[Immune-mediated / inflammatory and hereditary neuropathies - overview and diagnostic algorithm]. / Immunvermittelte / inflammatorische und hereditäre Neuropathien ­ Übersicht und diagnostischer Algorithmus.

This paper is a practical survey of immune-mediated, inflammatory and hereditary neuropathies along with recommendations for diagnostic procedures. The large group of immune-mediated, inflammatory neuropathies includes the Guillain-Barré syndrome and chronic-inflammatory demyelinating polyradiculoneuropathy and their subtypes, vasculitic, paraneoplastic and paraproteinemic neuropathies as well as neuropathies resulting from connective tissue disorders. Besides clinical features such as time-dependent progression and distribution of sensorimotor deficits, characteristic electroneurographic findings and antibody profiles are considered. Recent studies in hereditary neuropathies reveal a prevalence of 10-28 out of 100 000 persons in Europe. Research into the genetic causes has made significant progress in the last 20 years; up to now more than 80 genes mutated in hereditary neuropathies have been identified. Besides classification into axonal, demyelinating or intermediate neuropathies based on electroneurography, distinguishing between sensorimotor, pure motor and (autonomous) sensory neuropathies as well as consideration of particular clinical features and ethnic origin can be helpful in orientating molecular genetic analysis.

Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience.

BACKGROUND: Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. PATIENTS AND METHODS: Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. RESULTS: Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). CONCLUSIONS: Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted.

Bilateral radial nerve compression neuropathy in the newborn.

PURPOSE: This study aims to discuss the diagnosis and management of radial nerve compression neuropathy in the newborn. METHODS: A personal case is presented, followed by a review and analysis of clinically similar cases identified via a PubMed search of published medical literature. RESULTS: We report a case of a term newborn with bilateral radial neuropathy at the humerus level. Despite severe axonal involvement in the electrophysiological evaluation, the patient showed complete bilateral recovery after 3 months of follow-up. CONCLUSIONS: Isolated radial nerve palsy is a rare event in the newborn. The condition does not require surgical treatment and usually proceeds to full and rapid spontaneous recovery.

Treatment of chronic immune-mediated neuropathies: impact of the rare diseases centers network in Italy.

Chronic immune-mediated neuropathies represent a heterogeneous group of mostly demyelinating neuropathies thought to be caused by an autoimmune response to peripheral nerve antigens. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and related variants, multifocal motor neuropathy (MMN) and neuropathy associated with an IgM monoclonal gammopathy with antibody activity against myelin-associated glycoprotein (MAG). Most of these neuropathies respond to immune therapy even though their response to therapy may be different, thereby confirming that their distinct characteristics have relevant clinical implications. While clinicians and scientists are intrigued by the desire to better clarify the cause and pathogenesis of these disorders, the need to allow affected patients to be reimbursed by insurance companies or the national health system can lead to the risk of lumping all these neuropathies under the umbrella term of 'CIDP' to facilitate patients' access to costly therapies.

Inherited neuropathies.

With a prevalence of 1 in 2500 people, inherited peripheral nerve diseases, collectively called Charcot-Marie-Tooth disease (CMT), are among the most common inherited neurologic disorders. Patients with CMT typically present with chronic muscle weakness and atrophy in limbs, sensory loss in the feet and hands, and foot deformities. Clinical similarities between patients often require genetic testing to achieve a precise diagnosis. In this article, the author reviews the clinical and pathologic features of CMT, and demonstrates how electrodiagnostic and genetic tools are used to assist in the diagnosis and symptomatic management of the diseases. Several cases are presented to illustrate the diagnostic processes.

Neurological update: hereditary neuropathies.

In this update, we review the recent discovery of autosomal recessive variants in sorbitol dehydrogenase as one of the commonest and potentially treatable causes of hereditary motor neuropathy and CMT2. We also report on recent therapeutic advances in hereditary neuropathy including the use of lipid nanoparticle sequestered antisense oligonucleotides in CMT1A and lipid nanoparticle delivered CRISPR-Cas9 gene editing in ATTR amyloidosis.

Diagnosis and new treatments in genetic neuropathies.

The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

[Wide spectrum of hereditary motor sensory neuropathy (HMSN)].

Hereditary neuropathies are classified into HMSN/Charcot-Marie-Tooth disease (CMT), familial amyloid polyneuropathy (FAP), hereditary motor neuropathies (HMN) and hereditary sensory (and autonomic) neuropathies (HSAN). The clinical features of HMSN are generally characterized as distal dominant motor and sensory involvements. However, we have reported a novel HMSN with proximal dominancy (HMSN-P) originated in Okinawa and Shiga prefectures, Japan. The gene locus is located in the centromere region of chromosome 3. In 2008, a new family with the HMSN-P was reported from Brazilians of Japanese ancestry. This Brazilian family was initially diagnosed as having "a familial ALS". The HMSN-P linked to ch.3 is not limited in Japan, but may be present in the worldwide. The overseas scientific research for the elucidation of the mechanism of HMSN-P supported by JSPS KAKENHI (21406026) is planning. Recently several other types of HMSN-P have been reported; HMSN-P with urinary disturbance and paroxysmal dry cough, a patient with both CMT 1A and mild spinal muscular atrophy and CMT1A with severe paresis of the proximal lower limb muscles. Therefore the clinical concept of HMSN is not limited as the disease with distal dominant motor sensory involvement. HMSN has the wider spectrum from distal to proximal and motor/sensory to autonomic neuropathies.

A case report of hereditary neuropathy with liability to pressure palsies accompanied by type 2 diabetes mellitus and psoriasis.

RATIONALE: Hereditary neuropathy with liability to pressure palsy (HNPP) is an episodic, multifocal neuropathy, with a typical clinical presentation of recurrent transient pressure palsies, which is induced by a PMP22 deletion. Another neuropathy caused by a PMP22 duplication is Charcot-Marie-Tooth disease type 1A (CMT1A). PMP22 is a gene coding a protein called peripheral myelin protein 22 (PMP22), which plays an essential role in the formation and maintenance of compact myelin. Coexistence of type 2 diabetes mellitus (T2DM) and CMT1A has been reported in many work, however HNPP patients with T2DM are rare, and comorbidity of HNPP and psoriasis has not been reported previously. Electrophysiological features of HNPP has been found progressing with aging. Patient concerns: Here we present a 20-year-old man who exhibited lower extremity weakness and foot drop as the initial manifestation. DIAGNOSES: HNPP was diagnosed on the basis of clinical features, positive sural nerve biopsy findings, and genetic testing results. Moreover, physical examination, blood/urine glucose test, and diabetes-related autoantibodies investigations demonstrated that he had psoriasis and T2DM. The electrophysiological manifestations revealed profound demyelinating injuries and axonal injuries in distal peripheral nerves and facial nerves, which were more severe than general HNPP cases. INTERVENTIONS: The young patient was treated with continuous subcutaneous insulin infusion and blood glucose monitoring, and then transferred to oral acarbose therapy. The psoriatic lesions were treated with calcipotriol ointment. OUTCOMES: In the follow-up, the right leg weakness was alleviated, and his gait was improved. LESSONS: The findings indicate that diabetes mellitus may have an impact on the severity of HNPP. Physicians should consider that worsening of symptoms might result from newly diagnosed diabetes mellitus while treating patients with HNPP.

Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy.

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.

Hand compression neuropathy: An assessment guide.

When a patient presents with pain or paresthesias of the hand and fingers, knowing what to ask, what to look for, and which tests to consider is essential.

Small amounts of functional ATP7A protein permit mild phenotype.

Mutations in ATP7A lead to at least three allelic disorders: Menkes disease (MD), Occipital horn syndrome and X-linked distal motor neuropathy. These disorders are mainly seen in male individuals, but a few affected females have been described. More than 400 different mutations have been identified in the ATP7A gene. We have conducted several studies in the hope of uncovering the relationship between genotype and phenotype. We have examined the X-inactivation pattern in affected females, the effect of exon-deletions and--duplications, and splice-site mutations on the composition and amount of ATP7A transcript, and we have examined the structural location of missense mutations. The X-inactivation pattern did not fully explain the manifestation of MD in a small fraction of carriers. Most of the affected females had preferential inactivation of the X-chromosome with the normal ATP7A gene, but a few individuals exhibited preferential inactivation of the X-chromosome with the mutated ATP7A gene. The observed mild phenotype in some patients with mutations that effect the composition of the ATP7A transcript, seems to be explained by the presence of a small amount of normal ATP7A transcript. The location of missense mutations on structural models of the ATP7A protein suggests that affected conserved residues generally lead to a severe phenotype. The ATP7A protein traffics within the cells. At low copper levels, ATP7A locates to the Trans-Golgi Network (TGN) to load cuproenzymes with copper, whereas at higher concentrations, ATP7A shifts to the post-Golgi compartments or to the plasma membrane to export copper out of the cell. Impaired copper-regulation trafficking has been observed for ATP7A mutants, but its impact on the clinical outcome is not clear. The major problem in patients with MD seems to be insufficient amounts of copper in the brain. In fact, prenatal treatment of mottled mice as a model for human MD with a combination of chelator and copper, produces a slight increase in copper levels in the brain which perhaps leads to longer survival and more active behavior. In conclusion, small amounts of copper at the right location seem to relieve the symptoms.

Clinical features and anti-neural reactivity in neuropathy associated with IgG monoclonal gammopathy of undetermined significance.

Neuropathy has been frequently reported in patients with IgG monoclonal gammopathy of undetermined significance (MGUS) but it is still unclear whether this association has clinical or pathogenetic relevance. In order to clarify the possible role of IgG MGUS in the neuropathy we correlated the clinical and electrophysiological features of the neuropathy with the duration and anti-neural activity of the M-protein in 17 patients with neuropathy and IgG MGUS. Ten patients (59%) had a chronic demyelinating neuropathy clinically indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP) while 7 (41%) had a predominantly sensory axonal or mixed neuropathy. In 80% of patients in the CIDP-like and 28% in the sensory group the IgG M-protein became manifest several months to years after onset of the neuropathy. Antibodies to one or more neural antigens (including tubulin, a 35KD P0-like nerve myelin glycoprotein, GD1a, GM1 and chondrotin sulfate C) were found in 40% of patients with CIDP-like and 43% with sensory neuropathy but also in 37% patients with IgG MGUS without neuropathy. Neuropathy associated with IgG MGUS is probably less heterogeneous than previously considered suggesting that this association may not be merely casual. The evidence for primary pathogenetic role of IgG M-proteins in the neuropathy remains however elusive.

Congenital hypomyelinating neuropathy.

An eleven-month-old baby born out of non-consanguineous parentage presented with history of delayed motor milestones. The weakness was predominantly distal; there was intercostal muscle weakness, generalized hypotonia and areflexia. The nerve conduction velocities were unobtainable in all the four limbs. Sural nerve biopsy was consistent with the diagnosis of congenital hypomyelinating neuropathy, a rare form of hereditary motosensory neuropathy.

Orthotic management of the lower limb in children with hereditary motor sensory neuropathy (HMSN).

The lower limbs of 55 paediatric patients, with the diagnosis of hereditary motor sensory neuropathy (HMSN) referred to the Orthotics and Biomechanics Department of Hacettepe University, were assessed for appropriate orthotic intervention. Since in the natural history of HMSN symptoms and complaints are variable there is a wide range of interventions possible. The biomechanics of deforming forces and the consequential incidence of deformities in these 55 children, its orthotic implications and the efficacy of orthotic applications are discussed in detail.

Hereditary induced peripheral neuropathies.

The hereditary neuropathies, representing up to 20 per cent of the total of peripheral neuropathies, present a considerable problem in neurology, rehabilitation medicine, and orthopedics. Patients have predominant foot abnormalities such as pes cavus and talipes equina varus. The largest section is the Charcot-Marie-Tooth syndrome or peroneal muscular atrophy, followed by the leucodystrophies and adrenal myloneuropathy. Information is burgeoning with the advent of molecular genetics, and we anticipate therapeutic options when gene products are discovered.

[Clinical aspects and diagnostic and therapeutic approaches to motor and sensory hereditary neuropathies (NHMS)]. / Aspectos clínicos y abordaje diagnóstico y terapéutico de las neuropatías hereditarias sensitivomotoras.

INTRODUCTION: The classifications of peripheral neuropathies are continually being revised in the light of advances in genetic and biochemical investigation. OBJECTIVE: We establish a classification based on the pathology found in different anatomical structures of nerves: the Schwann cell, myelin, axon and the different genes involved in causing neuropathies. Diagnosis is based on data from the clinical history, physical examination and electromyography and their correlation with the type of inheritance in relation to the different genes localized to (a) the Schwann cell: periaxin gene (PRX) encoding L and S periaxin. Stabilisation of the myelin acting as a signal tranducer. NDRG1 down stream regulated gene 1 and 2 acting as transcription factors in embryogenesis. EGR2/Krox 20 has an important function in myelinization. (b) Myelin: P0 membrane protein zero (MPZ) stabilizes the myelin. P1 myelin basic protein (MBP), is analogous to the myelin protein of the central nervous system (CNS) P2 found in the cytoplasm. PMP22 (peripheral myelin protein) also stabilizes the protein. MAG (myelin associated glycoprotein) has antigenic properties. (c). Axon. A foundational mutation (892C Y) in the gene of the lamina (LMNA) of the light neurofilaments (NF L). Mutations in the KIF1Bb gene which encodes the protein kinesin. We also make an aetiological analysis of some classical syndromes, especially the D jerine Sottas syndrome. CONCLUSION: The systematization used, based on clinical and electrophysiological data in relation to the different genes involved in the various anatomical structures constitutes a logical, diagnostic approach which is very useful.