Genetic heterogeneity in giant axonal neuropathy: an Algerian family not linked to chromosome 16q24.1

Giant axonal neuropathy is a rare severe autosomal recessive childhood disorder affecting both the peripheral nerves and the central nervous system. Peripheral nerves characteristically show giant axonal swellings filled with neurofilaments. The giant axonal neuropathy gene was localised by homozygosity mapping to chromosome 16q24.1 and identified as encoding a novel, ubiquitously expressed cytoskeletal protein named gigaxonin.We describe a consanguineous Algerian family with three affected sibs aged 16, 14 and 12 years who present a mild demyelinating sensory motor neuropathy, hypoacousia and kyphoscoliosis which was moderate in the two elder patients, severe in the third one, with no sign of central nervous system involvement and normal cerebral magnetic resonance imaging. This clinical picture is different from the classical severe form, with kinky hairs and early onset of central nervous system involvement and from the less severe form, with protracted course and late involvement of central nervous system. Nerve biopsy showed a moderate loss of myelinated fibers and several giant axons with thin or absent myelin, filled with neurofilaments. This neuropathological aspect is similar to the previously described families linked to the gigaxonin gene. Genetic study in this family showed absence of linkage to chromosome 16q24.1, indicating for the first time, a genetic heterogeneity in giant axonal neuropathy. We propose to call this form of giant axonal neuropathy giant axonal neuropathy 2, and to use the name of giant axonal neuropathy 1 for the form linked to 16q24.1.     

Sensory nerve pathology in multifocal motor neuropathy

The nosological status of multifocal motor neuropathy remains controversial. The clinical and electrodiagnostic hallmarks suggest selective motor fiber involvement. In this study, we asked to what extent sensory nerves might be involved pathologically in multifocal motor neuropathy. Examination of sensory nerve biopsy specimens from II patients did reveal pathological findings in all, but they were very mild. An increased number of thinly myelinated, large-caliber fibers was the unifying feature common to each specimen. By electron microscopy, each biopsy specimen had thinly myelinated fibers surrounded by minor onion bulbs. Active demyelination, though scant, was seen in 3 nerves. Myelinated fiber density was normal. Subperineurial edema and inflammation were not present. We conclude that multifocal motor neuropathy is not an exclusively motor abnormality, although it appears to be so clinically and electrophysiologically. The frequent, albeit mild, pathological abnormalities in sensory fibers suggest that the demyelinating pathophysiology also affects sensory fibers, but to a lesser degree than motor fibers. Some investigators maintain that multifocal motor neuropathy is within the spectrum of chronic inflammatory demyelinating polyneuropathy. The very mild degree of sensory fiber involvement, the absence of inflammation or edema, and the distinctive clinical features support the concept of multifocal motor neuropathy as distinct from chronic inflammatory demyelinating polyneuropathy.     

Acute autonomic sensory and motor neuropathy associated with central nervous system disturbance.

We report a 45-year-old woman with acute autonomic sensory and motor neuropathy (AASMN) showing central nervous system (CNS) disturbance. She presented with disturbance of consciousness, complex partial seizures with automatisms, autonomic, sensory and motor neuropathy, showing severe orthostatic hypotension and neurogenic bladder. Nerve conduction studies and nerve biopsy indicated axonal degeneration involving both the myelinated and unmyelinated fibers. Muscle biopsy revealed neurogenic muscular atrophy. Electroencephalogram revealed theta wave activities and sharp wave abnormalities in the frontal lobe. Intravenous immunoglobulin therapy resulted in complete recovery of consciousness levels, but no obvious improvement of the other symptoms. Only eight patients with AASMN have been reported. This is the first report of AASMN showing CNS disturbance. Perivascular lymphocytic infiltration into the temporal lobe and brain stem was described in an autonomic neuropathy patient. An inflammatory pathogenesis of the CNS disturbance associated with this autonomic neuropathy was proposed.     

Terminal changes in hereditary sensory and autonomic neuropathy: a long-term follow-up of a sporadic case

We describe terminal changes in a long-term follow-up of a 51-year-old man with sporadic hereditary sensory and autonomic neuropathy (HSAN). From the age of 15 years onwards, he suffered from multiple painless ulcers of his feet and fingers, necessitating amputation. Neurological studies revealed almost complete sensory loss affecting all modalities in the upper and lower limbs, minimal involvement of motor fibers, and areflexia. A neurophysiological abnormality involved an absence of sensory action potentials with relatively normal motor nerve conduction velocities. Biopsy of the sural nerve showed almost total loss of myelinated fibers with a mild decrease in unmyelinated fibers. Despite the late onset of the disease, the progressive course, and the lancinating pain, the terminal features of this patient, which involved a selective loss of myelinated fibers and widespread sensory loss, seem to be symptomatic of HSAN II, the progressive form of autosomal recessive sensory neuropathy, and emphasize the clinical heterogeneity of HSAN.     

Clinical and pathological features of an autosomal recessive neuropathy

Two siblings are described, ages 49 and 45 years, having a distinct hereditary motor and sensory neuropathy (HMSN) with severe peroneal nerve involvement. The neuropathic symptoms began in childhood. Both patients have sensorineural deafness. The proband was found to have a cardiac conduction abnormality in the absence of known ischemic heart disease. Electrodiagnostic studies were consistent with a demyelinating peripheral neuropathy. The presence of parental consanguinity and absence of affected individuals in succeeding or preceding generations suggested that the sensorimotor neuropathy in this family is inherited in an autosomal recessive manner. The sural nerve of the proband had significant loss of myelinated fibers and demyelination but few regenerating myelinated fibers and no onion-bulbs. The pathological findings, while nonspecific, are not characteristic of the hypertrophic, neuronal or intermediate types of HMSN.     

Peripheral nervous system and central nervous system pathology in rapidly progressive lower motor neuron syndrome with immunoglobulin M anti-GM1 ganglioside antibody

Pathological studies, including novel teased peripheral nerve fiber studies, were performed in a patient who presented with a rapidly progressive, lower motor neuron syndrome and high titer of immunoglobulin M anti-GM1 ganglioside antibody. In the central nervous system, there was a severe loss of motor neurons and central chromatolysis with ubiquitin immunopositive cytoplasmic inclusions in residual motor neurons. In the peripheral nervous system, axonal degeneration of myelinated fibers in the anterior nerve roots was evident. Pathologic evidence of sensory nerve involvement was also found despite the absence of clinical or electrophysiological sensory abnormalities. Sectional studies of single myelinated nerve fibers from an antemortem sural nerve biopsy showed remyelination and globular paranodal swellings due to focal complex myelin folding and degeneration in 13% of fibers. Postmortem studies of the sural nerves 4 weeks later showed paranodal demyelination (90% of fibers), but no paranodal swellings and similar findings were present in samples of the ulnar, radial, median, tibial, and common peroneal nerves. Paranodal abnormalities of enlargement of the adaxonal space, myelin degeneration, and axonal compaction were found on cross-sectional studies of individual teased fibers, which on conventional light microscopic assessment appeared normal. These changes suggest a disturbance of paranodal axonal-myelin adhesion due to binding of the anti-GM1 ganglioside antibody to the common epitope known to be present on the myelin sheath and nodal axolemma in the paranodal region of both motor and sensory nerves.     

Neuropathy caused by cisplatin. Clinical, electrophysiological and morphological study

Seven patients with cancer presented a sensory peripheral neuropathy induced by cisplatinum. This drug was used alone in 1 case and, in 6 other cases it was associated with drugs without any toxicity for the peripheral nervous system. Every patient had an electromyogram and motor and sensory nerve conduction studies. A sural nerve biopsy was performed in 5 cases for light and electron microscopic studies as well as for teasing and quantitative studies. Electromyograms and motor nerve conductions were normal. Sensory nerve conductions were slowed with very low amplitude sensory action potentials. Such results suggested axonal changes. Nerve biopsies showed typical axonopathic changes with secondary demyelination. Morphometric studies confirmed a loss of myelinated fibers affecting the large fibers in all cases, according to the slowed sensory nerve conductions. This study confirmed that the cisplatinum-induced neuropathy is a new form of toxic distal axonal neuropathy. The hypothesis of a primary demyelination of peripheral nerves, which has been proposed, could not be retained.     

Neurophysiologic and histopathologic studies in a case of congenital sensory neuropathy with anhidrosis]

A three year-old boy with congenital sensory neuropathy with anhidrosis (CSNA) was described. Sural nerve biopsy specimens revealed an almost complete absence of unmyelinated fibers and a marked decrease of the density of small myelinated fibers with preservation of the density of large myelinated fibers. No evidence of active degeneration of unmyelinated or myelinated fibers was found. Skin biopsy specimens revealed the absence of nerve terminals and fibers innervating sweat glands, although sweat glands seemed to be apparently normal in their morphological findings. Therefore, it was concluded that the absence of pain and temperature sensations with preservation of touch sensation in our patient was compatible with the morphometric findings of nerve fibers of the sural nerve described. Similarly anhidrosis was concluded to be well explained by the absence of the innervation of sweat glands and the vessels around them. On the other hand, electrophysiologic studies, such as motor and sensory nerve conduction, short latency somatosensory evoked potential and auditory brainstem response, in which the function of the large myelinated fibers is presumably tested, were all normal. Therefore, the structure and function of such large myelinated fibers were spared in this case. From clinical viewpoints, electrophysiologic studies described above are useful to differentiate CSNA from other types of congenital sensory neuropathies, in which large myelinated fibers are affected.     

Autosomal recessive motor and sensory neuropathy with excessive myelin outfolding

Two Japanese persons with consanguinous parents had a motor and sensory neuropathy of the hypertrophic type with excessive myelin outfolding in the myelinated fibers. A morphometric analysis of the biopsied sural nerve was made. Excessive myelin outfolding, segmental demyelination, and remyelination and decrease in the density of both large and small myelinated fibers were evident. Using linear regression, myelin spiral length was shorter relative to axonal area. These patients may have a new variant of hereditary motor sensory neuropathy.     

Hereditary motor and sensory neuropathy type 1 (HMSN1) associated with cranial neuropathy: an autopsy case report

A family with hereditary motor and sensory neuropathy type 1 (HMSN1) is reported. Three patients suffered only pupillary abnormality, two patients showed Adie's syndrome and peripheral neuropathy, and one had cranial neuropathy. Adie's syndrome and severe peripheral neuropathy. Autopsy of the latter revealed reduction of myelinated nerve fibers in the trigeminal, facial and hypoglossal nerves. There was extensive degeneration of the posterior column of the spinal cord. At the anterior horns, loss of motor neurons was observed, particularly at the lumbar level. The anterior and posterior roots showed loss of myelinated fibers. HMSN1 is only rarely associated with cranial neuropathy, and this is probably the first autopsy-proved case.     

Symptom duration and clinical features in painful sensory neuropathy with and without nerve conduction abnormalities

BACKGROUND: The term "small fiber sensory neuropathy" (SFSN) refers to an axonal sensory polyneuropathy predominantly affecting cutaneous sensory modalities, often associated with pain and with no evidence of large fiber involvement. We hypothesized that, in most patients, SFSN is the earliest manifestation of a nonspecific axonal neuropathy and will usually progress to involve larger, heavily myelinated sensory and motor fibers. We sought indirect evidence of this through an analysis of the correlation between symptom duration and large fiber involvement in patients with painful sensory neuropathy (PSN). METHODS: A clinical diagnosis of PSN was supported by nerve conduction studies or measurement of epidermal nerve fiber (ENF) density in 43 patients. Symptom duration was correlated with the frequency of large fiber loss as measured by nerve conduction abnormalities. The severity and extent of clinical signs and symptoms were also evaluated in subjects with and without electrodiagnostic abnormalities. RESULTS: Patients with large sensory axon involvement had symptoms of longer duration than patients with SFSN. The frequency of electrodiagnostic abnormalities increased in direct proportion to disease duration. Patients with electrodiagnostic abnormalities also had more extensive pinprick sensory deficits, suggesting that small fiber loss was more advanced in this group as well. CONCLUSIONS: In PSN, the incidence of large fiber involvement appears to increase in proportion to symptom duration. This represents indirect evidence that SFSN usually progresses to involve both large and small fibers within 2-10 years.     

Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese

Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disorder of the peripheral nervous system characterized by marked progressive sensory loss, with variable autonomic and motor involvement. The HSAN I locus maps to chromosome 9q22.1–22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long chain base subunit 1 (SPTLC1). Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. Here we report the clinical, electrophysiological and pathological findings of a proband in a Chinese family with HSAN I. The affected members showed almost typical clinical features. Electrophysiological findings showed an axonal, predominantly sensory, neuropathy with motor and autonomic involvement. Sural nerve biopsy showed loss of myelinated and unmyelinated fibers. SPTLC1 mutational analysis revealed the C133W mutation, a mutation common in British HSAN I families.     

Clinical, electrophysiological and histological analysis of adult onset chronic sensory neuropathy

We reported clinical, electrophysiological and pathological findings in 10 patients with acquired, slowly progressive sensory neuropathy. Group I patients which had delayed sensory nerve conduction velocities (SNCV) or no response of SCV in electrophysiological studies were observed to have marked deep sensory disturbances. On the other hand, Group II who had abnormalities of both SNCV and motor nerve conduction velocities electrophysiologically has tendency to show superficial sensory disturbances more dominantly than that of deep sensation. Histological findings of biopsied sural nerve in Group I were mainly composed of diminution of large myelinated fibers, in Group II the diminution of large myelinated fibers with decreased unmyelinated fibers were observed. However, there were no significant difference between Group I and Group II in the quantitative analysis of myelinated fibers. There were no definite tendency under the basic disease or background factors of these 10 patients. Only 3 of these 10 patients had immunological abnormalities such as RA factors or antinuclear antibodies.     

IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is a chronic demyelinating neuropathy with predominant involvement of large sensory fibers and deposits of IgM and complement on sural nerve myelinated fibers. We assessed the presence of IgM deposits on skin myelinated nerve fibers and the involvement of unmyelinated axons in anti-MAG neuropathy. Skin biopsies were performed in 14 patients with anti-MAG neuropathy, in 8 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and in 2 patients with IgM paraproteinemic neuropathy. Biopsies were taken at the proximal thigh in 20 patients, at the distal leg in 21 patients, at the proximal arm in 13 patients, and at the hand or fingertip in 10 patients. We found IgM deposits on dermal myelinated fibers in all anti-MAG neuropathy patients, with a greater prevalence at the distal site of the extremities. Deposits were located throughout the length of the fibers and at the paranodal loops. CIDP and IgM paraproteinemic neuropathies did not show any deposit of IgM. Anti-MAG neuropathy and CIPD patients showed a decrease in epidermal nerve fiber density reflecting an associated axonal loss. In anti-MAG neuropathy, both large- and small-diameter nerve fibers are affected, and specific deposits of IgM are found on skin myelinated nerve fibers.     

Primary Sjögren's syndrome associated neuropathy

Primary Sj?gren's syndrome (PSS) mainly affects exocrine glands and is clinically characterized by keratoconjunctivitis sicca and xerostomia. Among several possible extraglandular manifestations, involvement of the peripheral nervous system may occur with reported frequencies from 10% to 60%. Peripheral nerve manifestations constitute sensory neuropathy, including sensory ganglioneuronopathy, sensorimotor, including polyradiculoneuropathy and demyelinating neuropathy, motor neuropathy, multiple mononeuropathy, trigeminal and other cranial neuropathies, autonomic neuropathy, and mixed patterns of neuropathy. Knowledge of the neurological manifestations of PSS is hampered by evolving classification criteria of PSS over the years, and by use of highly selected patient populations on the basis of a primary neurological diagnosis. Sural nerve biopsy may show vascular or perivascular inflammation of small epineurial vessels (both arterioles and venules) and in some cases necrotizing vasculitis. Loss of myelinated nerve fibers is common and loss of small diameter nerve fibers occurs. Pathology in cases of sensory ganglioneuronopathy consists of loss of neuronal cell bodies and infiltration of T cells. Peripheral neuropathy in PSS often is refractory to treatment although newer biological agents may provide more effective treatment options. Current treatment strategies used in autoimmune neuropathies may be tried depending upon characteristics of the neuropathy and results obtained by a thorough clinical and laboratory investigation.     

Hereditary motor and sensory neuropathy with absence of large myelinated fibers due to absence of large neurons in dorsal root ganglia and anterior horns, clinically associated with deafness, mental retardation, and epilepsy (HMSN-ADM)

Hereditary motor and sensory neuropathy (HMSN) with autosomal recessive inheritance represents a genetically heterogeneous group of disorders with variable clinical, pathologic and electrophysiologic manifestations. A new variant of autosomal recessive HMSN, clinically defined by sensorimotor polyneuropathy associated with deafness and mental retardation, has recently been described. We report on the first autopsy case with this type of HMSN: a girl of non-consanguineous parents with a presumably autosomal recessive type of motor and sensory neuropathy clinically associated with deafness, mental retardation, and epilepsy. The autopsy showed complete absence of large myelinated fibers in peripheral motor and sensory nerves corresponding to a lack of large neurons in dorsal root ganglia and anterior horns of the spinal cord, moderate neurogenic muscle atrophy, and nearly complete absence of neurons in the dentate nucleus of the cerebellum. Molecular genetic analyses in our case revealed neither genetic alterations in the survival motor neuron gene nor in the PMP-22 gene.     

AIDS--associated predominantly sensory neuropathy. The role of herpes viruses

Three patients with predominantly sensory neuropathy in course of HIV-1 infection are reported. In all cases ultrastructural examination showed herpes virus-like particles in the axoplasmic matrix of myelinated fibers and in endoneurial macrophages. In 2 cases clinical patterns of posterior column involvement were observed.     

Quantitative changes of sural nerves in various neurological diseases

Summary Quantitative histological studies were made on sural nerve biopsies from 123 patients with various neurological disorders. The myelinated fibre density, nuclear density, and the thickness of the perineurium were measured and compared with the average and standard deviation of control material in different age groups.Specimens from chronic polyneuritis and heredodegenerative neuropathy showed a reduction of myelinated fibres and an increase of nuclei, the decrease of large myelinated fibres being greater than that of small myelinated fibres.In acute polyneuritis the large and small myelinated fibres decreased equally in number. In the sensory type of SMON, small myelinated fibres decreased more than large myelinated fibres, while in the sensorimotor type of SMON, the change was the reverse. Nuclear population remained unchanged in these diseases.In spinocerebellar degeneration there was a close correlation between the decrease in myelinated fibres and the clinical findings such as sensory disturbance and diminished tendon reflexes, suggesting the presence of peripheral nerve involvement.Myelinated fibres were reduced in cases of neurological diseases hitherto considered to be free of pathological changes in sensory nerves, including motor neurone disease, myopathy, tumours or vascular diseases of the brain and spinal cord. In motor neurone disease and myopathy the large fibres were decreased more than small fibres, and nuclear population was increased. In tumours or vascular disease of the central nervous system, the large and small fibres were decreased equally in number, and the nuclear population was within normal range.     

Peripheral neuropathy in mutant diabetic mouse [C57BL/Ks (db/db)]

Summary A new animal model for the study of diabetic neuropathy is presented. The homozygote (db/db) of the mouse strain C57BL/Ks shows severe diabetes with longstanding hyperglycemia. Electrophysiological studies showed severely decreased motor nerve conduction velocity. Morphometric examination of sensory and motor nerves at different levels revealed absence of large myelinated fibers, with morphological features indicative of axonal atrophy.Supported by Grant No. MA-5857 from the Medical Research Council of Canada     

Impairment of the peripheral nervous system in Creutzfeldt-Jakob disease

BACKGROUND: The clinical manifestations of Creutzfeldt-Jakob disease (CJD) primarily reflect involvement of the central nervous system. The coexistence of CJD with peripheral nervous system involvement has also been reported. OBJECTIVE: To analyze peripheral neuron electrophysiologic changes and to compare these data with neuropathologic features of spinal motor neurons in patients with definite CJD. DESIGN AND PATIENTS: Electrophysiologic examinations were performed on 16 patients with sporadic CJD. The diagnosis was confirmed by neuropathologic examinations (15 patients) or by intravital detection of the 14-3-3 protein in the cerebrospinal fluid (1 patient). The spinal cord was neuropathologically examined in 8 patients. SETTING: Department of Clinical Neurophysiology, I Neurological Department, Institute of Psychiatry and Neurology, Warsaw, Poland. MAIN OUTCOME MEASURES: Electromyography, compound muscle and sensory nerve action potentials, distal latencies, F waves, peripheral motor and sensory conduction velocity, and spinal motor neuron numbers and morphologic characteristics. RESULTS: All patients had signs of central nervous system damage typical of sporadic CJD. Only 3 patients had clinical signs of peripheral nervous system involvement. Electrophysiologic examinations confirmed peripheral nervous system damage in these patients and revealed preclinical peripheral nervous system impairment in 11 more patients. In 1 patient, electrophysiologic examination revealed features of motor neuron disease; in 9, axonal disease; and in 4, axonal-demyelinating neuropathy. Neuropathologic examination results confirmed severe loss of spinal motor neurons in 1 patient with motor neuron disease and revealed the features of motor neuron chronic disease in 4. In 2 of them, electrophysiologic data were normal. CONCLUSION: In sporadic cases of CJD, peripheral nervous system impairment should be considered to be an integral component of disease.