Axonal transport is a highly complex process essential for sustaining proper neuronal functioning. Disturbances can result in an altered neuronal homeostasis, aggregation of cargoes, and ultimately a ...dying-back degeneration of neurons. The impact of dysfunction in axonal transport is shown by genetic defects in key proteins causing a broad spectrum of neurodegenerative diseases, including inherited peripheral neuropathies. In this review, we provide an overview of the cytoskeletal components, molecular motors and adaptor proteins involved in axonal transport mechanisms and their implication in neuronal functioning. In addition, we discuss the involvement of axonal transport dysfunction in neurodegenerative diseases with a particular focus on inherited peripheral neuropathies. Lastly, we address some recent scientific advances most notably in therapeutic strategies employed in the area of axonal transport, patient-derived iPSC models, in vivo animal models, antisense-oligonucleotide treatments, and novel chemical compounds.
Myotubular myopathy, also called X-linked centronuclear myopathy (XL-CNM), is a severe congenital disease targeted for therapeutic trials. To date, biomarkers to monitor disease progression and ...therapy efficacy are lacking. The Mtm1−/y mouse is a faithful model for XL-CNM, due to myotubularin 1 (MTM1) loss-of-function mutations. Using both an unbiased approach (RNA sequencing RNA-seq) and a directed approach (qRT-PCR and protein level), we identified decreased Mstn levels in Mtm1−/y muscle, leading to low levels of myostatin in muscle and plasma. Myostatin (Mstn or growth differentiation factor 8 Gdf8) is a protein released by myocytes and inhibiting muscle growth and differentiation. Decreasing Dnm2 by genetic cross with Dnm2+/− mice or by antisense oligonucleotides blocked or postponed disease progression and resulted in an increase in circulating myostatin. In addition, plasma myostatin levels inversely correlated with disease severity and with Dnm2 mRNA levels in muscles. Altered Mstn levels were associated with a generalized disruption of the myostatin pathway. Importantly, in two different forms of CNMs we identified reduced circulating myostatin levels in plasma from patients. This provides evidence of a blood-based biomarker that may be used to monitor disease state in XL-CNM mice and patients and supports monitoring circulating myostatin during clinical trials for myotubular myopathy.
Display omitted
X-linked centronuclear myopathy (XL-CNM) is a severe congenital disease targeted for therapeutic trials. The authors identified decreased plasma myostatin levels in XL-CNM patients and mice. Decreasing Dnm2 in mice blocked or postponed disease progression and resulted in an increase in circulating myostatin, supporting monitoring circulating myostatin in XL-CNM clinical trials.
Abstract Background Autosomal recessive axonal neuropathy with neuromyotonia is a recently described entity associated to the HINT1 gene, encoding histidine triad nucleotide-binding protein 1. ...Patient The authors report a Portuguese 16-year-old girl of Roma ethnicity, descendant of consanguineous parents, with progressive distal muscular atrophy and weakness, beginning at age 6. After several years of extensive investigation with inconclusive results, clinical myotonia was identified. Electrophysiologic studies revealed neuromyotonia associated with a severe chronic predominantly motor axonal neuropathy and homozygous mutation (c.334 C > A, p.H112 N) in HINT1 was detected. Conclusion This report emphasizes the late onset of clinical myotonia essential to the diagnosis.
Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive ...genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (
ganglioside-induced differentiation protein 1
—
GDAP1
,
SH3 domain and tetratricopeptide repeats-containing protein 2
—
SH3TC2
,
histidine-triad nucleotide binding protein 1
—
HINT1
) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in
GDAP1
, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the
SH3TC2
gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.
This article focuses on recent advances in Charcot-Marie-Tooth disease, in particular additions to the genetic spectrum, novel paradigms in molecular techniques and an update on therapeutic ...strategies.
Several new Charcot-Marie-Tooth disease-causing genes have been recently identified, further enlarging the genetic diversity and phenotypic variability, including: SBF1, DHTKD1, TFG, MARS, HARS, HINT1, TRIM1, AIFM1, PDK3 and GNB4. The increasing availability and affordability of next-generation sequencing technologies has ramped up gene discovery and drastically changed genetic screening strategies. All large-scale trials studying the effect of ascorbic acid in Charcot-Marie-Tooth 1A have now been completed and were negative. Efforts have been made to design more robust outcome-measures for clinical trials. Promising results with lonaprisan, curcumin and histone deacetylase 6 inhibitors have been obtained in animal models.
Charcot-Marie-Tooth is the most common form of inherited peripheral neuropathy and represents the most prevalent hereditary neuromuscular disorder. The genetic spectrum spans more than 70 genes. Gene discovery has been revolutionized recently by new high-throughput molecular technologies. In addition, the phenotypic diversity has grown tremendously. This is a major challenge for geneticists and neurologists. No effective therapy is available for Charcot-Marie-Tooth. Several large trials with ascorbic acid were negative but research into novel compounds continues.
Hereditary neuropathies (HN) are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission, age of occurrence, and, in selected cases, ...pathological findings. The combination of these parameters frequently orients towards specific genetic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first pediatric concern. Primary, motor-sensory are the most frequent HN and are dominated by demyelinating AD forms (CMT1). Others are demyelinating AR forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Pure motor HN represent<10% of HN but exhibit large clinical and genetic heterogeneity. Sensory/dysautonomic HN cover five classical subtypes, each one related to specific genes. However, genetic heterogeneity is largly greater than initially suspected. Syndromic HN distinguish: "purely neurological syndromes", which are multisystemic, usually AD disorders, such as spinocerebellar atrophies +, spastic paraplegias +, etc. Peripheral Neuropathy may be the presenting feature, including in childhood. Clearly degenerative, AR forms prompt to investigate a large set of pleiotropic genes. Other syndromes, expressed in the perinatal period and comprising malformative features, are mainly developmental disorders, sometimes related to specific transcription factors. Altogether, >40 genes with various biological functions have been found responsible for HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait: for the pediatric neurologist, phenotype/genotype correlations constitute a permanent bidirectional exercise.
International consortia, novel sequencing techniques, and variant interpretation tools continue to drive genetic discoveries.Current genetic research increasingly exposes loci with phenotypical ...spectra (locus pleiotropy) in rare inherited neurological disorders. We illustrate this notion through overlaps between inherited peripheral neuropathies, hereditary spastic paraplegias, and spinocerebellar ataxias.The growing awareness of this genetic overlap strains historically defined (clinical) classifications but reveals vulnerable loci and key cellular processes.Enhanced focus on pathomechanisms and uniting cohorts of patients with different neurogenetic disorders could increase effectiveness of diagnosis, scientific discovery, and therapy design.
International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development. We highlight common cellular alterations that underlie this genetic landscape, including alteration of cytoskeleton, axonal transport, mitochondrial function, and DNA repair response. Finally, we discuss venues for future research using the long axonopathies of the PNS as a model to explore other neurogenetic disorders.
International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development. We highlight common cellular alterations that underlie this genetic landscape, including alteration of cytoskeleton, axonal transport, mitochondrial function, and DNA repair response. Finally, we discuss venues for future research using the long axonopathies of the PNS as a model to explore other neurogenetic disorders.
•SLONM can present with subacute or slowly progressive limb girdle muscular weakness.•Slowly progressing SLONM is mostly a diagnosis of exclusion.•A SLONM diagnosis can be substantiated by supportive ...criteria.•Enrichment of SLONM cases is likely in cohorts of WES-negative myopathy patients.
Sporadic late-onset nemaline myopathy (SLONM) is an enigmatic, supposedly very rare, putatively immune-mediated late-onset myopathy, typically presenting with subacutely progressive limb-girdle muscular weakness, yet slowly progressing cases have been described too. We systematically studied (para)clinical and histopathological findings in a cohort of 18 isolated yet suspected inherited myopathy patients, showing late-onset, slowly progressive limb-girdle muscle weakness, remaining unsolved after whole-exome sequencing. The presence of a monoclonal gammopathy of unknown significance (MGUS) and anti-HMGCR antibodies was determined. Biopsies were systematically re-evaluated and systematic immunohistochemical and electron microscopy studies were performed to particularly evaluate the presence of rods and/or inflammatory features. Ten patients showed rods as core feature on muscle biopsy on re-evaluation, four of these had an IgG κ MGUS in blood. As such, these ten patients represented suspected slowly progressing SLONM patients, with auxiliary data supporting this diagnosis: 1) additional muscle biopsy features pointing towards Z-disk and myofibrillar pathology; 2) a common selective pattern of muscle involvement on MRI; 3) inflammatory features on muscle biopsy. Findings in this proof-of-concept study highlight difficulties in reliably diagnosing slowly progressing SLONM and the probably underestimated prevalence of this entity in cohorts of whole exome sequencing negative myopathy patients, initially considered having an inherited myopathy.
•Contracturing granulomatous myositis (GM) is a rare treatable myopathy.•We present a patient with finger flexor contractures and proximal weakness that responded very well to treatment with ...IVIG.•Only a few cases of CGM have been reported in the literature. A point of discussion remains whether GM can present in isolation as an idiopathic form or if this form constitutes an exceptional manifestation of sarcoidosis without systemic features.
Contracturing granulomatous myositis is a rare myopathy in which patients present with flexion contractures of the upper limbs in addition to slowly progressive muscle weakness and pain. Whether it represents a distinct nosological entity remains a point of discussion. We present a patient with isolated granulomatous disease of the muscle that responded very well to intravenous immunoglobulins after treatment failure of corticosteroids and methotrexate.
PDF
