Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei.

We studied 19 symptomatic female carriers of the Duchenne muscular dystrophy (DMD) gene. Most of these dystrophinopathy patients had had an erroneous or ambiguous diagnosis prior to dystrophin immunofluorescence testing. We assessed clinical severity by a standardized protocol, measured X-chromosome inactivation patterns in blood and muscle DNA, and quantitated the dystrophin protein content of muscle. We found that patients could be separated into two groups: those showing equal numbers of normal and mutant dystrophin genes in peripheral blood DNA ("random" X-inactivation), and those showing preferential use of the mutant dystrophin gene ("skewed" X-inactivation). In the random X-inactivation carriers, the clinical phenotype ranged from asymptomatic to mild disability, the dystrophin content of muscle was > 60% of normal, and there were only minor histopathologic changes. In the skewed X-inactivation patients, clinical manifestations ranged from mild to severe, but the patients with mild disease were young (5 to 10 years old). The low levels of dystrophin (< 30% on average) and the severe symptoms of the older patients suggested a poor prognosis for those with skewed X-inactivation, and they all showed morphologic changes of dystrophy. The random inactivation patients showed evidence of biochemical "normalization," with higher dystrophin content in muscle than predicted by the number of normal dystrophin genes. Seventy-nine percent of skewed X-inactivation patients (11/14) showed genetic "normalization," with proportionally more dystrophin-positive nuclei in muscle than in blood. In 65% of the skewed X-inactivation patients, dystrophin was not produced by dystrophin-positive nuclei; an average of 20% of myofiber nuclei were genetically dystrophin-positive but did not produce stable dystrophin. Biochemical normalization seems to be the main mechanism for rescue of fibers from dystrophin deficiency in the random X-inactivation patients. In the skewed X-inactivation patients, genetic normalization is active, but production failure of dystrophin by dystrophin-normal nuclei may counteract any effect of biochemical normalization. In the skewed X-inactivation patients, the remodeling of the muscle through cycles of degeneration and regeneration led to threefold increase in the number of dystrophin-competent nuclei in muscle myofibers (3.3 +/- 4.6), while dystrophin content was on the average 1.5-fold less then expected (-1.54 +/- 3.38). Our results permit more accurate prognistic assessment of isolated female dystrophinopathy patients and provide important data with which to estimate the potential effect of gene delivery (gene therapy) in DMD.

Selective type II muscle fiber hypertrophy in severe infantile spinal muscular atrophy.

The diagnostic muscle biopsy finding in severe infantile spinal muscular atrophy (Werdnig-Hoffmann disease, SMA type 1) is considered to be large-group atrophy with isolated clusters of hypertrophic type I myofibers. We present a unique case of severe infantile spinal muscular atrophy with selective hypertrophy of type II myofibers. A male infant presented at age 2 months with breathing difficulties and by age 4 months was hypotonic and weak. Electromyography revealed denervation in all extremity muscles, and nerve conduction velocities were normal but with small compound muscle action potentials. Quadriceps muscle biopsy revealed many hypertrophied type II myofibers (myofibers with a mean least diameter of 25.4 microns). In contrast, the largest type I myofibers were 20 microns in least diameter (mean diameter, 14.9 microns), and there was a normal-size population of type II fibers (mean diameter, 15.7 microns). In addition, sheets of atrophic type I and type II fibers averaged 2.0 microns in least diameter. Sural nerve biopsy was normal. Breathing difficulties progressed, with death ensuing at age 5 1/2 months. Autopsy revealed atrophy of ventral spinal roots with normal dorsal roots. There was loss of anterior horn cells, while remnant neurons were reduced in size. No other pathologic changes were identified. This case indicates that in severe infantile spinal muscular atrophy, relative sparing of the motor units with type II myofibers may occur.

HLA patterns in children with parainflammatory leukoencephalomyelitis.

We have evaluated the human leukocyte antigen (HLA) phenotype of six children with parainflammatory leukoencephalomyelitis (PIL). Patients with PIL demonstrate an increased prevalence of the HLA-A1, -A28, -B44, -DR6, and -DR7 antigens. These HLA associations are different from those reported in other inflammatory demyelinating diseases, including multiple sclerosis, optic neuritis, Guillain-Barré syndrome, and chronic relapsing inflammatory polyneuropathy. The HLA constitution of the patient appears to be one important host factor in determining the nature of the immune response to an encephalitogenic challenge.

An adult-onset myopathy characterized by a double ring appearance of muscle fibers.

We report a 33-yr-old man with an unusual neuromuscular disorder characterized by progressive generalized weakness of 3 yr duration whose muscle biopsy showed a double ring appearance in most muscle fibers. This double ring appearance was due to a peripheral outer sarcoplasmic mass and an inner ring of annular myofibrils surrounding a core of normal longitudinally oriented myofibrils. Nerve conduction studies were normal. Electromyography showed fibrillations, positive waves, and increased brief duration, low amplitude, polyphasic potentials.

Bacterial meningitis: an update.

Antibiotics and improvements in supportive care have greatly reduced the mortality from bacterial meningitis. Nevertheless, the incidence of neurodevelopmental sequelae remains unacceptably high. Ampicillin and chloramphenicol remain the standard for antimicrobial therapy against which other agents must be compared. A number of adjunct therapies are being investigated for their possible effectiveness in reducing hearing loss and other neurologic effects of this disease. There continues to be a need for carefully performed follow-up studies to assess any possible benefit of these agents. A significant percentage of children surviving an episode of bacterial meningitis have obvious or subtle neurodevelopmental deficits. The role of the pediatric neurologist should not end with management of acute problems such as seizures but should be expanded to aid in close developmental monitoring of these high-risk children.

Neuroimaging findings in Alexander's disease.

We present the findings from magnetic resonance imaging, computed tomographic scan, and single photon emission computed tomography of the brain in a 2-year-old girl with Alexander's disease. Computed tomographic scans showed prominent low-density white matter throughout the cerebral hemispheres. Magnetic resonance imaging showed increased T2 signal from the cerebral white matter but not the cerebellum or brain stem. Single photon emission computed tomography revealed diminished cerebral metabolism, particularly in the frontal regions, as compared with the cerebellum.

Acidophil stem-cell pituitary adenoma in a prepubescent female. Case report.

Acidophil stem-cell pituitary adenomas account for less than 5% of pituitary tumors. Only 15 cases have previously been reported, with a mean age of occurrence of 38.7 years. A case of this unusual tumor is reported in a prepubertal girl. Clinical symptoms included prominent behavioral disturbance with associated headache and visual disturbance. There was marked elevation of serum growth hormone concentration without clinical features of growth hormone excess, suggesting that this tumor has the capacity to excrete biologically inactive hormones. The clinical and pathological features of this unusual invasive pituitary tumor are reviewed; the age spectrum for this neoplasm must be expanded to include prepubertal children.

Cerebral degenerations producing dementia: importance of neuropathologic confirmation of clinical diagnoses.

Dementia is a major public health concern with our increasing elderly population and currently affects more than three million Americans at an annual cost of $50 billion. The marked overlap in symptomatology between Alzheimer's disease and other primary parenchymal degenerations makes antemortem diagnosis based on clinical assessment tentative at best, with error rates of 25% commonly reported. Accurate diagnosis is of vital importance in order to improve our understanding of these illnesses, evaluate potential therapies, and provide appropriate genetic counseling to family members. Direct neuropathologic examination at autopsy is currently the only reliable method for assuring accurate diagnosis, and should be undertaken in all demented patients. To illustrate the importance of these principles, we present three patients who were clinically diagnosed with Alzheimer's disease, and subsequently found to have other dementing illnesses by careful postmortem neuropathologic examination.

Macro cisterna magna: a marker for maldevelopment of the brain?

Enlargement of the cisterna magna occurs in as many as 0.4% of reported patients and generally has been believed to represent a normal variant. Differentiation from Dandy-Walker malformations and other cystic structures has been emphasized. We reviewed 1,260 consecutive computed tomography reports in patients younger than 21 years of age and examined all scans in which enlargement of the cisterna magna was considered an isolated finding. Fourteen patients were identified (incidence: 1%). The primary reasons for obtaining computed tomographic scans included various clinical conditions but excluded symptoms indicative of posterior fossa disease. Developmental or neurologic abnormalities were present in 62% of these patients. Macro cisterna magna should not be dismissed as a normal variant, although the neurologic findings may not be specifically localized to the posterior fossa. This finding may be a marker for abnormal brain function most likely due to subtle disturbances in brain development.

Gastritis with valproate therapy.

We have identified ten children who developed gastritis after prolonged anticonvulsant therapy that included either valproic acid or divalproex sodium. Presenting symptoms were primarily feeding difficulties, including anorexia and refusal to eat. Vomiting was present in two thirds of the patients, with diarrhea, weight loss, and abdominal pain occurring less frequently. Occult blood in stool samples was a late development. All patients responded to therapy with H2-receptor antagonists, oral antacids, or both, with prolonged treatment often necessary to prevent relapse. Although gastrointestinal tract side effects are common with the initiation of valproate sodium therapy, feeding difficulties after long-term treatment are less common. Gastritis should be suspected in children receiving valproate therapy when feeding difficulties arise, particularly if the symptoms are persistent or recurrent.

Parainflammatory leukoencephalomyelitis: clinical and magnetic resonance imaging findings.

Parainflammatory leukoencephalomyelitis is a broad term used to include the spectrum of disorders that affect the central nervous system following infection, immunization, or other noxious stimuli. There is a wide range of clinical and pathologic severity, ranging from acute cerebellar ataxia to acute hemorrhagic leukoencephalopathy. With the improved survival of these patients, magnetic resonance imaging provides a window to the pathologic process, which can aid in the long-term management of these patients. Although lesions of the brainstem and spinal cord correlate well to clinical symptoms, multiple cortical lesions may be present without specific localizing signs. The distribution of magnetic resonance lesions is different from that commonly seen in multiple sclerosis. In some cases, prolonged immunosuppression may be required to prevent recrudescence of the inflammatory response.

Infantile botulism.

We present the first two known cases of infantile botulism in Oklahoma. The first case was due to type B toxin; the second was due to type A toxin. Both cases demonstrate most of the classic features of what now appears to be the most common form of botulism. Infantile botulism is an underrecognized but reversible cause of hypotonia. In most cases, the prognosis is excellent with institution of appropriate supportive care. The recognition of cranial nerve palsies or a history of constipation should raise the suspicion of infantile botulism. Aminoglycoside antibiotics and other agents that may precipitate or exacerbate neuromuscular blockade should be used with extreme caution in hypotonic infants until the cause of the hypotonia is clearly identified.

Anterior cervical epidural abscess with pneumococcus in an infant.

Spinal epidural abscess is a rare infection in childhood. We report the first documented case of pneumococcal epidural abscess in an infant and review the literature regarding this entity. In children, the signs and symptoms of spinal epidural abscess may not be as helpful as those in older patients. Furthermore, the offending organism may not be the usual Staphylococcus seen in adults. Infants may recover neurologic function even after prolonged cord compression; however, a high index of suspicion is needed to make the diagnosis in a timely fashion.

Cefuroxime versus ampicillin plus chloramphenicol in childhood bacterial meningitis: a multicenter randomized controlled trial.

In a multicenter randomized trial, 107 children with bacterial meningitis were initially given either cefuroxime or ampicillin plus chloramphenicol. Patients were alternately assigned to 7- or 10-day courses of the designated antimicrobial regimen. CSF isolates included Haemophilus influenzae type b (89, of which 25% were beta-lactamase positive), Streptococcus pneumoniae, and Neisseria meningitidis. Although mean CSF bactericidal titers against Haemophilus isolates were 1:6 in each treatment group, H. influenzae was cultured from CSF in four of 39 patients receiving cefuroxime, 24 to 48 hours after initiation of therapy, compared with none of 40 patients given ampicillin plus chloramphenicol (P = 0.11). Clinical cure rates were similar (95%); one death occurred in each group. One child given cefuroxime had persistent meningitis after 5 days of therapy, and mastoiditis with secondary bacteremia developed in one on day 10. Three patients had relapse or reinfection. One patient who received cefuroxime for 10 days had a relapse of epiglottitis 17 days later, and of the patients given ampicillin plus chloramphenicol, one had a relapse of meningitis 1 week after 7 days of therapy, and bacteremia developed in one 42 days after completion of 10 days of therapy. No increase in either in-hospital complications or relapses occurred with a 7-day treatment course. Proof of the equivalence of the antibiotic regimens and the efficacy of 7-day courses of treatment, as well as the consequences of delayed CSF sterilization, will require additional investigation.