ABSTRACT
BACKGROUND: Histiocytosis, both Langerhans and non-Langerhans cell type, can be associated with cerebellar white matter abnormalities, thought to be paraneoplastic. The associated clinical picture consists of ataxia, spasticity, and cognitive decline. Hormonal dysfunction is frequent. MRI shows cerebellar white matter abnormalities, as well as brainstem and basal ganglia abnormalities. This so-called "neurodegenerative syndrome" may occur years before or during manifest histiocytosis and also years after cure. We discovered similar MRI abnormalities in 13 patients and wondered whether they could have the same syndrome. METHODS: We reviewed the clinical and laboratory information of these 13 patients and evaluated their brain MRIs. Seven patients underwent spinal cord MRI. RESULTS: All patients were isolated cases; 10 were male. They had signs of cerebellar and pyramidal dysfunction, behavioral problems, and cognitive decline. MRI showed abnormalities of the cerebellar white matter, brainstem, basal ganglia, and, to a lesser extent, cerebral white matter. Three patients had spinal cord lesions. Three patients had laboratory evidence of hormonal dysfunction. No evidence was found of an underlying metabolic defect. In two patients biopsy of nodular brain lesions revealed histiocytic infiltrates. CONCLUSIONS: Considering the striking clinical and MRI similarities between our patients and the patients with this neurodegenerative syndrome in the context of proven histiocytosis, it is likely that they share the same paraneoplastic syndrome, although we cannot exclude a genetic disorder with certainty. The fact that we found histiocytic lesions in two patients substantiates our conclusion. Patients with cerebellar white matter abnormalities should be monitored for histiocytosis.
Subject(s)
Cerebellar Diseases/diagnosis , Histiocytosis/diagnosis , Posterior Leukoencephalopathy Syndrome/diagnosis , Adult , Cerebellar Ataxia/complications , Cerebellar Ataxia/diagnosis , Cerebellar Ataxia/pathology , Cerebellar Diseases/complications , Cerebellar Diseases/pathology , Child , Female , Histiocytosis/complications , Histiocytosis/pathology , Humans , Magnetic Resonance Imaging/methods , Male , Posterior Leukoencephalopathy Syndrome/complications , Posterior Leukoencephalopathy Syndrome/pathology , Retrospective StudiesABSTRACT
Multiple congenital anomalies/mental retardation syndromes due to genomic rearrangements involving chromosome 17p11.2 include deletion resulting in Smith-Magenis syndrome and a reciprocal duplication of the same region resulting in the 17p11.2 duplication syndrome. We present the clinical and molecular analysis of an 8-year-old male with a dup(17p11.2p12) who was evaluated for unusual severity of the phenotype. Fluorescent in situ hybridization (FISH) analysis not only confirmed the 17p duplication but also identified an approximately 25% mosaicism for tetrasomy 17p11.2p12. Whole-genome array comparative genomic hybridization (aCGH) was performed to identify other genomic rearrangements possibly contributing to the severe phenotype and the unusual features in the patient. The 17p duplication was determined by FISH and aCGH to encompass approximately 7.5 Mb, from COX10 to KCNJ12. An approximately 830 Kb deletion of 17q11.2q12, including exon 1 of an amiloride-sensitive cation channel neuronal gene, ACCN1, was also identified by aCGH; breakpoints of the deletion were confirmed by FISH. Sequencing the non-deleted allele of ACCN1 did not show any mutations. Western analysis of human tissue-specific proteins revealed that ACCN1 is expressed not only in the brain as previously reported but also in all tissues examined, including heart, liver, kidneys, and spleen. The large-sized 17p11.2p12 duplication, partial triplication of the same region, and the 17q11.2q12 deletion create a complex chromosome 17 rearrangement that has not been previously identified. This is the first case of triplication reported for this chromosome. Our study emphasizes the utility of whole-genome analysis for known cases with deletion/duplication syndromes with unusual or severe phenotypes.
Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 17/genetics , Intellectual Disability/genetics , Acid Sensing Ion Channels , Amino Acid Sequence , Base Sequence , Child , Chromosome Deletion , DNA Primers/genetics , Degenerin Sodium Channels , Epithelial Sodium Channels/genetics , Genotype , Humans , In Situ Hybridization, Fluorescence , Male , Molecular Sequence Data , Nerve Tissue Proteins/genetics , Phenotype , Sequence Homology, Amino Acid , SyndromeABSTRACT
A 10-year-old boy developed corticosteroid-responsive relapsing neurologic signs, including nystagmus and ataxia. MRI revealed multifocal T2 white matter hyperintensities; several were gadolinium-enhancing. CSF contained oligoclonal bands. Although the patient met criteria for multiple sclerosis (MS), the proteolipid protein-1 gene (PLP1) contained a mutation in exon 3B (c.409C>T), predicting a tryptophan-for-arginine substitution. This case raises questions about the role of inflammation in PLP1-related disorders and, conversely, PLP1 mutations in MS.
Subject(s)
Genetic Predisposition to Disease/genetics , Membrane Proteins/genetics , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Multiple Sclerosis, Relapsing-Remitting/genetics , Mutation/genetics , Myelin Proteolipid Protein/genetics , Steroids/therapeutic use , Amino Acid Substitution/genetics , Central Nervous System/metabolism , Central Nervous System/pathology , Central Nervous System/physiopathology , Cerebellar Diseases/genetics , Cerebellar Diseases/immunology , Cerebellar Diseases/physiopathology , Child , DNA Mutational Analysis , Disease Progression , Exons/genetics , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/physiopathology , Interferon beta-1a , Interferon-beta/therapeutic use , Magnetic Resonance Imaging , Male , Methylprednisolone/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/immunology , Neuroprotective Agents/therapeutic use , Oligoclonal Bands/cerebrospinal fluid , Remission Induction , Treatment OutcomeABSTRACT
Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene encoding myelin proteolipid protein (PLP). Analysis of mutations affecting PLP, the major protein in central nervous system myelin, has revealed previously unsuspected roles for myelinating glia in maintaining the integrity of the nervous system. The disease spectrum for PMD and SPG2 is extraordinarily broad and can be best understood by accounting not only for the wide range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells. Appreciating the wide range of genetic and cellular effects of PLP1 mutations is important for patient and family counseling, understanding disease pathogenesis, and, ultimately, for developing future disease-specific therapies.
Subject(s)
Myelin Proteolipid Protein/genetics , Pelizaeus-Merzbacher Disease/genetics , Pelizaeus-Merzbacher Disease/metabolism , Animals , Axons/physiology , Central Nervous System/cytology , Central Nervous System/metabolism , Central Nervous System/physiopathology , Humans , Mutation , Myelin Proteolipid Protein/chemistry , Myelin Proteolipid Protein/metabolism , Myelin Sheath/physiology , Neuroglia/physiology , Neurons/physiology , Pelizaeus-Merzbacher Disease/physiopathologyABSTRACT
In vivo and in vitro studies have shown that alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor-mediated excitotoxicity causes cytoskeletal damage to axons. AMPA/kainate receptors are present on oligodendrocytes and myelin, but currently there is no evidence to suggest that axon cylinders contain AMPA receptors. Proteolipid protein (PLP) and DM20 are integral membrane proteins expressed by CNS oligodendrocytes and located in compact myelin. Humans and mice lacking normal PLP/DM20 develop axonal swellings and degeneration, suggesting that local interactions between axons and the oligodendrocyte/myelin unit are important for the normal functioning of axons and that PLP/DM20 is involved in this process. To determine whether perturbed glial-axonal interaction affects AMPA-receptor-mediated axonal damage, AMPA (1.5 nmol) was injected into the caudate nucleus of anesthetized Plp knockout and wild-type male mice (n = 13). Twenty-four hours later, axonal damage was detected by using neurofilament 200 (NF 200) immunohistochemistry and neuronal damage detected via histology. AMPA-induced axonal damage, assessed with NF 200 immunohistochemistry, was significantly reduced in Plp knockout mice compared with wild-type mice (P = 0.015). There was no significant difference in the levels of neuronal perikaryal damage between the Plp knockout and wild-type mice. In addition, there was no significant difference in the levels of glutamate receptor subunits GluR1-4 or KA2 in Plp knockout compared with wild-type littermates. The present study suggests that PLP-mediated interactions among oligodendrocytes, myelin, and axons may be involved in AMPA-mediated axonal damage.
Subject(s)
Axons/drug effects , Brain Injuries/chemically induced , Excitatory Amino Acid Agonists/toxicity , Myelin Proteolipid Protein/deficiency , Nerve Tissue Proteins/deficiency , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/toxicity , Animals , Axons/metabolism , Axons/pathology , Blotting, Western/methods , Brain Injuries/pathology , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/physiology , Immunohistochemistry/methods , Male , Mice , Mice, Mutant Strains , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Receptors, Glutamate/genetics , Receptors, Glutamate/metabolismABSTRACT
Fourteen consecutive clinically definite relapsing-remitting multiple sclerosis (MS) patients were treated with monthly intravenous cyclophosphomide (CTX) for 6 months. All had experienced severe dinical deterioration during the 12 months prior to treatment with CTX despite treatment with conventional immunomodulating agents and intravenous methylprednisolone. Treatment with CTX led to improvement and neurologic stability within 6 months which was sustained for at least 18 months after the onset of treatment with CTX. Therapy with CTX was well tolerated. CTX may be of benefit in MS patients who experience rapid clinical worsening and are resistant to conventional therapy.
Subject(s)
Cyclophosphamide/administration & dosage , Immunosuppressive Agents/administration & dosage , Multiple Sclerosis/drug therapy , Adult , Female , Humans , Injections, Intravenous , Male , Middle Aged , Treatment OutcomeABSTRACT
A prospective, non-randomized, open-label treatment trial was performed in patients with relapsing-remitting multiple sclerosis (RRMS), with follow up for 12 months. Our primary objective was to prospectively compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and glatiramer acetate (GA, Copaxone) on the relapse rate in patients with RRMS. Between August 1996 and September 1999, 156 consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 12 months, from the time of initiating therapy or electing to remain untreated. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrolment. Thirty-three of 156 elected no treatment (mean age 32.5 years; mean EDSS 2.64) at enrolment; 40 elected IFNbeta-1a (mean age 32.4 years; mean EDSS 2.69), 41 IFNbeta-1b (mean age 32.1 years; mean EDSS 2.56), and 42 chose GA (mean age 31.5 years; mean EDSS 2.57). Annual relapse rate based upon the 2 years prior to enrolment was 1.08 in the untreated group, 1.20 in the AV group, 1.21 in the BE group, and 1.10 in the GA group. There were no statistically significant differences among the four groups at enrolment. After 12 months of treatment, patients in the untreated groups had a relapse rate of 0.97, whereas patients in the IFNbeta-1a, IFNbeta-1b, and GA groups had relapse rate of 0.85, 0.61, and 0.62, respectively. Compared to the untreated group, reduction in the relapse rate was statistically significant only in the GA (P=0.003) and IFNbeta-1b (P=0.002) groups, in contrast to the IFNbeta-1a treated patients, who did not show a significant reduction (P=0.309). Compared to the untreated patients, mean EDSS was significantly reduced only in the GA (P=0.001) and IFNbeta-1b (P=0.01), in contrast to IFNbeta-1a treated patients (P=0.51). In this prospective, controlled, open-label, non-randomized 12-month study, treatment with only GA and IFNbeta-1b significantly reduced the relapse rate compared to untreated patients, supporting early treatment in RRMS. Our results are similar to the observations made after 12 months of therapy in phase III studies of IFNbeta-1a, IFNbeta-1b, and GA. Despite some limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment-naïve RRMS patients.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Interferon-beta/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Peptides/therapeutic use , Adult , Female , Glatiramer Acetate , Humans , Interferon beta-1a , Interferon beta-1b , Male , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Prospective Studies , Recurrence , Severity of Illness Index , Treatment OutcomeABSTRACT
We previously reported results of a 12 month prospective, non-randomized, open-label treatment trial of immunomodulatory therapy in patients with relapsing-remitting multiple sclerosis (RRMS). We now report the results after 18 months of follow-up. Our primary objective was to compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and Glatiramer Acetate (GA, Copaxone) to no treatment on the relapse rate in patients with RRMS. One hundred and fifty-six consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 18 months. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrollment Thirty-three of 156 elected no treatment at enrollment; 40 elected IFNbeta-1a, 41 IFNbeta-1b, and 42 chose GA. There were no statistically significant differences among the four groups at enrollment. After 18 months of treatment 122 patients remained in their original treatment group. Compared to the untreated group (1.02), mean annualized number of relapses was significantly reduced only in the GA (0.49, P>0.0001) and IFNbeta-1b groups (0.55, P=0.001) in contrast to the IFNbeta-1a treated patients (0.81, P=0.106) who did not show a significant reduction. Despite limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment naive RRMS patients.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Immunosuppressive Agents/therapeutic use , Interferon-beta/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Peptides/therapeutic use , Adult , Disability Evaluation , Female , Glatiramer Acetate , Humans , Interferon beta-1a , Interferon beta-1b , Male , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Prospective Studies , Secondary Prevention , Time FactorsABSTRACT
Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disorder of the central nervous system typically caused by duplications or missense mutations of the proteolipid protein (PLP) gene. Most investigators have found that peripheral nerve function and structure is normal in PMD patients. We have found that null mutations of the PLP gene cause demyelinating peripheral neuropathy, whereas duplications and a proline 14 to leucine mutation do not affect nerve function. A family with a nonsense mutation at position 144, which affects only PLP but not the alternatively spliced gene product DM20, has a very mild syndrome, including normal peripheral nerve function. Our findings suggest that DM20 alone is sufficient to maintain normal nerve function and that there may be domains of PLP/DM20 that have a relatively more active role in the peripheral nervous system compared with that in the central nervous system.
Subject(s)
Myelin Proteolipid Protein/genetics , Nerve Fibers, Myelinated/pathology , Pelizaeus-Merzbacher Disease/genetics , Peripheral Nerves/pathology , Amino Acid Sequence , Animals , Family , Female , Humans , Male , Mice , Models, Molecular , Molecular Sequence Data , Mutation , Myelin Proteolipid Protein/chemistry , Nerve Fibers, Myelinated/ultrastructure , Pelizaeus-Merzbacher Disease/pathology , Peripheral Nerves/ultrastructure , Protein ConformationABSTRACT
Alternative products of the proteolipid protein gene (PLP), proteolipid protein (PLP) and DM20, are major components of compact myelin in the central nervous system, but quantitatively minor constituents of Schwann cells. A family with a null allele of PLP has a less severe CNS phenotype than those with other types of PLP mutations. Moreover, individuals with PLP null mutations have a demyelinating peripheral neuropathy, not seen with other PLP mutations of humans or animals. Direct analysis of normal peripheral nerve demonstrates that PLP is localized to compact myelin. This and the clinical and pathologic observations of the PLP null phenotype indicate that PLP/DM20 is necessary for proper myelin function both in the central and peripheral nervous systems.
Subject(s)
Central Nervous System/metabolism , Cerebral Cortex/pathology , Demyelinating Diseases/genetics , Myelin Proteins/metabolism , Myelin Proteolipid Protein/genetics , Peripheral Nervous System/metabolism , Adolescent , Adult , Child , Child, Preschool , Demyelinating Diseases/metabolism , Humans , Magnetic Resonance Imaging , Middle Aged , Myelin Proteins/physiology , Myelin Proteolipid Protein/physiology , PedigreeABSTRACT
Gerstmann-Sträussler-Scheinker disease (GSS) is caused by several different point mutations of the prion protein (PrP) gene, each of which generally produces a distinct clinical phenotype. An ataxic form of GSS is genetically linked to a mutation at codon 102 (CCG-->CTG) leading to the substitution of leucine for proline, while a "telencephalic" variant of GSS, in which dementia is the predominant symptom and ataxia is minimal, has been described in two kindreds with a mutation at codon 117 (GCA-->GTG) resulting in the substitution of valine for alanine. In this report, we present a family with ataxic GSS that has, however, the same mutation at codon 117 as is present in the telencephalic variant of GSS. Other than an additional silent mutation (GCA-->GCG) at codon 117 on the normal allele, there were no other mutations detected. At the polymorphic codon 129, valine was encoded by both alleles in the proband that we studied. Why this family with prion disease (PrP-A117V) should present with ataxia instead of dementia, which was found in two previously identified families with the same PrP gene mutation, remains to be established.
Subject(s)
Ataxia/physiopathology , Prion Diseases/genetics , Prion Diseases/physiopathology , Adult , Base Sequence , DNA/analysis , Dementia/physiopathology , Humans , Immunohistochemistry , Magnetic Resonance Imaging , Male , Molecular Sequence Data , Polymerase Chain Reaction , Prion Diseases/pathologyABSTRACT
The expansion of trinucleotide repeat sequences underlies a number of hereditary neurological disorders. To study the stability of a trinucleotide repeat and to develop an animal model of one of these disorders, spinal and bulbar muscular atrophy (SBMA), we have generated transgenic mice carrying either the normal or expanded repeat human androgen receptor (AR) gene. Unlike the disease allele in humans, the AR cDNA containing the expanded repeat in transgenic mice showed no change in repeat length with transmission. Expression of the SBMA AR was found in transgenic mice, but at a lower level than normal endogenous expression. The lack of a physiological pattern of expression may explain why no phenotypic effects of the transgene were observed.
Subject(s)
Mice, Transgenic/genetics , Receptors, Androgen/genetics , Repetitive Sequences, Nucleic Acid , Transcription Factors/chemistry , Transcription Factors/genetics , Animals , Base Sequence , Female , Gene Expression , Male , Mice , Molecular Sequence Data , Molecular Structure , Muscular Atrophy, Spinal/genetics , Mutation , Nucleotides/chemistry , Nucleotides/genetics , Phenotype , Polymerase Chain Reaction , Receptors, Androgen/chemistry , Receptors, Androgen/immunologyABSTRACT
Clathrin has been purified to electrophoretic homogeneity by initial extraction of clathrin from purified coated vesicle fraction, followed by column chromatographies with gel filtration, DEAE-cellulose, and hydroxylapatite and finally by preparative sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Antibody specific to clathrin has also been obtained. Two forms of native clathrin, fast and slow components, have been prepared to about 95% purity by hydroxylapatite column chromatography. Both fast and slow components are believed to represent two different aggregates of clathrin subunit because they comigrate in agarose electrophoresis, pH 7.4, and also migrate as clathrin subunit on SDS-PAGE with a molecular weight of 175,000. Furthermore, both components cross-react with antibody against purified clathrin and compete for antibody binding site with labeled fast component. The fast component can also be converted to the slow component. In addition to clathrin, two proteins of about 38,000 and 35,000 M.W. that consistently copurified with native clathrin are probably also intrinsic to coated vesicle.