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Idiopathic lactic acidemia with developmental delay and type 1 muscle fiber atrophy: report of two patients
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BRADEV 0()082
Idiopathic lactic acidemia with developmental delay and type 1 muscle fiber atrophy: report of two patients Ayako
Iso, MD,
Nobuyuki
Murakami,
Toru
Kurokawa,
MD, MD
Hitoshi Yoneyama, and Ikuya Nonaka,
MD,
Shigeru Hanaoka,
MD,
MD
Dit,ision o[Child Neurology. National Center Hospitaljbr Mental, Nervous and Muscular Disorders. National ('enter of Neurology and Psychiato' (NCNP;, Kodaira, Tokyo, Japan Received 9 February 1993; accepted 23 June 1993 Two infants with generalized muscle hypotonia with mild muscle weakness and markedly delayed developmental milestones, had high lactate levels in serum and ccrebrospinal fluid from early infancy. Biochernical and morphologic studies of biopsied muscles disclosed no abnormality except for type ] fiber atrophy, which was quite different from patients with central nervous system involvement with type 2 fiber atrophy. In both patients, the disease was not progressive and lactate levels gradually decreased. Although no metabolic defect was l\mnd, these patients probably shared common pathogenetic mechanism. Kel' words: Idiopathic lactic acidemia: LacLate; Pyruvate; Developmental delay: Type I fiber atrophy
INTRODUCTION Lactic acidemia is seen in a number of different metabolic disorders. Despite detailed morphologic, biochemical and DNA analyses, only a few patients with lactic acidemia are shown to have demonstrable metabolic defects, such as deficiencies in mitochondrial enzymes [1]. All the other patients have no detectable enzyme defects or clinical characteristics of Leigh disease, and they have been tentatively classified as having "idiopathic' lactic acidemia [2,3]. From i980 to 1991, twelve patients, 7 females and 5 males, were referred to our hospital because of central nervous system (CNS) abnormalities associated with high serum lactate levels above 25 mg/dl on at least two examinations. Two patients had cytochrome c oxidase deficiency. In the other 10 patients with the idiopathic lactic acidemia, two patients showed unique features, including myopathic muscle biopsy finding with type I muscle fiber atrophy and a non-progressive course. Since patients with CNS involvement and lactic acidemia usually show type 2 muscle fiber atrophy, these two patients were unusual and probably had a common metabolic defect involving skeletal muscle. Correspondence ad~b'ess: 1 Nonaka, MD. National Center Hospital for Mental. Nervous and Muscular Disorders, NCNP, Kodaira, Tokyo 187, Japan. Fax: (81) (423) 461 749.
384
PATIENTS AND METHODS Patient I
A Japanese girl was noted to have ventricular dilatation on ultrasonographic study at gestational week 28. She was born after 38 weeks gestation by normal delivery and weighed 2,450 g. She remained in an incubator for 10 days because of low birth weight, hypotonia and poor sucking. CT scan of the brain showed biventricular dilatation. Lactate and pyruvate levels were elevated in both serum and cerebrospinal fluid (CSF). She had no relatives with similar clinical symptoms. Developmental milestones were delayed. She smiled at age 3 months and gained head control at 5 months of" age. She had no convulsions, hypoglycemic attacks or developmental deterioration. She was admitted to our hospital at 9 months of age for further evaluation. On admission, she was able to smile, but had little interest in toys and did not roll over. She was hypotonic with mild generalized muscle weakness. Bodyrighting and parachute reflexes were not observed. On laboratory examination, lactate and pyruvate levels were elevated to 34.5 mg/dl (normal: 3.3 14.9) and 3.52 mg/dl (0.30-0.94) in serum, and 48.7 mg/dl and 5.28 mg/dl in CSF, respectively. Blood gas analysis showed normal pH, but base excess (B.E.) was decreased to - 4 . 8 mmol/l. CT and MRI scans showed cerebral atrophy, dilated ventricles, predominantly in Brain & Developmenl, Vol 15, No 5. 1993
the right, and bilateral subependymal cysts. In auditory brainstem evoked responses, only an equivocal 5th wave with a latency of 6.5 ms on 100 dB stimulation was present. Rectus femoris muscle biopsy showed mild variation in fiber size. Type 1, 2A, and 2B fibers comprised 54%, 21% and 25%, respectively. Type 1 fibers ranged from 5 to 25 #m in diameter, averaging 17.5 #m, and type 2 fibers from 10 to 30 #m, averaging 23 #m in diameter, showing type 1 fiber atrophy (Fig. 1A). Ragged-red fibers and strongly succinate dehydrogenase (SDH)-reactive blood vessels [4] were not identified. Enzyme activities of the mitochondrial electron transport system in muscle, and pyruvate carboxylase (PC) and pyruvate dehydrogenase complex (PDHC) in muscle and cultured skin fibroblasts, were within normal limits. No deletions or point mutations at nucleotide pairs 3,243, 3,271 or 8,344 in mitochondrial D N A were found. After vitamin Bi and bicarbonate administration, serum lactate levels decreased slightly. When she was last examined at 22 months of age, she was not able to roll over alone, but moved her extremities more actively and showed no apparent deterioration.
Patient 2 A Japanese girl was born uneventfully at full term with birth weight of 3,400 g. The clinical course was similar to that of Patient 1, including delayed developmental milestones and muscle hypotonia. She had no relatives who had the same symptoms. On admission at 8 months of age, she was mildly hypotonic with mild muscle weakness. Developmental quotient (DQ) was about 55. Lactate and pyruvate levels were elevated to 35.5 mg/ dl and 2.01 mg/dl in serum, and 31.5 mg/dl and 3.61 mg/dl in CSF, respectively. Blood gas analysis revealed a pH of 7.385 and B.E. of - 6 . 5 mmol/1. CT and M R I scans showed moderate cerebral atrophy with dilated ventricles. The visual and auditory brainstem evoked responses revealed no abnormalities. Muscle biopsy specimen obtained from the rectus femoris muscle at 21 months of age showed mild variation in fiber size with type 1 fiber atrophy; type 1 fibers measured from 5 to 30 #m, averaging 20 #m and type 2 fibers from 5 to 35 #m, averaging 25 /tm in diameter (Fig. I B). Enzymes in mitochondrial electron transport system in muscle, and PC and P D H C in fibroblasts were normal. No mitochondrial D N A mutations were detected.
Fig. I. Myopathic muscle change with type 1 fiber atrophy in Patient 1 (A) and 2 (B). Note variation in fiber size, including type 1 (1), 2A (2A) and 2B (2B) fibers. A: ATPase with preincubation at pH 4.6 × 80. B: same at pH 4.2, × 100 Brain & Development, Vol 15, No 5, 1993
385
She sat alone and crawled on her knees at 2 years of age. At 3 years of age, she could neither verbalize meaningful words nor stand up. However, she spoke jargon well and her hypotonia was improved. Both serum and CSF lactate levels were decreased to 20.2 mg/dl and 19.5 mg/dl, respectively.
DISCUSSION Lactic acidemia with CNS and neuromuscular involvement is seen in a number of different conditions which include abnormal metabolism in mitochondria, organic acids, amino acids and glycogen. Leigh encephalomyelopathy, the best example of lactic acidemia, is also heterogenous in its pathogenetic mechanism. Although the underlying mechanism for lactic acidemia is diverse and clinical symptoms differ from disease to disease, psychomotor retardation, failure to thrive and hypotonia are seen in most of these patients. Of 12 patients with lactic acidemia in our hospital, only two had enzyme defects in the mitochondrial electron transport system. On reviewing the literature, Robinson et al. [5] reported that 26 of 40 patients with lactic acidemia had no detectable enzyme defect in cultured skin fibroblasts. According to Tulinius et al. [6], 20 of 50 children with lactic acidemia had mitochondrial disorders, 8 encephalopathy, 4 other rnetabolic disorders, 2 encephalitis, and one had recurrent Reye syndrome-like episodes. Although our patients were initially thought to have well-known mitochondrial enzyme defects, including P D H C deficiency [7], no diagnostic metabolic disorder was found by morphologic and biochemical analyses. The only striking finding in these two patients was type 1 fiber atrophy. Since all patients with CNS involvement and lactic acidemia, including Leigh disease,
386
have predominantly type 2B fiber atrophy [8], type 1 fiber atrophy seen in our patients is probably not a secondarily induced phenomenon. Type 1 fiber atrophy is seen in patients with hereditary neuromuscular diseases, including congenital myotonic dystrophy, and congenital non-progressive myopathies such as nemaline myopathy and congenital fiber type disproportion. Although these two patients had muscle hypotonia, no muscle symptom characteristic of the above named diseases were present. Therefore, the muscle pathology in these two patients does not appear to be due to a hereditary muscle disease, but may reflect a certain primary metabolic defect involving the skeletal muscle. REFERENCES 1. Israels S, Haworth JC, Dunn HG, Applegarth DA. Lactic acidosis in childhood, Adv Pediatr 1976: 22:267 303. 2. Robinson BH, Taylor J, Sherwood WG. The genetic heterogeneity o1" lactic acidosis: occurrence of recognizable inborn errors of metabolism in a pediatric population with lactic acidosis. Pediatr Res 1980; 14:956 62. 3. Tulinius MH, Holme E, Kristiansson B, Larsson NG, Oldfors A. Mitochondrial cncephalomyopathies in childhood: biochemical and morphologic investigations. J Pediatr 199l: l l 9 : 2 4 2 50. 4. Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succihate dchydrogenase-reactive blood vessels in muscles from patients with mitochondria[ myopathy, encephalopathy, lactic acidosis, and stroke-like episodcs. Aml Neurol 1991: 29:601 5. 5. Miyabayashi S, Narusawa K. Clinical biochemical approach for mitochondrial abnormalities: pyruvate dehydrogenase complex deficiency (in Japanese). No to ttattatsu 1987: 19:125 31. 6. Zeviani M. Peterson P, Servidei S, Bonilla E, DiMauro S. Benign reversible muscle cytochrome c oxidase deficiency: a second case. Neurology 1987: 3"/: 64 7. 7. Kuroda Y, Naito E. Congenital lactic acidemia (in Japanese). Tanpakushitsu Kakusan Ko.vo (Tokyo) 1988; 33:657 61. 8. Nagai T, Goto Y. Matsuoka T, Sakuta R, Naito E, Kuroda Y, Nonaka I. Leigh encephalopathy: histologic and biochemical analyses of muscle biopsies. Pediatr Neurol 1992: 8:328 32.
Brain & Development, Vol 15, No 5, 1993
BRADEV 0()082
Idiopathic lactic acidemia with developmental delay and type 1 muscle fiber atrophy: report of two patients Ayako
Iso, MD,
Nobuyuki
Murakami,
Toru
Kurokawa,
MD, MD
Hitoshi Yoneyama, and Ikuya Nonaka,
MD,
Shigeru Hanaoka,
MD,
MD
Dit,ision o[Child Neurology. National Center Hospitaljbr Mental, Nervous and Muscular Disorders. National ('enter of Neurology and Psychiato' (NCNP;, Kodaira, Tokyo, Japan Received 9 February 1993; accepted 23 June 1993 Two infants with generalized muscle hypotonia with mild muscle weakness and markedly delayed developmental milestones, had high lactate levels in serum and ccrebrospinal fluid from early infancy. Biochernical and morphologic studies of biopsied muscles disclosed no abnormality except for type ] fiber atrophy, which was quite different from patients with central nervous system involvement with type 2 fiber atrophy. In both patients, the disease was not progressive and lactate levels gradually decreased. Although no metabolic defect was l\mnd, these patients probably shared common pathogenetic mechanism. Kel' words: Idiopathic lactic acidemia: LacLate; Pyruvate; Developmental delay: Type I fiber atrophy
INTRODUCTION Lactic acidemia is seen in a number of different metabolic disorders. Despite detailed morphologic, biochemical and DNA analyses, only a few patients with lactic acidemia are shown to have demonstrable metabolic defects, such as deficiencies in mitochondrial enzymes [1]. All the other patients have no detectable enzyme defects or clinical characteristics of Leigh disease, and they have been tentatively classified as having "idiopathic' lactic acidemia [2,3]. From i980 to 1991, twelve patients, 7 females and 5 males, were referred to our hospital because of central nervous system (CNS) abnormalities associated with high serum lactate levels above 25 mg/dl on at least two examinations. Two patients had cytochrome c oxidase deficiency. In the other 10 patients with the idiopathic lactic acidemia, two patients showed unique features, including myopathic muscle biopsy finding with type I muscle fiber atrophy and a non-progressive course. Since patients with CNS involvement and lactic acidemia usually show type 2 muscle fiber atrophy, these two patients were unusual and probably had a common metabolic defect involving skeletal muscle. Correspondence ad~b'ess: 1 Nonaka, MD. National Center Hospital for Mental. Nervous and Muscular Disorders, NCNP, Kodaira, Tokyo 187, Japan. Fax: (81) (423) 461 749.
384
PATIENTS AND METHODS Patient I
A Japanese girl was noted to have ventricular dilatation on ultrasonographic study at gestational week 28. She was born after 38 weeks gestation by normal delivery and weighed 2,450 g. She remained in an incubator for 10 days because of low birth weight, hypotonia and poor sucking. CT scan of the brain showed biventricular dilatation. Lactate and pyruvate levels were elevated in both serum and cerebrospinal fluid (CSF). She had no relatives with similar clinical symptoms. Developmental milestones were delayed. She smiled at age 3 months and gained head control at 5 months of" age. She had no convulsions, hypoglycemic attacks or developmental deterioration. She was admitted to our hospital at 9 months of age for further evaluation. On admission, she was able to smile, but had little interest in toys and did not roll over. She was hypotonic with mild generalized muscle weakness. Bodyrighting and parachute reflexes were not observed. On laboratory examination, lactate and pyruvate levels were elevated to 34.5 mg/dl (normal: 3.3 14.9) and 3.52 mg/dl (0.30-0.94) in serum, and 48.7 mg/dl and 5.28 mg/dl in CSF, respectively. Blood gas analysis showed normal pH, but base excess (B.E.) was decreased to - 4 . 8 mmol/l. CT and MRI scans showed cerebral atrophy, dilated ventricles, predominantly in Brain & Developmenl, Vol 15, No 5. 1993
the right, and bilateral subependymal cysts. In auditory brainstem evoked responses, only an equivocal 5th wave with a latency of 6.5 ms on 100 dB stimulation was present. Rectus femoris muscle biopsy showed mild variation in fiber size. Type 1, 2A, and 2B fibers comprised 54%, 21% and 25%, respectively. Type 1 fibers ranged from 5 to 25 #m in diameter, averaging 17.5 #m, and type 2 fibers from 10 to 30 #m, averaging 23 #m in diameter, showing type 1 fiber atrophy (Fig. 1A). Ragged-red fibers and strongly succinate dehydrogenase (SDH)-reactive blood vessels [4] were not identified. Enzyme activities of the mitochondrial electron transport system in muscle, and pyruvate carboxylase (PC) and pyruvate dehydrogenase complex (PDHC) in muscle and cultured skin fibroblasts, were within normal limits. No deletions or point mutations at nucleotide pairs 3,243, 3,271 or 8,344 in mitochondrial D N A were found. After vitamin Bi and bicarbonate administration, serum lactate levels decreased slightly. When she was last examined at 22 months of age, she was not able to roll over alone, but moved her extremities more actively and showed no apparent deterioration.
Patient 2 A Japanese girl was born uneventfully at full term with birth weight of 3,400 g. The clinical course was similar to that of Patient 1, including delayed developmental milestones and muscle hypotonia. She had no relatives who had the same symptoms. On admission at 8 months of age, she was mildly hypotonic with mild muscle weakness. Developmental quotient (DQ) was about 55. Lactate and pyruvate levels were elevated to 35.5 mg/ dl and 2.01 mg/dl in serum, and 31.5 mg/dl and 3.61 mg/dl in CSF, respectively. Blood gas analysis revealed a pH of 7.385 and B.E. of - 6 . 5 mmol/1. CT and M R I scans showed moderate cerebral atrophy with dilated ventricles. The visual and auditory brainstem evoked responses revealed no abnormalities. Muscle biopsy specimen obtained from the rectus femoris muscle at 21 months of age showed mild variation in fiber size with type 1 fiber atrophy; type 1 fibers measured from 5 to 30 #m, averaging 20 #m and type 2 fibers from 5 to 35 #m, averaging 25 /tm in diameter (Fig. I B). Enzymes in mitochondrial electron transport system in muscle, and PC and P D H C in fibroblasts were normal. No mitochondrial D N A mutations were detected.
Fig. I. Myopathic muscle change with type 1 fiber atrophy in Patient 1 (A) and 2 (B). Note variation in fiber size, including type 1 (1), 2A (2A) and 2B (2B) fibers. A: ATPase with preincubation at pH 4.6 × 80. B: same at pH 4.2, × 100 Brain & Development, Vol 15, No 5, 1993
385
She sat alone and crawled on her knees at 2 years of age. At 3 years of age, she could neither verbalize meaningful words nor stand up. However, she spoke jargon well and her hypotonia was improved. Both serum and CSF lactate levels were decreased to 20.2 mg/dl and 19.5 mg/dl, respectively.
DISCUSSION Lactic acidemia with CNS and neuromuscular involvement is seen in a number of different conditions which include abnormal metabolism in mitochondria, organic acids, amino acids and glycogen. Leigh encephalomyelopathy, the best example of lactic acidemia, is also heterogenous in its pathogenetic mechanism. Although the underlying mechanism for lactic acidemia is diverse and clinical symptoms differ from disease to disease, psychomotor retardation, failure to thrive and hypotonia are seen in most of these patients. Of 12 patients with lactic acidemia in our hospital, only two had enzyme defects in the mitochondrial electron transport system. On reviewing the literature, Robinson et al. [5] reported that 26 of 40 patients with lactic acidemia had no detectable enzyme defect in cultured skin fibroblasts. According to Tulinius et al. [6], 20 of 50 children with lactic acidemia had mitochondrial disorders, 8 encephalopathy, 4 other rnetabolic disorders, 2 encephalitis, and one had recurrent Reye syndrome-like episodes. Although our patients were initially thought to have well-known mitochondrial enzyme defects, including P D H C deficiency [7], no diagnostic metabolic disorder was found by morphologic and biochemical analyses. The only striking finding in these two patients was type 1 fiber atrophy. Since all patients with CNS involvement and lactic acidemia, including Leigh disease,
386
have predominantly type 2B fiber atrophy [8], type 1 fiber atrophy seen in our patients is probably not a secondarily induced phenomenon. Type 1 fiber atrophy is seen in patients with hereditary neuromuscular diseases, including congenital myotonic dystrophy, and congenital non-progressive myopathies such as nemaline myopathy and congenital fiber type disproportion. Although these two patients had muscle hypotonia, no muscle symptom characteristic of the above named diseases were present. Therefore, the muscle pathology in these two patients does not appear to be due to a hereditary muscle disease, but may reflect a certain primary metabolic defect involving the skeletal muscle. REFERENCES 1. Israels S, Haworth JC, Dunn HG, Applegarth DA. Lactic acidosis in childhood, Adv Pediatr 1976: 22:267 303. 2. Robinson BH, Taylor J, Sherwood WG. The genetic heterogeneity o1" lactic acidosis: occurrence of recognizable inborn errors of metabolism in a pediatric population with lactic acidosis. Pediatr Res 1980; 14:956 62. 3. Tulinius MH, Holme E, Kristiansson B, Larsson NG, Oldfors A. Mitochondrial cncephalomyopathies in childhood: biochemical and morphologic investigations. J Pediatr 199l: l l 9 : 2 4 2 50. 4. Hasegawa H, Matsuoka T, Goto Y, Nonaka I. Strongly succihate dchydrogenase-reactive blood vessels in muscles from patients with mitochondria[ myopathy, encephalopathy, lactic acidosis, and stroke-like episodcs. Aml Neurol 1991: 29:601 5. 5. Miyabayashi S, Narusawa K. Clinical biochemical approach for mitochondrial abnormalities: pyruvate dehydrogenase complex deficiency (in Japanese). No to ttattatsu 1987: 19:125 31. 6. Zeviani M. Peterson P, Servidei S, Bonilla E, DiMauro S. Benign reversible muscle cytochrome c oxidase deficiency: a second case. Neurology 1987: 3"/: 64 7. 7. Kuroda Y, Naito E. Congenital lactic acidemia (in Japanese). Tanpakushitsu Kakusan Ko.vo (Tokyo) 1988; 33:657 61. 8. Nagai T, Goto Y. Matsuoka T, Sakuta R, Naito E, Kuroda Y, Nonaka I. Leigh encephalopathy: histologic and biochemical analyses of muscle biopsies. Pediatr Neurol 1992: 8:328 32.
Brain & Development, Vol 15, No 5, 1993