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1.  Autogenous Immunity to Endogenous RNA Tumor Virus: Differential Reactivities of Immunoglobulins M and G to Virus Envelope Antigens 
Journal of Virology  1974;14(4):773-781.
The autogenous humoral immune response of mice to their endogenous leukemia virus has been examined in terms of the reactivities of individual classes of antibody present in normal B6C3F1 serum. Whole serum and the immunoglobulin (Ig) M and IgG fractions of serum from animals of different age groups were compared by radioimmune precipitation assays and viral infectivity neutralization assays. Both IgM and IgG fractions were able to precipitate virus, although not as effectively as whole serum. Virus-specific antibody levels, as well as total antibody concentrations in whole serum, appeared to increase with age. Sodium dodecyl sulfate gel electrophoresis analysis was performed with immune precipitates obtained when whole serum or 19 or 7S fractions from animals of different age groups were reacted with disrupted virus. The 19S antibody fraction reacted with three antigenic determinants on the viral envelope. These antigens have apparent molecular weights of 17,000, 43,000, and 68,000. The last two appear to be glycoproteins and may correspond to the M2 and M1 antigens. In contrast, the 7S component reacted only with the 17,000-molecular-weight protein. Neutralization assays against BALB:virus-2, a xenotropic endogenous mouse type C virus, revealed that 19S and whole serum but not the 7S fraction possessed neutralizing activity. These findings indicate that there are differential reactivities of IgM and IgG antibodies in normal serum of B6C3F1 mice, with respect to both recognition of viral envelope antigens and neutralization of endogenous MuLV. These results are consistent with the hypothesis that the autogenous humoral immune response is a systemic host function that may be important in the regulation of endogenous type C virus expression in vivo.
PMCID: PMC355582  PMID: 4138466
2.  Episodic ataxia and hemiplegia caused by the 8993T→C mitochondrial DNA mutation 
Journal of Medical Genetics  2007;44(12):797-799.
The m.8993T→C MTATP6 mutation of mitochondrial DNA (mtDNA) usually causes mitochondrial disease in childhood, but was recently described in a family with adult onset ataxia and polyneuropathy. Cytochrome c oxidase muscle histochemistry, which is the standard clinical investigation for mitochondrial disease in adults, is usually normal in patients with MTATP6 mutations. This raises the possibility that these cases have been missed in the past. We therefore studied 308 patients with unexplained ataxia and 96 patients with suspected Charcot–Marie–Tooth disease to determine whether the m.8993T→C MTATP6 mutation is common in unexplained inherited ataxia and/or polyneuropathy. We identified a three‐generation family with the m.8993T→C mutation of mtDNA. One subject had episodic ataxia (EA) and transient hemipareses, broadening the phenotype. However, no further cases were identified in an additional cohort of 191 patients with suspected EA. In conclusion, m.8993T→C MTATP6 should be considered in patients with unexplained ataxia, CMT or EA, but cases are uncommon.
PMCID: PMC2652821  PMID: 18055910
3.  Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis 
Neurology  2009;72(18):1544-1547.
Several missense mutations of CACNA1S and SCN4A genes occur in hypokalemic periodic paralysis. These mutations affect arginine residues in the S4 voltage sensors of the channel. Approximately 20% of cases remain genetically undefined.
We undertook direct automated DNA sequencing of the S4 regions of CACNA1S and SCN4A in 83 cases of hypokalemic periodic paralysis.
We identified reported CACNA1S mutations in 64 cases. In the remaining 19 cases, mutations in SCN4A or other CACNA1S S4 segments were found in 10, including three novel changes and the first mutations in channel domains I (SCN4A) and III (CACNA1S).
All mutations affected arginine residues, consistent with the gating pore cation leak hypothesis of hypokalemic periodic paralysis. Arginine mutations in S4 segments underlie 90% of hypokalemic periodic paralysis cases.
= hypokalemic periodic paralysis.
PMCID: PMC2848101  PMID: 19118277
4.  Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype 
Neurology  2011;77(22):1960-1964.
Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it is not known whether therapy response relates to genotype. We undertook a clinical and genetic study to evaluate the response rate of patients treated with acetazolamide and to investigate possible correlations between response and genotype.
We identified a total of 74 genotyped patients for this study. These included patients who were referred over a 15-year period to the only UK referral center or to a Chinese center and who underwent extensive clinical evaluation. For all genotyped patients, the response to acetazolamide therapy in terms of attack frequency and severity was documented. Direct DNA sequencing of CACNA1S and SCN4A was performed.
Only 46% of the total patient cohort (34 of 74) reported benefit from acetazolamide. There was a greater chance of benefit in patients with mutations in CACNA1S (31 responded of 55 total) than in those with mutations in SCN4A (3 responded of 19 total). Patients with mutations that resulted in amino acids being substituted by glycine in either gene were the least likely to report benefit.
This retrospective study indicates that only approximately 50% of genotyped patients with hypokalemic periodic paralysis respond to acetazolamide. We found evidence supporting a relationship between genotype and treatment response. Prospective randomized controlled trials are required to further evaluate this relationship. Development of alternative therapies is required.
PMCID: PMC3235354  PMID: 22094484
5.  Predicting steroid response in muscle disease 
Granulysin expression or glucocorticoid receptor polymorphisms may be factors underlying the variable steroid response in patients with myopathies
PMCID: PMC2077543  PMID: 16980654
6.  Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins(Video) 
Neurology  2010;75(4):367-372.
Episodic ataxia type 1 (EA1) is a monogenic channelopathy caused by mutations of the potassium channel gene KCNA1. Affected individuals carrying the same mutation can exhibit considerable variability in the severity of ataxia, neuromyotonia, and other associated features. We investigated the phenotypic heterogeneity of EA1 in 2 sets of identical twins to determine the contribution of environmental factors to disease severity. One of the mutations was also found in a distantly related family, providing evidence of the influence of genetic background on the EA1 phenotype.
We evaluated 3 families with an EA1 phenotype, 2 of which included monozygotic twins. We sequenced the KCNA1 gene and studied the biophysical consequences of the mutations in HEK cells.
We identified a new KCNA1 mutation in each pair of twins. Both pairs reported striking differences in the clinical severity of symptoms. The F414S mutation identified in one set of twins also occurred in a distantly related family in which seizures complicated the EA1 phenotype. The other twins had an R307C mutation, the first EA1 mutation to affect an arginine residue in the voltage-sensor domain. Both mutants when expressed exerted a dominant-negative effect on wild-type channels.
These results broaden the range of KCNA1 mutations and reveal an unexpectedly large contribution of nongenetic factors to phenotypic variability in EA1. The occurrence of epilepsy in 1 of 2 families with the F414S mutation suggests an interplay of KCNA1 with other genetic factors.
= episodic ataxia type 1.
PMCID: PMC2918890  PMID: 20660867
7.  Sodium and chloride channelopathies with myositis: coincidence or connection? 
Muscle & nerve  2011;44(2):283-288.
A proximal myopathy develops in some patients with muscle channelopathies, but the causative molecular mechanisms are unknown.
We reviewed retrospectively all clinical and muscle biopsy findings of three patients with channelopathy and additional myositis. Direct DNA sequencing was performed.
Pathogenic mutations were identified in each case. Biopsies illustrated inflammatory infiltrates.
Clinicians should consider muscle biopsy in channelopathy patients with severe myalgia and/or subacute weakness and accompanying elevated CK. Chance association of myositis and channelopathy is statistically unlikely. An alternative hypothesis suggests that inflammatory insults could contribute to myopathy in some patients.
PMCID: PMC3136616  PMID: 21698652
neuromuscular; channelopathy; myositis; histopathology; treatment
9.  Genetic association studies of complex neurological diseases 
Genetic association studies offer a powerful approach to identify the multiple variants of small effect that modulate susceptibility to common, complex disease. They, however, have a poor reputation, mainly because of the consistent lack of replication of all but a few. Thousands of genetic studies have been carried out on multifactorial diseases in the past 30 years, yielding only about 50 variants that can be considered to be true positives. Although the positive studies show proof of principle, the multitude of negative studies indicate fundamental problems in the design and execution of association studies. Here, we discuss some of the more pertinent study design and data analysis issues which can affect the outcome of genetic association studies.
PMCID: PMC2077426  PMID: 17110744
Neurology  2008;71(21):1740-1742.
PMCID: PMC2676969  PMID: 19015492
12.  The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)-linked adPEO 
Neurology  2010;74(20):1619-1626.
Mutations in the Twinkle (PEO1) gene are a recognized cause of autosomal dominant progressive external ophthalmoplegia (adPEO), resulting in the accumulation of multiple mitochondrial DNA (mtDNA) deletions and cytochrome c oxidase (COX)-deficient fibers in skeletal muscle secondary to a disorder of mtDNA maintenance. Patients typically present with isolated extraocular muscle involvement, with little apparent evidence of the clinical heterogeneity documented in other mtDNA maintenance disorders, in particular POLG-related disease.
We reviewed the clinical, histochemical, and molecular genetics analysis of 33 unreported patients from 26 families together with all previous cases described in the literature to define the clinical phenotype associated with PEO1 mutations.
Ptosis and ophthalmoparesis were almost universal clinical features among this cohort, with 52% (17/33) reporting fatigue and 33% (11/33) having mild proximal myopathy. Features consistent with CNS involvement were rarely described; however, in 24% (8/33) of the patients, cardiac abnormalities were reported. Mitochondrial histochemical changes observed in muscle showed remarkable variability, as did the secondary mtDNA deletions, which in some patients were only detected by PCR-based assays and not Southern blotting. Moreover, we report 7 novel PEO1 variants.
Our data suggest a shared clinical phenotype with variable mild multiorgan involvement, and that the contribution of PEO1 mutations as a cause of adPEO may well be underestimated. Direct sequencing of the PEO1 gene should be considered in adPEO patients prior to muscle biopsy.
= autosomal dominant progressive external ophthalmoplegia;
= cytochrome c oxidase;
= infantile-onset spinocerebellar ataxia;
= mitochondrial DNA;
= progressive external ophthalmoplegia;
= sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;
= succinate dehydrogenase.
PMCID: PMC2875130  PMID: 20479361
13.  Spontaneous intracranial hypotension, hygromata and haematomata 
BMJ Case Reports  2009;2009:bcr2007132019.
PMCID: PMC3106085  PMID: 21687310
14.  The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment 
Brain  2009;133(1):9-22.
The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.
PMCID: PMC2801326  PMID: 19917643
ion channels; neuromuscular; genetics; EMG
15.  A new explanation for recessive myotonia congenita 
Neurology  2012;78(24):1953-1958.
To assess whether exon deletions or duplications in CLCN1 are associated with recessive myotonia congenita (MC).
We performed detailed clinical and electrophysiologic characterization in 60 patients with phenotypes consistent with MC. DNA sequencing of CLCN1 followed by multiplex ligation-dependent probe amplification to screen for exon copy number variation was undertaken in all patients.
Exon deletions or duplications in CLCN1 were identified in 6% of patients with MC. Half had heterozygous exonic rearrangements. The other 2 patients (50%), with severe disabling infantile onset myotonia, were identified with both a homozygous mutation, Pro744Thr, which functional electrophysiology studies suggested was nonpathogenic, and a triplication/homozygous duplication involving exons 8–14, suggesting an explanation for the severe phenotype.
These data indicate that copy number variation in CLCN1 may be an important cause of recessive MC. Our observations suggest that it is important to check for exon deletions and duplications as part of the genetic analysis of patients with recessive MC, especially in patients in whom sequencing identifies no mutations or only a single recessive mutation. These results also indicate that additional, as yet unidentified, genetic mechanisms account for cases not currently explained by either CLCN1 point mutations or exonic deletions or duplications.
PMCID: PMC3369509  PMID: 22649220
The Journal of Experimental Medicine  1974;139(6):1568-1581.
The viral antigenic determinants recognized in an autogenous immune response in mice against their endogenous C-type virus have been identified by SDS-polyacrylamide gel electrophoresis of immune precipitates between various sera and H3-labeled intact or disrupted AKR leukemia virus. Normal B6C3F1 [(C57BL/6 x C3H/Anf)F1] serum reacts with viral envelope antigens having mol wt of approximately 68,000, 43,000, and 17,000. In addition, minor reactions with viral antigens having mol wts of approximately 19,000 and 15,000 are demonstrable. The 68,000 and 43,000 mol wt antigens can be labeled with [3H]glucosamine and may correspond to the major viral envelope antigens M2 and M1, respectively. The antigens recognized by autogenous immune sera do not differ with respect to age of the animal, nor are they significantly different in sera from various strains of mice (BALB/c, C57BL/6, and C3H/Anf). These results suggest that the age-asociated and strain variations in the autogenous immune response, as determined by radioimmune precipitation assays against intact virus, are due to quantitative and qualitative alterations of antibody levels against common antigens.
PMCID: PMC2139675  PMID: 4364335
The radioimmune precipitation assay using 3H-labeled AKR leukemia virus was applied to the detection and quantitation of natural serum antibodies directed against endogenous murine leukemia virus (MuLV) envelope antigens B6C3F1 and BALB/c mice, which have low natural incidences of leukemia and lymphoma, and AKR mice, which have a high incidence, were used in this study. Sera from mice of various age groups were assayed. A marked difference in age-associated levels of the autogenous immune response to endogenous murine leukemia virus was detected, and the quantitative differences among these strains were inversely related to the incidence of lymphoma. The radioimmune precipitation test as applied was 500 times more sensitive than virus neutralization. That the reactions we have observed are specific is suggested by several lines of evidence, including the nonreactivity of normal hamster and absorbed rat serum, the positive reaction of absorbed rat anti-AKR serum, the inhibition of precipitation of labeled virus by purified unlabeled virus, and isopycnic gradient analysis of the reactive products.
PMCID: PMC2180542  PMID: 4352105
The essential role of continuous antigenic stimulation in the development and differentiation of antibody-forming cells as defined in the X-Y-Z immune cell maturation scheme was examined in these studies. Mice were primed with sheep erythrocytes (SRBC) in an attempt to induce maximum immune progenitor cell conversion (X → Y). Subsequently antigen was depleted at 1 or 4 days after priming with isologous specific antibody in order to interrupt further immune cell differentiation (Y → Z). It was reasoned that this condition would result in depression of the functional antibody-producing cell compartment as measured in the intact mice and subsequently in enhancement of the sensitized (Y cell) compartment as measured in the spleen cell transfer system. These data were also correlated with systematic studies of the hyperplasia of the spleen germinal centers. The effect of passive antibody on the primary response to SRBC was a marked decrease indirect and indirect hemolysin-producing cells (DPFC and IPFC). However, there was a lack of correlation in the degree of antibody-mediated 19S and 7S immune cell suppression during the primary response, the DPFC being much less depressed than the IPFC. As measured in the transfer system there was an enhanced 19S sensitized cell compartment and a depressed 7S sensitized cell compartment in 1 day passively immunized mice. This was true whether or not transfers were performed 1, 2, or 4 wk after priming. Similarly, there was an enhanced 19S-sensitized cell compartment with little or no effect on the 7S-sensitized. cell compartment in 4 day passively immunized mice. These data suggest that progeny of the antigen-stimulated progenitor cells (X cell), as a consequence of lack of further antigenic stimulation, were forced into maturation arrest. These studies further demonstrate that isologous passive antibody suppresses germinal center growth regardless of whether the antibody is infused 1, 2, or 4 days after priming. In terms of formation of sensitized cells, the marked depression of 7S sensitized cell compartment after passive immunization at 24 hr in contrast to the enhancement of the 19S sensitized cell compartment corresponds to the suppressed growth of germinal centers during the primary response. Thus, if the germinal center is, as suggested, the site of proliferative expansion of immunocompetent cells, these data indicate that the germinal center growth is related to the 7S antibody response and in the formation of "7S memory."
PMCID: PMC2138635  PMID: 5778791
The Journal of Cell Biology  1965;25(3):109-119.
The fine structure of tritiated thymidine-labeled cells in antigen-stimulated mouse spleen germinal centers is described. In studies on the ultrastructural level, two labeled cell types found in germinal centers are observed. Large lymphocytes are characterized by their very numerous free ribosomes, a paucity of endoplasmic reticulum, relatively few mitochondria, and a poorly developed Golgi region. The nuclei are large and vesicular, and large nucleoli are present. A second labeled cell type appears to contain more mitochondria and has a higher development of the Golgi area. The nucleus contains large, numerous blocks of chromatin, indicative of a more differentiated cell type. Reticular cells, both phagocytic and non-phagocytic, were not observed to be labeled in the germinal centers.
PMCID: PMC2106673  PMID: 5840793
21.  Vitamin E deficiency. 
BMJ : British Medical Journal  1995;310(6995):1673.
PMCID: PMC2550041  PMID: 7795478
22.  Immunotherapy of guinea pigs with dermal and visceral tumor implants: comparison of living and nonliving BCG. 
Infection and Immunity  1979;24(2):565-566.
Emulsified cell walls of Mycobacterium bovis (BCG) were immunotherapeutically at least as active as living BCG in prolonging survival of guinea pigs with established dermal tumors and microscopic lymph node and visceral metastases.
PMCID: PMC414338  PMID: 378859

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