What's new in neuromuscular disorders? The congenital myopathies.

The congenital myopathies are a heterogeneous group of early-onset neuromuscular conditions with characteristic findings on muscle biopsy, comprising central core disease, minicore myopathy (multi-minicore disease), nemaline myopathy and myotubular myopathy. Recent years have seen genetic resolution of a proportion of these conditions. The following review summarizes recent genetic findings in the congenital myopathies and outlines implications for our understanding of their pathophysiological basis and their relation to other neuromuscular disorders.     

Clinical variability of congenital myopathy with type I fiber atrophy: A long-term observation of three cases

The variable clinical courses of three cases of congenital fiber type disproportion (CFTD) over a period of 10 years are presented. All showed improvement in early childhood, but subsequently, varying degrees of deterioration were noted: specifically, marked deterioration in case 2 and decreased muscle strength in case 3. Maximal motor function levels were attained differently among the cases. Histological findings included type 1 fiber hypotrophy and increased internal nuclei in common in all cases. Fine structural changes, such as patchy areas of myofibrillar degeneration, were noted in cases 1 and 2 (second biopsy), and cytoplasmic bodies were seen in case 2 (second biopsy). Myotubes were noted in case 3. The degree of cyto-architectural changes did not correlate with clinical severity. The heterogeneity of CFTD is also discussed.     

Is there a relationship between Helicobacter pylori infection and erosive reflux disease in children?

Aim:  The aim of this study was to investigate the relationship between Helicobacter pylori infection and erosive reflux disease in children.
Methods:  A total of 206 children [mean age 8.4 ± 4.9 (0.16–18) years] who underwent diagnostic upper endoscopy were tested for H. pylori infection between 2002 and 2005 and the relationship between H. pylori infection and gastro-oesophageal reflux disease was investigated retrospectively. Endoscopic and histopathological findings were examined retrospectively. When reflux-related oesophageal damage was identified as a result of the histological examination of endoscopic biopsy samples collected from distal oesophagus, the patients were diagnosed with gastro-oesophageal reflux disease and divided into two groups: those with macroscopic erosions or ulceration constituted the erosive oesophagitis group; those without constituted the non-erosive reflux disease group.
Results:  Prevalence of H. pylori infection was 31.3% in the patients with gastro-oesophageal reflux disease and 36.7% in the control group (p > 0.05). Prevalence of erosive oesophagitis was found to be 23.8% in the patients with H. pylori infection and 41.3% in those without (p > 0.05).
Conclusion:  No negative significant association was found between the prevalence of H. pylori infection and erosive oesophagitis. Presence of H. pylori infection did not influence the severity of oesophagitis either.     

Oculocutaneous albinism associated with motor neuron disease

The patient described is a 14-year-old girl who suffered from an oculocutaneous albinism. The developmental milestones were reached with some delay. Gradually she experienced fatiques, and wasting of the pelvic girdle muscles and weakness appeared. In suralis nerve biopsy sections no abnormalities were found. In muscle biopsy sections the characteristic findings of a primary central neuronal muscular atrophy were seen. Based on clinical and histopathological findings it may be stated that the patient is suffering from a motor neuron disease. The chance of the combined occurrence of oculocutaneous albinism and motor neuron disease can be estimated to be one out of 750 X 10(6), unless an incestuous relation is supposed.     

Familial cases of Henoch-Schönlein purpura in eight families

Abstract Background : Familial cases of Henoch‐Schönlein purpura (HSP) have rarely been reported. Methods : Familial cases of HSP were reviewed by medical records of 418 children with HSP. Results : Two members developed HSP in eight families. HSP occurred in a mother and her daughter in one family and in siblings, including one pair of twin sisters, in seven other families. Four pairs of patients developed HSP at the same age. Three pairs presented HSP within 1 month of each other and the other pairs presented HSP between 9 months and 5 years. Seven patients had a history of allergic diseases. The clinical courses of 12 patients were reviewed. Upper respiratory tract infection preceded HSP in 10 patients, two of whom had elevated antistreptolysin‐O titers. No pairs of patients in a family received the same drugs before the onset of HSP. Abdominal pain was noted in eight patients, arthralgia in six and nephritis in four. Severity of skin lesions, presence of abdominal pain and nephritis, and serum IgA levels at the acute stage varied among family members of HSP. Conclusions : The incidence of HSP in family members of children with HSP seems to be high. Onset at the same age and onset of HSP within 1 month in siblings have not previously been reported. There were no characteristic or similar findings between two patients of the same family. No trigger or genetic factor causing HSP was identified.     

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.     

A retrospective study of patients with the hereditary syndrome of congenital cataract,mitochondrial myopathy of heart and skeletal muscle and lactic acidosis

The objectives of this study were to describe the course of two forms of an hereditary syndrome characterised by congenital cataract, mitochondrial myopathy of heart and skeletal muscle and lactic acidosis. We also sought to determine clinical, physicochemical and histopathological data which might allow early distinction between the two forms. We compared the ages at which clinical and physicochemical signs appeared in 16 patients. In 5 patients, enzyme-histochemical and ultrastructural data of skeletal muscle were available and muscle fibre composition analysed morphometrically. In any particular family only one form of the syndrome occurred. Amongst the patients who did not survive (range 14–34 years) 4 patients died in the neonatal period and 7 died at a median age of 23 years. The median age of the survivors was 19 years (range 15–42 years). Outflow obstruction of the left ventricle was noted in four deceased patients at variable times prior to death. The other deceased patients were not examined, but the cause of death was invariably heart failure. In none of the surviving patients was outflow obstruction noted. Enzyme-histochemical and ultrastructural findings were not specific for the course of the disease. In one biopsy, taken at the age of 3.5 months from a patient who survived, strong lipid accumulation was noted. Morphometric analysis showed proliferation of the mitochondria in muscle fibres, which increased during the course of the disease.     

Parents, siblings and grandparents in the Neonatal Intensive Care Unit A survey of policies in eight European countries

Objective:  To describe policies towards family visiting in Neonatal Intensive Care Units (NICU) and compare findings with those of a survey carried out 10 years earlier.
Methods:  A questionnaire on early developmental care practices was mailed to 362 units in eight European countries (Sweden, Denmark, the UK, the Netherlands, Belgium, France, Spain and Italy). Of them 78% responded, and among those responded, 175 reported caring for at least 50 very low birth weight infants every year and their responses were analysed further.
Results:  A majority of all units allowed access at any time for both parents. This was almost universal in northern Europe and the UK, whereas it was the policy of less than one-third of NICU in Spain and Italy, with France in an intermediate position. Restrictions on visiting of grandparents, siblings and friends, as well as restricting parents' presence during medical rounds and procedures followed the same pattern. A composite visiting score was computed using all the variables related to family visiting. Lower median values and larger variability were obtained for the southern countries, indicating more restrictive attitudes and lack of national policy.
Conclusions:  The presence of parents and other family members in European NICUs has improved over a 10-year period. Several barriers, however, are still in place, particularly in the South European countries.     

Kawasaki disease associated with streptococcal infection within a family

Objective: To describe the illness occurring in four members of a family, which had clinical and laboratory features of Kawasaki disease and streptococcal infection.
Methodology: A retrospective report of three siblings and an adult male living in one household. The children had serology, blood counts, cultures and echocardiography performed and were treated with antibiotics and gammaglobulin infusions.
Results: The patients developed clinical, and exhibited laboratory, features suggesting streptococcal infection and 4/5 criteria suggesting the diagnosis of Kawasaki disease. All made a good clinical recovery but the youngest developed a coronary artery aneurysm.
Conclusions: It may be difficult to distinguish streptococcal infection and Kawasaki disease. It is possible that some cases of Kawasaki disease are precipitated by streptococcal infection.     

Mitochondrial encephalomyopathies with the mutation of the mitochondrial tRNA(Leu(UUR)) gene.

Four families with mitochondrial encephalomyopathy are described. Probands of three families had typical clinical presentations of mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS), but the proband of family 4 lacked strokelike episodes. The mitochondrial DNA mutation of tRNA(Leu(UUR)) (transfer ribonucleic acid specific to leucine (UUR codon)) found in MELAS was examined in muscle DNA obtained from biopsy samples of the probands of four families and the maternal relatives of family 2. The mutation was detected in all muscle samples, and the degree of the mutated DNA was 68% to 84% by Southern blot analysis. However, the clinical patterns of the maternal relatives of family 2 were mild and distinctly different from MELAS. The same mutation was also detected in blood-derived DNA samples of all family members examined, including healthy mothers but not fathers, although the degree of mutation did not correlate with the clinical severity. These results confirmed the maternal inheritance of this disease and suggested that the mitochondrial DNA mutation (tRNA(Leu(UUR))) may cause clinical symptoms other than MELAS. The clinical findings of mitochondrial encephalomyopathy should be reinvestigated in terms of the mitochondrial gene mutation; the polymerase chain reaction method will be useful for screening for this mutation of mitochondrial DNA in blood samples.     

Familial aplasia of the inferior rectus muscles

PURPOSE: We describe inferior rectus aplasia in three members of a family. No family member showed signs of craniofacial dysostosis syndromes or neurofibromatosis. PATIENTS AND FINDINGS: A woman with abnormal head posture, right exotropia, and right hypotropia presented to our clinic. She mentioned that her two children had similar problems. A provisional diagnosis of ocular fibrosis or atypical Duane syndrome was made and she underwent surgery. During surgery, the inferior rectus muscle could not be identified in either eye. Subsequently, her children were examined and orbital magnetic resonance imaging (MRI) was performed for all family members. MRI confirmed bilateral absence of the inferior rectus muscles in the mother and unilateral absence with atrophic and fibrotic contralateral inferior rectus muscles in the children. CONCLUSION: This is the first report in the literature of a family with aplastic inferior rectus muscles with no signs of craniosynostosis or neurofibromatosis.     

Congenital fibre type disproportion myopathy. A histological diagnosis with an uncertain clinical outlook.

Nine children with congenital fibre type disproportion (CFTD) are described. Their muscle biopsies contained type 1 fibres which were smaller than the largest type 2 fibres by at least 13.5%. Attention is drawn to the variable natural history of this disorder which generally carries a good prognosis but may sometimes be associated with fatal respiratory problems. For important therapeutic, genetic, and prognostic reasons CFTD must be distinguished from other conditions with similar histochemical or clinical features.     

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.     

Surfactant protein deficiency in familial interstitial lung disease.

OBJECTIVE: To determine the contribution of surfactant protein abnormalities to the development of chronic lung injury in a familial form of interstitial lung disease. STUDY DESIGN: An 11-year-old girl, her sister, and their mother who were diagnosed with chronic interstitial lung disease underwent laboratory investigation of surfactant protein expression in bronchoalveolar lavage fluid and lung biopsy specimens. Nineteen patients with idiopathic pulmonary fibrosis and 9 patients who were investigated for pulmonary malignancy but who did not have interstitial lung disease served as control subjects. RESULTS: The 3 family members were found to have absent surfactant protein C (SP-C) and decreased levels of SP-A and SP-B in bronchoalveolar lavage fluid (BALF). Immunostaining for pulmonary surfactant proteins in lung biopsy specimens obtained from both children demonstrated a marked decrease of pro-SP-C in the alveolar epithelial cells but strong staining for pro-SP-B, SP-B, SP-A, and SP-D. No deviations from published surfactant protein B or C coding sequences were identified by DNA sequence analysis. All control subjects had a detectable level of SP-C in the BALF. CONCLUSION: The apparent absence of SP-C and a decrease in the levels of SP-A and SP-B are associated with familial interstitial lung disease.     

Cholestatic jaundice and congenital hypopituitarism

Objective: The prevalence of cholestatic jaundice as a presenting feature of congenital hypopituitarism is assessed.
Methodology: A retrospective case record analysis of the presenting features in all patients diagnosed as having congenital hypopituitarism between 1973–93.
Results: Seven of the 20 patients with congenital hypopituitarism presented with cholestatic jaundice as the major initial manifestation of the disorder. Liver biopsy findings in three revealed intracellular bile pigment accumulation and variable giant cell formation.
Conclusion: Cholestatic jaundice was the major manifestation of congenital hypopituitarism in 35% of patients presenting in the neonatal or early infancy period.     

Diagnostic value of the muscle biopsy in the neonatal period

Muscle biopsy specimens of 20 full-term neonates (13 surgical and seven necropsy specimens) with clinical evidence of neuromuscular disease were studied to determine the diagnostic usefulness of this procedure in the newborn. Characteristic pathologic alterations were identified in specific diseases. Some findings were similar to those seen later in life, but others differed from those expected in the same diseases at older ages. Persistence of fetal muscle cells was a characteristic common to several congenital myopathies and neuropathies. Lymphocytic infiltrates, muscle fiber necrosis, and architectural alterations of the muscle fibers were not seen at birth. Extramedullary hematopoiesis may involve newborn muscle. Muscle biopsy is a safe and simple procedure in the neonatal period and has a diagnostic reliability as good as at older ages, but histochemistry and sometimes electron microscopy are essential supplements to classical histology for interpretation. Recommended indications for muscle biopsy in the neonatal period are multiple joint contractures at birth or hypotonia and weakness, of unknown origin.     

Histopathological aspects of cardiac biopsy in pediatric patients with dilated cardiomyopathy

Background: Dilated cardiomyopathy (DCM) is a heart muscle disease with cardiac dysfunction and a heterogenous disorder. This disease may show various histopathological aspects of the myocardium, but little is known about these in children. Methods: Histopathological findings of endomyocardial biopsy from 20 pediatric patients with DCM were analyzed and compared with those in adult patients. Results: Advanced histopathology, including myocytolysis and/or fragmentation of muscle bundles, was frequently observed in patients with poor prognosis. Patchy fibrosis was predominantly demonstrated in the pediatric patients, whereas perivascular fibrosis was mostly observed in the older adults. The myocarditic index, assessed in terms of the findings of fibrosis, size variation of myocytes, disarrangement of muscle bundles and mononuclear cell infiltration was higher in the pediatric patients than in the older adults (P < 0.05). Bizarre myocardial hypertrophy with disorganization, which tends to be frequently demonstrated in hypertrophic cardiomyopathy, was revealed in 30% of the pediatric patients, whereas it was disclosed in none of the older adult patients (P < 0.05). Conclusion: These results suggest that the major pathogenetic factors of DCM in children may be different from those in adults.     

Sudden unexpected death in childhood associated with cardiac rhabdomyoma, involuting adrenal ganglioneuroma, and megalencephaly: another expression of tuberous sclerosis?

We report a 9-year-old, previously healthy girl who died suddenly and unexpectedly and was found at postmortem examination to have a cardiac rhabdomyoma, megalencephaly, and an involuting adrenal ganglioneuroma. Her death was possibly caused by a fatal cardiac arrhythmia resulting from interference of the ventricular septal rhabdomyoma with the cardiac conduction fibers. Her extended family history included a variety of disorders, including cleft lip and palate and ill-defined cardiac and neurologic diseases. The constellation of her autopsy findings suggested a diagnosis of tuberous sclerosis, for which there are gene defects that can be identified in surviving family members.     

A family presenting Goltz syndrome (focal dermal hypoplasia) in three generations

In this report we present three affected females of the same family in three generations. The cases have features of focal dermal hypoplasia (Goltz syndrome). One of the three affected females is the index case and the others are her mother and her grandmother. We performed skin biopsies on them. According to histopathological examinations skin lesions were compatible with Goltz syndrome. These cases exhibited focal dermal hypoplasia (FDH) manifestations including skin, dental and skeletal abnormalities. The affected females were seen in three generations of the same family which pointed to its X-linked dominance.     

Histopathologic aspects of endomyocardial biopsy in pediatric patients with idiopathic ventricular tachycardia

PURPOSE: The present study aimed to investigate the clinicopathologic findings and histopathologic characteristics of endomyocardial biopsy in pediatric patients with idiopathic ventricular tachycardia. METHODS: Histopathological findings of endomyocardial biopsy from 17 patients aged 7-15 years with idiopathic ventricular tachycardia (VT) but no organic heart disease were examined. Patients considered to have cardiomyopathy of the dilated, hypertrophic or specific form or arrhythmogenic right ventricular cardiomyopathy were excluded from this study. RESULTS: Advanced histopathologic findings, including myocyte hypertrophy, degeneration, interstitial fibrosis and disarrangement of muscle bundles, were disclosed in three cases (17.6%). One of these cases exhibited sustained VT with left bundle branch block configuration and showed increased frequency of VT during exercise testing. The remaining two cases had non-sustained VT with multifocal origin and had syncope episodes. Another 14 cases showed mild or no significant findings in the biopsy. CONCLUSIONS: These results indicate that advanced histopathology in endomyocardial biopsy is occasionally disclosed in cases of idiopathic VT, especially those of exercise-related VT or multifocal VT, and that these patients may be considered as having heart muscle disease.