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Biomedical subjects

A F Hahn

Publications and source records attributed to A F Hahn.

At least 37 records · Page 2Linked to original sources
PubMed1999

Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease.

We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females 7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.

Charcot-Marie-Tooth Disease↗
PubMed1998

Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is viewed as a reactive, self-limited, autoimmune disease triggered by a preceding bacterial or viral infection. Campylobacter jejuni, a major cause of bacterial gastroenteritis worldwide, is the most frequent antecedent pathogen. It is likely that immune responses directed towards the infecting organisms are involved in the pathogenesis of GBS by cross-reaction with neural tissues. The infecting organism induces humoral and cellular immune responses that, because of the sharing of homologous epitopes (molecular mimicry), cross-react with ganglioside surface components of peripheral nerves. Immune reactions against target epitopes in Schwann-cell surface membrane or myelin result in acute inflammatory demyelinating neuropathy (85% of cases); reactions against epitopes contained in the axonal membrane cause the acute axonal forms of GBS (15% of cases). Care for such patients may be challenging, yet the prognosis overall is favourable. Optimal supportive care and anticipation and prevention of complications are the mainstay of therapy. Admission to the intensive-care unit is necessary in 33% of patients who require intubation and assisted ventilation. Immunomodulation with infusions of IgG or plasma exchange treatments foreshorten the disease course.

Autoimmune Diseases↗
PubMed1998

Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene.

X-linked Charcot-Marie-Tooth disease (CMTX) is a peripheral nerve disorder that has been linked to mutations in the connexin 32 gene (Cx32). These mutations have been shown to be genetically heterogeneous, though recurrences of specific mutations in apparently unrelated families have been seen. The majority of mutations have been shown to be missense, resulting in non-conservative amino acid changes. A few mutations resulting in a premature termination of protein translation, including both nonsense mutations as well as frameshifting microdeletions, have been documented. We would like to report a deletion mutation that appears to eliminate the entire coding sequence of the Cx32 gene, but which has been shown to segregate with a clinical phenotype not unlike that seen in individuals with a less severe alteration of the Cx32 gene. The causes at a cellular level of the CMTX phenotype are still not fully clear, though there has been speculation that these may involve a dominant negative effect where the mutant connexin 32 suppresses the function of other connexins. Studies of kindreds such as this, where in CMTX-affected males the Cx32 gene product is totally absent, will help us to better understand the molecular mechanisms underlying the clinical phenotype associated with this disorder.

Aged↗
PubMed1998

Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphorylation and multiple mtDNA deletions frequently in skeletal muscle. We studied four ethnically distinct families affected with this apparently autosomal recessive disorder. Probands from each family were shown, by Southern blot, to have multiple mtDNA deletions in skeletal muscle. We mapped the MNGIE locus to 22q13.32-qter, distal to D22S1161, with a maximum two-point LOD score of 6.80 at locus D22S526. Cosegregation of MNGIE with a single chromosomal region in families with diverse ethnic backgrounds suggests that we have mapped an important locus for this disorder. We found no evidence to implicate three candidate genes in this region, by using direct sequence analysis for DNA helicase II and by assaying enzyme activities for arylsulfatase A and carnitine palmitoyltransferase.

Adolescent↗
PubMed1998

Treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulin.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a defined clinical entity with a chronic progressive or chronic relapsing course, lasting months to years. It causes variable but often severe chronic disability. CIDP is considered an autoimmune disorder caused by both cellular and humoral immune processes. Various immunomodulatory therapies, i.e., IVIg, therapeutic plasma exchange (PE), and prednisone, are of proven benefit. Comparative studies indicate that IVIg and PE confer equal short-term benefit. Efficacy of IVIg is maintained; regularly timed pulse treatments may stabilize relapsing CIDP. The combination of IVIg and prednisone may be advantageous in long-term management. Despite the high cost, IVIg is considered the preferred first treatment. The safety profile is similar to that reported for other conditions; close monitoring during the infusion is recommended. The precise mechanisms of IVIg action in CIDP are not known. Anti-idiotypic neutralization of autoantibodies, binding of complement, and blockade of macrophages may prevent the ongoing inflammatory demyelination.

Chronic Disease↗
PubMed1997

Migrant sensory neuropathy: report of 5 cases and review of the literature.

There are only a few case descriptions of migrant sensory neuropathy. We report the clinical, laboratory, and electrophysiological findings observed in 5 patients whose presentation conformed with Wartenberg's description of a chronic, disseminated migrant sensory mononeuritis. In one patient, intermittent cranial motor nerve involvement occurred as well. The sural nerve biopsy in this patient showed changes suggestive of focal ischemic nerve damage and electron microscopy confirmed a vasculopathy.

Adult↗
PubMed1996

Plasma-exchange therapy in chronic inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, cross-over study.

Eighteen patients with definite, untreated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (nine patients) or relapsing course (nine patients) were randomized prospectively to receive 10 plasma-exchange (PE) or sham plasma-exchange (SPE) treatments over 4 weeks in a double-blind trial. After a wash-out period of 5 weeks or when they returned to baseline scores, patients were crossed over to the alternate treatments. Neurological function was assessed serially using a quantitative neurological disability score (NDS), a functional clinical grade (CG) and grip strength (GS) measurements. Electrophysiological studies were done at the beginning and end of each treatment. A primary 'intention to treat' analysis showed significant improvement with PE in all clinical outcome measures: NDS by 38 points, P < 0.001; CG by 1.6 points, P < 0.001; GS by +13 kg, P < 0.003 and in selected electrophysiological measurements, sigma proximal CMAP, P < 0.01; sigma motor conduction velocities, P < 0.006; sigma distal motor latencies, P < 0.01. Fifteen patients completed the trial and of those, 12 patients (80%) improved substantially with PE; i.e. five out of seven patients with chronic progressive course and seven out of eight patients with relapsing CIDP improved. There were three drop-outs; one patient lost venous access; one patient suffered a stroke and one patient left the trial to receive open treatment elsewhere. The improvement in motor functions correlated with the electrophysiological data, i.e. with improved motor conduction velocities and reversal of conduction block. Eight of 12 PE responders (66%) relapsed within 7-14 days after stopping PE. All improved with subsequent open label PE; all but two patients required long-term immunosuppressive drug therapy for stabilization. The PE non-responders improved with prednisone. We conclude that PE is a very effective adjuvant therapy for CIDP of both chronic progressive and relapsing course; concurrent immunosuppressive drug treatment is required. Exchange treatments should be given two to three times per week until improvement is established; the treatment frequency should then be tapered over several months.

Adolescent↗
PubMed1996

Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study.

Thirty patients with definite or probable chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) of chronic progressive (16 patients) or relapsing (14 patients) course were randomly assigned to receive intravenous immunoglobulin (IvIg) 0.4 g per kg body weight or a placebo treatment on 5 consecutive days in a double-blind, cross-over trial. Neurological function was monitored by serial quantitative assessments [neurological disability score (NDS); clinical grade (CG) and grip strength (GS) measurements] and by electrophysiological studies before and after each treatment period. Twenty-five patients completed both treatment periods. A comparison of the observed changes in clinical outcome measures revealed statistically significant differences in favour of IvIg, with (mean +/- SD) improvements in NDS by 24.4 +/- 5.4 points (P < 0.002) in CG by 1 +/- 0.3 points (P < 0.001) in GS by +6.3 +/- 1.7 kg (P < 0.005), whereas scores were unchanged or worse with placebo. A secondary two-groups analysis of the first trial period included all 30 patients; 16 patients had been randomly assigned to IvIg and 14 to placebo treatments. Again significant differences in favour of IvIg were observed in all the clinical end-points: improvement in NDS was 35.6 +/- 25 points (P < 0.0001), in CG it was 1.3 +/- 1.9 points (P < 0.002) and in GS +9.8 +/- 7.7 kg (P < 0.001), whereas all scores worsened with placebo. Of the 30 patients, 19 (63%) improved with IvIg treatments; nine out of 16 patients (56%) with chronic progressive CIDP, and 10 out of 14 patients (71%) with relapsing CIDP (differences were not statistically significant). A placebo response was seen in five patients. Comparison of paired electrophysiological measurements before and 4 weeks after IvIg treatments revealed statistically significant improvements in the summed motor conduction velocities (sigma MCV; P < -0.0001) and in the summed compound muscle action potentials (CMAP) evoked with proximal stimulation (sigma proximal CMAP, P < 0.03) of median, ulnar, peroneal and tibial nerves. Eight of nine IvIg responders with chronic progressive CIDP improved gradually to normal function with a single 5 day course of IvIg; in five of these, small doses of prednisone were prescribed during follow-up. In 10 IvIg responders with relapsing CIDP, improvements lasted a median 6 weeks (range 3-22 weeks) and was reproducible with open label treatments. All 10 patients have been maintained and stabilized with IvIg pulse therapy of 1 g per kg body weight or less, given as a single infusion prior to the expected relapse. A beneficial response to IvIg was found to be most likely in patients with acute relapse or with disease of one year or less. Patients with predominantly sensory signs did not improve.

Adolescent↗
PubMed1996

Central and peripheral respiratory electrophysiological studies in myotonic dystrophy.

Acute and chronic respiratory failure is a common and potentially life-threatening feature in patients with myotonic dystrophy (MD). The causes may be varied, and can involve both the central and peripheral nervous system. To evaluate the incidence of respiratory muscle involvement and the function of the central motor inspiratory pathway to phrenic motor neurons we performed magnetic stimulation of the cortex and cervical spinal cord, phrenic nerve conduction studies and needle EMG of diaphragm and intercostal muscles in 25 patients with MD. The results were compared with those from 35 healthy subjects. In addition, pulmonary function tests, blood gas analyses and static mouth pressures were evaluated. Abnormalities in response to magnetic stimulation, including a reduced compound muscle action potential (CMAP) from the diaphragm and increased excitability threshold, indicated impaired central inspiratory drive in 20% of cases. Phrenic nerve conduction showed a reduced diaphragmatic CMAP amplitude in 20%, and a delayed negative peak onset latency in 4% of cases. Abnormalities in diaphragm and intercostal muscle needle EMG were found in 76% of cases, these were mainly myotonic discharges (68%) and a decrease in the number of active motor units (36%). Patients with abnormal respiratory electrophysiological parameters had a significantly lower functional vital capacity (FVC; P = 0.005). The duration of the disease correlated negatively with diaphragmatic CMAP amplitude to phrenic nerve, but not magnetic, stimulation. Our results demonstrate that the involvement of the central inspiratory pathway is common in MD patients. Central and peripheral electrophysiological studies of the diaphragm should be considered in the diagnosis and management of patients with MD and dyspnoea.

Adult↗
PubMed1996

Respiratory electrophysiological studies in Guillain-Barré syndrome.

Respiratory failure is a common and potentially life threatening complication in patients with Guillain-Barré syndrome. The incidence of phrenic nerve involvement and the predictive value of phrenic nerve conduction and diaphragmatic needle EMG were studied in 40 patients with Guillain-Barré syndrome within the first three days of admission to hospital. The negative peak onset latency of the diaphragmatic compound muscle action potential (CMAP), and its amplitude, duration, and area were abnormal in 83%. The need for ventilation was correlated with diaphragmatic CMAP amplitude (P = 0.005), and area (P = 0.001), but not with latency or duration. Abnormalities in diaphragmatic needle EMG were found in 45%, mainly a decreased number of motor unit potentials. The abnormalities correlated with the need for ventilation (P = 0.013). Of the 40% who required ventilation, all had either abnormal phrenic conduction, abnormal diaphragmatic needle EMG, or both. Eighty one per cent of the ventilated patients had abnormal forced vital capacity on the day of the electrophysiological examination. The results indicate that phrenic nerve conduction studies and diaphragmatic EMG are useful in detecting respiratory involvement in patients with Guillain-Barré syndrome and in identifying those at risk of respiratory failure.

Adolescent↗
PubMed1996

Experimental allergic neuritis (EAN) as a model for the immune-mediated demyelinating neuropathies.

The inflammatory demyelinating neuropathies (GBS and CIDP) are autoimmune disorders; their pathogenesis and the precise immunological target(s) remain unknown. Valuable insights into the immune mechanisms have been gained from the animal models: Lewis rat EAN and chronic EAN of rabbits. Lewis rats immunized with myelin or myelin proteins P2 and P0 in Freund's adjuvant develop transient paralysis. The pathological findings of nerve edema, perivenular lymphocyte infiltrates and macrophage-mediated demyelination are identical to those of GBS. Severity of clinical EAN and of the pathology correlate with the antigen dose used for immunization. In Lewis rat EAN there is firm evidence of a cell-mediated process. The strongest support for T-cell autoimmunity has come from the adoptive transfer of EAN to syngeneic animals with antigen-specific (P2 and P0) autoreactive T-cells. Humoral factors play a role in the demyelination. Both mechanisms may function synergistically, in that activated neuritogenic T-cells breach the blood-nerve-barrier and thus provide circulating anti-myelin antibodies access to the target tissues. Rabbits immunized with a single large multiportal dose of myelin predictably develop EAN with a chronic progressive or relapsing course. The clinical, electrophysiological and pathological features are identical to human CIDP. IgM and IgG anti-Gal C antibody titres parallel the disease course and have demyelinating activity. T-cell responses have not yet been characterized in this model. Both forms of EAN lend themselves to the study of very specific immunotherapies.

Animals↗
PubMed1996

Management of Guillain-Barré syndrome (GBS).

GBS is an acute immune-mediated neuropathy which, in one-third of cases, leads to total paralysis requiring ICU admission for assisted ventilation and management of autonomic cardiovascular instability. The management can be challenging and even with most expert care and modern ICU facilities the mortality remains at 5-8%. This chapter gives an outline of the natural history and pathophysiology of the condition with emphasis on newer concepts. Guidelines are given for the management of patients prior to and during the admission to an ICU by highlighting the potential complications. An up-to-date account is given on the specific immunomodulatory therapies.

Critical Care↗
PubMed1995

Mapping the gene for acetazolamide responsive hereditary paryoxysmal cerebellar ataxia to chromosome 19p.

Acetazolamide responsive hereditary paroxysmal cerebellar ataxia (APCA) is a rare autosomal dominant disorder characterized by attacks of cerebellar ataxia and dysarthria with normal or near normal neurologic function between attacks. A genome-wide search using polymorphic di- and tri-nucleotide repeats was initiated and the APCA locus was found to be linked to the short arm of chromosome 19 in two large kindreds. The microsatellite marker UT705 was found to be linked to the APCA locus with two point analysis yielding a maximum lod score of 8.20 at theta max = 0.000 in a five generation pedigree. Linkage to this region was confirmed in a second kindred. The absence of known candidate genes in the region may necessitate a positional cloning approach in order to identify the gene for this disorder.

Acetazolamide↗
PubMed1994

Nerve biopsy findings in Niemann-Pick type II (NPC)

The severe infantile form of Niemann-Pick disease type II was diagnosed in a 4-year-old girl and confirmed by demonstrating in cultured skin fibroblasts a deficiency of low-density lipoprotein-stimulated cholesterol ester synthesis of < 5% of normal. Electrodiagnostic studies revealed changes of a predominantly demyelinating motor and sensory polyneuropathy. Light microscope and ultrastructural examination of a peroneal nerve biopsy showed unique changes. Compacted myelin sheaths were disproportionately thin with marked globular irregularities in single teased nerve fibres and evidence of chronic demyelination. The majority of axons were preserved but axonal spheroids and cytoskeletal abnormalities akin to neuroaxonal dystrophy were noted. Membrane-bound multi-lobulated lysosomal inclusions of floccular and electron-dense material were present in Schwann cells (SC), endoneurial fibroblasts, macrophages, pericytes and endothelial cells. SC of myelinated fibres were stuffed with whorls of concentric osmiophilic membraneous profiles and electron-lucent material. The findings are diagnostic and differ from those of classical Niemann-Pick disease.

Axons↗
PubMed1994

Lewis rat EAN is suppressed by the 21-aminosteroid tirilazad mesylate (U-74006F).

Lewis rat experimental allergic neuritis (EAN) was treated with the 21-aminosteroid, tirilazad mesylate (U-74006F). High doses of tirilazad mesylate, begun just before the onset of clinical signs, reduced the clinical and pathological severity of the disease. In rats immunized with a high dose of myelin, axonal degeneration was a major pathological feature. Tirilazad mesylate reduced the amount of axonal degeneration but had little effect on the other pathological features of EAN, such as inflammation and demyelination. Tirilazad mesylate may block axonal degeneration by inhibiting lipid peroxidation of axonal membranes. Inhibition of axonal degeneration is an important goal in the treatment of human neuropathies.

Animals↗