Neonatal respiratory insufficiency due to centronuclear myopathy

Two neonates showing generalized hypotonia, weakness of limbs, trunk, and oral musculature died because of muscular respiratory distress. The diagnosis of centronuclear (or myotubular) myopathy was established by histological and histochemical techniques. The genetic situation and routine laboratory data including electromyography were compared with similar cases in the literature; findings were inconclusive with respect to this diagnosis. These results indicate the need for a muscle biopsy and the use of histochemical stainings and/or electronmicroscopical investigation for a proper diagnosis in hypotonic newborns under respiratory distress after exclusion of etiologies other than neuromuscular diseases. Still the diagnosis of centronuclear myopathy in a neonate does not allow a precise prognosis. Increased awareness of this disorder and adequate diagnostic workup is needed in order to extend our understanding and to clarify the prognosis.     

X-Linked Myotubular Myopathy: A Case Report of Prenatal and Perinatal Aspects

Nine families have been reported in which male newborns presented with X-linked myotubular (centronuclear) myopathy. Little is known about the biochemical basis of this disorder or about its natural history in utero. We report a family in which an infant with myotubular myopathy presented in utero with polyhydramnios, poor fetal movement, and feta cardiac arrhythmias. Shortly after birth.the infant died from severe respiratory insufficiency. Gas chromatography-mass spectrophotometry for serum organic acids showed a large octanoic acid peak, but total acyl-Gao dehydrogenase activities in liver were normal. The maternal family history was significant for two perinatal male deaths. Postmortem examination revealed generalized muscle wasting, cardiac enlargement, cryptorchidism, and flexion contractures. Examination of muscle showed numerous fibers that had enlarged, centrally located nuclei and perinuclear clear zones. The muscle fibers were hypotrophic and predominantly of type I. Biopsy specimens of the muscles of the mother and maternal aunt had increased numbers of centrally located nuclei. Neurologic examination was normal. The case demonstrates the typical clinical course, pathology, and family history of severe X-linked myotubular myopathy. In addition, it confirms the reported detection of fetal cardiac arrhythmias and documents what may be an abnormality in fatty acid oxidation.     

肌肉、周围神经与皮肤病理检查对儿童神经肌肉病的诊断价值

目的 探讨肌肉、周围神经与皮肤活检在儿童神经肌肉病诊断中的价值。方法 对1999年1月至2004年12月在我科接受肌肉、周围神经与皮肤活检术患儿的临床资料进行回顾性分析。结果 102例患儿中82例接受肌肉活检,33例明确诊断,包括肌营养不良13例,炎症性肌肉病4例,先天性中央核肌肉病2例,空泡性肌肉病1例,线粒体肌肉病8例,脂肪累积性肌肉病1例,糖原累积性肌肉病1例,脊肌萎缩症3例。25例为非特异肌肉病理改变。24例肌肉活检未见异常。23例接受腓肠神经活检,9例诊断为遗传性运动感觉神经病,1例为异染性脑白质营养不良伴周围神经受累,11例为非特异性周围神经髓鞘或轴索病变,2例未见异常。8例接受皮肤活检,2例诊断为神经元蜡样质脂褐质沉积症,1例为婴儿神经轴索营养不良,1例为空泡性溶酶体病,4例皮肤活检未见异常。结论 肌肉、周围神经与皮肤活检对明确儿童神经肌肉病的诊断具有重要价值。     

Danon disease with typical early-onset cardiomyopathy in a male: focus on a novel LAMP-2 mutation

Abstract:  We report a case of a 16-yr-old male with Danon disease caused by a novel mutation in the LAMP-2 gene. Mutations in the LAMP-2 gene result in the absence of LAMP-2 on immunohistochemical staining of muscle tissue, thus defining Danon disease, a rare X-linked myopathy. It is characterized clinically by HCM or left ventricular hypertrophy, a WPW pattern on ECG, variable degrees of muscular weakness (skeletal myopathy), mental retardation, and retinal changes. The patient presented with severe skeletal muscular weakness and respiratory failure. He also had a history of two OHTs, the first one for severe HCM and the second for allograft rejection. The patient's myopathy was initially presumed to be exclusively related to steroid-induced "critical care myopathy." However, further evaluation with a thigh muscle biopsy revealed autophagic vacuoles with sarcolemnal features suggestive of a lysosomal storage disorder. DNA analysis ultimately identified a previously unreported hemizygous IVS6+3_+6delGAGT splice site deletion mutation in the LAMP-2 gene located within the 5' splice site of intron 6, consistent with Danon disease.     

Severe neonatal asphyxia due to X-linked centronuclear myopathy

Severe neonatal centronuclear myopathy is inherited as an X-linked condition characterized by primary asphyxia, extreme muscular hypotonia and absent spontaneous movements. We report seven cases from three families to point out the importance of diagnosis with regard to prognosis, outcome and genetic counselling. In hypotonic diseases, analysis of cerebrospinal fluid, electromyography, nerve conduction velocity creatine kinase and a skin biopsy for fibroblast cultures for metabolic investigations are usually carried out. Needle muscle biopsy is an additional valuable investigation to establish diagnosis. In all our patients we found an increased number of centrally located nuclei with perinuclear halos confirming the diagnosis of centronuclear myopathy. The diagnosis of this disorder will become of greater importance as soon as carrier detection and prenatal diagnosis by DNA-technology are routinely available.     

Neonatal nemaline myopathy presenting with multiple joint contractures

A sporadic case of the rare and most severe neonatal form of nemaline myopathy is reported. Intrauterine manifestation included reduced fetal movements and breech position with a normal amount of amniotic fluid. After delivery by Caesarian section at 34 weeks of gestation the infant boy, who was not asphyctic, failed to establish spontaneous breathing and required immediate intubation and ventilation. Marked muscular hypotonia and weakness persisted and reflexes remained absent. Hip dislocation, joint contractures, absent palmar creases, prominent lateral palatal ridges and cryptorchidism were interpreted as consequent to prenatal paralysis. The boy died after 5 h due to hyaline membrane disease and meconium aspiration. At autopsy the skeletal muscles were found to be hypoplastic. The muscle fibres contained numerous rods, a typical finding of nemaline myopathy.Nemaline myopathy should be considered in fetuses and newborns with multiple joint contractures, severe muscular weakness and respiratoy insufficiency.     

Myopathy and neurogenic muscular atrophy in unexpected cardiopulmonary arrest

Background: Neuromuscular disorders can be the cause of sudden death of infants because of their weakness and gastroesophageal reflux (GER). Methods: Muscle biopsy and genetic studies were performed by usual method. Results: In this report four cases of infants with neuromuscular disorders (two cases of congenital myopathy and two cases of spinal muscular atrophy) who had unexpected cardiopulmonary arrest on arrival (CPAOA) are presented. Two of the cases did not show any symptoms, such as muscle weakness prior to CPAOA. The diagnosis was based on the results of the muscle biopsy and genetic examination. Conclusion: These results suggest that sudden infant death caused by neuromuscular disorders should be considered.     

Mutation studies in X-linked myotubular myopathy in three Indian families

Congenital myopathies are a group of genetic disorders characterized by generalised muscle hypotonia and weakness of varying severity. They are distinct entities and do not include muscular dystrophies, metabolic myopathies and mitochondrial disorders. Myotubular myopathy is a rare sub type within this group of disorders. Clinical differentiation of the various types is difficult and requires muscle biopsy with histopathological and immunohistochemical studies for specific diagnosis. Gene studies are a prerequisite for genetic counseling adn prenatal diagnosis. Here presented three cases of X-linked myotubular myopathy in three Indian families where the diagnosis was established by mutation analysis in the MTM1 gene in all, and supported his histopathology in two. All three families had history of previous male neontal deaths with similar complaints. Molecular analysis revealed hemizygous mutations in the MTM1 gene including c.1261-10A>G in case, 1, c.70C>T (R24X) in case 2, and a previously unreported mutation, c.924_926delCTT(p. F308del), in case 3. Genetic counseling was performed regarding the X-linked inheritance, their 50% risk of recurrence in boys in subsequent pregnancies, and a feasibility of prenatal diagnosis. This is the first report of cases of X-linked Myotubular myopathy from India.     

Central core disease

Central core disease is a congenital myopathy characterized by generalized hypotonia, muscle weakness and presence of central cores on muscle biopsy. It generally presents during infancy. It is familial with autosomal dominant inheritance [Chromosome 19q13.1; Gene Locus RyR1 (Ryanodine receptor gene)]. We report here two cases of central core disease in a 3-year-old male child and 8 year old female child.     

Neonatal muscular manifestations in mitochondrial disorders

During the last decade rapid development has occurred in defining nuclear gene mutations causing mitochondrial disease. Some of these newly defined gene mutations cause neonatal or early infantile onset of disease, often associated with severe progressive encephalomyopathy combined with other multi-organ involvement such as cardiomyopathy or hepatopathy and with early death. Findings suggesting myopathy in neonates are hypotonia, muscle weakness and wasting, and arthrogryposis. We aim to describe the clinical findings of patients with mitochondrial disease presenting with muscular manifestations in the neonatal period or in early infancy and in whom the genetic defect has been characterized. The majority of patients with neonatal onset of mitochondrial disease have mutations in nuclear genes causing dysfunction of the mitochondrial respiratory chain, leading to defective oxidative phosphorylation.     

Metabolische Myopathien

In addition to structural abnormalities of muscle, inborn errors of metabolism can be responsible for muscular disease. Symptoms of metabolic myopathies are muscular pain and/or weakness. They can become symptomatic at any age. As the energy demand of skeletal muscle for contraction is high, disorders of energy metabolism can often cause clinical symptoms of muscle disease. Disorders of fatty acid oxidation, of the citric acid cycle, of pyruvatedehydrogenase complex or of the mitochondrial respiratory chain can all lead to muscular symptoms. In the initial phase of fast twitch the muscle relies on its own glycogen reserves for energy supply, as vasodilation is not yet adequate to supply enough fuel and oxygen. Therefore, some glycogen storage diseases can also lead to myopathy (glycogenoses type II, type III, types V–VII). Some inborn errors of metabolism primarily affect other organs, but secondary involvement of skeletal muscle is also possible in these.     

Diaphragmatic paralysis due to spinal muscular atrophy. An unrecognised cause of respiratory failure in infancy?

An unusual form of spinal muscular atrophy presenting with respiratory failure was observed in four infants from two families. In one, whose death was attributed to pneumonia, the diagnosis was inferred retrospectively after two siblings died from an identical illness and were shown to have diaphragmatic paralysis and the typical electrophysiological and histological features of spinal muscular atrophy. Other signs of skeletal muscular weakness were absent or inconspicuous. The fourth, unrelated infant presented in an identical way but has survived for over a year on a ventilator. Two months after the onset of respiratory paralysis, more extensive skeletal muscular weakness was seen. Other infants, dying of unexplained respiratory illness, may have this disorder and some may be included in the miscellany of disorders that constitute the sudden infant death syndrome.     

Congenital muscular dystrophy with laminin-a2 deficiency in early infancy: diagnosis and long-term follow-up

Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders characterized by muscle weakness and hypotonia at birth or within the first few months of life. It is inherited in an autosomal recessive pattern. About half of the patients have a deficiency of the alpha-2-chain of laminin (merosin). We describe a case of congenital muscular dystrophy in an infant with laminin-a2-chain deficiency, which appeared hypotonia in early infancy. Diagnosis was made by clinical features and the histological and immunohistochemical studies on muscle biopsy.     

线状体肌病1例报告并文献复习

目的 探讨线状体肌病的临床、病理特点和目前相关研究.方法 分析1例线状体肌病患儿临床表现、病理活检、电镜超微结构观察并结合文献复习.结果 患儿5岁时出现双下肢无力,病情进展缓慢,近端肌和远端肌均有受累.血清酶学正常,肌电图示所检肌肉无自发电位,神经传导均有不同程度异常.肌肉病理改变为肌纤维萎缩变细小,间质有少量纤维组织及脂肪细胞增生取代萎缩消失的肌纤维,肌纤维横纹清晰可见,无炎症细胞浸润.超微结构观察:核旁肌纤维中可见线状体,肌纤维呈灶性断裂缺失,肌纤维间隙增宽,肌萎缩,线粒体基本正常,未见线粒体内出现类晶体物,肌原纤维损害,肌丝溶解融合不清,部分局部可见肌节受挤压而排列紊乱或消失.通过电镜观察,结合临床,诊断为线状体肌病.结论 肌肉病理活检是确诊线状体肌病的唯一方法,而电镜为最后诊断该病的先决条件.     

Muscular magnetic resonance imaging for evaluation of myopathies in children

BACKGROUND: Myopathies present with a broad diagnostic spectrum which may ultimately require muscle biopsy. MRI has been established as a non-invasive method in diagnosing adult myopathies; not only does MRI reveal characteristic findings which point in a diagnostic direction, but also aids in determining optimal biopsy sites and controlling therapeutic interventions. Muscle MRI is increasingly finding application to pediatric myopathies, especially dystrophies and myositides. The following paper serves to illustrate the use of MRI using exemplary clinical vignettes. PATIENTS/METHODS: From 1999 until 2006, 180 children with myopathies of unknown aetiology, ages 10 months to 18 years, were examined with a standardised MRI protocol (axial T1-SE and T2-weighted TIRM sequences). The protocol included imaging of the lower extremities whereas sequences displaying the upper extremities were only acquired in selected patients. Furthermore, intravenous contrast agent was only administered in selected children. RESULTS: All investigations could be performed without sedation due to an examination time of 12 to 15 minutes. The illustrated cases of limb-girdle muscular dystrophy, Duchenne's muscular dystrophy, dermatomyositis, pyomyositis, and chronic neurogenic disease with secondary myopathy all showed disease-characteristic MRI patterns which substantially helped to reach the ultimate diagnosis. CONCLUSIONS: Muscle MRI is a non-invasive and effective instrument in helping to diagnose pediatric myopathies of unknown aetiology. It may facilitate muscle biopsy and serves to control therapeutical effects and disease course. Furthermore, muscle MRI may be applicated even to children of less than 4 years of age without sedation.     

Glycogen storage disease,Fanconi nephropathy,abnormal galactose metabolism and mitochondrial myopathy

We present a 4-year-old male suffering from profound muscular weakness, enzymatically undefined glycogen storage disease. Fanconi nephropathy and impaired galactose utilization. Distorted mitochondria, intramitochondrial fat droplets and partial deficiencies of pyruvate dehydrogenase complex, succinate: cytochrome c oxidoreductase, and cytochrome c oxidase have been found in muscle tissue. The causal relationship between mitochondrial myopathy, glycogen storage disease, Fanconi nephropathy and impaired utilization of galactose is discussed.     

Muscle weakness as presenting symptom of osteogenesis imperfecta

A young boy presented with severe muscle weakness of his legs at the age of 2 years. Muscle morphology and computer tomography imaging findings were compatible with a metabolic myopathy. Additional investigation showed an osteopenic skeleton and signs of healing fractures. A skin biopsy showed an abnormal electrophoresis pattern of collagen, consistent with a variant of osteogenesis imperfecta. The patient improved with intravenous treatment with pamidronate.     

先天性肌型比例失调的诊疗进展

先天性肌型比例失调是一种罕见的先天性肌病.临床表现为儿童早期起病的相对静止的全身肌无力,伴或不伴眼球运动障碍、面肌无力、吞咽障碍、呼吸肌无力等.确诊主要依据特征性肌肉病理改变,即Ⅰ型肌纤维显著小于Ⅱ型且不伴有其他特异性改变.关于此病能否作为独立的临床诊断一直存有争议.但近年来许多致病基因陆续被发现,如TPM3、ACTA1、RYR1等.因此,目前大多数学者仍支持保留先天性肌型比例失调的临床诊断.该文主要就先天性肌型比例失调的临床、病理、基因诊断、基因型和表型相关性及治疗进展进行综述.     

HIV with Juvenile Dermatomyositis

Dermatomyositis with HIV infection has been very rarely reported. The authors report an 8-y-old boy who presented with skin rashes and edema, muscle weakness and polymicrobial infection along with mild immunosupression. Diagnosis of dermatomyositis was established by raised enzymes, suggestive MRI and muscle biopsy findings. Child responded to systemic steroids and low dose weekly methotrexate.