Nemaline rod myopathy: a rare form of myopathy

Nemaline rod myopathy (NM) is a rare form of congenital myopathy characterized by slowly progressive or nonprogressive muscle weakness and pathognomonic rod-like structures within the muscle fibers. To the best of our knowledge, this is first documentation of the clinicopathological features of this rare entity from India. All cases of NM diagnosed in our laboratory were retrieved. Clinical and pathological features were reviewed. During a period of 1.5 years (Jan 2004 to June 2005), we received 750 muscle biopsies for various reasons. Of which, 15 were diagnosed as congenital myopathies and four as nemaline rod myopathies. Thus, NM comprises 0.53% of all muscle diseases and 22.6% of all congenital myopathies. All of them presented in childhood (first five years of life) with generalized hypotonia, feeding problems, repeated respiratory infections and muscle weakness. Both males and females were equally affected. The CPK levels were normal and EMG was myopathic. Microscopic examination revealed minimal changes but characteristic red-colored material was seen on modified Gomori trichrome staining which was immunopositive to alpha actinin. Ultrastructural examination confirmed this material to be nemaline rods. NM, although a rare form of congenital myopathies, should be suspected in children who present with generalized hypotonia, repeated chest infections and slowly progressive muscle weakness. This report highlights the importance of histochemistry and ultrastructural examination in the diagnosis of this entity, in the absence of the availability of methodology for genetic studies.     

Multi-minicore myopathy: a clinical and histopathological study of 17 cases

Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the multifocal lack of oxidative activity on light microscopy (LM) and multiple small zones of sarcomeric disorganization on electron microscopy (EM) as the main findings in muscle biopsy. We report on clinical and pathomorphological features of 17 patients diagnosed with multi-minicore myopathy at our department. Clinically, axial and proximal muscle weakness was the predominant distinguishing feature. Dysmorphic features such as high-arched palate and chest deformities were frequent findings. Limitation in cervical spine mobility was found in 4 cases. Most of our cases were slowly progressive but three fatal cases also occurred. Multifocal lack of oxidative activity was found in 16/22 biopsies on LM. Examination on EM enabled the final diagnosis of MmD in all cases. It is of special interest that in 3 patients fulfilling the criteria of pure congenital fibre type disproportion and in 2 cases of centronuclear myopathy, the findings of ultrastructural examination led us to a revised diagnosis of MmD. We postulate that all muscle biopsies with abnormal fibre proportion or centrally located nuclei as the only pathology on LM need to undergo careful EM evaluation to identify possible underlying multi-minicore disease.     

A recessive form of central core disease,transiently presenting as multi-minicore disease,is associated with a homozygous mutation in the ryanodine receptor type 1 gene

Multi-minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi-minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome-wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi-minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency ("classical" phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi-minicore disease.     

A novel mutation in NEB causing foetal nemaline myopathy with arthrogryposis during early gestation

Nemaline myopathies are a clinically and genetically heterogeneous group of congenital myopathies, mainly characterized by muscle weakness, hypotonia and respiratory insufficiency. Here, we report a male foetus of consanguineous parents with a severe congenital syndrome characterized by arthrogryposis detected at 13 weeks of gestation. We describe severe complex dysmorphic facial and musculoskeletal features by post mortem fetal examination confirming the prenatal diagnosis. Histomorphological and ultrastructural studies of skeletal muscle reveal mini-rods in myotubes caused by a novel homozygous splice-site mutation in NEB (NM_001164508, chr2:g.152,417,623C>A GRCh37.p11 | c.19,102–1G>T ENST00000397345.3). No rods were seen in the myocardium. We discuss the relevance of this mutation in the context of nemaline myopathies associated with early developmental musculoskeletal disorders.     

Mutations in MYH7 cause Multi-minicore Disease (MmD) with variable cardiac involvement

Central Core Disease (CCD) and Multi-minicore Disease (MmD) (the “core myopathies”) have been mainly associated with mutations in the skeletal muscle ryanodine receptor (RYR1) and the selenoprotein N (SEPN1) gene. A proportion of cases remain unresolved. Mutations in MYH7 encoding the beta myosin heavy chain protein have been implicated in cardiac and, less frequently, skeletal muscle disorders.Here we report four patients from two families with a histopathological diagnosis of MmD, presenting in childhood with slowly progressive muscle weakness, more proximal in Family 1 and more distal in Family 2, and variable degrees of cardiorespiratory impairment evolving later in life. There was also a strong family history of sudden death in the first family. Muscle biopsies obtained in early childhood showed multiple minicores as the most prominent feature. Sequencing of the MYH7 gene revealed heterozygous missense mutations, c.4399C>G; p.Leu1467Val (exon 32) in Family 1 and c.4763G>C; p.Arg1588Pro (exon 34) in Family 2.These findings suggest MYH7 mutations as another cause of a myopathy with multiple cores, in particular if associated with dominant inheritance and cardiac involvement. However, clinical features previously associated with this genetic background, namely a more distal distribution of weakness and an associated cardiomyopathy, may only evolve over time.     

Myotubular/centronuclear myopathy and central core disease

The term congenital myopathy is applied to muscle disorders presenting with generalized muscle weakness and hypotonia from early infancy with delayed developmental milestones. The congenital myopathies have been classified into various categories based on morphological findings on muscle biopsy. Although the clinical symptoms may seem homogenous, the genetic basis is remarkably variable. This review will focus on myotubular myopathy, centronuclear myopathy, central core disease, and congenital neuromuscular disease with uniform Type 1 fiber, myopathies that are subjects of our ongoing examinations.     

Adult-onset mixed myopathy with nemaline rods,minicores, and central cores: a muscle disorder mimicking polymyositis

Summary A woman, aged 75 years, presented with a 15-year history of progressive, generalized, painful muscle weakness and wasting. Clinical and laboratory investigation revealed a sporadic muscle disorder. Muscle biopsy showed a mixed pattern of nemaline myopathy with minicores and central cores and severe atrophy of type-1 and type-2 fibers. A trial of immunosuppressive treatment did not improve her condition, which clinically mimicked chronic progressive polymyositis. Mixed myofibrillar myopathies of this type have so far only been described among the group of congenital myopathies.     

Congenital fiber type disproportion: a rare type of congenital myopathy: a report of four cases

Congenital fiber type disproportion is a rare type of congenital myopathy which presents as hypotonia, delayed motor milestones and dysmorphic facies. During the past 2 years we received 449 muscle biopsies, of which 4 cases were diagnosed as congenital fiber type disproportion (CFTD). In addition to CFTD, one case also had centronuclear features. Three of them were females and one was a male child. Although rare, it should be considered in the differential diagnosis of childhood muscle diseases. Histochemical staining is necessary for the diagnosis of this entity.     

Myopathology in congenital myopathies

Congenital myopathies are clinically and genetically a heterogeneous group of early onset neuromuscular disorders, characterized by hypotonia and muscle weakness. Clinical severity and age of onset are variable. Many patients are severely affected at birth while others have a milder, moderately progressive or nonprogressive phenotype. Respiratory weakness is a major clinical aspect that requires regular monitoring. Causative mutations in several genes have been identified that are inherited in a dominant, recessive or X‐linked manner, or arise de novo. Muscle biopsies show characteristic pathological features such as nemaline rods/bodies, cores, central nuclei or caps. Small type 1 fibres expressing slow myosin are a common feature and may sometimes be the only abnormality. Small cores (minicores) devoid of mitochondria and areas showing variable myofibrillar disruption occur in several neuromuscular disorders including several forms of congenital myopathy. Muscle biopsies can also show more than one structural defect. There is considerable clinical, pathological and genetic overlap with mutations in one gene resulting in more than one pathological feature, and the same pathological feature being associated with defects in more than one gene. Increasing application of whole exome sequencing is broadening the clinical and pathological spectra in congenital myopathies, but pathology still has a role in clarifying the pathogenicity of gene variants as well as directing molecular analysis.     

Nonspecific congenital myopathy (minimal change myopathy): a case report

A 28-month-old male with generalized hypotonia and muscle weakness, a myopathic face, skeletal dysmorphism and delayed motor milestones from birth is reported. He gradually developed the ability of sitting and rolling over, but could not stand without support until 28 months. There was no intellectual impairment or seizures. Deep tendon reflexes were absent. The serum CK value, peripheral nerve conduction velocity and EMG were within normal limits. A muscle biopsy specimen showed mild variation in fiber size, and an increased number of type 2C fibers on histochemical examination, but no apparent abnormalities on electron microscopy. The baby was tentatively diagnosed as having minimal change myopathy or nonspecific congenital myopathy which is thought to be one of the congenital nonprogressive myopathies.     

Myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy

BACKGROUND: Multicore disease and congenital fibre type disproportion myopathy are diseases assigned to the heterogeneous group of congenital myopathies. Although hypotonia and muscle weakness appearing in early life are the commonest manifestations of these diseases, distinct phenotypes and late onset cases have been described. OBJECTIVE: To report the occurrence of myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. METHODS: The clinical cases of three patients with fibre type disproportion myopathy and one with multicore disease are described. Skeletal muscle biopsies were processed for routine histological and histochemical studies. RESULTS: The clinical picture was unusual in that the symptoms were of late onset and the predominant complaint was muscle pain exacerbated by exercise. Muscle weakness was found in only a single patient, the mother of a patient with fibre type disproportion myopathy. Physical examination was unremarkable in the other patients. Muscle biopsies from patients 1 and 2 contained type I fibres that were considerably smaller than the type II fibres, supporting the diagnosis of fibre type disproportion myopathy. Skeletal muscle of patient 4 showed multiple areas, predominantly but not exclusively in the type I fibres, from which oxidative enzyme activities were absent, as seen in multicore disease. CONCLUSIONS: Muscle pain was the main clinical manifestation in our patients. Recognition of the broader clinical expression of these myopathies is important for prognostic reasons and for genetic counselling of the family members.     

Congenital myopathies

This review focuses on congenital myopathies, a distinct but markedly heterogeneous group of muscle disorders that present with muscle weakness and typically appear at birth or in infancy. These myopathies have characteristic histopathologic abnormalities on muscle biopsy, allowing a preliminary morphologic classification. Advances in molecular genetics have allowed a more rational classification of these disorders and have reshuffled taxonomy for some of these conditions. Here, we focus on recent research advances in specific congenital myopathies, including nemaline myopathy, myotubular myopathy, centronuclear myopathy, central core myopathy, multi-minicore myopathy, congenital fiber-type disproportion myopathy, and hyaline body myopathy. Scientific progress has not only elucidated the pathologic mechanisms of these disorders, but it has also provided the basis for therapeutic strategies.     

Abnormal distribution of calcium-handling proteins: a novel distinctive marker in core myopathies

Central core disease (CCD) and multi-minicore disease (MmD) are muscle disorders characterized by foci of mitochondria depletion and sarcomere disorganization ("cores") in muscle fibers. Although core myopathies are the most frequent congenital myopathies, their pathogenesis remains elusive and specific diagnostic markers are lacking. Core myopathies are mostly caused by mutations in 2 sarcoplasmic reticulum proteins: the massive Ca-release channel RyR1 or the selenoprotein N (SelN) of unknown function. To search for distinctive markers and to obtain further pathophysiological insight, we identified the molecular defects in 12 core myopathy patients and analyzed the immunolocalization of 6 proteins of the Ca-release complex in their muscle biopsies. In 7 cases with RYR1 mutations (6 CCD, one MmD), RyR1 was depleted from the cores; in contrast, the other proteins of the sarcoplasmic reticulum (calsequestrin, SERCA1/2, and triadin) and the T-tubule (dihydropyridine receptor-alpha1subunit) accumulated within or around the lesions, suggesting an original modification of the Ca-release complex protein arrangement. Conversely, all Ca-related proteins were distributed normally in 5 MmD cases with SelN mutations. Our results provide an appropriate tool to orientate the differential and molecular diagnosis of core myopathies and suggest that different pathophysiological mechanisms lead to core formation in SelN- and in RyR1-related core myopathies.     

Pontocerebellar hypoplasia type 1

Pontocerebellar hypoplasias are heterogeneous disorders that share a reduction in the size of brainstem and cerebellum. We describe a patient with features of the rare combination of pontocerebellar hypoplasia and spinal motor neuron disease. Parental consanguinity, low Apgar scores, facial weakness, dysphagia, tongue fasciculations, stridor, generalized hypotonia, severe muscle weakness, areflexia, and congenital joint contractures were evident. Cranial magnetic resonance imaging revealed a small cerebellum and brainstem, and a muscle biopsy revealed neurogenic changes. These abnormalities suggested pontocerebellar hypoplasia type 1.     

Clinical and genetic aspects of distal myopathies.

Although most muscle disorders produce proximal weakness, some myopathies may manifest predominantly or exclusively distal weakness. Although several congenital, inflammatory, or metabolic myopathies may produce mainly distal weakness, there are several distinct entities, typically referred to as distal myopathies. Most of these are inherited conditions. The distal myopathies are rare, but characteristic clinical and histological features aid in their identification. Advances in molecular genetics have led to the identification of the gene lesions responsible for several of these entities and have also expanded our understanding of the genetic relationships of distal myopathies to other inherited disorders of muscle. This review summarizes current knowledge of the clinical and molecular aspects of the distal myopathies.     

Congenital myopathies with secondary neuromuscular transmission defects; A case report and review of the literature

Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anticholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission.     

Severe lethal spinal muscular atrophy variant with arthrogryposis

Spinal muscular atrophies are a clinically and genetically heterogeneous group of disorders. Atypical forms of the disease have also been described, including those with associated sensory deficits, hearing loss, cerebellar hypoplasia, congenital heart defects, arthrogryposis, and bone fractures at birth. The patient described here is a male infant, born to a 30-year-old mother at 34 weeks of gestation complicated with polyhydramnios. The first son of consanguineous parents had died with the same clinical features. The patient required ventilatory support because of respiratory failure after the birth and died on day 13. His physical examination revealed profound generalized hypotonia, absence of deep tendon and neonatal reflexes, dysmorphic facies, arthrogryposis, clinodactyly, and left femur fracture. A muscle biopsy revealed variation in fiber size with occasional hypertrophic fibers. The postmortem examination revealed loss and degeneration of anterior horn cells. We propose that the patient, who presented with severe hypotonia, femur fracture, arthrogryposis, dysmorphic features, history of early death of his brother with the same clinical features and parental consanguinity, had probable X-linked spinal muscular atrophy. However, autosomal-recessive inheritance can not be completely excluded.     

SEQUENTIAL STUDIES OF A CHILDHOOD MYOPATHY: A CLINICAL, HISTOCHEMICAL AND MORPHOMETRIC INVESTIGATION

An unusual inherited progressive distal myopathy of early childhood onset is described in two sisters from a consanguineous Asian family. Motor milestones were normal but gait deteriorated slowly thereafter with development of generalized hypotonia and muscle weakness particularly in the wrist extensors and hand muscles. Muscle biopsies obtained at the ages of 6 and 10 years respectively (Case 1) showed significant differences. At 6 years muscle morphology and histochemical appearance were normal although type I fibres predominated (79%) and a substantial pool of 'undifferentiated' fibres (12%) was present. By 10 years there was a significant reduction in type I fibres (-13%) and in 'undifferentiated' fibres (-10%) with a concomitant increase in type II fibres (+23%). Fibre size and shape were normal at the age of 6 years but no further fibre growth was evident 4 years later. The older sister (Case 2, age 13 years) was similarly affected. The possibility of this progressive myopathy being caused by loss of neural control at two separate stages of development is discussed. The importance of performing sequential morphometric studies of muscle biopsies from patients with unusual childhood myopathies is emphasized.     

Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores

ACTA1 gene encodes the skeletal muscle alpha-actin, the core of thin filaments of the sarcomere. ACTA1 mutations are responsible of several muscle disorders including nemaline, cores, actin aggregate myopathies and fiber-type disproportion. We report clinical, muscle imaging, histopatological and genetic data of an Italian family carrying a novel ACTA1 mutation. All affected members showed a late-presenting, diffuse muscle weakness with sternocleidomastoideus and temporalis atrophy. Mild dysmorphic features were also detected. The most affected muscles by muscle MRI were rectus abdominis, gluteus minimus, vastus intermedius and both gastrocnemii. Muscle biopsy showed the presence of nemaline bodies with several unusual dark areas at Gomori Trichrome, corresponding to unstructured cores with abundant electrodense material by electron microscopy. The molecular analysis revealed missense variant c.148G>A; p.(Gly50Ser) in the exon 3 of ACTA1, segregating with affected members in the family. We performed a functional essay of fibre contractility showing a higher pCa₅₀ (a measure of the calcium sensitivity of force) of type 1 fibers compared to control subjects’ type 1 muscle fibers. Our findings expand the clinico-pathological spectrum of ACTA1-related congenital myopathies and the genetic spectrum of core-rod myopathies.     

A distinctive autosomal dominant vacuolar neuromyopathy linked to 19p13.

OBJECTIVE: To characterize a kindred with a distinctive autosomal dominant neuromuscular disorder. BACKGROUND: The authors studied a large Italian family affected by a progressive neuromyopathy. Ten individuals over three generations were affected. The disease was characterized by onset from the late teens to early 50s with distal leg weakness and atrophy, development of generalized muscle weakness with distal-to-proximal progression sparing facial and ocular muscles, dysphonia and dysphagia, pes cavus and areflexia, variable clinical expression ranging from subclinical myopathy to severely disabling weakness, and mixed neurogenic and myopathic abnormalities on electromyography. METHODS: Morphologic, immunocytochemical, and ultrastructural studies were performed in muscle biopsies from three affected patients. A genomewide linkage analysis through the genotyping of 292 microsatellite markers spanning the 22 autosomes was undertaken to map the disorder segregating in this family. RESULTS: All muscle biopsies showed variation of fiber size, panesterase-positive angular fibers, mild to severe fibrosis, and numerous "rimmed vacuoles." Electron microscopy failed to demonstrate the nuclear or cytoplasmic filamentous inclusions specific of inclusion-body myopathies and, accordingly, immunohistochemistry did not show any positivity with SMI-31 antibodies detecting hyperphosphorylated tau. Preliminary analysis of 292 microsatellite markers provided evidence for linkage to chromosome 19p13. CONCLUSIONS: This distinctive autosomal dominant disorder is characterized by a vacuolar neuromyopathy. Localization to chromosome 19p13 will allow the genetic relationship between this disease and inherited myopathies with rimmed vacuoles, in particular autosomal dominant inclusion-body myopathies, to be defined.