Ataxia pancytopenia syndrome due to SAMD9L mutation presenting as demyelinating neuropathy.

Ataxia pancytopenia (ATXPC) syndrome due to gain-of-function pathogenic variants in the SAMD9L gene has been described in 38 patients to date. It is characterized by variable neurological and hematological phenotypes including ataxia, pyramidal signs, cytopenias, and hematological malignancies. Peripheral neuropathy with slowing of conduction velocities has been reported in only two affected individuals. We describe a female with childhood onset neuropathy diagnosed as Charcot-Marie-Tooth disease type 1 with onset of cerebellar ataxia in her 50s. Cerebellar, pyramidal, and neuropathic features were found on examination. Additionally, she also had conjunctival telangiectasia. Nerve conduction studies confirmed a demyelinating neuropathy. MRI brain showed cerebellar atrophy with diffuse white matter hyperintensities. OCT demonstrated global thinning of the retinal nerve fiber layer (RNFL). Full blood count has always been normal. A previously described pathogenic variant in SAMD9L [c.2956C>T p.(Arg986Cys)] was identified on whole exome sequencing. This case extends the previously described phenotype to include conjunctival telangiectasia and RNFL thinning and suggests that ATXPC syndrome should be considered in the differential for inherited demyelinating neuropathies.

Subacute demyelinating polyradiculoneuropathy complicating Epstein-Barr virus infection in GATA2 haploinsufficiency.

INTRODUCTION: Autosomal dominant haploinsufficiency of GATA2 causes monocytopenia and natural killer cell lymphopenia, resulting in predisposition to mycobacterial, fungal, and viral infections. METHODS: Herein we report on the clinical, serologic, electrophysiologic, and pathologic evaluations of a 29-year-old woman with GATA2 haploinsufficiency and active Epstein-Barr virus (EBV) infection complicated by subacute painful neuropathy. RESULTS: Nerve conduction and electromyography studies showed predominantly demyelinating sensorimotor polyradiculoneuropathy. Lumbar spine MRI showed thickening and enhancement of the cauda equina nerve roots. Serum and cerebrospinal fluid anti-IgG and IgM EBV capsid and nucleic acid antibodies were positive. Sural nerve biopsy showed microvasculitis and an increased frequency of fibers with segmental demyelination. Intravenous immunoglobulin and steroids improved the patient's neuropathy. CONCLUSION: GATA2 mutation-related immunodeficiency may predispose to EBV-associated subacute demyelinating polyradiculoneuropathy by both viral susceptibility and immune dysregulation. In patients who present in this manner, immunodeficiency syndromes should be considered when lymphomatous infiltration is excluded. Immunotherapy can be helpful. Muscle Nerve 57: 150-156, 2018.

Myelin protein zero Arg36Gly mutation with very late onset and rapidly progressive painful neuropathy.

Mutations in myelin protein zero (MPZ) protein result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms. In some patients, neuropathic pain can be a prominent symptom, making the diagnosis challenging mainly in those with other risk factors for neuropathy. We describe a 77-year-old woman with impaired glucose tolerance presenting with rapidly progressive axonal neuropathy leading to excruciating pain and severe weakness of lower limbs within 2 years from the onset. Her son abruptly complained of similar painful symptoms at the age of 47 years. Molecular analysis revealed a novel heterozygous missense mutation (c.106A>G) in MPZ exon 2, causing the substitution of arginine-36 with glycine in the extracellular domain. Our observation suggests that MPZ-related neuropathy should be considered in the diagnostic work up of patients with painful axonal neuropathy even presenting with rapid progression and at a very late age of onset.

Molecular mechanisms of inherited demyelinating neuropathies.

The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies.

Polymorphisms of CD1 genes in chronic dysimmune neuropathies.

CD1 are MCH-like glycoproteins specialized in capturing and presenting glycolipid to T cells. Expression of CD1 molecules has been observed on endoneurial machrophages in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and vasculitis and polymorphisms of CID1A and CD1E genes have been associated with susceptibility to develop Guillain-Barré syndrome. In 46 patients with CIDP, in 13 patients with multifocal motor neuropathy and in 132 controls we genotyped exon 2 of CD1A and CD1E genes. We found no association between chronic dysimmune neuropathies, with or without anti-ganglioside antibodies, and polymorphisms of CD1A and CD1E genes.

A new POLG1 mutation with peo and severe axonal and demyelinating sensory-motor neuropathy.

BACKGROUND: Progressive external ophthalmoplegia (PEO) is a mitochondrial disorder associated with defective enzymatic activities of oxidative phosphorylation (OXPHOS), depletion of mitochondrial DNA (mtDNA) and/or accumulation of mtDNA mutations and deletions. Recent positional cloning studies have linked the disease to four different chromosomal loci. Mutations in POLG1 are a frequent cause of this disorder. METHODS: We describe two first-cousins: the propositus presented with PEO,mitochondrial myopathy and neuropathy, whereas his cousin showed a Charcot- Marie-Tooth phenotype. Neurophysiological studies, peroneal muscle and sural nerve biopsies, and molecular studies of mtDNA maintenance genes (ANT1, Twinkle, POLG1, TP) and non dominant CMT-related genes (GDAP1, LMNA, GJB1) were performed. RESULTS: A severe axonal degeneration was found in both patients whereas hypomyelination was observed only in the patient with PEO whose muscle biopsy specimen also showed defective OXPHOS and multiple mtDNA deletions. While no pathogenetic mutations in GDAP1, LMNA, and GJB1 were found, we identified a novel homozygous POLG1 mutation (G763R) in the PEO patient. The mutation was heterozygous in his healthy relatives and in his affected cousin. CONCLUSIONS: A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory-motor neuropathy. Most likely, his cousin had an axonal polyneuropathy with CMT phenotype of still unknown etiology.

Recurrent polyradiculoneuropathy and PMP22 defects.

BACKGROUND: Although immunologic factors play an important role in the pathogenesis of the inflammatory neuropathies, the mechanisms of recurrent episodes of Guillain-Barré syndrome (GBS) and chronic relapsing polyneuropathies (CRP) are not known. Hereditary neuropathy with liability to pressure palsy (HNPP) is an inherited disease caused by a deletion or point mutation in the peripheral myelin protein 22 (PMP22) gene, which may manifest as a recurrent polyradiculoneuropathy. This study tried to elucidate the relationship between PMP22 and recurrent GBS and CRP. METHODS: Between 1993 and 2003, we saw 114 patients with polyradiculoneuropathies or their variants. Only 4 patients had recurrent episodes: 2 had recurrent GBS and 2 had CRP. We analyzed the PMP22 gene to determine its genetic role in these 4 patients. Genomic DNA was extracted from peripheral lymphocytes of all 4 patients using a previously described procedure, and molecular detection of PMP22 deletion was performed. RESULTS: The results showed no duplication, deletion or point mutation in the PMP22 gene. CONCLUSION: PMP22 gene deletion did not play a role in our patients with recurrent GBS and CRP.

Interferon-gamma, interleukin-4 and transforming growth factor-beta mRNA expression in multiple sclerosis and myasthenia gravis.

BACKGROUND: Multiple sclerosis (MS) is characterized by perivascular inflammation and high levels of circulating T and B lymphocytes that respond to the myelin antigens myelin basic protein (MBP) and proteolipid protein (PLP), thereby suggesting a role for immunoregulatory cytokines. MATERIALS AND METHOD: Blood mononuclear cells (MNC) were prepared from patients with MS, optic neuritis (ON), myasthenia gravis (MG), other inflammatory (OIND) and non-inflammatory neurological diseases (OND), and from patients with HIV infection and healthy controls. MNC expressing cytokine mRNA were detected by in situ hybridization with radiolabelled cDNA oligonucleotide probes. Numbers of cytokine mRNA expressing cells were presented per standard numbers of MNC. RESULTS: MS patients had elevated numbers of MNC in blood expressing T helper type 1 (Th1) cell related interferon-gamma (IFN-gamma), Th2 cell associated interleukin-4 (IL-4) and the endogenously produced immunosuppressant transforming growth factor-beta (TGF-beta). IFN-gamma and TGF-beta correlated with MS disability: EDSS score < 3 was associated with high numbers of TGF-beta mRNA positive cells while IFN-gamma mRNA positive cells tended to be low. The reverse was seen in patients with EDSS > or = 3. Cultures of MNC in presence and absence of antigen revealed that MBP and PLP induced strong responses in MS reflected by high levels of IFN-gamma, IL-4 and TGF-beta mRNA expressing cells. Recombinant (r) TGF-beta 1 dose-dependently suppressed MBP-induced upregulation of the proinflammatory cytokines IFN-gamma, IL-4, IL-6, tumor necrosis factor-alpha, (TNF-alpha), TNF-beta and perforin, but not of the immunosuppressive and probably advantageous IL-10. Cytokine mRNA expressing cells were enriched in the MS patients' cerebrospinal fluid, as were the cytokine mRNA positive cells detected after culture in presence of MBP and PLP, reflecting an autonomy of the immune response in this compartment. ON, in many instances representing early MS, did not differ from clinically definite MS regarding profiles of IFN-gamma, IL-4 and TGF-beta. Also patients with MG had elevated numbers of IFN-gamma, IL-4 and TGF-beta mRNA expressing blood MNC. They were further augmented upon culture of the MG patients' MNC in presence of acetylcholine receptor (AChR). An upregulation of AChR-induced TGF-beta was observed in thymectomized patients. rTGF-beta suppressed AChR-induced upregulation of proinflammatory cytokines but not IL-10. Elevated numbers of IFN-gamma, IL-4 and TGF-beta mRNA expressing blood MNC were also found in patients with OIND (aseptic meningo-encephalitis, chronic inflammatory demyelinating polyneuropathy, polymyositis, Eaton-Lambert syndrome) and in HIV-infected patients. In HIV infection, numbers of IL-4 mRNA positive cells correlated inversely with CD4+ cell counts, reflecting the involvement of IL-4 in later stages of the disease. Patients with non-inflammatory neurological diseases and healthy subjects had either no or low numbers of IFN-gamma, IL-4 and TGF-beta mRNA expressing cells when blood MNC were examined without previous culture, and after culture in presence and absence of MBP, PLP and AChR as antigens. An exception was a healthy pregnant lady who showed high levels especially of IL-4 and IL-10 mRNA expressing cells, probably reflecting pregnancy-associated upregulation of Th2 cell related cytokines. Numbers of myelin antigen- and AChR-reactive IFN-gamma and IL-4 mRNA expressing cells were also elevated, implicating upregulation of natural T cell autoimmunity in normal pregnancy. CONCLUSION: High numbers of in vivo activated and of organ-specific antigen-responsive Th1 and Th2 like cells expressing IFN-gamma and IL-4 mRNA are characteristic for MS and MG. Upregulation of TGF-beta in MS patients with little disability and in MG after thymectomy implicates that TGF-beta has desirable effects in human diseases with autoimmune background.

Clinical correlation with serum-soluble interleukin-2 receptor levels in Guillain-Barré syndrome.

In patients with Guillain-Barré syndrome (GBS) soluble interleukin-2 receptor (sIL-2R) levels were elevated compared with those of patients with other neurologic diseases (OND), and of healthy controls. Smaller increases in sIL-2R levels occurred in OND patients compared to healthy subjects. Monitoring of GBS patients clearly demonstrated that decreases in sIL-2R levels correlated with clinical recovery. Thus, T-cell activation may be relevant in the pathogenesis of GBS.

HLA and T-cell receptor gene polymorphisms in Guillain-Barré syndrome.

OBJECTIVE: We examined a possible involvement of genetic factors influencing the development of Guillain-Barré syndrome (GBS). METHODS: We studied T-cell receptor (TCR), alpha-chain constant (AC), and beta-chain variable (BV) gene polymorphisms using microsatellite markers and serologic HLA class I antigens, HLA-DRB1, and HLA-DQB1 alleles in 81 Japanese patients with GBS and 87 controls. RESULTS: There were no significant differences in these genetic markers between GBS patients and controls. Subgrouping of GBS patients according to recent Campylobacter jejuni infection, the presence of anti-GM1 antibody in the sera, or their combinations also failed to reveal significant associations with these genetic markers. There was, however, a tendency for an increased frequency of HLA-DRB1*0803 in the C. jejuni + GM1 + GBS group, when compared with controls. CONCLUSIONS: The data suggest that the roles of TCRAC, T-cell receptor beta-chain variable (TCRBV), HLA class I or class II in the development of GBS are not critical, and further research is necessary to clarify other genes encoded within the HLA region for genetic susceptibility to GBS.

No association with HLA-DR, -DQ or -DP alleles in Guillain-Barré syndrome.

The distribution of HLA class II alleles in Guillain-Barré syndrome (GBS) has previously been reported only for HLA-DR. We report here the results of genomic typing for HLA-DR, -DQ and -DP allelic variability by restriction fragment length polymorphism analysis in 49 patients with a history of GBS. No association was found to HLA-DR, -DQ or -DP alleles or HLA-DR-DQ haplotypes. Subgrouping of patients according to severity of disease, as measured by disability or muscular weakness, or response to plasmapheresis treatment, also failed to reveal significant associations. These data suggest that HLA class II genes do not confer susceptibility to GBS.

Major histocompatibility complex class I and class II polymorphism in chronic idiopathic demyelinating polyradiculoneuropathy.

Thirty-one chronic idiopathic demyelinating polyradiculoneuropathy (CIDP) patients have been typed for HLA-A, -B and -C antigens serologically and for HLA-DR, -DQ and -DP class II genes by RFLP analysis. Our results confirm a previously reported slight association with HLA-B8 and identify a stronger association with HLA-Cw7.

HLA-DR antigens in Mexican patients with Guillain-Barré syndrome.

The distribution of HLA-DR antigens was investigated in 38 Mexican Mestizo patients with Guillain-Barré syndrome (GBS) and in 100 healthy controls belonging to the same population. IgG, IgM, IgA, CH50, C3, C4 and the number of T and B lymphocytes were also evaluated in the patients. Only DR3 was significantly increased in the patients (Yates' chi 2 = 9.943, Pc = 0.014) and the relative risk for developing the disease was 3.49. These findings support the hypothesis that DR3 or a closely linked Ir gene may play some role in the susceptibility to GBS.

HLA-class II alleles in Guillain-Barré syndrome and Miller Fisher syndrome and their association with preceding Campylobacter jejuni infection.

HLA typing for class II alleles was performed on 97 patients with Guillain-Barré syndrome or Miller Fisher syndrome and compared with 100 controls. There was a significant association between HLA-DQB1*03 and preceding Campylobacter jejuni infection (Pc = 0.05).

Prednisone-responsive hereditary motor and sensory neuropathy.

Neurologic improvement with use of prednisone, in some cases on several occasions, was demonstrated in seven patients who had a chronic progressive polyradiculoneuropathy with nerve conduction velocity and electromyographic findings consistent with segmental demyelination and axonal degeneration and increases protein concentration in the cerebrospinal fluid. These patients seemed to have the progressive form of chronic inflammatory-demyelinating polyradiculoneuropathy and, in addition, had clinical features of hereditary motor and sensory neuropathy including pes cavus and hammer toes. On systematic examination, bony abnormalities or asymptomatic neuropathy typical of subclinical inherited neuropathy was discovered among their kin. There patients might therefore be identified as having inflammatory-demyelinating hereditary motor and sensory neuropathy. These cases may represent a chance association of chronic inflammatory-demyelinating polyradiculoneuropathy and hereditary motor and sensory neuropathy, a causally linked association of these disorders, or a prednisone-responsive inherited neuropathy only. We wish to draw attention to this treatable neuropathy and to raise the question of whether environmental factors play role in the expression of dominantly inherited mutant genes.

PCR-based restriction fragment length polymorphism (RFLP) analysis and serotyping of Campylobacter jejuni isolates from diarrheic patients in China and Japan.

A molecular typing approach for Campylobacter jejuni was applied with restriction fragment length polymorphism (RFLP) analysis of a 702-bp PCR-amplified portion of the flagellin-A (flaA) gene. We analyzed a total of 179 strains, including 69 independent clinical isolates from diarrheic patients in Japan, 85 isolates in China, and 25 heat-stable (HS) serotype strains by Penner and Hennessy (1980) J. Clin. Microbiol. 12, 732-737). Six AfaI, seven MboI, and five HaeIII RFLPs were found in the 702-bp flaA segment from the 179 strains. Using a combination of these three enzymes, 25 separate RFLP groups were recognized. While 59 of 154 (38.3%) strains obtained in Japan and China were nontypeable by the HS antigenic scheme, all but two of 154 (98.7%) could be typed by RFLP typing. All 11 isolates of HS-19 strains, which are frequently isolated from Guillain-Barré syndrome (GBS) patients, showed an identical RFLP pattern (Cj-1), and Cj-1 consisted only of HS-19 strains. This suggests that the HS-19:Cj-1 strain is distinct among C. jejuni strains. This molecular typing method provides a rapid and reliable typing scheme for epidemiological studies of C. jejuni, and may also be useful for the analysis of C. jejuni subtypes from GBS patients.

Macrophage-related demyelination in peripheral nerves of mice deficient in the gap junction protein connexin 32.

Mice deficient in the gap junction protein connexin 32 (Cx32) develop a slowly progressing demyelinating neuropathy, with enlarged periaxonal collars, abnormal non-compacted myelin domains and axonal sprouts. These mice serve as a model for the X-linked form of inherited demyelinating neuropathies in humans. Based on our previous findings that macrophages are involved in demyelination in other myelin mutants (i.e. mice heterozygously deficient in P0), we considered the possibility that macrophages might be also mediators of demyelination in Cx32-deficient mice. Indeed, we detected an age-related increase in the number of macrophages in demyelinating nerves of Cx32-deficient mice. In addition, immunoelectron microscopy revealed macrophages in an apposition to degenerating myelin reminiscent of a macrophage-mediated demyelinating neuropathy. We conclude that involvement of macrophages might be a widespread phenomenon in genetically-determined demyelination.

T cell receptor V beta gene usage in Guillain-Barré syndrome.

We set out to determine whether the T cell receptor (TCR) V beta gene usage in acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is restricted. We separated activated from non-activated peripheral blood T cells with anti-IL2 receptor (anti-CD25) antibody-labelled magnetic beads from four AIDP patients and four normal control (NC) subjects. The TCR V beta gene usage of circulating activated and non-activated T cells was heterogeneous in all the patients and controls, but the activated T cells of all four of the AIDP patients showed a more limited usage of V beta genes and enhanced V beta 15 usage, as compared to the non-activated T cells. This was not seen in the healthy controls. The activated and non-activated T cells from a patient with acute motor and sensory axonal neuropathy (AMSAN) showed a similar V beta gene usage to that of the controls. From a further patient with AIDP, we studied the V beta gene usage of short-term T cell lines reactive to the peripheral nerve myelin proteins P2, P0 and the P0 peptide amino acid sequence 194-208. The V beta gene usage of the lines was heterogeneous, with enhanced usage of V beta 15 in the cell line responsive to the Pzero peptide. We conclude that T cells activated during the immune response associated with AIDP preferentially used V beta 15, which may indicate a restricted response to a common antigen, or a role for an as yet undefined superantigen in the pathogenesis of AIDP.

Rare adverse events associated with oral poliovirus vaccine in Brazil.

Oral poliovirus vaccine (OPV) developed by A. Sabin has been effectively used to control poliomyelitis in Brazil, and the last case with the isolation of a wild poliovirus strain occurred in March 1989. Although the vaccine controlled the circulation of wild strains and poliomyelitis cases associated with these strains were not detected during the last eight years, rare cases classified as vaccine-associated paralytic poliomyelitis (VAPP) have been detected. Molecular characterization studies of poliovirus strains isolated from VAPP cases and from healthy contacts have confirmed that the isolates are derived from the Sabin vaccine strains and also detected genomic modifications known or suspected to increase neurovirulence such as mutations and recombination. The molecular characterization of polioviruses isolated during the last eight years from paralysis cases classified as Guillain-Barré (GBS) syndrome and transverse myelitis (TM), and from facial paralysis (FP) cases also confirmed the vaccine origin of the strains and demonstrated mutations known to increase neurovirulence. Analysis of the epidemiologic data of these GBS, TM and FP cases demonstrated that in most of them the last OPV dose was given months or years before the onset of the disease and the isolation of the polioviruses. The temporal association between the isolation of these strains and the GBS, TM and FP suggested that the Sabin vaccine-derived poliovirus strains could also rarely trigger the diseases.