. Similar to the defective binding of the pyridine nucleotides on complex I, a secondary deficiency in FAD binding was also recently hypothesized as to account for the abnormal metabolic profile evocative of an acyl-CoA dehydrogenase deficiency in siblings with complex II deficiency (26). However, it is not yet understood why patients, like patient 2, with complex IV defects should present with biochemical features resembling those of 3-hydroxy-acyl-CoA or acyl-CoA dehydrogenases deficiencies (27, 28, 29).

The absence of correlation between a given acylcarnitine profile and a specific respiratory chain defect suggests a more general dysfunctioning of the respiratory chain in a number of cases (30), with various cofactors such as nicotinamide adenine dinucleotide (NAD) or FAD, possibly missing for the ß-oxidation’s pathway. Interestingly, fatty acid oxidation defects are also known to possibly result in secondary impairment of the respiratory chain (31). Moreover, as evidenced from the study of patient 1, who presented with a gluconeogenic defect, the connections among the different mitochondrial pathways is even wider. Because most of the gluconeogenic enzymes are ATP dependent (32, 33), the ATP deficiency resulting from any respiratory chain defect is likely to impair gluconeogenesis. However, patient 1 is the first reported patient presenting with a deficiency of gluconeogenesis potentially secondary to a mitochondrial deficiency. The mechanism explaining why one of these two pathways (gluconeogenesis vs. fatty acid oxidation) would be preferentially impaired in respiratory chain deficiencies is still to be determined and might also depend on the moment at which the patient is investigated.

Because of chronically elevated plasma lactate, the mechanism for the hypoglycemia affecting patient 3 is much more complex to understand and is probably partly related to his growth hormone insufficiency. To our knowledge, GH deficiency has been reported twice associated with respiratory chain defects (34, 35). For one patient diagnosed with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (34), a chronic ischemia and energy deficiency of the diencephalon was hypothesized as the cause for the hypothalamic dysfunction. GH is well known to be implicated in glucose metabolism by decreasing glucose use (36), enhancing gluconeogenesis through the protein catabolism, glycogen storage (37), and NEFA release (38) through the induction of lipolysis. However, the mechanisms underlying its glycemic regulatory role remain partially elucidated and still controversial (39, 40, 41, 42, 43, 44, 45). Insufficiency of GH secretion, partly accounting for the reduced fasting tolerance of our patient, is not known to induce short fast hypoglycemia (17). By contrast, a defect in glycogenolysis may be responsible for the short-fast hypoglycemia observed in our patient because GH deficiency was described as possibly associated with impaired glycogenolysis (45). Similarly, oxidative phosphorylation defects may also secondarily impair glycogenolysis through the decrease in NAD, possibly resulting in the inhibition of glyceraldehyde-3-phosphate dehydrogenase and therefore in the accumulation of glucose-6-phosphate (46, 47). In addition, despite the appropriately low levels of insulin that we measured in hypoglycemia, an increased sensitivity to insulin has been reported in GH deficiency (48) and could be implicated in short-fast hypoglycemia.

In conclusion, hypoglycemia could be the primary symptom of oxidative phosphorylation deficiency in the absence of hepatic failure due to impairment of either gluconeogenesis or fatty acid oxidation or glycogenolysis. We suggest that the reduced cofactors, ATP, NAD, or FAD, resulting from respiratory chain defects may interfere with the different pathways involved in glucose homeostasis.

	Footnotes

 
First Published Online March 22, 2005

Abbreviations: COX, Cytochrome c oxidase; ETF, electron transfer flavoprotein; FAD, flavin adenine dinucleotide; mtDNA, mitochondrial DNA; NAD, nicotinamide adenine dinucleotide; NEFA, nonesterified fatty acid.

Received January 4, 2005.

Accepted March 14, 2005.

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