Primary Hodgkin lymphoma of the central nervous system: two case reports and review of the literature.

CNS involvement by systemic Hodgkin lymphoma (HL) is quite rare, but the disease limited to the CNS is an exceptionally rare entity. The incidence of CNS-HL has been estimated at 0.2-0.5% of cases, but a more recent study has modified that figure to less than 0.02%. Like the conventional form, the diagnosis of primary CNS-HL rests upon distinct morphological and immunohistochemical characteristics, including diagnostic Reed-Sternberg cells, in addition to staging studies demonstrating a lack of disease elsewhere. The paucity of cases in the literature precludes reliable clinical and demographic data, as well as a consensus on treatment and prognosis. We present two cases of primary cerebellar HL, one with 10-year follow-up, and a relevant review of the literature.

Increased disease severity of parasite-infected TLR2-/- mice is correlated with decreased central nervous system inflammation and reduced numbers of cells with alternatively activated macrophage phenotypes in a murine model of neurocysticercosis.

In a murine model for neurocysticercosis (NCC), intracranial inoculation of the helminth parasite Mesocestoides corti induces multiple Toll-like receptors (TLRs), among which TLR2 is upregulated first and to a relatively high extent. Here, we report that TLR2(-/-) mice displayed significantly increased susceptibility to parasite infection accompanied by increased numbers of parasites in the brain parenchyma compared to infection in wild-type (WT) mice. This coincided with an increased display of microglial nodule formations and greater neuropathology than in the WT. Parasite-infected TLR2(-/-) brains exhibited a scarcity of lymphocytic cuffing and displayed reduced numbers of infiltrating leukocytes. Fluorescence-activated cell sorter (FACS) analyses revealed significantly lower numbers of CD11b(+) myeloid cells, γδ T cells, αß T cells, and B cells in the brains of parasite-infected TLR2(-/-) mice. This correlated with significantly reduced levels of inflammatory mediators, including tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), CCL2, CCL3, and interleukin-6 (IL-6) in the central nervous system (CNS) of TLR2(-/-) mice. As TLR2 has been implicated in immune regulation of helminth infections and as alternatively activated macrophages (AAMs) are thought to play a profound regulatory role in such infections, induction of AAMs in infected TLR2(-/-) mice was compared with that in WT mice. Parasite-infected WT brains showed larger numbers of macrophages/microglia (CD11b(+) cells) expressing AAM-associated molecules such as YM1, Fizz1 (found in inflammatory zone-1 antigen), and arginase 1 than TLR2(-/-) brains, consistent with a protective role of AAMs during infection. Importantly, these results demonstrate that TLR2-associated responses modulate the disease severity of murine NCC.

MyD88-deficient mice exhibit decreased parasite-induced immune responses but reduced disease severity in a murine model of neurocysticercosis.

The symptomatic phase of neurocysticercosis (NCC), a parasitic disease of the central nervous system (CNS) in humans, is characterized by inflammatory responses leading to neuropathology and, in some cases, death. In an animal model of NCC in which mice were intracranially inoculated with the parasite Mesocestoides corti, the infection in mice lacking the myeloid differentiation primary response gene 88 (MyD88(-/-)) resulted in decreased disease severity and improved survival compared with that in wild-type (WT) mice. The CNS of MyD88(-/-) mice was more quiescent, with decreased microgliosis and tissue damage. These mice exhibited substantially reduced primary and secondary microglial nodule formations and lacked severe astrogliotic reactions, which were seen in WT mice. Significantly reduced numbers of CD11b(+) myeloid cells, alphabeta T cells, gammadelta T cells, and B cells were present in the brains of MyD88(-/-) mice in comparison with those of WT mice. This decrease in cellular infiltration correlated with a decrease in blood-brain barrier permeability, as measured by reduced fibrinogen extravasation. Comparisons of cytokine expression indicated a significant decrease in the CNS levels of several inflammatory mediators, such as tumor necrosis factor alpha, gamma interferon, CCL2, and interleukin-6, during the course of infection in MyD88(-/-) mice. Collectively, these findings suggest that MyD88 plays a prominent role in the development of the hyperinflammatory response, which in turn contributes to neuropathology and disease severity in NCC.

Survival and invasiveness of astrocytomas promoted by erythropoietin.

OBJECT: The hypoxia-inducible pleiotropic hormone, erythropoietin (EPO), has recently been found to promote the development and survival of neurons and astrocytes. Since hypoxia has been implicated in the malignant progression of some human cancers, the authors investigated whether EPO signaling influenced the malignant properties of human astrocytoma cells. METHODS: Reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemical studies were used to measure EPO and its receptor (EPOR). Cell viability, Matrigel invasion assays, metalloprotease assays, EPO neutralizing antibodies, and EPOR overexpression were used to study the biological actions of EPO. Expression of both EPO and EPOR was observed in the hypoxic regions and invasive margins of glioma specimens obtained at biopsy, and expression of EPOR correlated with the stage of the tumor. The EPOR was also functionally upregulated by hypoxia in cultured glioblastoma multiforme (GBM) cells. Both hypoxia and EPO protected cultured GBM cells from cisplatin cytotoxicity and promoted the invasiveness of GBM cells through Matrigel by potentiating metalloprotease activity. Hypoxia-enhanced cell invasion was attenuated in cells that overexpressed a nonfunctional EPOR. CONCLUSIONS: Hypoxia-inducible autocrine and paracrine EPO signaling participates in the malignant progression of GBMs.

Ultrasound-accelerated tissue fixation/processing achieves superior morphology and macromolecule integrity with storage stability.

We demonstrate that high-frequency and high-intensity ultrasound (US) can be applied to both tissue fixation and tissue processing to complete the conventional overnight formalin-fixation and paraffin-embedding (FFPE) procedures within 1 hr. US-facilitated FFPE retains superior tissue morphology and long-term room temperature storage stability than conventional FFPE. There is less alteration of protein antigenicity after US-FFPE preservation so that rapid immunohistochemical reactions occur with higher sensitivity and intensity, reducing the need for antigen retrieval pretreatment. US-FFPE tissues present storage stability so that room temperature storage up to 7 years does not significantly affect tissue morphology, protein antigenic properties, RNA distribution, localization, and quantitation. In addition, during fixation, tissue displays physical changes that can be monitored and reflected as changes in transmission US signals. As far as we know, this is the first effort to monitor tissue physical changes during fixation. Further study of this phenomenon may provide a method to control and to monitor the level of fixation for quality controls. The mechanism of less alteration of protein antigenicity by US-FFPE was discussed.

The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.

The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids. Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions). Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype. We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects. Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis. Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.

More than hypomyelination in Pol-III disorder.

The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of 2 genes responsible for the syndrome demonstrates that these 3 main characteristics can be variably combined among "Pol-III (polymerase III)-related leukodystrophies." The pathophysiology of this group of diseases is still to be elucidated, and there are no neuropathologic descriptions of brain tissue. We report the clinical, neuroradiologic, and neuropathologic findings of a patient affected by 4H syndrome with confirmed POLR3A mutations. We found a marked loss of oligodendrocytes, varying in severity in different brain regions, and accompanied by severe loss of myelin, moderately severe loss of axons, and patchy perivascular regions of better preserved white matter. There was relatively mild white matter astrogliosis and microgliosis. A macrophage reaction involving viable normal-appearing oligodendroglia suggests the possibility of an immunologic process in this disorder. Cortical laminar astrogliosis and mineralization of Layers I and II in particular were present. Thus, despite the uniformly hypomyelinating pattern seen on magnetic resonance imaging, neuropathologic examination reveals a complex heterogeneous leukodystrophy with prominent neuroaxonal and glial involvement in this disorder.

Osteolipoma of the parapharyngeal space mimicking liposarcoma: a case report.

BACKGROUND: Lipomas are the most common benign neoplasm of the head and neck. However, osteolipomas, a rare variant of lipoma, are uncommon in this location. When they occur, variations in location and radiographic presentation may obscure the diagnosis. METHODS AND RESULTS: A 68-year-old man presented with left jaw pain and numbness in the maxillary (V-1) distribution. A CT angiography of the neck revealed a possible liposarcoma. Embolization of the mass was determined to be unfeasible. Consequently, surgical resection was performed revealing a benign osteolipoma. CONCLUSION: We report a rare case of osteolipoma of the parapharyngeal space. Clinicians should be aware that the clinical and radiological features of patients with head and neck osteolipomas may mimic malignant neoplasms. When given deserved consideration, inappropriate treatment of an otherwise benign lesion may be avoided.

Long-term radiosurgery effects in the treatment of temporal lobe epilepsy.

Epilepsy surgery is an effective treatment for medically resistant temporal lobe epilepsy (TLE). To minimize complication rates and potentially improve neuropsychology outcomes, stereotactic radiosurgery (SRS) has been explored as an alternative. Two pilot trials have demonstrated the effectiveness of SRS for the treatment of medically resistant TLE, with seizure-free outcomes for approximately 65% of patients at last follow-up. Despite encouraging results, no conclusive long-term outcomes are available for SRS. This article discusses a single patient who presented with recurrent seizures, worsening headaches, and persistent abnormal MRI findings 7 years and 8 months after SRS. This 29-year-old woman with a history of medically refractory complex partial seizures since childhood was referred for evaluation. Medical management had failed in this patient. The workup was compatible with left mesial temporal lobe onset, with MRI findings suggestive of mesial temporal sclerosis. In 2003, at the age of 23 years, she underwent Gamma Knife surgery (GKS) targeting the left temporal mesial area with a dose of 24 Gy at the 50% marginal isodose line. After GKS, the patient's seizures decreased in frequency over several months, but auras were persistent. Nine months after treatment, she developed worsening headaches. A follow-up MRI study demonstrated a thick, irregular, enhancing lesion in the medial part of the temporal lobe. She was placed on corticosteroids, with resolution of her headaches. Her seizures and headaches recurred in March 2010. An MRI study showed a 2.2-cm, ill-defined, enhancing cystic lesion in the left mesial temporal lobe with T2 and FLAIR hyperintensity, which was presumably radiation induced. At that time, the patient opted for left temporal lobe resection to control her seizures. Histological examination showed moderately severe, remote, longstanding sclerosis at the level of the hippocampus. A vascular lesion was identified, and it was most consistent with radiation-induced capillary hemangioma. The entorhinal region was severely damaged, with hemorrhage, necrosis, neuronal loss, astrogliosis, and hemosiderin deposition. There was evidence of radiation vasculopathy. Radiation-induced lesions after SRS for the treatment of epilepsy are not well documented. Although GKS is a promising technique for the treatment of medically resistant TLE, the ideal candidate is not yet well defined. The selection of the appropriate technical parameters to obtain a desirable functional effect without histological damage to the surrounding neural tissue remains a challenge. This case illustrates the need for long-term follow-up when radiosurgery is used for epilepsy.

Efficacy of temporal lobe surgery for epilepsy in patients with negative MRI for mesial temporal lobe sclerosis.

Epilepsy surgery is a successful treatment for refractory temporal lobe epilepsy (TLE). Reports suggest fewer seizure-free outcomes for patients with TLE and who have a negative brain MRI (nMRI) for mesial temporal sclerosis. Data were collected prospectively from patients with nMRI who underwent temporal lobe surgery for TLE characterized by unilateral ictal temporal lobe seizure onset based on a scalp video electroencephalogram or invasive subdural electrode recordings. A total of 86 patients were followed for at least 24 months after surgery. Outcome was evaluated using the Engel classification. Seizure control was obtained by 55% (47/86) of patients (Class [CL]-I), 27% (23/86) showed significant improvement (CL-II) and 19% (16/86) were deemed surgical failures. Shorter duration of epilepsy, later onset of seizures, and ictal theta rhythm (5-7 Hz) were the most significant predictors of postoperative seizure control. Although hypometabolism on positron emission tomography scan and significant memory disparity (>2.5/8) were not significant prognosticators independently, cumulatively they were predictors for favorable outcome.

Management of the great mimicker: Meckel cave tumors.

BACKGROUND: Meckel cave tumors are often asymptomatic and have a sufficiently characteristic magnetic resonance imaging/computed tomography signature that allows treatment/surveillance decisions to be made without biopsy confirmation. Radiographic diagnosis requires the surgeon to be fully aware of the plethora of unusual Meckel cave lesions that mimic benign tumors when they are malignant, inflammatory, or infectious and in need of a completely different and often timely intervention. When such a diagnosis is considered, it behooves the surgeon and benefits the patient to have a percutaneous biopsy technique available. OBJECTIVE: To use our recent experience with a patient with idiopathic inflammatory sensory neuropathy and another with Meckel cave lymphoma to review the management of tumors of the Meckel cave. METHODS: The technique of percutaneous biopsy of Meckel cave tumors through the foramen ovale with biopsy needles is detailed. CONCLUSION: Obtaining tissue biopsy percutaneously prevents patients with Meckel cave tumors best treated with nonsurgical management from undergoing open surgical resection with its concomitant morbidity.

Trimyelia with divergent cord pathways and three foramina magni.

OBJECT: We report the rare finding of trimyelia with divergent cord pathways in a 33 5/7-week-old fetus who died shortly after spontaneous vaginal delivery. METHODS: The main autopsy findings were three separate and distinct spinal cords, arising from the medulla and exiting through three separate foramina magni. The two lateral cords coursed toward each upper extremity and the medulla split into two halves that rejoined to form a central cervical cord. Further evaluation of this anomaly revealed agenesis of the cerebellar vermis and cystic dilation of the fourth ventricle. Microscopic cross-sections of the two lateral cords demonstrated well-formed central canals, white matter, and central gray with motor neurons. Sections of the abnormal mid-cervical cord demonstrated abnormally structured cord parenchyma without central canals. CONCLUSIONS: Some features were consistent with iniencephaly; however, defects of the occipital bone, anterior spina bifida, and shortening of the spinal cord were absent. Although agenesis of the cerebellar vermis and cystic dilation of the fourth ventricle indicate Dandy-Walker syndrome, other features such as hydrocephalus, agenesis of the corpus callosum, infundibular hamartomas, and malformations of the inferior olives or an occipital encephalocele were absent. The possible pathogenesis of this intriguing pathological entity is briefly discussed.

Primary extraneural myxopapillary ependymoma of the broad ligament.

Primary extraneural ependymomas are rare tumors that arise in ectopic sites, including pulmonary, sacrococcygeal region, ovarian, and paraovarian tissues. Four such ependymomas reported in the literature involve the paraovarian tissues, including 2 broad ligament ependymomas. Here we describe a myxopapillary ependymoma of the broad ligament in a 22-year-old woman, which may be the first tumor of this type to be reported in this location. Cytology, histology, cytochemistry, immunohistochemistry, and flow cytometry ploidy analysis are studied and described. Identification of perivascular ependymal rosettes, ependymal canals, vimentin and glial fibrillary acidic protein immunoreactivity, cytochemical staining of blepharoplasts or terminal bars by phosphotungstic acid hematoxylin, and presence of multiple foci of myxoid degeneration among the ependymal rosettes characterized a myxopapillary ependymoma.

Ultrasound-accelerated formalin fixation of tissue improves morphology, antigen and mRNA preservation.

Formalin fixation and paraffin embedding are conventional tissue preservation and processing methods used for histologic diagnosis in over 90% of cases. However, formalin fixation has three disadvantages: (1) slow fixation (16-24 h) hinders intraoperative decision making, (2) slow quenching of enzymatic activity causes RNA degradation, and (3) extensive molecule modification affects protein antigenicity. Applying high-frequency, high-intensity ultrasound to the formalin fixative cuts fixation time to 5-15 min. Fixation of various tissues such as lymph node, brain, breast, and prostate suggests that, compared to the conventional method, implementation of ultrasound retains superior and more uniform tissue morphology preservation. Less protein antigenicity is altered so that rapid immunohistochemical reactions occur with higher sensitivity and intensity, reducing the need for antigen retrieval pretreatment. Better RNA preservation results in stronger signals in in situ hybridization and longer RNA fragments extracted from fixed tissues, probably due to rapid inhibition of endogenous RNase activity. Molecules extracted from ultrasound-fixed tissues are of greater integrity and quantity compared to conventionally fixed tissues, and thus better support downstream molecular analyses. Overall, ultrasound-facilitated tissue preservation can provide rapid and improved morphological and molecular preservation to better accommodate both traditional and molecular diagnoses.

Spinal cord malignant astrocytomas. Clinicopathologic features in 36 cases.

BACKGROUND: Malignant astrocytomas of the spinal cord are uncommon neoplasms with a dismal prognosis. To the authors' knowledge, little information has been published to date regarding the prognostic impact of clinicopathologic factors. METHODS: The authors studied 36 cases to investigate the prognostic effect of the World Health Organization (WHO) tumor grade, tumor localization, cell proliferative activity, p53 expression, and therapy. RESULTS: Sixteen patients (44%) underwent biopsy alone, 11 (31%) underwent subtotal resection, and 7 (19%) underwent macroscopic total excision. For two patients, there were no data available regarding surgical treatment. Among the 36 patients (mean age, 32.4 years), there were 23 males (63%) and 13 (36%) females. Their initial biopsies showed 21 (63%) glioblastoma multiforme (GBM) cases (WHO Grade 4), 13 (36%) anaplastic astrocytomas (AA) (WHO Grade 3), and 2 (6%) astrocytomas (A) (WHO Grade 2). After initial surgery, 10 (29%) patients were treated with radiation therapy alone and 7 (19%) received radiation therapy with chemotherapy. Patterns of disease recurrence included extraneural metastases (two cases), brain metastases (five cases), local extension (one case), and diffuse spread along the neuraxis (six cases). Two A (100%) and six AA (46%) cases progressed to GBM. The overall median survival time was 33 months (range, 24-42 months) for A, 10 months (range, 1-84 months) for AA, and 10 months (range, 1-43 months) for GBM. CONCLUSIONS: Patients older than 40 years have a shorter survival period compared with younger patients. There is a high risk of central nervous system dissemination in patients with this disease.

Monocytic fasciitis: a newly recognized clinical feature of tumor necrosis factor receptor dysfunction.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a dominantly inherited autoinflammatory syndrome that results from mutations in TNFRSF1A, the gene that encodes the 55-kd tumor necrosis factor receptor. Clinically, patients present with recurrent episodes of fever in conjunction with localized inflammation at various sites. Myalgia is one of the most characteristic features of this syndrome and is frequently associated with an overlying erythematous, macular rash that, together with the myalgia, displays centrifugal migration. This has previously been believed to occur as a result of myositis. We describe herein the case of a 60-year-old man with TRAPS, in whom magnetic resonance imaging of the left thigh demonstrated edematous changes in the muscle compartments and surrounding soft tissues. A full-thickness wedge biopsy was performed, and hematoxylin and eosin staining and immunohistochemistry analysis of the specimen demonstrated normal myofibrils but a severely destructive monocytic fasciitis. These results suggest that the myalgia experienced by individuals with TRAPS is due to a monocytic fasciitis and not to myositis.

Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.

Cree leukoencephalopathy is a rapidly fatal infantile autosomal recessive leukodystrophy of unknown cause observed in the native North American Cree and Chippewayan indigenous population. We found in the brain of affected individuals the typical foamy cells with the oligodendroglial phenotype described in central hypomyelination syndrome/vanishing white matter, a syndrome related to mutations in the genes encoding the five subunits of the eucaryotic translation initiation factor eIF2B. In three patients of two Cree families, we found a homozygous missense mutation resulting in a histidine substitution at arginine 195 of epsilon-eIF2B.

Neuropathology provides clues to the pathophysiology of Gaucher disease.

To better understand the pathogenesis of brain dysfunction in Gaucher disease (GD), we studied brain pathology in seven subjects with type 1 GD (four also exhibited parkinsonism and dementia), three with type 2 GD and four with type 3 GD. Unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. While these findings were common to all three GD phenotypes, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all GD patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as type 1 GD had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal (45)Ca(2+) uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium release sensitive (CICR-sensitive). These findings match recent biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity. In two patients with type 1 GD and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD.

Insertion of mutant proteolipid protein results in missorting of myelin proteins.

Two brothers with a leukodystrophy, progressive spastic diplegia, and peripheral neuropathy were found to have proteinaceous aggregates in the peripheral nerve myelin sheath. The patients' mother had only subclinical peripheral neuropathy, but the maternal grandmother had adult-onset leukodystrophy. Sequencing of the proteolipid protein (PLP) gene showed a point mutation IVS4 + 1 G-->A within the donor splice site of intron 4. We identified one transcript with a deletion of exon 4 (Deltaex4, 169bp) encoding for PLP and DM20 proteins and lacking two transmembrane domains, and a second transcript with exon 4 + 10bp encoding three transmembrane domains. Immunohistochemistry showed abnormal aggregation in the myelin sheath of MBP and P0. Myelin-associated glycoprotein was present in the Schmidt-Lanterman clefts but significantly reduced in the periaxonal region. Using immunogold electron microscopy, we demonstrated the presence of mutated PLP/DM20 and the absence of the intact protein in the patient peripheral myelin sheath. We conclude that insertion of mutant PLP/DM20 with resulting aberrant distribution of other myelin proteins in peripheral nerve may constitute an important mechanism of dysmyelination in disorders associated with PLP mutations.