Causally treatable, hereditary neuropathies in Fabry's disease, transthyretin-related familial amyloidosis, and Pompe's disease.

OBJECTIVES: Most acquired neuropathies are treatable, whereas genetic neuropathies respond to treatment in Fabry's disease (FD), transthyretin-related familial amyloidosis (TTR-FA), and Pompe's disease (PD). This review summarizes and discusses recent findings and future perspectives concerning etiology, pathophysiology, clinical presentation, diagnosis, treatment, and outcome of neuropathy in FD, TTR-FA, and PD. METHODS: Literature review. RESULTS: Neuropathy in FD concerns particularly small, unmyelinated, or myelinated sensory fibers (small fiber neuropathy [SFN]) and autonomic fibers, manifesting as acroparesthesias, Fabry's crises, or autonomous disturbances. FD neuropathy benefits from agalsidase alpha (0.2 mg/kg every second week intravenously) or from beta (1.0 mg/kg every second week intravenously). Neuropathy in TTR-FA is axonal and affects large and small sensory, motor, and autonomous fibers. Neuropathy in TTR-FA profits from liver transplantation and the TTR kinetic stabilizer tafamidis (20 mg/d). Neuropathy in PD particularly occurs in late-onset PD and manifests as mononeuropathy, polyneuropathy, or SFN. PD neuropathy presumably responds to alglucosidase-alpha (20 mg/kg every second week intravenously). CONCLUSIONS: Neuropathy in FD, TTR-FA, and PD is predominantly a SFN and can be the dominant feature in FD and TTR-FA. SFN in FD, TTR-FA, and PD needs to be recognized and benefits from enzyme replacement treatment or TT-kinetic stabilizers.

Secondary myopathy due to systemic diseases.

BACKGROUND: Some systemic diseases also affect the skeletal muscle to various degrees and with different manifestations. This review aimed at summarizing and discussing recent advances concerning the management of muscle disease in systemic diseases. METHOD: Literature review by search of MEDLINE, and Current Contents with appropriate search terms. RESULTS: Secondary muscle disease occurs in infectious disease, endocrine disorders, metabolic disorders, immunological disease, vascular diseases, hematological disorders, and malignancies. Muscle manifestations in these categories include pathogen-caused myositis, muscle infarction, rhabdomyolysis, myasthenia, immune-mediated myositis, necrotising myopathy, or vasculitis-associated myopathy. Muscle affection may concern only a single muscle, a group of muscles, or the entire musculature. Severity of muscle affection may be transient or permanent, may be a minor part of or may dominate the clinical picture, or may be mild or severe, requiring invasive measures including artificial ventilation if the respiratory muscles are additionally involved. Diagnostic work-up is similar to that of primary myopathies by application of non-invasive and invasive techniques. Treatment of muscle involvement in systemic diseases is based on elimination of the underlying cause and supportive measures. The prognosis is usually fair if the causative disorder is effectively treatable but can be fatal in single cases if the entire musculature including the respiratory muscles is involved, in case of infection, or in case of severe rhabdomyolysis. CONCLUSION: Secondary muscle manifestations of systemic diseases must be addressed and appropriately managed. Prognosis of secondary muscle disease in systemic diseases is usually fair if the underlying condition is accessible to treatment.

Iatrogenic lesions of peripheral nerves.

Iatrogenic nerve lesions (INLs) are an integral part of peripheral neurology and require dedicated neurologists to manage them. INLs of peripheral nerves are most frequently caused by surgery, immobilization, injections, radiation, or drugs. Early recognition and diagnosis is important not to delay appropriate therapeutic measures and to improve the outcome. Treatment can be causative or symptomatic, conservative, or surgical. Rehabilitative measures play a key role in the conservative treatment, but the point at which an INL requires surgical intervention should not be missed or delayed. This is why INLs require close multiprofessional monitoring and continuous re-evaluation of the therapeutic effect. With increasing number of surgical interventions and increasing number of drugs applied, it is quite likely that the prevalence of INLs will further increase. To provide an optimal management, more studies about the frequency of the various INLs and studies evaluating therapies need to be conducted. Management of INLs can be particularly improved if those confronted with INLs get state-of-the-art education and advanced training about INLs. Management and outcome of INLs can be further improved if the multiprofessional interplay is optimized and adapted to the needs of the patient, the healthcare system, and those responsible for sustaining medical infrastructure.

Pompe disease in Austria: clinical, genetic and epidemiological aspects.

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.

The frequency of occurrence of atypical lymphocytes in peripheral blood smears of natalizumab-treated patients with multiple sclerosis.

INTRODUCTION: Aside from the extensive published data on immunophenotypic lymphocyte subsets in natalizumab-treated patients with multiple sclerosis (MS), an impact of natalizumab on lymphocyte morphology has rarely been studied. As patients treated with immunomodulating or immunosuppressive drugs are at risk for infectious disorders such as viral infections, knowledge of drug-derived changes in lymphocyte morphology may be beneficial in the diagnostic work-up in such clinical situations. This study aimed to determine the frequency of occurrence of atypical lymphocytes and defined subtypes of variant lymphocytes in natalizumab-treated patients with MS. METHODS: We compared eight defined morphological lymphocyte subtypes in peripheral blood smears between 14 natalizumab-treated, 13 interferon-treated and 10 untreated subjects with relapse-remitting MS. RESULTS: Atypical lymphocytes were significantly enhanced in natalizumab-treated patients compared to the interferon and control group (P<.0001). Binucleated lymphocytes were restricted to the natalizumab group (P=.0058, P=.018), and plasmacytoid lymphocytes were more frequently found in the natalizumab group (P<.0001). CONCLUSION: Our data indicate that natalizumab enhances the fraction of atypical lymphocytes, and thereby especially the binucleated and plasmacytoid lymphocytes. Knowledge of these natalizumab-associated changes in lymphocyte morphology may be relevant in clinical routine, to avoid unnecessary diagnostic procedures or even a discontinuation of natalizumab treatment.

Clinical phase I study of paclitaxel followed by cisplatin in advanced head and neck squamous cell carcinoma.

We performed a clinical phase I trial of the combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, using a 3-hour infusion of paclitaxel followed by a 1-hour infusion of cisplatin. Treatment with this combination was repeated every 21 days. Patients who had received prior treatment with platinum-containing regimens were excluded. However, patients who had received two or fewer courses of radiochemotherapy not including platinum compounds were eligible. At present, 21 patients have been entered into this ongoing study. Doses ranged from paclitaxel 135 mg/m2 plus cisplatin 75 mg/m2 to paclitaxel 250 mg/m2 plus cisplatin 100 mg/m2. The maximum tolerated dose was reached at paclitaxel 250 mg/m2 and cisplatin 100 mg/m2. The dose-limiting toxicity of this regimen was myelosuppression (leukopenia, granulocytopenia). Clinically, neurosensory toxicity was moderate. However, preliminary analyses of threshold electrotonus studies indicate the presence of subclinical neurotoxicity in most patients. One patient receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 developed grade 3 motor neurotoxicity. Profound orthostatic hypotension was observed in five patients receiving paclitaxel 200 mg/m2 plus cisplatin 100 mg/m2 or higher. Neurotoxicity was of delayed onset and slowly reversible, and its severity appeared to be dose related. Twelve patients are currently evaluable for response. Of these, three partial remissions were observed (6, 6+, and 3+ months). Five additional patients had stable disease. We conclude that the combination of paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer. In addition to myelosuppression, orthostatic hypotension may be a potentially significant clinical toxicity. Clinical phase II studies have been initiated, using a dose of paclitaxel 200 mg/m2 and cisplatin 100 mg/m2.

Differential diagnosis of periodic paralysis aided by in vitro myography.

In vitro twitch tests were performed on excised muscle bundles from 30 periodic paralysis (PP) patients in an attempt to verify the somatic origin of PP, and to differentiate between the hypokalemic (HypoPP) and the hyperkalemic forms (HyperPP). Seventeen PP patients with a definite diagnosis of familial HypoPP, familial HyperPP (subsequently confirmed by SCN4A mutations), or thyrotoxic PP entered the study, as well as 13 patients with a history of attacks of weakness but with negative clinical provocation tests and therefore ambiguous diagnosis; 15 normal subjects served as controls. In contrast to control, bundles from patients with clear diagnosis went into sustained paralysis on exposure to Cl-free solution. Exposure to K+ channel activators induced a large increase in force. Specifically for HypoPP muscle, low extracellular [K+] decreased twitch force which was further reduced by addition of insulin or adrenaline, whereas HyperPP bundles responded with an irreversible decrease in twitch force when extracellular [K+] was elevated. Out of the 13 patients with unclear diagnosis, the in vitro studies made it possible to classify 10 as HypoPP and one as HypePP (later confirmed by a M1592V mutation). In the remaining two patients who claimed to suffer from paralytic attacks, all in vitro tests were normal, questioning the occurrence of dyskalemic PP. The results demonstrate that in vitro tests can be used to ensure the proper diagnosis to a high percentage when clinical provocative tests have failed.

A special blocker reveals the presence and function of the hyperpolarization-activated cation current IH in peripheral mammalian nerve fibres.

Electrotonic responses recorded extra- or intracellularly from peripheral nerve preparations show a "sag" to hyperpolarizing current pulses. The biophysical nature of this "inward rectification" is still under discussion since the phenomenon has not been noted at voltage-clamped single nerve fibres, and since Cs+, which reduces inward rectification, is not a specific ion channel blocker. In this study, we found that low micromolar concentrations of ZD 7288, a specific blocker of the hyperpolarization-activated cationic current (Ih) in the soma of central mammalian neurons, result in a complete block of inward rectification in the electrotonic responses of isolated rat spinal dorsal roots. In addition, ZD 7288 enhanced the activity-dependent slowing of conduction seen in compound C fibre action potentials of isolated rat vagus nerves and augmented the post-tetanic hyperpolarization following trains of action potentials in unmyelinated and myelinated axons. The data suggest that ZD 7288 is a potent blocker and a useful research tool for the study of hyperpolarization-activated inward rectification (Ih) of peripheral nerve preparations.

Calcium potentials and tetrodotoxin-resistant sodium potentials in unmyelinated C fibres of biopsied human sural nerve.

Compound action potentials and electrotonic responses to 150 ms current pulses were recorded from isolated nerve fascicles of human sural nerve biopsies. Compound action potentials in normal bathing solution were characterized by previously described A beta, A delta and C fibre components. In addition, tetrodotoxin-resistant sodium- or calcium-dependent potential components were found when a mixture of tetrodotoxin and the potassium channel blockers 4-aminopyridine and tetraethylammonium was added to the bathing solution. In contrast to tetrodotoxin-sensitive action potentials, tetrodotoxin-resistant sodium- or calcium-dependent potentials could be recorded in the presence of high extracellular potassium concentrations (10-20 mM). Calcium action potentials were found to be sensitive to specific pharmacological antagonists or agonists of L-, N- and P-type calcium channels. Lidocaine, cadmium, verapamil and capsaicin showed unspecific blocking effects on calcium and tetrodotoxin-resistant potentials. Tetrodotoxin-resistant action potentials seem to originate from unmyelinated C fibres since a clear correlation was found between the number of C fibres and the amplitude of tetrodotoxin-resistant calcium and sodium spikes in preparations with different axon type composition. The evidence for tetrodotoxin-resistant Na+ and Ca2+ spikes in peripheral human axons offers new possibilities for a better understanding and/or treatment of abnormalities in the excitability of damaged or diseased peripheral nerves.

Expression of messenger RNA of the cardiac isoforms of troponin T and I in myopathic skeletal muscle.

In the absence of clinical signs, elevated values of the cardiac isoforms of troponin T (cTnT) and I (cTnI) can be found in the serum samples of some patients with skeletal muscle myopathies; the cause is unclear. We studied the messenger RNA (mRNA) expression of cTnT and cTnI in the skeletal muscles of 24 patients with histologically proven myopathies and in 18 patients in whom a myopathy could be excluded. For cTnT- and cTnI-mRNA determination, we designed specific primer pairs for nested polymerase chain reaction. After amplification, the products were digested with 2 restriction enzymes and visualized. We found cTnT mRNA in 7 skeletal muscle biopsy specimens (6 patients with Duchenne muscular dystrophy, 1 patient with a primary sarcoglycanopathy) and cTnI mRNA in 6 (5 with Duchenne muscular dystrophy, 1 patient with a histologically negative biopsy). The mRNA of the cardiac isoforms, cTnT and cTnI, is expressed in the skeletal muscles of patients with Duchenne muscular dystrophy, but also in some other myopathies. Further studies are needed to show whether the mRNA is translated into the protein, but serum levels of cTnT and cTnI in patients with Duchenne muscular dystrophy would seem to indicate this.

P2 purinoceptor-mediated intracellular Ca2+ transients in human sural nerve.

Segments of biopsied human sural nerve were stained with the Ca(2+)-sensitive fluorescent dyes Calcium Green-1 and Fura Red. The emission ratio was used to follow changes in the intracellular free Ca2+ concentration ([Ca2+]i). Application of ATP and analogues in concentrations between 0.3 and 300 microM via the bathing solution resulted in a transient rise in [Ca2+]i. The rank order of agonist potency, 2-methylthioATP > ATP > UTP, and the failure of adenosine, alpha,beta-MeATP and beta,gamma-MeATP to evoke rises in [Ca2+]i indicate the presence of P2Y/U subtypes of purinoceptors in this preparation. ATP-induced Ca2+ transients in biopsied human nerve preparations might serve as a diagnostic tool in neuropathies.

Immunohistochemical and electrophysiological evidence for omega-conotoxin-sensitive calcium channels in unmyelinated C-fibres of biopsied human sural nerve.

In vitro electrophysiological measurements of Ca2+ potentials in human sural nerve fascicles revealed that Ca2+ conductances might be present on unmyelinated C-fibres. Furthermore, these Ca2+ potentials were partially blocked by omega-conotoxin, a calcium antagonist for the N-type Ca2+ channels. Therefore, immunohistochemical staining with indirect immunofluorescent omega-conotoxin GVIA was used to localize N-type Ca2+ channels in intact and in enzymatically dissociated human sural nerve fascicles. Densities of toxin binding sites were highly heterogeneous throughout the different nerve fascicles investigated and putative N-type Ca2+ channels were localized in about 20% of the unmyelinated C-fibres. Myelinating Schwann cells as well as enzymatically demyelinated axons displayed no specific binding indicating the absence of N-type Ca2+ channels.

K+ channel openers suppress myotonic activity of human skeletal muscle in vitro.

Isolated fibre bundles from myotonic human skeletal muscle showed after-contractions and spontaneous mechanical activity. The K+ channel openers cromakalim (10-100 mumols/l) and EMD 52962 (1-10 mumols/l) completely suppressed these abnormalities in mechanical activity. Voltage-clamp experiments revealed that cromakalim (100 mumols/l) increased the membrane K+ conductance of isolated, non-myotonic human skeletal muscle fibres 4-fold; Cl- conductance was not altered. The data show that myotonia is suppressed by an increase in in membrane K+ conductance.

The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons.

The chemotherapeutic oxaliplatin causes a sensory-motor neuropathy with predominantly hyperpathic symptoms. The mechanism underlying this hyperexcitability was investigated using rat sensory nerve preparations, dorsal root ganglia and hippocampal neurons. Oxaliplatin resulted in an increase of the amplitude and duration of compound action potentials. It lengthened the refractory period of peripheral nerves suggesting an interaction with voltage-gated Na(+) channels. Application of oxaliplatin to dorsal root ganglion neurons resulted in an increase of the Na(+) current, a block of the maximal amplitude and a shift of the voltage-response relationship towards more negative membrane potentials. The effect was detectable on 13 of 18 tested cells. This observation, together with the absence of any effect on Na(+) currents of hippocampal neurons, suggests that the interaction of oxaliplatin is restricted to one or more channel subtypes. The effect of oxaliplatin could be antagonised by the Na(+) channel blocker carbamazepine which could be used to reduce side effects of oxaliplatin therapy in patients.

A mechanosensitive K+ channel with fast-gating kinetics on human axons blocked by gadolinium ions.

Current recordings from single mechanosensitive potassium channels were obtained from cell-attached and excised patches of human axons. The channel showed an inwardly rectifying I-V relationship with a slope conductance of 52 pS at negative potentials (symmetrical high potassium solution). The fast-gating kinetics of the channel were best described by one time constant for the open state and two time constants for the closed state. The open probability of this channel increased as negative pressure was applied to the patch pipette. The pressure dependence of the open probability of the mechanosensitive K+ channel followed a sigmoid relationship. Gadolinium (0.5-1 mM) acted as a potent blocker when applied to the intra- and extracellular side of the patch membrane.

Capsaicin blocks tetrodotoxin-resistant sodium potentials and calcium potentials in unmyelinated C fibres of biopsied human sural nerve in vitro.

Topical application of capsaicin has been tested recently for treatment of painful peripheral neuropathy. In the present study, effects of capsaicin were explored on compound action potentials of isolated fascicles from human sural nerve biopsies. Capsaicin reduced the C fibre component by 30-60%; the remaining C fibres were not sensitive to the drug. A good correlation was found between the sensitivity of C fibres to capsaicin and their resistance to tetrodotoxin (TTX), i.e. C fibre action potentials recorded in the presence of TTX were completely blocked by capsaicin. Calcium action potentials seen after inhibition of axonal potassium conductances were also completely suppressed. The data indicate that application of capsaicin nearby human peripheral nerves might prevent action potential conduction in specific subtypes of C fibres.

Two different types of potassium channels in human skeletal muscle activated by potassium channel openers.

The inside-out patch clamp technique was used to record the effects of K+ channel openers (EMD 52692, RP 49356 and Cromakalim) on single channel currents in membrane blebs of human skeletal muscle. Two types of K+ channels were activated by these drugs: an ATP-sensitive K+ channel which was inhibited by 3 mM ATP and 5 microM Glibenclamide and an ATP insensitive K+ channel. The open probability of both types was strongly increased by K+ channel openers. Glibenclamide antagonized the action of the K+ channel openers.

X-linked dominant Charcot-Marie-Tooth neuropathy: clinical, electrophysiological, and morphological phenotype in four families with different connexin32 mutations(1).

The sensorimotor neuropathy of the Charcot-Marie-Tooth type (CMT) is the most common hereditary disorder of the peripheral nervous system. The X-linked dominant form of CMT (CMTX) is associated with mutations in the gene for the gap junction protein connexin32. We examined four CMTX pedigrees two of which had potentially novel mutations in the only coding exon of connexin32. One previously unreported missense mutation, Ala39Val, was found in a family displaying a CMT phenotype with additional upper limb postural tremor reminiscent of a Roussy-Lévy syndrome. A novel single base insertion, 679insT, is among the first mutations found in the fourth transmembrane domain of connexin32. Frameshift and premature stop of translation are supposed to result in a non-functional carboxy-terminus. Two further families had the known missense mutations Arg15Trp and Arg22Gln. Several female carriers were found normal on clinical presentation, however, the genotype was paralleled by decreased nerve conduction velocities (NCV) and slowed central conduction of brain stem auditory evoked responses (BAER). Median motor NCVs showed mild (in women) to intermediate (in males) reduction, indicating a peripheral neuropathy with a predominating axonal component. Nerve biopsy findings were consistent with the electrophysiological data showing a marked loss of large myelinated fibres and clusters of regenerating axons. Electron microscopy revealed various alterations of the axoglial attachment zone. This suggests defective axon-Schwann cell interactions which may induce the axonopathy in CMTX.

Consequences of mutations within the C terminus of the FHL1 gene.

BACKGROUND: Mutations in the four-and-a-half LIM domain 1 gene (FHL1) cause X-linked late-onset scapuloaxioperoneal myopathy characterized by postural muscle atrophy with rigid spine syndrome with pseudoathleticism/hypertrophy (XMPMA), reducing body myopathy (RBM), and scapuloperoneal myopathy. Divergences in these diseases are hitherto unclear; therefore, we searched for additional families to elucidate differences and similarities of these allelic FHL1opathies. METHODS: Using genotyping and phenotyping (mutational analysis, muscle histopathology, and Western blotting) we characterized 10 affected men and 8 women from 7 families. RESULTS: All patients displayed the XMPMA phenotype. In 1 family with a novel missense mutation, 2 affected men had an aneurysm of the sinus of Valsalva in addition. In 5 affected men and 2 affected women from 4 families, the C224W missense mutation in FHL1 was detected, which putatively disrupts the fourth LIM domain. In 3 other families with 5 affected men and 1 female, 2 novel missense variants and a novel splice-site mutation in the C terminus of FHL1 were found. Muscle morphology revealed mild to moderate degenerative myopathy with myofiber hypertrophy of both fiber types at younger age and cytoplasmic bodies in the majority of the samples. Reducing bodies, pathognomonic for RBM, were not found. Western blotting revealed no detectable FHL1A protein in our patients. CONCLUSIONS: As a consequence of C terminal FHL1 gene mutations, the X-linked myopathy characterized by postural muscle atrophy (XMPMA) phenotype and morphotype with cytoplasmic bodies are found. In the spectrum of FHL1opathies, the preserved FHL1C protein is likely responsible for the moderate XMPMA phenotype compared with the more severe reducing body myopathy/scapuloperoneal myopathy phenotype.