Minicores and congenital fibre type disproportion observed in a family

Objective: To report a family in which congenital fibre type disproportion (CFTD) and minicore disease have been observed in members of the same family, and raise the question of the relationship between CFTD and minicores.
Methodology: A follow-up clinical and biopsy study of a girl who presented to hospital because of marked hypotonia and non-progressive weakness. She had muscle biopsies at the age of 18 months and again at 4 1/2 years. Her asymptomatic parents were also biopsied. The muscle specimens were processed for histopathological and morphometric studies.
Results: The histopathological findings of the muscle of the daughter were consistent with CFTD. The muscle biopsy of her father was normal whereas her mother's revealed minicore formation.
Conclusions: The findings of CFTD and minicore disease in members of the same family suggest that CFTD and minicore formation may both be the result of a common pathological mechanism rather than each being a distinct clinicopathological entity.     

Nemaline myopathy: an unusual course]

A girl presents immediately post partum with postures and movements typical for severe muscular hypotonia (floppy infant). Her sucking and swallowing abilities are reduced. There is marked drooling. Broad alveolar ridges give the impression of a high-arched palate. Floppy infant-screening (muscle enzymes, EMG, NCV) was within normal ranges apart from a slight elevation of aldolase. Muscle biopsy performed at the age of two years revealed the diagnosis of nemaline myopathy. An onset of the disease with severe muscular hypotonia during neonatal period usually is linked with rapidly progressing, mostly lethal outcome. Our patient--in contrast--seems to suffer from a mild form.     

Congenital hypomyelinating neuropathy

An eleven-month-old baby born out of non-consanguineous parentage presented with history of delayed motor milestones. The weakness was predominantly distal; there was intercostal muscle weakness, generalized hypotonia and areflexia. The nerve conduction velocities were unobtainable in all the four limbs. Sural nerve biopsy was consistent with the diagnosis of congenital hypomyelinating neuropathy, a rare form of hereditary motosensory neuropathy.     

'Juvenile' myasthenia gravis in early infancy

A previously well infant developed severe muscle weakness and hypotonia at 6 months of age. This was reversed by anticholinesterase medication. However, she had subsequent further weakness and died at 10 months after an acute respiratory arrest. The clinical pattern was that of the 'juvenile' form of myasthenia gravis rather than the 'congenital' forms which have previously been described in early infancy.     

The floppy infant: a practical approach

Cerebral, non paralytic and peripheral paralytic hypotonia are briefly discussed. Criteria which help in the differential diagnosis are emphasized. In the usual cerebral hypotonia, muscle strength is preserved but muscle tone is decreased. However, there are a few conditions in which cerebral hypotonia is severe enough to resemble paralytic hypotonia. These conditions include the Prader-Willi syndrome (first phase), the Zellweger syndrome and some cases of congenital myotonic dystrophy. In peripheral or paralytic hypotonia muscle weakness and hypotonia go hand-in-hand. A few practical diagnostic criteria are given which allow the differentiation between anterior horn cell disease, polyneuropathy, neonatal myasthenia and myopathy. Finally, essential or benign hypotonia is briefly alluded to.     

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.     

Merosin-deficient congenital muscular dystrophy and cortical dysplasia.

Congenital muscular dystrophy (CMD) encompasses a heterogenous group of muscle disorders with autosomal recessive inheritance, characterized by muscular weakness and hypotonia at birth or within the first few months of life and developmental delay. Merosin-deficient CMD is a clinically distinct form which may be associated with significant abnormalities of the brain detectable by neuroimaging. We report two siblings of consanguineous parents with merosin-deficient CMD in an Irish family who in addition to the characteristic white matter abnormalities on neuroimaging, had occipital dysplasia. Clinical, electrophysiological muscle biopsy findings and neuroimaging were very similar in both cases. Although merosin-deficient CMD with white matter abnormalities on neuroimaging is well documented in the literature, the association with occipital dysplasia has only rarely been reported. The appearance of an identical cortical defect in these siblings suggests an underlying genetic mechanism.     

'Juvenile' myasthenia gravis in early infancy.

A previously well infant developed severe muscle weakness and hypotonia at 6 months of age. This was reversed by anticholinesterase medication. However, she had subsequent further weakness and died at 10 months after an acute respiratory arrest. The clinical pattern was that of the ''juvenile'' form of myasthenia gravis rather than the ''congenital'' forms which have previously been described in early infancy.     

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.     

腓骨肌萎缩症一家系报告并文献复习

目的 探讨腓骨肌萎缩症1A型的临床特点.方法 回顾分析腓骨肌萎缩症1A型一家系的临床表现、神经电生理及基因检测结果.结果 先证者为12岁男孩,因双下肢乏力就诊.患儿四肢肌张力稍减低,四肢近端肌力V级,远端肌力Ⅳ级,双下肢膝关节以下及双上肢远端肌肉对称性萎缩,四肢末端感觉稍减退,膝反射、踝反射消失,双足高弓足,病理征阴性...     

Congenital myopathies: clinical phenotypes and new diagnostic tools

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis.     

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.     

Vitamin B12 deficiency in a one-year-old, exclusively breast fed child

Vitamin B12 deficiency is a rare condition in children. The most frequent cause is vegetarian diet. In infants it can happen in breast fed children whose mother is on this diet. The clinical feature of the disease presents with megaloblastic anemia and symptoms such as: weakness, refusing to eat, hypotonia, paraesthesia, delayed or regressed development. We present a case report of vitamin B12 deficiency in a one-year-old, exclusively breast fed child. The mother's diet during pregnancy and breast-feeding were normal. CONCLUSIONS: The quality of the mother's diet and her haematological status during pregnancy and breast-feeding should be carefully monitored. It is necessary to introduce a variety of foods to expand the infant's diet at the proper time. The diagnosis of anaemia in the mother and/or in the child requires a careful investigation.     

The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy.

The selenoprotein N1-related myopathies comprise rigid spine muscular dystrophy, the "classical" form of multiminicore disease, a desmin-related myopathy with Mallory body like inclusions and a form of congenital fiber-type disproportion. To define the phenotype and long-term clinical course in juvenile Selenoprotein N1-related myopathies 11 juvenile patients from eight families with SEPN1 mutations were assessed over a mean period of 7.2 years. Clinical findings, histomorphological studies, respiratory investigations and genetic data were analyzed: age of manifestation varied within the first 2 years of life with muscle hypotonia, lag of head control and delayed motor development. Further gross motor development was normal in 9/11 patients. All patients were ambulant for at least 1000 m at a mean age of 13.7 years. Eight patients exhibited a rigid spine diagnosed at a mean age of 10 years. All patients had respiratory impairment with a vital capacity ranging from 18% to 65%. Four patients were intermittently nocturnally ventilated at a mean age of 11 years. Body mass index was below 20 (kgm(-2)) in all patients. Muscle biopsies of eight individuals revealed multiminicores (n=2), congenital fiber-type disproportion (n=1), myopathic changes with single cores (n=2) and unspecific myopathic features (n=3). Mutations were distributed throughout the entire SEPN1 gene. Although the phenotype of juvenile selenoprotein N1-related myopathies is homogenous regarding the main symptoms we describe a variable degree of clinical severity. Major complications were early respiratory failure, impaired increase in weight and orthopedic problems. There seems to be no correlation between skeletal muscle weakness and respiratory failure.     

The hypotonic infant: case study of central core disease

Causes of hypotonia in the newborn can be broadly categorized into two classifications. Hypotonia with a supraspinal origin may be seen with systemic disease, hypoxic ischemic encephalopathy, cerebral malformations, syndromes (for example: Down, Prader-Willi, Lowe, Zellweger, Smith-Lemli-Opitz), and c-spine injury. Disorders of the motor unit that present with hypotonia in the newborn period include SMA, congenital myotonic dystrophy, congenital myasthenia gravis, and congenital myopathies. Central core disease is one of the classic congenital myopathies that can be differentiated based on characteristic histologic findings. Muscle fiber samples from patients with central core disease possess distinct morphology that can be diagnostic. Many infants may not exhibit muscle weakness in the newborn period, although there have been rare cases of profound hypotonia and respiratory failure. Clearly, muscle biopsy is the gold standard and is indicated for any infant with marked hypotonia that is not thought to be supraspinal in origin.     

Can clinical signs identify newborns with neuromuscular disorders?

OBJECTIVE: To evaluate retrospectively the prevalence of neuromuscular disorders in 83 newborns referred to a tertiary care center because of hypotonia and weakness and/or contractures, with a possible diagnosis of neuromuscular disorder. We also aimed to establish whether clinical signs could help to identify infants with neuromuscular disorders. STUDY DESIGN: Sixty-six of the 83 infants who fulfilled the inclusion criteria (79.5%) had an identifiable disorder, which was a neuromuscular disorder in 39 (46.9%). RESULTS: Absent or extremely reduced antigravity movements were mainly found in infants with neuromuscular disorders (sensitivity and specificity 97.4% and 75%), whereas partial range antigravity movements were more frequent in infants with other diagnosis. Contractures were mainly found in infants with peripheral nerve or muscle involvement but also were relatively frequent in infants with genetic or metabolic syndromes (sensitivity 69.2%, specificity 61.3%). Reduced fetal movements and abnormal liquor were frequent but not present consistently in infants with neuromuscular disorders (sensitivity 46.1% and 38.4%) and were found rarely in infants with other disorders (specificity 88.6% and 75.0%). CONCLUSIONS: Severe muscle weakness and contractures are the most reliable indicators of a neuromuscular disorder and should be carefully assessed in an infant with neonatal hypotonia.     

Diaphragmatic spinal muscular atrophy with bulbar weakness.

We present the clinical and histopathological features of a child affected by diaphragmatic spinal muscular atrophy. The child was born with mild distal arthrogryposis, mild hypotonia and developed marked diaphragmatic and bulbar muscle weakness in the first week of life. Electrophysiological and pathological investigations performed at presentation were not conclusive, while the investigations performed at 3 months showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that this syndrome represents a different entity from typical proximal spinal muscular atrophy.     

Neonatal hypotonias with congenital disproportion of various types of muscular fiber, especially type I fibers. Demonstration of the familial character of this new entity]

Two sisters presenting with benign congenital hypotonia are reported. In both cases the muscle biopsies demonstrated the same pathological pattern, consisting in an abnormal size disproportion between the two main cytoenzymological types of muscle fibers. Their father, exhibiting a slight and diffuse muscle weakness, showed a closely related histological aspect. These three cases bring the first evidence of a familial transmission of this new entity. Its relationship with the other types of "congenital myopathies" is discussed.     

Severe neonatal centronuclear (myotubular) myopathy: an X-linked recessive disorder

Prenatal onset and rapidly fatal course of centronuclear myopathy are described in four male newborns including two brothers. Diagnosis was established by muscle biopsy within the first week of life in two and at autopsy in the two other patients: Central nuclei, central aggregation of oxydative enzyme activity in the majority of muscle fibers and type 1 fibre hypotrophy were demonstrated. Prenatal manifestation included polyhydramnios, reduced fetal movements and breech presentation. All four newborns developed respiratory insufficiency requiring artificial ventilation immediately after birth. Severe muscular weakness and hypotonia as well as hardly elicitable grasping, deep tendon reflexes and Moro response were noticed. Additional findings included high arched palate, joint contractures, thin ribs, lung hypoplasia, abundant skin and cryptorchidism. In two families, the pedigree contains other affected males, suggesting X-linked inheritance. Seven female carriers were clinically healthy and one of them showed normal muscle histology. Fourteen previously published neonatal cases of centronuclear myopathy are reviewed and compared with our findings. This severe perinatal form of centronuclear myopathy has to be considered in male fetuses and newborns with polyhydramnios and respiratory failure due to muscular weakness or in infants who died of unexplained postnatal asphyxia. Diagnosis should be established by muscle biopsy.     

SURF1基因突变导致Leigh综合征家系1例

Leigh综合征是一种由于线粒体氧化磷酸化障碍所导致的严重退行性脑病。常染色体SURF1基因突变所致细胞色素C氧化酶缺乏是导致Leigh综合征的常见原因,国外已报道多种突变类型。该研究回顾了1例SURF1基因604G>C杂合性错义突变所致中国人Leigh综合征患者及其家系的临床与遗传学特点。患者,女, 9个月起病,表现为喂养困难,营养不良,进行性运动倒退,肌张力低下,眼震。17个月时来院就诊, 23个月时死于呼吸衰竭。脑MRI显示双侧基底节对称性损害,脑干、小脑萎缩。聚合酶链式反应扩增SURF1基因的全部外显子,进行序列测定及限制性片断长度多态性分析均显示患者及其母亲、舅舅的SURF1基因的外显子7存在一个604G>C杂合性错义突变,其父亲及正常对照的相关外显子序列未发现异常。该研究首次报道了1例中国人群中由于SURF1基因604G>C杂合性错义突变导致的Leigh综合征及其家系,不仅明确了病因,亦将有助于今后对患者家系的遗传咨询。