A review of multi-omics approaches towards understanding late onset and progressive glaucomatous neuropathies

Myelin protein zero (MPZ) is a member of the immunoglobulin gene superfamily with single extracellular, transmembrane and cytoplasmic domains. Homotypic interactions between extracellular domains of MPZ adhere adjacent myelin wraps to each other. MPZ is also necessary for myelin compaction since mice which lack MPZ develop severe dysmyelinating neuropathies in which compaction is dramatically disrupted. MPZ mutations in humans cause the inherited demyelinating neuropathy CMT1B. Some mutations cause the severe neuropathies of infancy designated as Dejerine-Sottas disease, while others cause a 'classical' Charcot-Marie-Tooth (CMT) disease Type 1B (CMT1B) phenotype with normal early milestones but development of disability during the first two decades of life. Still other mutations cause a neuropathy that presents in adults, with normal nerve conduction velocities, designated as a 'CMT2' form of CMT1B. To correlate the phenotype of patients with MPZ mutations with their genotype, we identified and evaluated 13 patients from 12 different families with eight different MPZ mutations. In addition, we re-analysed the clinical data from 64 cases of CMT1B from the literature. Contrary to our expectations, we found that most patients presented with either an early onset neuropathy with signs and symptoms prior to the onset of walking or a late onset neuropathy with signs and symptoms at around age 40 years. Only occasional patients presented with a 'classical' CMT phenotype. Correlation of specific MPZ mutations with their phenotypes demonstrated that addition of either a charged amino acid or altering a cysteine residue in the extracellular domain caused a severe early onset neuropathy. Severe neuropathy was also caused by truncation of the cytoplasmic domain or alteration of an evolutionarily conserved amino acid. Taken together, these data suggest that early onset neuropathy is caused by MPZ mutations that significantly disrupt the tertiary structure of MPZ and thus interfere with MPZ-mediated adhesion and myelin compaction. In contrast, late onset neuropathy is caused by mutations that more subtly alter myelin structure and which probably disrupt Schwann cell-axonal interactions.

Mutations of myelin protein zero gene (MPZ) are found in 5% of Charcot-Marie-Tooth patients. In 2004, Shy et al. identified two main phenotypes associated with them: an early-onset subtype with mainly demyelinating features and a late-onset subgroup with prominent axonal impairment. We evaluated whether novel MPZ mutations described in literature during the last 14years could still fit with this classification. We collected and revised reports of 69 novel MPZ mutations. Almost 90% of them could be alternatively classified as responsible for: (a) an early-onset phenotype, with first limitations starting before 3years (2.5 ± 0.50years), motor milestones delays, frequently severe course and upper limb MNCVs below 15m/s; (b) late-onset neuropathy, with mean age of onset of 42.8 ± 1.5years and mean upper limbs motor nerve conduction velocities (MNCVs) of 47.2 ± 1.4m/s; (c) a phenotype more similar to typical CMT1A neuropathy, with onset during the 2nd decade, MNCV in the range of 15-30m/s and slowly progressive course. The present work confirms that P0-related neuropathies may be separated into two main distinct phenotypes, while a third, relatively small, group comprehend patients carrying MPZ mutations and a childhood-onset disease, substantiating the subdivision into three groups proposed by Sanmaneechai et al. (Brain 138:3180-3192, 2015). Interestingly, during the last years, an increasing number of novel MPZ mutations causing a late-onset phenotype has been described, highlighting the clinical relevance of late-onset P0 neuropathies. Since the family history for neuropathy is often uncertain, due to the late disease onset, the number of patients carrying this genotype is probably underestimated.

Late-onset mitochondrial neuromyopathy: an age-related phenomenon?

Peripheral neuropathies caused by mutations in the myelin protein zero

The amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulin light chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis (ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associated with at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine for valine at position 30 is the most common mutation. Each variant has a different organ involvement, although clinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. This review combines clinical and laboratory findings of renal involvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteen nephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy. Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy is based on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, liver transplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is recommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in development may soon be available.

We studied three patients with late onset, chronic sensorimotor and autonomic neuropathy in course of plasma cell dyscrasia with Bence Jones proteinuria. Histopathological findings of nerve biopsies consisted in diffuse loss of myelinated and unmyelinated fibers associated with perivascular deposits of amorphous material with physico-chemical and ultrastructural features of amyloid. By immunohistochemistry, light chains of the same type as Bence Jones protein, components of the classic and lytic pathways of the complement and vitronectin were detected at the level of amyloid nodules. The colocalization of complement neoantigen and vitronectin suggests that this complex derives from the circulation. The elucidation of the chemical composition of amyloid might shed some light in the pathogenesis of these disorders.

Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 1214. CMT1 and CMT2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de novo mutations in CMT families was estimated to be 22.7%. Genotype- phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described. Two novel phenotypes were ascribed to the MFN2 gene, however further studies are needed to confirm that MFN2 mutations can cause CMT1 and dHMN.

MPZ gene mutations cause demyelinating and axonal Charcot-Marie-Tooth (CMT) disease. Two novel MPZ mutations are reported in very late onset and progressive CMT syndrome. The N60H caused axonal CMT in a large family, whereas the I62M occurred in a single patient presenting with a primary axonal neuropathy. Previously, chronic polyradiculoneuritis was assumed in two patients. Molecular genetic testing and particularly screening for MPZ mutations in late onset neuropathies are important to differentiate acquired and inherited neuropathies.

BackgroundThe differential diagnosis of chronic progressive multifocal asymmetric neuropathies is challenging. Vasculitic neuropathies, multifocal forms of chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathies, and asymmetric lower motor neuron disorders are important considerations.Case presentationWe report a patient with an unusually long 12-year course of nonsystemic vasculitic neuropathy prior to the development of systemic manifestations.ConclusionWe discuss some of the difficulties involved in the diagnosis of chronic progressive multifocal asymmetric neuropathies.

The transcription factor Miz1 (Myc-interacting zinc finger 1) is a known regulator of the cell cycle but also has cell cycle-independent functions. Here we analyzed the role of Miz1 in the peripheral nervous system, using an early embryonic conditional knock-out model in which the Miz1 POZ domain is ablated in Schwann cells. Although the development of myelinated nerve fibers was not impaired, Miz1ΔPOZ mice acquired behavioral signs of a peripheral neuropathy at the age of 3 months. At this time, ultrastructural analysis of the sciatic nerve showed de- and dysmyelination of fibers, with massive outfoldings and a focal infiltration of macrophages. Although the expression of genes encoding structural myelin proteins, such as periaxin, myelin basic protein, and myelin protein zero, was decreased, genes associated with a negative regulation of myelination, including c-Jun, Sox2, and Id2, were up-regulated in Miz1ΔPOZ mice compared with controls. In animals older than 4 months, the motor disabilities vanished, and the ultrastructure of the sciatic nerve exhibited numerous tomacula and remyelinated fibers, as indicated by thinner myelin. No second acute attack was observed up to the age of 1 year. Thus, the deletion of the Miz1 POZ domain in Schwann cells induces an acute neuropathy with a subsequent regeneration in which there is ongoing balancing between de- and remyelination. Miz1ΔPOZ mice are impaired in the maintenance of myelinated fibers and are a promising model for studying remyelination in adult peripheral nerves.

VOLUME 290 (2015) PAGES 727–743 PAGE 736: qRT-PCR data quantifying Emr1 expression were missing from Fig. 6. These results are included in panel E of the corrected figure. This correction does not affect the interpretation of the results or the conclusions of this work.

IS018 Early and late onset neuropathy in patients with CMT1B

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1577:"<h3>Background</h3> Two diagnoses to consider in late-onset, slowly progressive sensory neuropathy are anti-MAG neuropathy and CANVAS (Cerebellar Ataxia Neuropathy and Vestibular Apraxia Syndrome). <h3>Methods</h3> Retrospective case note review of two individuals referred to our centre for advice and management of presumed anti-MAG neuropathy were re-diagnosed with CANVAS with confirmed bi-allelic, pathogenic RFC1 repeat expansions. <h3>Results</h3> Two females presented initially with distal paresthesia (aged 48 and 65), which spread proximally over several years with an accompanying increasingly unsteady gait. Neither had constitutional symptoms. Both had absent SNAPs with mildly prolonged DMLs (APB 12.2ms (at the elbow)) in one. Anti-MAG antibodies were weakly positive in both patients, and an IgM paraprotein detected in one. One patient had previously been treated with Rituximab. On review one patient reported oscillopsia and both had chronic cough. In both patients their gait was broad based with pronounced ataxia and mild pseudoathetosis, tone was normal, strength full, JPS intact, and VS normalised at ankles bilaterally and costal margins bilaterally respectively. One patient had bilaterally impaired vestibulo-occular reflexes. Clinical features and sub-pathogenic anti-MAG antibody titres led to genetic diagnosis of CANVAS. <h3>Conclusion</h3> We highlight important positive and negative clinical features to facilitate differentiation of anti-MAG neuropathy and CANVAS. rebecca.johnson131{at}nhs.net ";}

<h3>Objective:</h3> We describe a patient with late-onset ataxia, parkinsonism, tremor, and neuropathy with a novel <i>FAT2</i> gene frameshift variant, a gene primarily expressed in the cerebellum and recently implicated in spinocerebellar ataxia type 45 (SCA45). <h3>Background:</h3> Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominant (AD), neurodegenerative disorders that manifest with cerebellar dysfunction. SCA45 is associated with <i>FAT2</i> gene variants and is characterized by late-onset, pure cerebellar ataxia with autosomal dominant inheritance pattern. So far, only two families and one sporadic case with likely pathogenic <i>FAT2</i> variants have been reported, all of which involved missense variants. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 57-year-old woman presented with 3 years of progressive ataxia, neuropathy and mild tremor in the setting of a mood disorder. Family history was notable for a mother, maternal grandfather, and maternal great grandmother with similar symptoms. Exam revealed limb and gait ataxia, normal eye movements, mild symmetric parkinsonism, subtle postural and action tremor, and length-dependent neuropathy. Medications included aripiprazole. Lab work-up for metabolic, inflammatory, and immune related etiologies was negative. MRI brain showed no significant atrophy or lesions. CT brain showed calcification in the globus pallidus internus bilaterally. Genetic testing revealed a heterozygous frameshift variant (c.3039_3040del; p.Cys1014Profs*11) in the <i>FAT2</i> gene. <h3>Conclusions:</h3> Our patient’s inheritance pattern, cerebellar dysfunction and age of onset are consistent with SCA45. However, her phenotype includes tremor and neuropathy in addition to cerebellar ataxia, which contrasts with previously reported cases of a pure cerebellar syndrome associated with <i>FAT2</i> missense variants. Our patient has a frame-shift mutation that likely resulted in a non-functional protein. This type of variant has not been reported before and can currently only be classified as a variant of unknown significance (VUS) as affected family members are deceased. This case adds to the growing body of information regarding <i>FAT2</i> gene variants and their relation to hereditary ataxia. <b>Disclosure:</b> Dr. Ameri has nothing to disclose. Dr. Rosenbaum has nothing to disclose. The institution of Dr. Kirby has received research support from Parkinson’s Foundation.