Mucolipidosis IV. Clinical, ultrastructural, histochemical, and chemical studies of a case, including a brain biopsy.

A 7-year-old Ashkenazi Jewish boy with normal early development started to regress at 8 months of age and made no further developmental progress. Corneal clouding was noted at age 10 months. Corneal and conjunctival biopsy at 14 months, cerebral biopsy at 24 months, and fibroblast cultures at 32 months showed lysosomal inclusions, suggesting the storage of lipid-like and mucopolysaccharide-like material. In the brain, dense fluorescent inclusions resembled those in ceroid-lipofuscinosis. Total ganglioside content of white matter was raised, but the pattern was normal. The level of nonlipid hexosamine in the brain was normal. The cornea and conjunctiva contained electronlucent vacuoles resembling those in the mucopolysaccharidoses. Cornea, brain, and lymphocytes contained concentric membranous lamellar structures reminiscent of those in the gangliosidoses. The clinical picture and ultrastructural findings support the impression that this case belongs to a new variant of the mucolipidoses, mucolipidosis IV.     

Infantile Pompe's disease, lipid storage, and partial carnitine deficiency

A diagnosis of infantile Pompe's disease (glycogenosis type II) was made by muscle biopsy on a 6-month-old infant boy seen with hypotonia, weakness, and developmental regression. Histochemistry and electron microscopy revealed a vacuolar myopathy with massive glycoge accumulation associated with increased neutral lipid as demonstrated on Oil Red O reactions. Pleomorphic, hypertrophic mitochondria with distortion of cristae and electron-dense deposits within the matrix were identified. Acid alpha-1,4-glucosidase activity was absent but associated with increased neutral maltase activity and a variable compensatory rise in activity of other lysosomal enzymes. Biochemical studies demonstrated low free carnitine, normal acylcarnitine, increased activity of carnitine palmityl and acyl transferases, and other enzymes of beta-oxidation with the notable exception of low normal beta-hydroxyacyl-CoA dehydrogenase activity. The explanation for the lipid accumulation is uncertain but is likely related to the combination of low carnitine concentration in muscle, low beta-hydroxyacyl CoA dehydrogenase, representing a rate limiting enzyme of beta-oxidation, and nonspecific defective mitochondrial function.     

电子转移黄素蛋白脱氢酶基因突变所致的核黄素反应性脂质沉积性肌病的临床、病理和基因特征分析

目的分析电子转移黄素蛋白脱氢酶(ETFDH)突变所致的核黄素反应性脂质沉积性肌病(RR-MADD)的临床特点、肌肉病理以及血、尿质谱筛查结果和基因突变特点,旨在为早期诊断和治疗提供帮助。方法回顾性分析该院2009年至2019年确诊的15例ETFDH突变所致的脂质沉积性肌病患者的各项资料。结果 15例患者平均发病年龄为(32.1±13.6)岁,均以肢体无力为首发症状,其中四肢起病者占53.3%,双下肢起病者占46.7%。所有患者的肌酶水平均升高;肌电图结果提示80%呈肌源性损害,13.3%为肌源性合并神经源性损害,6.7%结果正常。血、尿质谱的阳性检出率分别为66.7%和22.2%;基因检测提示所有患者存在ETFDH基因不同位点突变,其中单一杂合突变和复合杂合突变各占40%,纯合突变占20%。结论该病以波动性肌无力伴肌酶升高为主要表现,患者应尽快行肌肉病理检查,同时联合血、尿代谢筛查和基因检测有助于RR-MADD患者早期诊断和及时治疗。     

A female infant of mitochondrial myopathy with findings of active necrosis and regeneration of muscle fibers

An 8 year-old female infant with the clinical and pathological characteristics of both progressive muscular dystrophy and mitochondrial myopathy was described. Her maternal cousin had clinical and pathological findings of Duchenne muscular dystrophy (DMD). Since the patient had markedly elevated serum CK and calf muscle hypertrophy, her muscle was biopsied and she was diagnosed as having female DMD at the age of 5 years. She had generalized tonic-clonic convulsions and alternate hemiconvulsions for recent 4 years which brought her our hospital. On admission, she had mild generalized muscle atrophy and weakness predominantly in the proximal limbs. The lactate and pyruvate levels in both serum and cerebrospinal fluid were elevated, but with no metabolic acidosis. Serum CK was elevated to 4464 IU/L. Brain CT and MRI showed the expanding arachnoid cyst in the left middle fossa of cranium. In the biopsied left biceps crachii muscle, in addition to numerous ragged-red fibers, there were active muscular fiber necrosis and regeneration and interstitial fibrosis similar to those seen in progressive muscular dystrophy. Biochemically, no decrease or defect in the respiratory chain enzymes was detected. On electron microscopy, a large number of fibers contained aggregates of giant mitochondria with proliferated complicated cristae. Scattered throughout were necrotic muscle fibers filled with phagocytes and regenerating fibers. This patient had the diagnostic features of mitochondrial encephalomyopathy and progressive muscular dystrophy. We supposed that the patient provided very interesting evidences to study the relationship between mitochondrial myopathy and progressive muscular dystrophy.     

Hepatic involvement in a case of lysosomal glycogen storage disease with normal acid maltase]

A 19-year-old man, who could run only slowly since childhood and who walked on his toes since 12 years of age, noted difficulty in climbing upstairs at 17 years of age. He was admitted to Kyushu University Hospital because of elevated AST, ALT and CK levels. On admission, the liver was palpable two fingerbreadths beneath the right costal margin. A neurological examination revealed a low IQ on WAIS-R, a decreased muscle tonus in his four limbs, moderate weakness of the neck flexor and bilateral tibialis anterior muscles, contracture of the ankle joints, and bilateral pes cavus. The serum CK was elevated to 1,124U/l. Hepatic enzymes, such as AST, ALT, LDH and gamma-GTP were also moderately increased in the sera. A needle EMG disclosed myogenic patterns in the limb muscles. Biopsied biceps brachii muscle showed a mild variation in the fiber size and multiple tiny vacuoles in 5-10% of the muscle fibers. PAS and acid phosphatase were strongly positive in some vacuoles. On electron microscopy, numerous autophagic vacuoles containing glycogen granules were observed. The acid maltase activities were, however, normal in the peripheral blood lymphocytes, the biopsied muscle, and the cultured skin fibroblasts. He was thus diagnosed to have lysosomal glycogen storage disease with normal acid maltase. A histological examination of the biopsied liver revealed the portal and central veins to be slightly sclerotic. In addition, mild fatty changes and frequent nuclear vacuolization were present in the hepatocytes. On electron microscopy, enlarged mitochondria with irregular cristae were also observed. Due to the fact that the cardiac function was well preserved, these hepatic lesions were thought to result from the metabolic abnormalities underlying in this disorder.     

A case of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) with progressive cytochrome c oxidase deficiency

We report a 9 year-old boy with MELAS. High dosed oral thiamine administration and high fat diet induced remarkable neurological and biochemical improvement. His mother had episodic headaches and hemiplegia, probably MELAS. He complained muscle weakness and repeated episodes of vomiting started from 2 years of age. High levels of serum lactate and pyruvate were recognized, but with no metabolic acidosis. He developed generalized muscle weakness, growth retardation, generalized convulsions and stroke-like episodes at 5 years old. Optic nerve atrophy and mental retardation gradually appeared. A muscle biopsy at 5 years old revealed numerous ragged-red fibers with excess accumulation of lipid droplets and glycogen particles. Scattered fibers had no cytochrome c oxidase (CCO) activity representing focal CCO deficiency. An electron microscopy showed markedly increased number of giant mitochondria filled with markedly proliferated complicated cristae. Pyruvate dehydrogenase complex level in the fibroblasts was within normal ranges. Serum carnitine level was normal. With oral administration of thiamine hydrochloride (1000 mg) and high fat diet (60-70%), muscle weakness improved, and lactate and pyruvate levels in the serum reduced to normal ranges, whereas the mental deterioration, muscle atrophy, pes cavus progressed very slowly. He died from cardiac and renal failures at 9 years old. Autopsied muscles showed a marked decrease in cytochrome c oxidase activity (biochemically 12.8% of the normal level), and almost all muscle fibers had no cytochrome c oxidase activity histochemically. The progression of the MELAS was probably in parallel with the decrease in CCO activity.     

A boy with muscle weakness, hypercarbia, and the mitochondrial DNA A3243G mutation

The point mutation in the mitochondrial genome tRNA(Leu_ (A3243G) is associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). We report a boy presenting with respiratory compromise and hypercarbia owing to severe muscle weakness. Historically, he demonstrated idiopathic growth hormone deficiency, retarded bone age, and exercise avoidance. Owing to severe respiratory compromise out of proportion to expected recovery, a metabolic work-up was performed. Muscle biopsy demonstrated abnormal mitochondria structure and heteroplasmic A3243G mutation. Idiopathic growth hormone deficiency and retarded bone age have not been previously reported in MELAS, and these findings delayed testing for mitochondrial disease. This case demonstrates that isolated muscle weakness in the context of other organ system abnormalities should make the investigator consider MELAS. (J Child Neurol 2006;21:77-79).     

Morphologic and chemical biopsy findings in mucolipidosis IV

Based on typical clinical and morphologic features, biopsy findings in an 18-year-old girl afflicted with mucolipidosis IV are reported. She had had corneal clouding since early childhood, psychomotor retardation resulting in severe mental impairment, and pigmentary retinopathy. Biopsies of skeletal muscle, rectum, skin, and lymphocytes revealed by light microscopy increased activity of acid phosphatase and by electron microscopy, membranous and vacuolar lysosomal residual bodies in numerous cells, including striated muscle fibers and lymphocytes. An unidentified lipid was encountered by means of thin-layer chromatography in the muscle biopsy. Thus, skeletal muscle, rectum, skin, and lymphocytes are equally suitable for in vivo morphologic diagnosis of mucolipidosis IV.     

Lysosomal glycogen storage disease with normal acid maltase (Danon) without apparent cardiomyopathy and mental retardation]

A 29-year-old male who had a past history of mild ECG abnormality of arrhythmia at the age of 14 years, was referred to our hospital because of elevated serum creatine kinase (CK) level. He had never been aware of muscular weakness nor cardiac symptoms. Neurological examination revealed normal muscle strength of all extremities except marked back muscle weakness. He had normal intelligence. On laboratory examination, serum AST, ALT, LDH, aldolase, CK and myoglobin levels were elevated. Both lactate and pyruvate levels were normally responded after an ischemic exercises test. Acid maltase activity was normal in white blood cells. A muscle biopsy obtained from rectus femoris muscle revealed vacuolar myopathy with mildly increased PAS positive material. On electron microscopy, there were autophagic vacuoles scavenging glycogen particles and cytoplasmic debris, and sarcolemmal indentation, compatible with the findings of lysosomal glycogen storage disease with normal acid maltase. This patient had unusual clinical features of absent mental retardation and no apparent cardiomyopathy. Accordingly, mental retardation is probably not necessary to see later onset of cardiac muscle involvement.     

Carnitine deficiency: clinical, morphological, and biochemical observations in a fatal case.

A fatal case of carnitine deficiency is described. The patient had intermittent metabolic acidosis, fluctuating hepatomegaly, and progressive muscle weakness since 22 months of age. One of two liver biopsies revealed lipid accumulation in the hepatocytes, and a muscle biopsy at age 5 years showed a lipid storage myopathy. Type 1 fibres were the most severely affected. Satellite and vascular endothelial cells also contained abnormal lipid deposits. Quantitative electron microscopy demonstrated an approximately 50-fold increase in lipid material, and a twofold increase in mitochondria in myofibres. The muscle carnitine level was less than one-seventh of the lowest value encountered in 74 biopsies from non-weak or neuromuscular disease controls. The basic abnormality in this patient is assumed to be a defect in carnitine biosynthesis.     

Mitochondrial disorders and ataxia

Mitochondrial disorders are important causes of progressive ataxia in children. Clinical examination, metabolic studies, imaging studies, muscle biopsies, and mitochondrial DNA studies are required to arrive at a specific diagnosis. There is poor correlation between phenotype and genotype in mitochondrial disorders. Ataxia is a major clinical presentation in Kearns-Sayre syndrome; mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes; myoclonic epilepsy with ragged-red fibers; neurogenic muscle weakness, ataxia, and retinitis pigmentosa; Leigh's syndrome; and coenzyme Q10 deficiency.     

Fatal infantile mitochondrial myopathy due to cytochrome c oxidase deficiency

A case of cytochrome c oxidase deficiency primarily affecting skeletal muscle is described. The child was admitted at 4 weeks due to failure to thrive and examination at that time revealed weakness and hypotonia. His condition deteriorated until at 11 weeks respiratory arrest necessitated artificial ventilation and death occurred at 14 weeks. Biochemical investigation showed lactic acidaemia and generalised aminoaciduria. Histochemical examination of muscle obtained at biopsy showed strong reactions for some oxidative enzymes, but by contrast cytochrome c oxidase could not be detected. Cytochrome c oxidase activity was less than 5% of control values in an extract of fresh muscle. The reduced-minus oxidised absorption spectra of muscle mitochondrial fractions prepared from postmortem tissue showed an absence of cytochrome aa₃ and a partial deficiency of cytochrome b. Ultra-structural examination showed abnormal mitochondria with loss of cristae and an abnormal granular matrix. The family history suggests autosomal recessive inheritance.     

A novel mutation (8342G-->A) in the mitochondrial tRNA(Lys) gene associated with progressive external ophthalmoplegia and myoclonus

We describe a patient who suffered from impaired ocular motility from age 10 years and at 16 years developed ptosis, proximal weakness and progressive fatigability. At 35 years she developed massive myoclonic jerks, and head and distal tremor. A muscle biopsy showed a high percentage of cytochrome c oxidase negative fibers but no ragged-red fibers. A novel heteroplasmic mutation (8342G-->A) was found in the mitochondrial transfer RNA(Lys) gene by single-strand conformation polymorphism screening, followed by sequence and restriction fragment length polymorphism analysis. Approximately 80% of muscle mitochondrial DNA (mtDNA) harbored the mutation, while the mutation was absent in lymphocyte DNA of the proband, as well as of her mother, daughter and a maternal aunt. However, the pathogenicity of the mutation was confirmed by restriction fragment length polymorphism analysis of single muscle fibers, which revealed a significantly greater level of mutant mtDNA in cytochrome c oxidase negative over cytochrome c oxidase positive fibers.     

Muscle glycogen storage disease 0 presenting recurrent syncope with weakness and myalgia

Muscle glycogen storage disease 0 (GSD0) is caused by glycogen depletion in skeletal and cardiac muscles due to deficiency of glycogen synthase 1 (GYS1), which is encoded by the GYS1 gene. Only two families with this disease have been identified. We report a new muscle GSD0 patient, a Japanese girl, who had been suffering from recurrent attacks of exertional syncope accompanied by muscle weakness and pain since age 5 years until she died of cardiac arrest at age 12. Muscle biopsy at age 11 years showed glycogen depletion in all muscle fibers. Her loss of consciousness was gradual and lasted for hours, suggesting that the syncope may not be simply caused by cardiac event but probably also contributed by metabolic distress.     

Mitochondrial DNA deletion in a child with mitochondrial encephalomyopathy, growth hormone deficiency, and hypoparathyroidism

We report an 11-year-old boy with short stature, bilateral ptosis, sensorineural hearing loss, muscle weakness, and endocrine abnormalities. Brain magnetic resonance imaging (MRI) showed a bilateral abnormal signal in the globus pallidus and in the midbrain tegment. Muscle biopsy specimens showed ragged red and cytochrome c oxidase negative fibers, and biochemical analysis of muscle homogenate showed a partial defect of complex I and IV activities of the respiratory chain enzymes. Analysis of mitochondrial DNA by a polymerase chain reaction screening procedure and Southern blot revealed a novel heteroplasmic single mitochondrial DNA deletion of 7.8 kb in different tissues. This deletion was absent in the blood DNA of his mother and brother. This case further expands and confirms the wide clinical spectrum of mitochondrial disorders associated with single large-scale mitochondrial DNA deletions.     

Multicore disease in twins.

Multicore disease in identical twin boys presented in infancy as generalized weakness and torticollis. Motor milestones such as sitting, standing, and running were delayed, although by the age of 6 years marked improvement in muscle strength had occurred. Serum enzymes were normal. Muscle biopsy revealed multifocal areas of decreased oxidative enzyme activity. Ultrastructurally, these areas were characterized by myofilament disruption and Z-band streaming.     

Ergometric and pathologic study of a family with complex I deficiency]

We studied a family with a myopathic form of complex I deficiency with regard to the clinical symptoms, usefulness of the exercise tolerance test with an ergometer for screening of mitochondrial abnormalities, pathological findings in biopsied muscles and genetics. In this family, none of the members had disorders of the central nervous system, such as convulsions, mental deterioration or stroke-like episodes. In the two affected generations, three mothers and three children had mitochondrial abnormalities. Two children were diagnosed as having complex I deficiency. One of them, an 8-year-old girl with normal psychomotor development during infancy, began to experience easy fatigability at about 3 years of age. At the age of 5 years, she experienced respiratory distress and became unconscious. Thereafter, she had similar episodic respiratory problems with lactic acidosis. Ragged-red fibers and respiratory chain enzyme defects were detected in the biopsied muscle. Another child, a 15-year-old boy with easy fatigability but no muscle weakness, had normal respiratory chain enzyme activities and a normal oxysogram: oxygen consumption showed a normal responses when malate and pyruvate were added as substrates for the isolated mitochondria. His muscle pathology revealed rare ragged-red fibers and abnormal subsarcolemmal mitochondrial aggregation. An investigation with an ergometer showed elevated serum lactate and pyruvate levels. Only one mother had muscle weakness and hyper-lactic acidemia. The other two mothers had no muscle symptoms, but abnormal results were obtained with the ergometer.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of motor and sensory polyneuropathy with retinitis pigmentosa and diffuse idiopathic skeletal hyperostosis]

We here report a 53-year-old man who presented with motor and sensory polyneuropathy, retinitis pigmentosa and diffuse idiopathic skeletal hyperostosis (DISH). He had a 15-year history of diabetes mellitus (DM). Visual impairment appeared at 17 years of age. Since age 47, he showed a slowly progressive sensory impairment and muscle weakness of the extremities. On neurological examination, retinitis pigmentosa and severe muscle atrophy, muscle weakness and sensory disturbance of all modalities in the distal portions of all four extremities were observed. Deep tendon reflexes were absent. A plain X-P showed diffuse ossification of the spinal and extraspinal ligaments. The motor nerve conduction velocities were severely reduced and no sensory nerve action potentials were evoked. The CSF examination revealed an increased protein level without pleocytosis. The sural nerve biopsy showed a marked onion bulb formation and a loss of the myelinated nerve fibers, which could not be solely explained by DM. As the phytanic acids levels, beta-lipoprotein, lactate and pyruvate in the sera were within the normal ranges, Refsum disease, Bassen-Kornzweig syndrome and mitochondrial diseases were unlikely in this patient. The presence of demyelinating and axonal polyneuropathy in this patient may have been caused by a common metabolic disturbance which produced both retinitis pigmentosa and DISH.