Clinical course correlates poorly with muscle pathology in nemaline myopathy.

OBJECTIVE: To report pathologic findings in 124 Australian and North American cases of primary nemaline myopathy. METHODS: Results of 164 muscle biopsies from 124 Australian and North American patients with primary nemaline myopathy were reviewed, including biopsies from 19 patients with nemaline myopathy due to alpha-actin (ACTA1) mutations and three with mutations in alpha-tropomyosin(SLOW) (TPM3). For each biopsy rod number per fiber, percentage of fibers with rods, fiber-type distribution of rods, and presence or absence of intranuclear rods were documented. RESULTS: Rods were present in all skeletal muscles and diagnosis was possible at all ages. Most biopsies contained nemaline bodies in more than 50% of fibers, although rods were seen only on electron microscopy in 10 patients. Rod numbers and localization correlated poorly with clinical severity. Frequent findings included internal nuclei and increased fiber size variation, type 1 fiber predominance and atrophy, and altered expression of fiber type specific proteins. Marked sarcomeric disruption, increased glycogen deposition, and intranuclear rods were associated with more severe clinical phenotypes. Serial biopsies showed progressive fiber size variation and increasing numbers of rods with time. Pathologic findings varied widely in families with multiple affected members. CONCLUSIONS: Very numerous nemaline bodies, glycogen accumulation, and marked sarcomeric disruption were common in nemaline myopathy associated with mutations in skeletal alpha-actin. Nemaline myopathy due to mutations in alpha-tropomyosin(SLOW) was characterized by preferential rod formation in, and atrophy of, type 1 fibers. Light microscopic features of nemaline myopathy correlate poorly with disease course. Electron microscopy may correlate better with disease severity and genotype.

Nemaline myopathy: a clinical study of 143 cases.

We report 143 Australian and North American cases of primary nemaline myopathy. As classified by the European Neuromuscular Centre guidelines, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset nemaline myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Twenty-two patients had skeletal muscle actin mutations and 4 had mutations in the alpha-tropomyosin(slow) gene. Obstetric complications occurred in 49 cases. Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital nemaline myopathy.

Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children.

OBJECTIVE: To identify the clinical and neuroradiologic features of acute disseminated encephalomyelitis (ADEM) in childhood. METHODS: A retrospective review was conducted of the medical records and MRI of children who presented to the Royal Children's Hospital in Melbourne with ADEM between January 1993 and December 1998. RESULTS: Of the 31 patients included in this study, 22 (71%) experienced a prodromal illness. Two patients (6%) had received hepatitis B vaccine 3 to 6 weeks before developing their illness. Symptoms and signs typically evolved over several days. Ataxia was the most common presenting feature, occurring in 20 patients (65%). MRI findings were variable, but lesions were most commonly seen bilaterally and asymmetrically in the frontal and parietal lobes. The authors found a high incidence of the corpus callosal and periventricular changes more typically associated with MS, but they also found a high rate of deep gray matter involvement (61% of patients). The use of high-dose IV methylprednisolone was usually associated with rapid recovery. Eighty-one percent of patients recovered completely, with only mild sequelae recorded in the remaining children. CONCLUSION: In the absence of a biological marker, the distinction between ADEM and MS cannot be made with certainty at the time of first presentation, but the authors suggest that a viral prodrome, early-onset ataxia, high lesion load on MRI, involvement of the deep gray matter, and absence of oligoclonal bands are more indicative of ADEM.

Benign acute childhood myositis: laboratory and clinical features.

BACKGROUND: Benign acute myositis of childhood is a disorder of midchildhood, typically affecting boys. Symptoms include calf pain and difficulty walking after a viral illness. There is an epidemiologic association with influenza. OBJECTIVES: To describe the clinical and laboratory features of benign acute myositis. RESULTS: Thirty-eight children (32 boys, 6 girls) were seen with 41 episodes of myositis between 1978 and 1997. Two were siblings and three had recurrent episodes. Mean age at onset of symptoms was 8.1 years. Children remained ambulant during 33 of 41 episodes. Two characteristic gaits were noted: toe-walking in 13, with a wide-based stiff-legged gait in another 7. Muscle tenderness was isolated to the gastrocnemius-soleus muscles in 82% of episodes. Recovery occurred within 1 week. Creatine kinase levels were elevated during all episodes. Viral studies were positive in 10 of 24 episodes, 5 because of influenza B. CONCLUSION: Benign acute myositis is a syndrome of midchildhood that can be differentiated from more serious causes of walking difficulty by the presence of calf tenderness, normal power, intact tendon reflexes, and elevated creatine kinase. The gait patterns noted may minimize power generation of the calf muscles by splinting the ankles. Onset in childhood may reflect an age-related response to viral infection, and occurrence primarily in boys may reflect a genetic predisposition or an as-yet unknown metabolic defect.

The mitochondrial DNA C3303T mutation can cause cardiomyopathy and/or skeletal myopathy.

OBJECTIVE: Several mutations in mitochondrial DNA have been associated with infantile cardiomyopathy, including a C3303T mutation in the mitochondrial transfer RNA(Leu(UUR)) gene. Although this mutation satisfied generally accepted criteria for pathogenicity, its causative role remained to be confirmed in more families. Our objective was to establish the frequency of the C3303T mutation and to define its clinical presentation. STUDY DESIGN: Families with cardiomyopathy and maternal inheritance were studied by polymerase chain reaction/restriction fragment length polymorphism analysis looking for the C3303T mutation. RESULTS: We found the C3303T mutation in 8 patients from 4 unrelated families. In one, the clinical presentation was infantile cardiomyopathy; in the second family, proximal limb and neck weakness dominated the clinical picture for the first 10 years of life, when cardiac dysfunction became apparent; in the third family, 2 individuals presented with isolated skeletal myopathy and 2 others with skeletal myopathy and cardiomyopathy; in the fourth family, one patient had fatal infantile cardiomyopathy and the other had a combination of skeletal myopathy and cardiomyopathy. CONCLUSIONS: Our findings confirm the pathogenicity of the C3303T mutation and suggest that this mutation may not be rare. The C3303T mutation should be considered in the differential diagnosis of skeletal myopathies and cardiomyopathy, especially when onset is in infancy.

Detection of Epstein-Barr virus (EBV) genomes in the serum of patients with EBV-associated Hodgkin's disease.

DNA from malignant cells is present in the serum/plasma of cancer patients and DNA from this source is amenable to analysis by polymerase chain reaction (PCR). In the present study, we evaluated whether Epstein-Barr virus (EBV) DNA is present in the serum of patients with EBV-associated Hodgkin's disease (HD). Using conventional PCR, EBV DNA was detected in serum from 30/33 patients with EBV-associated HD but in only 6/26 patients with non-EBV-associated disease (p < 0.001). Samples from healthy individuals were negative and only 5/12 infectious mononucleosis samples were positive. Real-time quantitative PCR was subsequently employed to determine the concentration of EBV DNA present in serum; among positive samples the level ranged from 1 to 705 copies per 125 microliter of serum. Post-treatment samples from 5/14 cases with EBV-associated HD contained detectable EBV DNA; analysis of this small group of cases suggests that positivity in post-treatment samples correlates with risk factors indicative of a poor prognosis. Overall, our results are consistent with the notion that DNA from Reed-Sternberg cells is present in the serum of HD patients, and further suggest that serum EBV should be evaluated as a prognostic marker. Int. J. Cancer (Pred. Oncol.) 84:442-448, 1999.

Bethlem myopathy and engineered collagen VI triple helical deletions prevent intracellular multimer assembly and protein secretion.

Mutations in the genes that code for collagen VI subunits, COL6A1, COL6A2, and COL6A3, are the cause of the autosomal dominant disorder, Bethlem myopathy. Although three different collagen VI structural mutations have previously been reported, the effect of these mutations on collagen VI assembly, structure, and function is currently unknown. We have characterized a new Bethlem myopathy mutation that results in skipping of COL6A1 exon 14 during pre-mRNA splicing and the deletion of 18 amino acids from the triple helical domain of the alpha1(VI) chain. Sequencing of genomic DNA identified a G to A transition in the +1 position of the splice donor site of intron 14 in one allele. The mutant alpha1(VI) chains associated intracellularly with alpha2(VI) and alpha3(VI) to form disulfide-bonded monomers, but further assembly into dimers and tetramers was prevented, and molecules containing the mutant chain were not secreted. This triple helical deletion thus resulted in production of half the normal amount of collagen VI. To further explore the biosynthetic consequences of collagen VI triple helical deletions, an alpha3(VI) cDNA expression construct containing a 202-amino acid deletion within the triple helix was produced and stably expressed in SaOS-2 cells. The transfected mutant alpha3(VI) chains associated with endogenous alpha1(VI) and alpha2(VI) to form collagen VI monomers, but dimers and tetramers did not form and the mutant-containing molecules were not secreted. Thus, deletions within the triple helical region of both the alpha1(VI) and alpha3(VI) chains can prevent intracellular dimer and tetramer assembly and secretion. These results provide the first evidence of the biosynthetic consequences of structural collagen VI mutations and suggest that functional protein haploinsufficiency may be a common pathogenic mechanism in Bethlem myopathy.

Congenital muscular dystrophy, white-matter abnormalities, and neuronal migration disorders: the expanding concept.

The congenital muscular dystrophies are a heterogeneous, recessively inherited group of disorders that have been subclassified on the basis of clinical central nervous system involvement. We report two children with "pure" congenital muscular dystrophy, one merosin negative and one merosin positive with extensive white matter and occipital cortical neuromigration abnormalities on magnetic resonance imaging (MRI). The first patient (merosin-negative congenital muscular dystrophy) presented with hypotonia and weakness in the neonatal period and subsequently was found to have a leukoencephalopathy and occipital cortical dysplasia on magnetic resonance imaging. The second patient presented with developmental delay without definite weakness. Initial investigations revealed a leukoencephalopathy and cortical dysplasia, but the patient subsequently was shown to have merosin-positive congenital muscular dystrophy. These patients illustrate that white-matter changes are not specific for merosin-negative congenital muscular dystrophy alone and that extensive cortical abnormality can be found in both groups of patients. In addition, our second patient illustrates a nonmuscular mode of congenital muscular dystrophy presentation that should be considered in patients with a "nonprogressive leukodystrophy."

Benign intracranial hypertension and recombinant growth hormone therapy in Australia and New Zealand.

Benign intracranial hypertension (BIH) is reported in three children from Australia and one from New Zealand, who were being treated with recombinant human growth hormone (rhGH). Three males and one female, aged between 10.5 and 14.2 y, developed intracranial hypertension within 2 weeks to 3 months of starting treatment. A national database, OZGROW, has been prospectively collecting data on all 3332 children treated with rhGH in Australia and New Zealand from January 1986 to 1996. The incidence of BIH in children treated with growth hormone (GH) is small, 1.2 per 1000 cases overall, but appears to be greater with biochemical GHD (<10 IU ml(-1)), i.e. 6.5/1000 (3 in 465 cases), relative risk 18.4, 95% confidence interval 1.9-176.1, than in all other children on the database. The incidence in patients with Turner's syndrome was 2.3/1000 (1 in 428 cases). No cases in patients with partial GHD (10-20 IU ml(-1)) or chronic renal failure were identified. Possible causative mechanisms are discussed. The authors' practice is now to start GH replacement at less than the usual recommended dose of 14 IU m(-2) week(-1) in those children considered to be at high risk of developing BIH. Ophthalmological evaluation is recommended for children before and during the first few months following commencement of rhGH therapy and is mandatory in the event of peripheral or facial oedema, persistent headaches, vomiting or visual symptoms. The absence of papilloedema does not exclude the diagnosis.

Lack of involvement of known oncogenic DNA viruses in Epstein-Barr virus-negative Hodgkin's disease.

Epstein-Barr virus (EBV) is associated with around one-third of cases, but young adult cases are rarely EBV associated. In this study, known oncogenic DNA viruses, including human adenoviruses, papovaviruses and the human herpesviruses-6 (HHV-6) and -8 (HHV-8) were not detected in Hodgkin's disease lesions. These results suggest that an as yet unidentified infectious agent is involved in the pathogenesis of non-EBV-associated Hodgkin's disease.

Paroxysmal tonic upgaze: a reappraisal of outcome.

Paroxysmal tonic upgaze (PTU) of childhood is a distinctive neuro-ophthalmological syndrome of unknown etiology and pathogenesis that is characterized by episodes of sustained upward deviation of the eyes, often with incomplete downward saccades on attempted downgaze. It is generally regarded as having a benign outcome. We observed 16 children with PTU, from 10 months to 11 years from onset (mean, 5.4 years), to study the natural history and possible etiology. Five cases were from two unrelated families. Onset of PTU occurred either during or after an intercurrent infection or vaccination in 5 children. No antecedent was identifiable in the rest. PTU had completely resolved in 10 children (62%) (mean age at offset, 2.5 years), whereas 2 children intermittently manifest a modified form of the disorder. At follow-up, 11 children (69%) had developmental delay, intellectual disability, or language delay and 9 (56%) had ocular motility problems other than PTU. Only 3 children (19%) had normal development and neurological findings. PTU is a heterogeneous syndrome with respect to associations and outcome and may simply be an age-dependent manifestation of a variety of disorders affecting corticomesencephalic control of vertical eye movement. This disorder may be an early sign of more widespread neurological dysfunction.

Muscle abnormalities in idiopathic toe-walkers.

The cause of toe-walking is unknown. Muscle biopsies were taken from a group of 25 toe-walkers who were treated at this hospital to try to identify the pathological cause of the condition. The most common abnormality noted was an increase in the proportion of type I muscle fibers with type grouping; other less common changes included the presence of angulated atrophic fibers and thickened capillaries and cases in which occasional fibers were undergoing active degeneration and regeneration. The combination of these changes suggests that there may be an underlying neuropathic process in idiopathic toe-walkers.

Childhood chronic inflammatory demyelinating neuropathies: clinical course and long-term follow-up.

Chronic inflammatory demyelinating neuropathy (CIDP) is a rare disease in childhood. We reviewed the clinical characteristics, response to therapy, and long-term prognosis in 13 children (1.5 to 16 years of age) diagnosed with CIDP at Washington University Medical Center, St. Louis, and the Royal Children's Hospital, Melbourne, Australia, between 1979 and 1994. The most common presenting symptom (in 11/13 [85%]) was lower extremity weakness associated with difficulty in walking. Preceding events within 1 months of onset, mostly intercurrent infections or vaccinations, occurred in seven children (54%). The disease was monophasic in three children (23%). One relapse occurred in four (30%) and multiple relapses in six (46%). All patients had at least short-term response to steroids. Three children (23%) recovered completely during the first year. Ten children (77%) had residual weakness after an average follow-up of 6 years. There seems to be two populations of children with CIDP. One subgroup, with a favorable prognosis, progressed to peak disability over less than 3 months; these children often have a monophasic course with complete resolution of symptoms and signs and withdrawal from all medications by 1 year after onset. A second subgroup progressed for 3 months or longer; these children all required substantial does of prednisone for prolonged periods and had considerable long-term morbidity with persistent weakness.

Sinusitis and intracranial sepsis: the CT imaging and clinical presentation.

The CT imaging and clinical presentation in 14 children with coexistent intracranial sepsis and sinusitis were reviewed. A routine CT head scan (10-mm thick semi-axial slices through the cranium done before and after intravenous contrast medium administration) was found to be an inadequate initial investigation as the intracranial collection was missed in four patients and the abnormal sinuses not shown in six. In half the children the diagnosis of sinusitis was unsuspected at the time of admission. The dominant clinical features were fever, intense headache and facial swelling in early adolescent males. In this clinical setting we recommend: (1) the routine scan is extended through the frontal and ethmoidal sinuses and photographed at a window level and width showing both bone detail and air/soft tissue interfaces; (2) direct coronal projections are performed through the anterior cranial fossa if no collection is seen on the routine study; (3) an early repeat scan within 48 h if the initial study shows no intracranial pathology but the fronto-ethmoidal sinuses are abnormal and there is a high clinical suspicion of intracranial sepsis; and (4) in the presence of intracranial sepsis the vault is viewed at bone window settings to exclude cranial osteomyelitis.

Frontal lobe epilepsy: clinical seizure characteristics and localization with ictal 99mTc-HMPAO SPECT.

We evaluated ictal 99mtechnetium hexamethyl propylene-amine-oxime single-photon emission computed tomography (SPECT) in 22 children with electroclinical features of frontal lobe epilepsy (FLE). Ictal SPECT demonstrated unilateral frontal hyperperfusion in 20 of 22 children (91%) (one lobar, two frontocentral, six dorsolateral, six frontopolar, three orbitofrontal, one medial frontal, and one insula), concordant with electroclinical lateralization in 19 of 20 (95%). Hyperperfusion was evident in the ipsilateral basal ganglia in 16 of 22 (73%) and the contralateral cerebellum in 14 of 22 children (64%). Interictal SPECT showed unilateral, localized frontal hypoperfusion concordant with electroclinical lateralization in only two of 22 children (9%). Ictal SPECT localization to the frontocentral, media frontal, or dorsolateral regions was associated with asymmetric tonic posturing, contralateral head/eye deviation, and unilateral clonic jerking (p < 0.01). Ictal SPECT localization to the frontopolar or orbitofrontal regions was associated with vocalization, hyperventilation, truncal flexion, and complex gestural automatisms (p > or = 0.05). Ictal SPECT has the potential to (1) localize seizures in patients with intractable FLE, and (2) advance understanding of the in vivo anatomico-clinical relationships of frontal lobe seizures.

Ictal 99mTc-HMPAO single photon emission computed tomography in children with temporal lobe epilepsy.

Seventeen ictal 99mTc-HMPAO single photon emission computed tomography (SPECT) studies were performed in 15 children with temporal lobe epilepsy (TLE) aged 7-14 years (mean 10.3 years). Ictal SPECT was informative in 16 of 17 (94%) studies in 14 of 15 (93%) children, showing unilateral temporal lobe hyperperfusion. In all 16 informative ictal SPECT studies, lateralization was concordant with ictal EEG, magnetic resonance imaging (MRI), and pathology. In 4 children, ictal SPECT provided additional localizing information that was not apparent from concurrent ictal EEG recording. Blinded interpretation of ictal SPECT studies by two independent investigators showed correct lateralization of the epileptic focus in every child. Results of visual analysis of ictal SPECT images were corroborated by quantitative analysis. Although interictal SPECT studies showed a degree of temporal lobe hypoperfusion in all children, in 9 of 15 hypoperfusion was either minimal, bilateral, contralateral, or associated with extratemporal hypoperfusion. In children with TLE, ictal SPECT provides reliable lateralizing information to corroborate or supplement that obtained from surface EEG and MRI.

Subacute sclerosing panencephalitis presenting as simple partial seizures.

Subacute sclerosing panencephalitis is reported in a 16-year-old girl with a 2 1/2-year history of right-sided simple partial sensory and motor seizures. The seizures were verified with video-electroencephalographic monitoring, showing left frontal epileptic activity. After an initial response to antiepileptic medication, her seizures became intractable, and mild, right-hemisphere signs developed. Magnetic resonance imaging showed an extensive right-hemisphere infiltrative lesion, thought to be a neoplasm. Cortical brain biopsy raised the possibility of subacute sclerosing panencephalitis, and this was confirmed serologically. The case highlights the importance of considering subacute sclerosing panencephalitis in the differential diagnosis of intractable seizures and demonstrates that strikingly asymmetrical magnetic resonance imaging abnormalities are not inconsistent with this diagnosis.