α-Synuclein in motor neuron disease: an immunohistologic study

-Synuclein (ASN) has been implicated in neurodegenerative disorders characterized by Lewy body inclusions such as Parkinsons disease and dementia with Lewy bodies. Lewy body-like inclusions have also been observed in spinal neurons of patients with amyotrophic lateral sclerosis (ALS) and reports suggest possible ASN abnormalities in ALS patients. We assessed ASN immunoreactivity in spinal and brain tissues of subjects who had died of progressive motor neuron disorders (MND). Clinical records of subjects with MND and a comparison group were reviewed to determine the diagnosis according to El-Escariol Criteria of ALS. Cervical, thoracic and lumbar cord sections were stained with an antibody to ASN. A blinded, semiquantitative review of sections from both groups included examination for evidence of spheroids, neuronal staining, cytoplasmic inclusions, anterior horn granules, white and gray matter glial staining, corticospinal tract axonal fiber and myelin changes. MND cases, including ALS and progressive muscular atrophy, displayed significantly increased ASN staining of spheroids (P0.001), and glial staining in gray and white matter (P0.05). Significant abnormal staining of corticospinal axon tract fibers and myelin was also observed (P0.05 and 0.01). Detection of possible ASN-positive neuronal inclusions did not differ between groups. Significant ASN abnormalities were observed in MND. These findings suggest a possible role for ASN in MND; however, the precise nature of this association is unclear.     

An autopsy case of peroneal muscular atrophy with rigidity and tremor

Summary An autopsy case of hereditary peroneal muscular atrophy (PMA) with rigidity and static tremor is presented. The patient developed slowly progressive distal muscular atrophy of the legs at the age of 15 years. By the age of 52 years, PMA became marked associated with pes cavus, and tremor and rigidity of the extremities were noted. Motor and sensory conduction velocities gradually depressed and lost near the end of his life. At autopsy, the major neuropathological abnormalities involved the peripheral nervous systems, and were characterized by axonal atrophy and loss of myelinated fibres. These changes involved both the proximal and distal nerves, being more severely affected in the distal. The pathological changes in other regions of the nervous systems were mainly confined to the spinal cord, dorsal ganglia and spinal nerve roots, and pigmented neurons in the brain stem. Morphometrically, the total fascicular area was much smaller than in control, but the total number of myelinated fibers greatly outnumbered that of control 75 200 to 48 200 at the proximal sciatic nerve and then gradually decreased towards the periphery; however, even in the distal sural nerve, the total number of myelinated fibers exceeded that of control (6820 to 5469). Thus, the density of myelinated fibers were much higher, being 1.5 to 2 times greater, than in control. Its abrupt decline at the distal nerve might account for neurogenic atrophy of the distal musculature. Unmyelinated fibers were slightly increased in density and not atrophic. This case is unique in its clinicopathology and does not belong to any subtypes of PMA including neuronal plus.     

Variability of morphological features in early infantile polyneuropathy with defective myelination

Summary Four cases of early infantile polyneuropathy with defective myelination are reported. The peripheral nerve was studied by light and electron microscopy; different morphological characteristics have been noticed in these patients. Case 1 presented aspects of defective myelination with atypical onion bulb formation composed of multiple layers of basement membrane. In case 2, defective myelination and atypical onion bulb formation were associated with aberrant hypermyelination. Cases 3 and 4 were brothers, who presented axonal damage and atypical onion bulb formation.     

Autonomic neurons of the sacral spinal cord in amyotrophic lateral sclerosis,anterior poliomyelitis and “neuronal intranuclear hyaline inclusion disease”: Distribution of sacral autonomic neurons

Summary Further evidence is presented that the Onuf's nucleus (or colonne en torsade of Laruelle) and the intermediolateral nucleus of the sacral cord share common selective vulnerability with the thoracolumbar intermediolateral nucleus in ALS, anterior poliomyelitis and neuronal intranuclear hyaline inclusion disease. Sparing of the sacral nuclei in the motor neuron diseases and neuronal loss of the nuclei in the multisystem atrophy are correlated well with normal and disturbed vesicorectal function. The clinicopathological evidence strongly supports the view that the Onuf's nucleus represents autonomic neurons much as the intermediolateral nucleus.Supported by the Research Grant awarded by the American Diabetes Association of Minnesota, USA     

Effect of tri-o-cresyl phosphate (TOCP) poisoning on sensory nerve terminations of slow loris

Summary Sensory nerve terminations in the oral and digital tissues of slow loris (Nycticebus coucang coucang) were studied after topical or systemic administration of TOCP. Histochemical studies revealed a reduction of AChE and complete absence of ChE in sensory nerve terminations. In electron microscopy the light cells of taste buds showed vacuolization, degenerating mitochondria, distended endoplasmic reticulum, vesicle formation and cytosegregosomes while dark cells also has unusual shaped dense core granular vesicles (1,200–2,500 Å diameter). The axons were ballooned with fragmenting mitochondria, some agranular vesicles and disorientated neurotubules lying in a dispersed, lightly granular axoplasm. Moreover, the Nauta-Gygax method (1954) revealed degenerative changes in the digital sensory end-organs as well as in the distal portion of the sensory nerve fibres. The significance of these findings is discussed.     

Amyotrophic cerebellar hypoplasia

Summary Lower motor neuron degeneration, cerebellar hypoplasia, atrophy of pons, olives, and cerebellum, sclerosis of thalamus and pallidum, and deficient myelination were found in a 2-months-old baby with laryngeal paralysis, mental retardation, progressive amyotrophy, and slow nerve conduction velocity. Such changes seem characteristic of an unusual syndrome previously referred to as cerebellar hypoplasia in Werdnig-Hoffmann disease, or anterior horn cell disease with pontocerebellar hypoplasia. Although the pathologic changes in lower motor neurons are indistinguishable from those in other cases of infantile spinal muscular atrophy, the consistent reproducibility of a complex pathologic pattern suggests that this is probably a manifestation of a separate disease process. The term amyotrophic cerebellar hypoplasia (ACH) is a convenient designation for the syndrome.Supported in part by National Institutes of Health grant no. RR75     

Effects of riluzole on combined MPTP + 3-nitropropionic acid-induced mild to moderate striatonigral degeneration in mice

Summary. We investigated the potency of riluzole, an anti-glutamatergic drug, to affect ongoing neuronal death process following combined MPTP+3-nitropropionic acid (3-NP) intoxication producing combined striatal and nigral degeneration (SND) in mice. We used a neuronal rescue strategy by administering riluzole after the end of intoxication. The motor disorder, its recovery, behavioral performances at motor and sensorimotor integration tasks and histopathological outcome were compared in the saline and riluzole groups (10mg/kg and 20mg/kg), matched by triplets for motor severity. While riluzole did not produce any effect on the gross motor disorder nor on rotarod task, open-field kinetic variables or on the traversing beam task, it had a subtle effect on the performances at the pole test. The histopathological outcome was significantly better in the riluzole-treated mice regarding both nigral and dorsolateral striatal cell loss and astroglial activation, with a dose-effect relationship. Thus, riluzole has limited neuronal rescue properties from an histopathological point of view with a subtle motor behavior improvement in a MPTP+3-NP-induced SND in mice.     

On areas of transition between entorhinal allocortex and temporal isocortex in the human brain. Normal morphology and lamina-specific pathology in Alzheimer's disease

Summary The allocortical entorhinal region does not gradually transform into the temporal isocortex. Instead, there is an extended stretch of transentorhinal cortex with interdigitation of allocortical and isocortical laminae. The main feature of this transition zone is that the superficial layer of large multipolar nerve cells (Pre-) of the entorhinal region gradually sweeps downward and follows an oblique course through the outer layers. During this course the starshaped nerve cells of Pre- are transformed into pyramidal cells.The layer Pre- projection cells are particularly prone to the development of neurofibrillary changes of the Alzheimer type. In cases of presenile and senile dementia almost all of the layer Pre- projection neurons are changed pathologically. The isocortical pyramidal cells of layers II to IV are far less inclined to develop neurofibrillary changes. In the transentorhinal cortex, the tangle-bearing neurons follow an oblique course through the superficial laminae and are finally located between the isocortical layers III and IV, findings that confirm the assumption that these neurons are constituents of the allocortical layer Pre-.Layer-specific pathology of the profound stratum as well confirms the transentorhinal region as being formed by interdigitating allocortical and isocortical layers.Supported by grants from the Deutsche Forschungsgemeinschaft     

Peroneal muscular atrophy with hereditary spastic paraparesis (HMSN V) is pathologically heterogeneous

Summary Peroneal muscular atrophy (PMA) associated with hereditary spastic paraparesis (HSP) is a nosologically ill-defined disease, which has been classified by Dyck as hereditary motor and sensory neuropathy type V (HMSN V). Nerve biopsy has been rarely reported in this condition. We examined sural nerve biopsies in four patients, demonstrating the following: severe myelinated fiber loss especially of large fibers, with moderate (one case) or prominent (one case) onion bulb formation; selective decrease of large fibers with moderate Schwann cell hyperplasia (one case); normal myelinated fiber population with minimal changes (one case). After reviewing previously reported cases, we conclude that in PMA with HSP sural nerve biopsy may show features either of hypertrophic type of PMA, of neuronal type, or of spinal type; thus, it seems inappropriate to allocate PMA with HSP in a unique subtype of HMSN. In addition, HSP may be not associated with peripheral neuropathy, and thus the classification in the HMSN group may be incongrous. A proper classification of PMA with HSP may be in the complicated forms of HSP according to Harding [Lancet I: 1151–1155 (1983)]; however, the nosology of this condition needs to be further elucidated, possibly on the basis of the underlying molecular genetic mechanisms of HSP and PMA.Supported in part by a grant from the Ministero dell'Università e della Ricerca Scientifica e Tecnologica (quota 40% per ricerche di rilevante interesse nazionale)     

The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is genetically and clinically distinct from classic spinal muscular atrophy (SMA1). It results from mutations in the gene encoding immunoglobulin -binding protein 2 (IGHMBP2) on chromosome 11q13. Patients develop distally pronounced muscular weakness and early involvement of the diaphragm, resulting in respiratory failure. Sensory and autonomic nerves are also affected at later stages of the disease. We investigated peripheral nerves, skeletal muscles and neuromuscular junctions (NMJ) ultrastructurally in five unrelated patients and three siblings with genetically confirmed SMARD1. In mixed motor and sensory nerves we detected Wallerian degeneration and axonal atrophy similar to the ultrastructural findings described in SMA1. Isolated axonal atrophy was evident in purely sensory nerves. All investigated NMJ of patients with SMARD1 were dysmorphic and lacked a terminal axon. Moreover, we also observed characteristics of neuropathies, such as abnormalities in myelination, that have not been described in spinal muscular atrophies so far. Based on these findings we conclude that impairment of IGHMBP2 function leads to axonal degeneration, abnormal myelin formation, and motor end-plate degeneration.     

Experimental autoimmune neuropathy with anti-GM1 antibodies and immunoglobulin deposits at the nodes of Ranvier

Summary Antibodies to GM1 or Gal(1–3)GalNAc are associated with motor or sensorimotor neuropathy and with motor neuron disease. To investigate the role of these antibodies in the neurological disorder, rabbits were immunized with GM1 or with Gal(1–3)GalNAc-BSA, and studied serologically, electrophysiologically and pathologically. Development of antibodies to the immunizing antigens was associated with a fall in the ratio of the amplitudes of the compound muscle action potential evoked by proximal versus distal stimulation of the sciatic nerve. Pathological studies revealed mild axonal degeneration and immunoglobulin deposits at the nodes of Ranvier in peripheral nerve, resembling those reported in a patient with motor neuropathy, motor conduction block and anti-GM1 antibodies. These studies provide evidence that anti-GM1 or anti-Gal(1–3)GalNAc antibodies cause conduction abnormalities and indicate that the antibodies may exert their effect, in part, by binding at the nodes of Ranvier in peripheral nerve.Supported by center grants from the Muscular Dystrophy Association and NINCDS (NS11766) to Columbia University. F.P. Thomas and S. A. Sadiq were fellows of the Muscular Dystrophy Association and the Charles A. Dana Foundation; F.P.Thomas is a fellow of the German Cancer Research Center (DKFZ)     

Rosenthal fibers,eosinophilic inclusions,and anchorage densities with desmosome-like structures in astrocytes in Alzheimer's disease

Ultrastructural study of the cerebral cortex of nine brains of individuals with Alzheimer's disease (AD) revealed four types of pathological changes of astrocytes. Rosenthal fibers were found in three cases, eosinophilic inclusions in one, anchoraged densities with desmosome-like structures in two, and corpora amylacea in four. In two biopsies, Rosenthal fibers were seen in less than 5% of astrocytes, but in a third biopsy with numerous plaques, tangles, and severe neuronal loss, they were present in about 40% of astrocytes. In one case with severe AD pathology and numerous Rosenthal fibers, the cytoplasm of some astrocytes was occupied by inclusions composed of electron-dense granules 3–6 m in diameter or aggregates of inclusions greater than 12 m in diameter. Ultrastructurally, they were similar to eosinophilic inclusions observed in Aicardi syndrome and brain malformations. The presence of eosinophilic inclusions in the brain of elderly persons with Alzheimer's disease does not confirm the previous suggestion that this form of astrocyte pathology is typical for protoplasmic astrocytes and developmental brain malformations. Development anchorage densities associated with hemidesmosome-like structures, which reinforce astrocyte cell membranes facing the perivascular space, may reflect adaptation of astrocytes to the complex of changes that occurs in atrophic brain. Morphological changes in astrocytes in areas with numerous plaques and massive infiltration of intercellular space with -amyloid fibrils and remnants of neurons and ghost tangles suggest that astrocyte pathology is a late unspecific reaction to the cascade of changes induced by -amyloid deposition that causes neuronal degeneration and brain atrophy.Supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities and a grant from the National Institutes of Health, National Institute of Aging No. P01-AGO-4220     

Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology—a pilot study

Data on the relationship between cerebral amyloid angiopathy (CAA) (congophilic angiopathy) and Alzheimers disease (AD) pathology are conflicting. In the present study, CAA and capillary CAA (CapCAA) (dyshoric angiopathy) were examined in the frontal cortex of 100 human brains obtained at autopsy from both male and female, demented and non-demented patients (mean age ± SD 84.3±9.3 years); 50 brains with high (mean 5.0) and 50 with low (mean 2.4) Braak stages. CAA was assessed according to the method of Olichney et al. [25]; CapCAA was grouped into four grades by counting the affected capillaries in 10 high power fields. General CAA was present in 61% (87.5% demented, 55.6% non-demented; 70% with high and 52% low Braak stages). CAA did not correlate with either clinical diagnosis of dementia or high-grade AD pathology; CapCAA showed a low correlation with dementia and a medium positive correlation with high Braak stages. The severity of both lesions did not correlate with clinical dementia; whereas that of CAA showed low correlation with CERAD, Braak, and NIA-Reagan-Institute criteria, the severity of CapCAA correlated significantly with all three AD criteria. The presence and severity of CAA and CapCAA showed only low correlation, suggesting a different pathogenesis of these types of lesion. Since CapCAA represents insoluble amyloid peptide (A) deposits in and around capillaries, its correlation with neuritic AD pathology supports the concept of neuronal origin of A via drainage from interstitial fluid from the central nervous system to capillary walls. Studies to answer the question whether CapCAA represents an epiphenomenon or an indicator of a pathogenic association between tau cytopathology and A deposition in capillaries are in progress.     

“Echoing approval”: A new speech disorder

We report the cases of two patients presenting a peculiar speech disorder, which we have named echoing approval, in which the patients echo, in replying to questions in a dialogue with short phrases, the positive or negative syntactical construction of a question, or its positive or negative intonation, but without any repetition of whole or part of sentences. When asked about their symptoms, the patients replied 80% of the time with yes, yes, that's right, or exactly to positive questions and no, no or absolutely not to negative questions, regardless of their actual symptoms and oblivious to self-contradiction. In addition, when the examining doctor was speaking to a medical colleague in the patient's presence and using medical terminology that the patient did not understand, he/she agreed or disagreed with any sentence and technical word uttered in a way entirely dependent on the syntax or intonation used. To distinguish this speech disorder from echolalia or verbal perseverations, with which it may be superficially confused, we suggest that it be called echoing approval, as it may be part one of the manifestations of the environment-dependency syndrome. This clinical picture was found to be associated with features of transcortical motor aphasia and frontal lobe signs. One patient had a bilateral callosofrontal malignant glioma and the other a probable multiple system atrophy with global deterioration, pre-eminent frontal release signs, diffuse leukoencephalopathy and multiple lacunes. On the basis of these clinical deficits and neuroimaging features, we are unable to delineate the common, or minimal, lesioned network required for this symptomatology to occur, especially in the absence of a series of patients, and with such a difference in both the location and causes of the lesions. However, bilateral frontosubcortical dysfunction was pre-eminent in the clinical picture in both patients, even though more diffuse brain pathology was seen in one, and it might be speculated that dysfunction of the bilateral orbitofrontal and frontomesial motor frontosubcortical circuits might be involved in the aetiology of this peculiar speech disorder.     

Early detection of axonal injury after human head trauma using immunocytochemistry for β-amyloid precursor protein

Severe non-missile head injury commonly results in a form of brain damage known as diffuse axonal injury (DAI). The histological diagnosis of DAI is made by silver staining for the presence of axonal retraction balls. This feature takes about 24 h to develop and does not allow for the early histological diagnosis of DAI. We have used immunocytochemistry for the -amyloid precursor protein (APP) as a marker for axonal injury in formalin-fixed, paraffin-embedded sections of human brain. Axonal APP immunoreativity was present in all cases which had survived for 3 h or more. This was true even where the degree of head injury did not appear to be severe, supporting the theory that DAI is a severe form of a more common phenomenon of axonal injury which occurs after cerebral trauma. APP immunoreactivity was also found in some non-head injured cases and so cannot be considered to be a specific marker for trauma. The results show that APP immunocytochemistry may be useful in the detection of traumatic axonal injury in its early stages, before the formation of axonal retraction balls, provided care is taken to exclude other causes of such immunoreactivity.Supported by the Home Office Policy Advisory Board for Forensic Pathology (UK)     

Effects of chronic vitamin E deficiency on the nervous system of the rat

Summary Light- and electron-microscopic studies were carried out on the central nervous system (CNS) and the peripheral nervous system (PNS) of vitamin E-deficient rats. Extensive axonal degeneration and dystrophic changes were observed in posterior columns and their medullary relay nuclei, respectively. The changes were more prominent in gracile tracts and nuclei than cuneate tracts and nuclei. Alteration in the PNS were less severe than those in the CNS. The posterior roots and sciatic nerves showed only a mild degree of axonal degeneration, while more distal segments of axons in s.c. nerves, in cutaneous sensory corpuscles, and in muscle spindles of hind paws were more severely affected. The neurons in the dorsal root ganglia showed only accumulation of lipofuscin. The above findings in chronic vitamin E deficiency indicate that (a) in addition to the degeneration of central extensions of sensory neurons, their peripheral axons are also affected, (b) the distribution of lesions is similar to those seen in distal axonopathies or a dying back process.     

Diffuse form of argyrophilic grain disease: a new variant of four-repeat tauopathy different from limbic argyrophilic grain disease

Argyrophilic grain disease (AGD) is characterized by the occurrence of argyrophilic grains and coiled bodies in brain tissue, mainly in limbic areas located in the temporal lobe. Recent biochemical data have shown that inclusions in AGD consist of aggregates of pathological microtubule-associated tau protein isoforms of 64/69 kDa. We report here a study on two AGD patients, belonging to a series of demented patients affected by several tauopathies, prospectively followed until death. In both patients, clinical, neuropathological and biochemical investigations clearly demonstrated AGD. Diffuse tau pathology was shown by Gallyas silver stain, tau immunohistochemistry and tau protein variant biochemical analysis, not only in temporal lobes but also in all cortical and subcortical areas that were assessed. Primary motor, primary sensory, and associative brain cortices were involved, as well as brain stem, but not cerebellum. We suggest that diffuse AGD might be a subgroup of AGD, the specific profile of which is different from that of limbic AGD.     

Morphometric study of the sensory neuron and peripheral nerve changes induced by chronic cisplatin (DDP) administration in rats

Summary We performed a morphological, morphometric and toxicological study on the spinal ganglia and peripheral nerves of the rat after chronic administration of cisplatin (cis-dichlorodiammineplatinum II; DDP) with two different schedules. Severe damage of the spinal ganglia neurons was demonstrated with predominant involvement of the nucleus and nucleolus associated with a decrease in the cell size. Morphological and morphometric changes also occurred in the sciatic and peroneal nerves with the features of axonopathy. All these changes were more marked in the group of rats which underwent the most intense DDP treatment and the tissue platinum concentrations were also higher in this group. This experimental model is the first available for chronic DDP administration in which concomitant spinal ganglia and peripheral nerve damage has been confirmed pathologically. Our study supports the hypothesis that DDP-induced peripheral nerve fiber degeneration may result from nuclear and nucleolar changes in the sensory ganglion cell perikaryon.Supported by the grant no. 91.00220.PF41 from the Italian National Research Council (CNR)-targeted project Prevention and control disease factors     

Refraktärperioden und frequente Impulsfortleitung im gemischten N. ulnaris des Menschen bei Polyneuropathien

Zusammenfassung Bei 30 Patienten mit Neuropathien unterschiedlichen Schweregrades (subklinisch, leicht, mittelschwer und schwer) wurden am N. ulnaris neben den üblichen neurophysiologischen Parametern [distale Latenz, maximale motorische und gemischte Nervenleitgeschwindigkeit (Nlg.)] die Refraktärperioden (Rp.) (absolute Rp. und relative Rp.-Amplitude und -Latenz) und die unteren Grenzfrequenzen (u. F.) (u. F.-Amplitude und -Latenz) bestimmt.Beim Vergleich mit einem Normalkollektiv (n=31, s. Lowitzsch u. Hopf, (1972a)) war die Nlg. nur in 37% der Fälle pathologisch verlangsamt, während die relative Rp.-Latenz in ca. 80% und die u. F.-Latenz in ca. 60% pathologisch verändert waren.In zwei Stichproben (13 Normalfälle und 13 Polyneuropathien) mit einer normalen gemischten Nlg. von 51,0–63,5 m/sec unterschieden sich die Mittelwerte für die distale Latenz sowie die motorische und gemischte Nlg. statistisch nur auf dem 1%-Niveau, für die relative Rp.-Latenz und die u. F.-Latenz hingegen auf dem 0,5-Niveau.Die Bestimmung der Refraktärperioden, insbesondere der rel. Rp. L., sowie der unteren Grenzfrequenz (u. F. L.), stellt eine im Vergleich mit den üblichen neurophysiologischen Verfahren (Nlg.-Bestimmung) wesentlich empfindlichere Untersuchungsmethode zur Erfassung auch geringer (subklinischer) Funktionsstörungen des peripheren Nervensystems dar.Die unterschiedliche Beeinflussung der Refraktärperioden und der Grenzfrequenzen durch die Art des zugrundeliegenden pathologischen Prozesses (axonale Degeneration — segmentale Demyelinisierung — Mischtyp) wird an Hand der in 9 Fällen nervenbioptisch (N. suralis) gewonnenen Befunde diskutiert.

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Refractory periods and frequent impulse conduction in mixed N. ulnaris of man in polyneuropathies

Summary Some electrophysiological parameters were studied in the ulnar nerve of 30 patients suffering from neuropathy of various origin and severity.Absolute and relative refractory periods and lower limiting frequencies were measured and compared to the usual parameters (distal motor latency, conduction velocity of motor fibres, and the mixed nerve action potential).The conduction velocity was indicative of the diseased function in 37% whereas the relative refractory period (latency) was abnormal in nearly 80% and the lower limiting frequency (latency) in about 60%.Two samples taken at random, each of them consisting of 13 patients with normal conduction velocities between 51.0 and 63.5 m/sec showed differences only at the 1% level (p<0.01) as far as the mean values of the distal latency and the maximum conduction velocity were concerned. The difference between the mean values of the relative refractory period (latency) and of the lower limiting frequency (latency), however, was highly significant (p<0.0005). Thus, in our experience, the relative refractory period (latency) and the lower limiting frequency (latency) are more sensitive indicators of mild functional disturbances of peripheral nerves than the maximum conduction velocity.

Die Untersuchungen wurden in dankenswerter Weise von der Deutschen Forschungsgemeinschaft unterstützt.     

Peripheral neuropathy in the Chediak-Higashi syndrome

Summary The clinical features of a brother and sister with the Chediak-Higashi syndrome (CHS) are reported. Both showed evidence of a sensory neuropathy associated with central nervous system involvement. Nerve conduction studies indicated an axonal neuropathy. Sural nerve biopsy in the brother demonstrated a loss of myelinated nerve fibres, particularly those of larger size, and of unmyelinated axons. In contradistinction to some previous reports, giant lysosomes in Schwann cells were not observed and there were no inflammatory changes. Electron microscopy and teased-fibre studies showed no evidence of demyelination. It is concluded that the neuropathy of CHS is of axonal type. Its mechanism remains obscure.Supported in part by grants from the Medical Research Council of Great Britain, Ciba-Geigy Ltd, Basel and the Central Research Fund of London University. Financial support was also received from Mr. Michael Holmes. V.P.M. is an Efamol Research fellow