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Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy Leigh's Syndrome)

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Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy Leigh's Syndrome) Pediat. Res. 7: 832-841 (1973) Lactate pyruvate carboxylase Leigh's syndrome (encephalomyelitis) renal tubular acidosis Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy Leigh's Syndrome) ALAN B. GRUSKIN, [50] MULCHAND S. PATEL, MICHAEL LINSHAW, ROBERT ETTENGER, DALE HUFF, AND WARREN GROVER St. Christopher's Hospital for Children and Departments of Pediatrics, Neurology, Biochemistry, and Pathology, Temple University School of Medicine, Philadelphia, Pennsylvania, USA Extract Proximal renal tubular acidosis has been observed in two infants who had lactic acidosis associated with subacute necrotizing encephalomyelitis. Reduced renal thresholds for bicarbonate (18-19.2 niM/liter) were found in both, in conjunction with the ability to excrete normal quantities of acid. In order to raise the level of serum bicarbonate, increasing rates of infusion of solutions containing bicarbonate were required, because of a progressive increase in serum lactate from 18 to 54 mg/dl. The infusion of sodium bicarbonate expanded the extracellular space, as measured by an increase in chloride space of 12.9%. Volume expansion was associated with a progressive fall in bicarbonate reabsorption from a maximum of 1.91 to 1.02 mM/100 ml glomerular filtration rate. In addition, the tubular reabsorption of phosphate fell from 80 to 60%, urate clearance increased from 8.7 to 20 ml/min/1.73 m2, lactate clearance increased from 0.23 to 22.9 ml/min/1.73 m2, and chloride excretion in- creased from 0.7 to 3.14 /iEq/min/1.73 m2. At autopsy, reduced activity of renal pyruvate carboxylase was demonstrated for the first time in this disease. Speculation As a reflection of impaired lactate metabolism in subacute necrotizing encephalo- myelitis (SNE), generation of ATP may be reduced in the renal cortex. This reduced supply of energy might be expected to impair reabsorption of normal quantities of filtered bicarbonate; proximal renal tubular acidosis may be the result. The fact that other evidence of proximal tubular dysfunction was not observed in the normohy- drated state further suggests that failure to reabsorb filtered sodium bicarbonate may be the initial abnormality observed when the supply of energy diminishes in the renal cortex. The changes in the chloride space observed during bicarbonate infusions may provide data useful in the interpretation of changes in the renal threshold both for bicarbonate and for other solutes. Finally, it appears that subacute necrotizing encephalomyelitis may include a spectrum of biochemical abnormalities, and that only certain forms may be asso- ciated with renal tubular acidosis. 832 Subacute necrotizing encephalomyelopathy 833 Introduction probably had early SNE because the serum alanine and blood lactate levels were elevated and methylama- One hundred cases of SNE have been reported since lonicaciduria was not found. No beneficial effect oc- the original description of the disease by Leigh in 1951 curred after therapy with biotin and lipoic acid, 10 mg [26]. Affected individuals may appear normal during of each daily. Chemical determinations over the next early infancy. With increasing age, progressive neuro- 17 months revealed a persistent anion gap and hyper- logic involvement is manifested by hypotonia, incoor- lacticacidemia, without hyperchloremia. On several oc- dination, oculomotor palsies, visual disturbances, and casions the urinary specific gravity exceeded 1.016 and regressive behavior. The course is progressive, variable 2+ proteinuria was seen. Glycosuria was never found. in duration, and usually fatal. Pathologic changes in- clude symmetrical necrotizing lesions scattered through- When the patient was 7 months old, the presence of out the basal ganglia, brainstem, cerebellum, and proximal RTA was established. Gradually increasing spinal cord [29]. quantities of sodium bicarbonate, ultimately exceeding 120 mEq/24 hr, were required to maintain the serum A major feature of SNE is the periodic occurrence of CO content of the patient above 18 mM/liter. Neutro- acidosis, which may be associated with increased levels 2 penia did not recur. At 19 months of age there was the of lactic acid. We will describe a child with SNE in rapid development of coma and the patient died whom there was persistent acidosis with a normal within a day. serum lactate level. Following this finding we have At postmortem examination the patient's weight was demonstrated proximal renal tubular acidosis (RTA) 4,050 g. No cardiac defect was found. On light micros- in two subjects with SNE and have examined renal copy the kidneys were not remarkable. Examination of function extensively in one. the brain revealed bilateral scattered areas of enceph- This report will present: (1) the clinical course of alomalacia, with gliosis and neovascularization both patients; (2) the changes of venous lactate in re- throughout the white matter of the cerebellum, hippo- sponse to the administration of bicarbonate; (3) stud- campal gyrus, dentate nucleus, and white matter of the ies of the renal mechanisms involved in the reabsorp- brainstem. tion of urate, phosphate, lactate, sodium, and bicar- MG (SCHC 68-00-230) was a boy born after a full bonate; (4) the changes in transport which occurred as term, uncomplicated gestation. Birth weight was 3,930 a result of expansion of extracellular volume; and (5) g. The parents were well, and unrelated. A male sib- data concerning the renal activity of pyruvate carbox- ling had died at the age of 2 years, with SNE con- ylase. firmed at postmortem examination. On monthly exam- ination our patient's early growth and development Case Reports appeared to be normal. His blood lactate level, exam- SW (SCHC 68-00-538) was a girl born to a 23-year-old ined initially at the age of 7 months, was found to be mother after an uncomplicated gestation of 39 weeks' 56 mg/dl; the serum alanine was 5 mg/dl. Blood-urea duration. Birth weight was 2,670 g and length was 50 nitrogen was 10 mg/dl, serum Na 135 mEq/liter, cm. The Apgar score was 9 at 1 min. Over the next 26 serum Cl 103 mEq/liter, serum K 4.1 mEq/liter, total hr, the child became jittery, hypothermic (92° F), and CO2 17.9 mM/liter, pH 7.26, and PC02 38 mm Hg. He- developed pneumonitis. Recovery followed treatment mogram, urinalysis, blood sugar, electroencephalogram, with intravenous fluids, ampicillin, and kanamycin. and roentgenograms of the skeletal system were nor- The patient did not thrive, and at 6 weeks of age mal. Over the ensuing 2.5 years it was found that the weighed 3,150 g. Studies elsewhere revealed multiple serum bicarbonate level of the patient would fall below urinary colony counts exceeding 105 Escherichia coli, 10 mM/liter unless he was given bicarbonate in excess and the patient was treated with sulfisoxazole. Our of 5 mEq/kg/24 hr. On several occasions his serum studies included blood-urea nitrogen 25 mg/dl, serum chloride exceeded 110 mEq/liter without any evidence Na 138 mEq/liter, serum K 5.3 mEq/liter, serum Cl of an anion gap. On other occasions he had an anion gap exceeding 20 mEq/liter. Over 30 measurements of 105 mEq/liter, CO2 content 16.1 mM/liter, pH 7.25, venous lactate were made. Values ranged from 9 to 62 and PC02 35.5 mm Hg. Blood lactate levels ranged from 25 to 140 mg/dl (normal <30 mg/dl). Neutropenia mg/dl. was found. The diagnosis of a variant of hyperglycine- During his 2nd year of life the patient stopped grow- mia was considered, but it was felt the subject more ing and developed progressive neurologic impairment. 834 GRUSKIN ET AL. He received thiamine and lipoic acid therapy, the de- dose of inulin and 2% p-aminohippurate (PAH) in tails of which are reported elsewhere [19]. No major 0.9% NaCl, sufficient quantities of both were adminis- therapeutic response occurred. tered to maintain the blood level of inulin at 50 mg/dl The patient was first shown to have proximal RTA and of PAH at 1-3 mg/dl. After the control specimens at the age of 12 months, and a more detailed evalua- were obtained, bicarbonate was added to the infusion tion of his renal function was made at 32 months. and no further chloride was given. Three separate in- Roentgenograms did not at any time show evidence of fusion rates were utilized: 3.3 ml/min/1.73 m2 until rickets. There was gradual clinical deterioration; the urinary pH exceeded 6.1 (the corresponding serum death came at 38 months of age. bicarbonate value defines the renal threshold for bicar- Postmortem examination of the brain revealed nu- bonate); 6.2 ml/min/1.73 m2 after the threshold was merous punctate areas of red and gray softening scat- ascertained; and 13.2 ml/min/1.73 m2 when it became tered throughout the nuclear structures of the central apparent that the rate of rise of serum bicarbonate was neuronal axis, from the head of the caudate nucleus inadequate to reach levels at which tubular maximum rostral and/or caudad to the lower cervical spinal (Tm) for bicarbonate can be measured. Blood samples cord. The largest lesion almost totally destroyed the were obtained at 20-30-min intervals, and midpoint putamen and extended into the adjacent globus palli- serum levels were calculated by interpolation for each dus, thalamus, and amygdala. The subthalamic nu- urine collection period. cleus and substantia nigra were extensively involved. The mammillary bodies were spared. Numerous le- Laboratory Methods sions were present in the central nuclear structures of Blood pH was measured at 38° with an IL pH meter the midbrain, pons, and medulla. The dentate nucleus [40]. Urine pH was measured at 25° with a Corning was totally destroyed. The gray matter was involved, pH meter [41] and subsequently corrected for body especially in the anterior horns of most of the cervical temperature.
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