Atypical Prader-Willi syndrome with severe developmental delay and emaciation

A young boy showed features of Prader-Willi syndrome including hypotonia, cryptorchidism, a mildly dysmorphic facial appearance, a high-arched palate and an open triangular-shaped mouth, but had additional symptoms such as simian creases and multiple joint ankylosis in early infancy. Deletion of the long arm of chromosome 15(q11.2 to q13) was recognized. A muscle biopsy specimen showed variation in fiber size with hypertrophic type 1 fibers, type 2 fiber smallness, type 2B fiber paucity and an increased number of type 2C fibers. At the age of 4 1/2 years, he still showed severe developmental delay with severe muscle hypotonia, weakness and emaciation.     

Congenital familial myopathy with type 2 fiber hypoplasia and type 1 fiber predominance

A 12-month-old girl with delayed developmental milestones, due to muscle hypotonia and weakness from early infancy, exhibited type 2 fiber hypoplasia. A muscle biopsy specimen disclosed type 1 fiber predominance and type 2B fiber deficiency compatible with congenital myopathy. During the following 4 years, she continued to have mild muscle weakness, but no mental retardation. Her mother had similar symptoms from early infancy with minimal progression. Although type 2 fiber hypoplasia is a non-specific finding in various diseases, it may be a specific finding in a limited number of patients with hereditary congenital non-progressive myopathy.     

Muscle histochemistry in myotubular (centronuclear) myopathy

We report the clinical and histochemical findings in 7 patients with myotubular (centronuclear) myopathy aged from 2 months to 32 years. The clinical symptoms varied from patient to patient. Three patients developed severe muscle weakness and hypotonia with respiratory distress from infancy, and 4 had muscle weakness from 2-5 years of age with no apparent delay in developmental milestones. In addition to an increased number of fibers with centrally placed nuclei, there were 3 other histochemical characteristics of this disorder, i.e., type 1 fiber predominance, type 1 fiber hypotrophy and type 2B fiber deficiency. Other histological findings included a peripheral halo in the sarcoplasm on NADH-TR staining and an increased number of undifferentiated type 2C fibers, indicating a delay in muscle fiber growth and differentiation due to a probable defective neural supply in the developing muscles.     

Complete external ophthalmoplegia in a patient with congenital myopathy without specific features (minimal change myopathy)

An 11-month-old female infant with mild asphyxia at birth had severe generalized muscle hypotonia and weakness, predominantly in the neck flexors, a high-arched palate and a funnel chest from early infancy. Her facial muscles were also markedly involved. In addition, she showed striking non-progressive, complete external ophthalmoplegia and mild ptosis. A muscle biopsy specimen showed non-specific myopathic changes, including mild variation in fiber size, mild type 1 fiber predominance, type 2B fiber deficiency and slightly increased acid phosphatase activity. Complete ophthalmoplegia may thus be seen not only in myotubular myopathy but also in various forms of congenital non-progressive myopathy.     

Respiratory muscle involvement in nemaline myopathy

A boy who had experienced generalized muscle weakness and hypotonia since early infancy was diagnosed as having nemaline myopathy on the basis of muscle biopsy at 3 years of age. At 8 years of age, he developed severe respiratory failure and required respiratory support during sleep. Because of recurrent pneumothorax, he underwent thoracic surgery, at which time biopsy specimens were obtained from the respiratory and truncal muscles. The histologic findings of the respiratory muscles included marked variation in fiber size with a notable increase in fibrous tissue, type 2 fiber deficiency, elevated acid phosphatase activity, and a disorganized intermyofibrillar network. The findings from the truncal muscles were similar to those of the biceps brachii muscle: little variation in fiber size, numerous nemaline bodies in all fibers, and type 1 fiber predominance. The preferential damage to the respiratory muscles was probably responsible for the sudden onset of severe respiratory failure.     

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.     

King-Denborough Syndrome: report of two Brazilian cases

We report on two boys aged 2 and 6 years-old respectively with dysmorphic face, ptosis, down-slanting palpebral fissures, hypertelorism, epicanthic folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, palmar simian line, pectus excavatum, winging of the scapulae, lumbar lordosis and mild thoracic scoliosis who present congenital hypotonia, slightly delayed motor development, diffuse joint hyperextensibility and mild proximal weakness. The muscle biopsy revealed minimal but identifiable changes represented by size fiber variability, type I fiber predominance and atrophy, perimysial fibrous infiltration and some disarray of the intermyofibrillary network. These cases correspond to the first Brazilian reports of the King-Denborough syndrome and our objective is increasing the awareness of this disorder as these patients are predisposed to developing malignant hyperthermia.     

Fingerprint inclusions. Ultrastructural demonstration of muscle fiber type specificity.

Fingerprint inclusions were identified in the skeletal muscle of a child with severe hypotonia. The mean Z-line and M-line widths from each of 19 muscle fibers containing the fingerprint inclusions were calculated. The mean Z-line widths were 85-99 nm, and the mean M-line widths were 75-101 nm. According to out present system of fiber typing, all of these fibers would be classified as Type I. The possible pathogenesis and fiber type specificity of the fingerprint inclusion is discussed.     

Concentric laminated bodies. Ultrastructural demonstration of muscle fiber type specificity.

Concentric laminated bodies were identified in the skeletal muscle of 3 children affected by muscle weakness and hypotonia with probable cerebral involvement. The mean Z-line and M-line widths from each of 11 muscle fibers containing the concentric laminated bodies were calculated. The mean Z-line widths were 61-81 nm and the mean M-line widths from 7 out of 11 fibers were 54-65 nm. According to our present system of fiber typing, the majority of these fibers would be classified as subtype IIB. The possible pathogenesis and fiber type specificity of the concentric laminated body is discussed.     

Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case report

A Japanese boy had marked generalized hypotonia and weakness and progressive respiratory failure since birth. Left biceps brachii muscle biopsy at 47 days of age showed marked variation in muscle fiber size, and nemaline and/or cytoplasmic bodies in approximately 10% of the muscle fibers. To our knowledge, the presence of nemaline and cytoplasmic bodies in the same muscle has not been previously reported. The severity of his respiratory failure and muscle weakness were thought to be related to muscle immaturity since there were many undifferentiated type 2C fibers.     

Neonatal ophthalmoplegia with microfibers: a reversible myopathy?

An infant born with marked hypotonia showed prompt regression of skeletal muscle weakness, but by 7 weeks of age had total external ophthalmoplegia. Biopsy of the gluteus muscle at 14 days showed marked variation in fiber size with a large proportion of very small fibers (less than 3 mu). By 10 months of age, biopsy of the vastus was virtually normal. The inferior oblique muscle was replaced by fibrous tissue containing a few remaining degenerating fibers. The child was normal at 2 years of age except for mild facial weakness and ophthalmoplegia. This syndrome may be the result of a reversible intrauterine process.     

Congenital fiber type disproportion: severe form with marked improvement.

A 30-month-old male exhibited marked hypotonia at birth accompanied by respiratory distress necessitating ventilator support. He subsequently demonstrated marked improvement in muscle power. He became independent of the respirator at 21 days of age and was able to sit without support at 11 months and walked alone at 24 months. Histopathologic analysis of the quadriceps femoris muscle confirmed the diagnosis of congenital fiber type of disproportion at 11 months of age. No other studies have described a patient with a severe neonatal form of congenital fiber type of disproportion who demonstrated such clear improvement. Physicians should be aware of this possibility when they interact with such patients and their families.     

Congenital focal muscle dysplasia in the lower extremities from probable abnormal innervation: a case report.

A two-year-seven-month-old girl with pes equinovarus congenita, muscle hypotonia and weakness limited to the lower extremities is presented. Upon admission to our hospital, she could stand with support but could not walk alone. Serum creatine kinase level was normal and the electromyogram was nondiagnostic. The muscle CT disclosed an almost total absence of bilateral vastus lateralis and medialis, rectus femoris and gastrocnemius muscles. The biopsied vastus lateralis muscle was almost completely replaced by fat tissue, and a small amount of muscle tissue showed uniform type 1 fiber and an aggregate of atrophic fibers in one fascicle. Because of an absence of progressive muscle weakness and neurogenic EMG findings, the authors conclude that the muscle pathology was due to the congenital anomalous condition of probable abnormal innervation to developing muscles.     

Congenital muscular dystrophy with severe infantile scoliosis

A girl with congenital muscular dystrophy with severe scoliosis from birth was presented. No positive family history was obtainable. She developed muscle hypotonia and weakness, and feeding difficulty during the neonatal period. Her developmental milestones were delayed; she learned to walk at the age of 2 years when she walked with a "waddling gait" and stood up with Gowers' maneuver. On physical examination at 2 years old, she had mild proximal dominant muscle weakness and atrophy, and severe scoliosis with a Cobb's angle of 74 degrees but no joint contractures in the extremities. Creatine kinase was slightly elevated. Biopsied muscle showed myopathic changes, including variation in fiber size, moderate fibrous tissue proliferation, some necrotic and regenerating fibers and type 1 fiber predominance, consistent with those seen in chronic progressive muscular dystrophy.     

Clinical and histologic changes in the follow-up of a congenital myopathy

A 19-year-old woman was born with congenital hypotonia, generalized weakness, and dysmorphic features. A muscle biopsy performed at age 18 months found that type I fibers were smaller and more numerous than type II fibers, and she was diagnosed with congenital fiber type disproportion. She grew up with moderate motor impairment, but after a stationary period her weakness progressed gradually and she developed a severe ophthalmoplegia. When she was 18 years old a second muscle biopsy still indicated the predominance of type I fibers but also the presence of central nuclei and strong oxidative enzyme activity in the center of most of the fibers; this was compatible with centronuclear myopathy. The diagnostic reconsideration raises questions about the pathogenesis of these diseases and the recognition of congenital fiber type disproportion as a distinct nosologic entity.     

Nemaline myopathy and a mitochondrial neuromuscular disorder in one family

A family composed of parents and four children is reported. Two brothers presented from early infancy with hypotonia and non-progressive weakness. Muscle biopsy in both revealed numerous typical nemaline rods. The father, suffering from backache, had a slow MNCV of both common peroneal nerves. His muscle revealed variation in fiber size, splitting, type 1 atrophy and numerous pleomorphic mitochondria with crystalline inclusions. The mother's muscle showed type 2 atrophy, foci of myofibrillar degeneration, and lipofuscin bodies. In a 12-year-old daughter and a 5-year-old son the muscle revealed an excess of small, bizarre mitochondria and lipid droplets. The coexistence of nemaline myopathy and a mitochondrial neuromuscular disorder in one family has never been reported in the literature. It might be a coincidence of two rare muscle disorders in one family, or it might be the polymorphic expression of a single etiological factor causing a defect in protein synthesis.     

Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset

We report four heterozygous dynamin 2 (DNM2) mutations in five centronuclear myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related centronuclear myopathy from the classic mild form to the more severe neonatal phenotype.     

Type III collagen deficient EDS IV producing muscular hypotonia with abnormal muscle fibroblasts.

Muscle biopsy and fibroblast culture of a floppy child with Ehlers-Danlos syndrome type IV were studied. Biochemical analysis of the tissue showed drastically reduced amount of collagen type III. Electron microscopic examination of muscle as well as of cultured fibroblasts showed grossly dilated and dominated the cytoplasm endoplasmic reticulum. Dilatation may result from storage of an abnormal collagen type III molecule. Our observations indicate that type III collagen deficiency may be present clinically as a congenital muscle hypotonia. Specific ultrastructural abnormalities of fibroblasts found in muscle biopsy can enable the proper diagnosis.     

Novel autosomal dominant TPM3 mutation causes a combined congenital fibre type disproportion-cap disease histological pattern

Tropomyosin 3 (TPM3) gene mutations associate with autosomal dominant and recessive nemaline myopathy 1 (NEM1), congenital fiber type disproportion myopathy (CFTD) and cap myopathy (CAPM1), and a combination of caps and nemaline bodies. We report on a 47-year-old man with polyglobulia, restricted vital capacity and mild apnea hypopnea syndrome, requiring noninvasive ventilation. Physical assessment revealed bilateral ptosis and facial paresis, with high arched palate and retrognathia; global hypotonia and diffuse axial weakness, including neck and upper and lower limb girdle and foot dorsiflexion weakness. Whole body MRI showed a diffuse fatty replacement with an unspecific pattern. A 122 gene NGS neuromuscular disorders panel revealed the heterozygous VUS c.709G>A (p.Glu237Lys) on exon 8 of TMP3. A deltoid muscle biopsy showed a novel histological pattern combining fiber type disproportion and caps. Our findings support the pathogenicity of the novel TPM3 variant and widen the phenotypic gamut of TMP3-related congenital myopathy.     

Congenital hypotonia with favorable outcome

Congenital hypotonia with favorable outcome is characterized by an early neonatal onset and a benign clinical course. The old term, proposed by Walton, was benign congenital hypotonia, denoting the presence of muscle weakness and hypotonia, with the exception of Werdnig-Hoffmann disease. It has been clear that this term includes congenital myopathies with definite changes in the muscle fiber. However, many cases remain unclarified. The term congenital hypotonia with favorable outcome includes only these last cases. A long-term follow-up study of children with congenital hypotonia with favorable outcome is presented, and a hypothetical mechanism underlying muscle shortening is discussed. The study was carried out at the Department of Child Neuropsychiatric Sciences, University “La Sapienza” of Rome, during the period 1985-2000, and included 41 patients with congenital hypotonia. Our study confirms the good prognosis of congenital hypotonia with favorable outcome and suggests a correlation with joint hyperlaxity, which is observed in many parents of our children, as if the latter developed from the former. On the basis of experimental changes occurring in the muscles, we believe that in our cohort the main cause of shortening is caused by an increase in joint mobility, which keeps muscles shortened in both the passive and active states for a long time. If this view is confirmed by other studies, we suggest continuous muscle exercise as a preventive treatment.