HEREDITARY SENSORY NEUROPATHY WITH NEUROTROPHIC KERATITIS · brain (1987), 110, 563-583 hereditary...

Brain (1987), 110, 563-583

HEREDITARY SENSORY NEUROPATHY WITHNEUROTROPHIC KERATITIS

DESCRIPTION OF AN AUTOSOMAL RECESSIVE DISORDER WITH

A SELECTIVE REDUCTION OF SMALL MYELINATED NERVEFIBRES AND A DISCUSSION OF THE CLASSIFICATION OF THE

HEREDITARY SENSORY NEUROPATHIES

by MICHAEL DONAGHY,1 R. N. HAKIN,2 J. M. BAMFORD,2 A. GARNER,3

G. R. KIRKBY,4 B. A. NOBLE,4 M. TAZIR-MELBOUCY,5 R. H. M. KING5

and p. K. THOMAS1-5

(From the ^Institute of Neurology and the National Hospital for Nervous Disease, Queen Square,London, 2St. Luke's Hospital, Bradford, West Yorkshire, 3Department of Pathology, Institute ofOphthalmology, London, ^Department of Ophthalmology, Leeds General Infirmary, and the 'Depart-

ment of Neurological Science, Royal Free Hospital School of Medicine, London)

SUMMARY

A Kashmiri family with 3 members affected by a congenital sensory and autonomic neuropathy andcorneal opaciiication is described. The 3 affected cases were offspring of consanguinous marriages intwo generations; autosomal recessive inheritance is therefore probable. Pain and temperature sen-sation was lost in the limbs with a resulting mutilating acropathy. Sudomotor function was alsoimpaired. Motor function, tendon reflexes, kinaesthetic sensation and sensory nerve action potentialswere normal. Sural nerve biopsy showed a selectively reduced small myelinated nerve fibre popu-lation. Corneal histology revealed neurotrophic keratitis.

The classification of the hereditary sensory and autonomic neuropathies is discussed. This familyrepresents a previously unrecognized variant.

INTRODUCTION

The early literature contains reports of familial cases in which the salient clinicalabnormality was the development of a mutilating acropathy, predominantly affect-ing the lower limbs. Such cases were frequently ascribed to lumbosacral syringo-myelia (Nelaton, 1852;Bruns, 1903; Gobell and Runge, 1917;Schultze, 1917; Weitz,1924; Riley, 1930; Van Epps and Kerr, 1940). They are difficult to assess inretrospect because of the lack of pathological documentation, but probably rep-resent instances of hereditary sensory neuropathy. The recognition that such casescould be due to a hereditary sensory neuropathy came with the report by Ogryzlo

Correspondence to: Professor P. K. Thomas, Department of Neurological Science, Royal Free Hospital Schoolof Medicine, Rowland Hill Street, London NW3 2PF, UK.

© Oxford University Press 1987

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564 MICHAEL DONAGHY AND OTHERS

(1946) on 4 affected individuals from a sibship of 12 from Newfoundland, theparents being clinically normal. The inheritance was probably autosomal recessive.The onset of symptoms was in early life with distal sensory loss affecting allmodalities. Nerve biopsy demonstrated loss of nerve fibres.

The fact that the sensory loss in some cases mainly affected pain and temperaturesensibility was the reason why many earlier authors had attributed this to'lumbosacral syringomyelia'. In these cases, the inheritance was usually autosomaldominant. The first demonstration that they were also due to a sensory neuropathywas provided by Jughenn et al. (1949) in a single case that came to autopsy. Loss ofmyelinated nerve fibres, perineurial thickening and Schwann cell proliferation wereobserved. Subsequently Denny-Brown (1951), again in a dominantly inheritedfamily previously reported by Hicks (1922) as hereditary perforating ulceration ofthe feet, considered that the primary defect was a degeneration of dorsal rootganglion cells and introduced the term 'hereditary sensory radicular neuropathy'.

In an attempt to classify hereditary sensory neuropathies in terms of their geneticand clinical features, Dyck and Ohta (1975) later categorized these former caseswhich showed autosomal recessive inheritance and congenital sensory loss affectingall modalities distally in the limbs as hereditary sensory neuropathy (HSN) typeII. Those with autosomal dominant inheritance and an onset of symptoms mostfrequently during the second and third decades of life and who showed apredominant loss of pain and temperature sensibility were classified as HSN type1. Nevertheless there is considerable clinical overlap between the two conditions(Asbury and Johnson, 1978).

The term congenital insensitivity to pain was formerly employed to indicate theabsence of recognition of pain and a lack of reaction to painful stimuli from birth.In such cases in which there was accompanying anhidrosis, Swanson et al. (1965)and Bischoff and Curti (1977) established that there was a selective loss ofunmyelinated axons in the peripheral nerves and a deficiency of Lissauer's tract.Similarly, congenital insensitivity to pain in association with familial dysautonomiawas shown by Aguayo et al. (1971) to be related to a severe deficiency ofunmyelinated axons and a lesser depletion of large myelinated axons. Both of theseconditions are of autosomal recessive inheritance and were classified by Dyck andOhta (1975) as HSN IV and III, respectively.

In the present study, a family is described in which a sensory neuropathy,probably congenital and of autosomal recessive inheritance was found to beassociated with loss of small myelinated fibres. The family is unique in that theneuropathy was consistently associated with neurotrophic keratitis.

CASE REPORTS

All the family members originated from Kashmir. The 3 members affected by sensory neuropathyand corneal opacification (IV.4, IV.7, V.4) result from two first cousin marriages (fig. 1). Familymembers III.4, IV.3,6,7,8,10,12,13 were all normal on examination and were unaware of any otheraffected family members.


HEREDITARY SENSORY NEUROPATHY 565

V- ?=

III

IV

T' T' ?« T' ?'

°

FIG. 1. Pedigree.

Case IV.4This 26-yr-old man had a normal birth and did not suffer unexplained fevers during infancy.

Bilateral corneal opacification had been noted at about 4 months of age. Ulceration of the tip of thetongue developed at the age of 3 yrs. A sore on the lip became a cleft through which drinking fluidswould leak until the defect was closed surgically (fig. 2). From the age of 5 yrs he was aware that hedid not feel pain if he cut his hand and that wounds took a long time to heal. He has never been ableto feel pain or temperature with his hands or feet. Frequent whitlows have led to loss of terminalfinger pulp and deformities of the toes, and autoamputation of one toe. Skin ulcers requiring graftinghave affected his feet (fig. 3). He can feel pain and temperature on the trunk and face, has experiencedabdominal pain and suffers discomfort if foreign objects lodge in his conjunctivae. Deterioratingvision due to comeal opacities led to a corneal transplant to the right eye at the age of 25 yrs.

Examination revealed mutilating acropathy affecting the feet (fig. 3) and fingers with loss ofterminal digital pulp. The tip of the tongue was absent (fig. 2). Mentation, muscle bulk and power,the tendon reflexes, light touch, vibration and joint position sense, and 2-point discrimination werenormal. The painful elements of pin-prick sensation, and tickle sensation, were totally absent in thelimbs below the elbows and knees, over the tip of the tongue and on the scalp. Mild hyperpathia topin prick was present on the trunk. Temperature sensation was impaired over the whole body. Thecorneal reflex was normal on the left but absent from the right-sided corneal graft. Tear secretionwas normal.

Ophthalmological examination. Visual acuity was 6/12 in the left eye. The left cornea showedscarring affecting the mid and deeper zones of the stroma with cysts, clefts and pigment spiculeswithin it, and clumping of pigment on the endothelium in the region of the scar (fig. 4). The cornealepithelium was intact and there was no clinical evidence of vascularization of the scar.

Laboratory investigations. The following were normal: routine haematology, plasma urea andelectrolytes, blood sugar, scrum immunoglobulins and protein electrophoresis, thyroid function,blood lead, vitamin Bl2 and syphilis serology, 24 h urinary vanillyl mandelic acid excretion, audio-metry and psychometry.



Fio. 2 (left). Case IV.4, showing traumatic amputation of the tip of the tongue and perioral scars. The rightcornea is cloudy, related to chronic rejection of a corneal graft.

FIG. 3 (right). Case IV.4, showing chronic ulceration of the feet and loss of the left hallux.

FIG. 4. Case IV.4, showing opaafication of the central portion of the left cornea.



Neurophysiological investigations. Sensory and motor nerve conduction, and needle electro-myography of the first dorsal interosseous muscle of the hand and the tibialis anterior were normal(Table 1), as were somatosensory evoked potentials on stimulation of the posterior tibial nerve atthe ankle (N20 lumbar 25 ms, 12 /JV; P40 cortex 39 ms, 0.9 fiV).

Autonomic function. Sweating was examined on the ventral surface of the body and limbs whichwere coated with Edicol Pinceau 4R 1G starch BPC and inspected for discolouration after raisingthe body temperature by 1° C. Sweating was incomplete and occurred only in the areas recorded infig. 5.

Blood pressure lying was 122/74 mmHg and with 60° tilt was 115/64 mmHg. Sinus arrhythmiawas present during deep breathing (55 to 85 beats/min). Carotid massage caused bradycardia.

FIG. 5. Case IV.4. Sweat test. The shaded areas indicate residual areas of sweating.

TABLE 1. NERVE CONDUCTION STUDIES

Motor Sensory action potentials

Ulnar

Case

IV.4IV.7

MCV DL F

56 3.1 28

Median

MCV DL

Peroneal Ulnar Sural

MCV DL

41 7

F

59— — — 63 3.2 — — —

Amp. Latency Amp. Latency

10 3 7 3.78 2.1 5 3.5

MCV =» motor conduction velocity, m-s"1; DL = distal motor latency, ms; F = Fwave latency, ms; Amp. = amplitude, y\; Latency = latency to peak, ms.



Case IV.7

This 11-yr girl, sister of Case IV.4, had a normal birth and infancy. Bilateral corneal opacificationwas noted at 1 yr of age. An ulcer appeared on the tip of the tongue at the age of 3 yrs and evenwhen she subsequently bit off the tip of her tongue she appeared free of pain. At the age of 4 | yrsbilateral keratitis with perforation and adherence of the iris to the cornea on the right was recordedat ophthalmological consultation. By the age of 5 it was clear that she could not appreciate pain ortemperature with her hands, feet, anterior tongue or around the nose. Trophic skin ulcers and bonydeformity subsequently appeared in the feet. Muscle bulk, power, tendon reflexes and joint positionsense were normal. Histamine flare was normal in the areas of reduced pain sensation. There was nopostural hypotension and sinus arrhythmia was normal. The cornea and conjunctivae of both eyeswere anaesthetic. Tear secretion was normal.

Ophthalmological examination. The visual acuity was no light perception in the right eye and 6/60in the left. The periphery of the right cornea was clear but its centre bore a dense scar that wassuperficially vascularized. The iris was adherent to the scarred area. A penetrating keratoplasty hadbeen performed on the left cornea and the specimen was available for histological examination.

Nerve conduction studies. Motor conduction velocity and sensory nerve action potentials werenormal (Table 1).

Case V.4

This girl had a normal birth. The eyes were said by the family to have been normal at birth butbilateral corneal opacification was noted at 6 months of age. She may have had a seizure when aged6 months. When examined at 18 months of age she walked normally, did not speak, and had earlytrophic changes on the lips and fingertips. A response to pin prick was absent from the hands andnormal from the trunk. Both conjunctivae were anaesthetic.

Ophthalmological examination. By 2 yrs of age penetrating keratoplasty for central corneal opacityhad been performed on both eyes and one cornea was available for histological examination.

MORPHOLOGICAL INVESTIGATIONS

Nerve BiopsySural nerve fascicular biopsy from a site immediately posterior to the lateral

malleolus was obtained under local anaesthetic from Case IV.4 in February, 1985.Methods. The specimen was fixed for 3 h at 4° C in 3% glutaraldehyde in PIPES

buffer (Baur and Stacey, 1977), washed in buffer and postfixed in 2% osmiumtetroxide in PIPES buffer. After dehydration through graded concentrations ofethanol, the specimen was embedded in Araldite using 1, 2 epoxypropane as anintermediary. Semithin sections (1 fim) for light microscopy were stained withthionin and acridine orange (Sievers, 1971). Thin sections for electron micro-scopy (JEOL 100 SX) were stained with 12.5% methanolic uranyl acetate and leadcitrate. Myelinated fibre density and size-frequency distributions were obtainedusing a Kontron Videoplan image analysis system connected to a Leitz Ultraphot.Morphometry of unmyelinated axons was undertaken on electron microscopemontages of approximately 10% of the fascicular area at a final magnificationof x 8000. Single fibre preparations were obtained by teasing in Araldite,employing the method described by Spencer and Thomas (1970); 136 fibres wereisolated.



FIG. 6. Case IV. 4. Transverse section of portion of sural nervebiopsy specimen showing relative lack of small myelinated nervefibres. Thionin and acridine orange stain, x 530.

A20-

c 10

n=1167

llllll L5.0 10.0 15.0Fibre diameter (;/m)

(I 0.2 0.4 0.6 O.X 1.0 1.2 1.4 1.6 1.8 2.0

Axon diameter f//m)

6 HI

5.(1 10.0Fibre diameter (jim)

15.1

FIG. 7. Case IV.4. Size-frequency distributions ofmyelinated nerve fibres (A) and unmyelinated axons(c) in the sural nerve, B shows the myelinated nervefibre distribution from a control subject aged 38 yrs.



Results. Transverse sections of the nerve biopsy specimens showed a lack ofsmall myelinated fibres (fig. 6). Myelinated fibre density was reduced at 4726/mm2

(normal range 7500-10 000/mm2, Jacobs and Love, 1985). A fibre size-frequencyhistogram confirmed a striking selective reduction in the smaller diameter myelin-ated fibre peak (fig. 7A, B). NO active fibre degeneration or demyelination wasseen in the semithin sections, but occasional regenerative clusters, in slightly exces-sive numbers for the patient's age, were present. No hypertrophic changes wereencountered. The teased fibre preparations showed a normal relationship betweeninternode length and fibre diameter, apart from three fibres with inter-calated remyelinated segments and one regenerated fibre with uniformly reducedinternode length. This amount of abnormality is within normal limits for thepatient's age.

On electron microscopy, the unmyelinated fibres were morphologically normal(fig. 8). The density of unmyelinated axons was increased at 76 000/mm2 (normalrange 30 000-40 000/mm2, Jacobs and Love, 1985), this presumably being relatedmainly to the reduction in numbers of small myelinated fibres. As a whole nervebiopsy was not performed, total fascicular area and hence an estimate of the

Fio. 8. Case IV.4. Electron micrograph of sural nerve biopsy showing group of morphologically normal unmyelin-ated nerve fibres. Bar = 2 /an.



FIG. 9. Case IV.4. Electron micrograph of sural nerve biopsy showing regenerative cluster comprised of onemyelinated fibre (Mf) and several nonmyelinated axons (Uax) with associated Schwann cell processes (Sp).Bar = 1 /jm.

absolute unmyelinated axon count could not be obtained. The size distribution ofunmyelinated axons was normal (fig. 7c). The presence of regenerative clustersderived from myelinated fibres was confirmed (fig. 9). There were also occasionalstacks of flattened Schwann cell processes of the type that follow the degenerationof Remak fibres (Ochoa, 1978). No giant vacuolated fibroblasts of the type reportedby Schoene et al. (1970) in hereditary sensory neuropathy were observed.

Corneal HistologyCorneal tissue was available for histological study from Cases IV.7 and V.4,

obtained at the time of corneal grafting performed at the ages of 13 yrs and 18months, respectively. The specimens were fixed in formalin, embedded in paraffinwax and stained with haematoxylin and eosin and the periodic acid-Schiff tech-nique.

IV.7. The epithelium was variable in thickness with atrophy in several placesand loss of much, but not all, of Bowman's zone. There was some stromal vascular-ization and scarring with a very few scattered lymphoctyes. Descemet's membraneand the endothelium were normal.


MICHAEL DONAGHY AND OTHERS

\

.; -X, '-

FIG. 10. Case V.4. Cross-section of the full thickness of the cornea showing a slightly thickened epithelium indirect contact with the substantia propria, the normal acellular Bowman's zone between these two structureshaving failed to develop. There is focal hypcrcellularity of the collagenous stroma associated with some vascular-lzation (arrows). Descemet's membrane is narrow and difficult to identify at this magnification. Haematoxylinand eosin, x 180.

V.4. The corneal epithelium was acanthotic and thickened, but without keratin-ization, and rested on a basement membrane that was in direct apposition to thelamellar collagen and the substantia propria, there being no identifiable Bowman'szone (fig. 10). A few lymphocytes were present in the stroma, chiefly in the vicinityof infiltrating blood vessels. Descemet's membrane was intact if slightly narrow(fig. 11). Oxytalan fibres were not present (these are an elastic tissue precursornormally found in Descemet's membrane in early childhood which disappear inlater life). The endothelium was morphologically normal and of normal density.

DISCUSSION

Hereditary Sensory Neuropathy with Neurotrophic KeratitisThe cases described in this report, from a single family, may represent a unique

disorder. All affected individuals exhibited insensitivity to pain, manifested fromchildhood and possibly congenitally, related to a sensory neuropathy. Clinicalexamination showed selective loss of pain and temperature sensation which wasmaximal distally. This had led to a mutilating acropathy and also to facial andtongue injury. Motor function and large fibre sensory modalities were preserved.



The only detectable autonomic manifestation was widespread anhidrosis. This mayhave contributed to the acropathy by causing dryness and fissuring of the skin.

Sural nerve biopsy revealed selective loss of small myelinated fibres and a normaldensity of unmyelinated axons. The presence of occasional stacks of flattenedSchwann cell processes unassociated with axons suggests that some degenerationof unmyelinated axons may have occurred. No evidence of active myelinated fibrebreakdown was encountered, but the finding of occasional regenerative clustersindicates that some degeneration and subsequent regeneration of myelinated fibreshad also occurred. These appearances were not frequent but were considered to beexcessive for the patient's age. Some continued progression of the neuropathy istherefore implied although, clinically, there was no positive indication of this. Thedevelopment of increasing mutilating changes may merely represent the conse-quences of persisting pain and temperature sensory loss.

FIG. 11. Case V.4. Deep aspect of the cornea showing an even but marginally narrow Descemet's membrane(2.5 /an compared with the 3-4 //m usual at this age). The endothelial lining is continuous and not unduly sparse.Periodic acid-Scruff, x450.

This pattern of fibre loss, namely a selective reduction in the small myelinatednerve fibre population with preservation of the large myelinated and unmyelinatedaxons, has been observed previously in 2 cases, both of whom had a congenitalsensory neuropathy. The first (Low et al., 1978) was a 6-yr-old girl with recurrentulceration of her extremities dating back to the age of 7 months, associated withdegenerative arthropathy of the ankles. There were no motor abnormalities, the



tendon reflexes were preserved and the only detectable sensory loss was for painand temperature distally in the lower limbs and for pain distally in the upper limbs.Autonomic function was normal, including sweating, apart from anisocoria,and defective pupillary reaction to light on one side. Nerve conduction studieswere normal. The second case (Dyck et al., 1983) was a 14-month-old child withselective and universal loss of pain sensation but no other apparent neurologicalabnormalities except for some evidence of reduced sudomotor function andprobable psychomotor retardation. Neither case had a positive family history andthere was no definite evidence of consanguinity. It was assumed by Dyck et al.(1983) that these 2 cases were likely to have a genetic basis, although it would notbe possible to exclude an environmental factor operating in utero in the absenceof a family history and evidence of a progressive neuropathy.

The unique features of our family are, first, that this form of sensory impairmentwith the same pattern of nerve fibre loss on nerve biopsy has been observed as anautosomal recessive trait. The second feature is its association with bilateral cornealopacification, the corneal periphery remaining clear. This corneal opacificationwas probably not present at birth but developed simultaneously in both eyes ofeach patient during the first few months or years of life.

A major question is whether the corneal abnormality was merely secondary tothe neuropathy or whether it was a separate manifestation of the abnormal genewhich caused the neuropathy. Since the relatives recalled that the corneas of CaseV.4 were initially clear, a congenital disorder such as sclerocornea or Peter'sanomaly has to be discounted. Definite clinical evidence of a traumatic keratitiswas only obtained for one of the six corneas, the right eye of Case IV. The natureof the stromal scarring and vascularization, together with the presence of a fewscattered leucocytes, is consistent with a postinflammatory disorder. So far as thepathogenesis is concerned, the bilateral simultaneous onset observed in all 3patients points to an underlying endogenous disturbance, as opposed to a simpleinfective or traumatic episode. In view of the evidence in other tissues of a sensorynerve defect it is conceivable that the basic pathogenesis of the corneal changes isalso neurotrophic, the precise mechanism being obscure but possibly an outcomeof vasomotor disturbance at the periphery and associated metabolic consequences(Sigelman and Friedenwald, 1954). Certainly the histological findings comparewith those previously described in neurotrophic keratitis (Spencer, 1985).

Of the numerous reported cases with hereditary sensory neuropathy, only onesibship apart from our own has exhibited central corneal opacification. A disorderin Navajo Indian children with the autosomal recessive inheritance of cornealopacity associated with mutilating acropathy, painless long bone fractures,cutaneous ulceration, areflexia, abnormal nerve conduction and severe loss ofmyelinated fibres in the sural nerve was described by Appenzeller et al. (1976).The corneal opacification in these cases was attributed to trauma rather thandevelopmental anomaly. Corneal histology was not reported. Moreover, thepattern of nerve fibre loss resembles that of type II HSN (Ohta et al., 1973) rather



that the selective diminution in the small myelinated fibre population seen in ourfamily.

The rarity with which corneal opacification is encountered in hereditaryneuropathy suggests that it is not an automatic consequence of the neuropathy.Its invariable association with the neuropathy in our cases and those of Appenzelleret al. (1976) raises the possibility that it is a postnatal anomaly of the cornea causedby the abnormal gene responsible for the neuropathy, or by a closely linked gene.The association of the neuropathy and the keratopathy in two generations in ourfamily makes it unlikely that more than one gene is involved.

Classification of the Hereditary Sensory NeuropathiesThe classification of the hereditary sensory neuropathies has so far been based

on a combination of the clinical and genetic features (Dyck and Ohta, 1975;Thomas, 1975; Asbury and Johnson, 1978). These conditions may be associatedwith autonomic manifestations which are sometimes the salient aspect of theclinical presentation. Dyck et al. (1983) therefore suggested that this group ofdisorders could appropriately be termed the hereditary sensory and autonomicneuropathies in view of the overlap between these two manifestations. Ultimatecharacterization will depend upon identification of the abnormal genes and geneproducts. Until then it is clinically useful to categorize them in terms of theirpattern of inheritance in combination with their clinical and pathological features.Autosomal dominant, autosomal recessive and possible X-linked recessive pedi-grees have been identified. A tentative classification is given in Table 2. Occasionalpatients with peroneal muscular atrophy display a severe distal sensory loss leadingto a mutilating acropathy (England and Denny-Brown, 1952; Dyck et al., 1965;

TABLE 2. CLASSIFICATION OF HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES(HSAN)

Autosomal dominant inheritanceDominantly inherited sensory neuropathy (Denny-Brown, 1951) (HSAN I*)Dominantly inherited sensory neuropathy with paraplegia (Cavanagh et al., 1979)

Autosomal recessive inheritanceRecessively inherited sensory neuropathy (Ohta el al., 1973) (HSAN II*)Hereditary anhidrotic sensory neuropathy (Swanson, 1963) (HSAN IV*)Familial dysautonomia (Riley et al., 1949) (HSAN III*)Hereditary sensory neuropathy with neurotrophic keratitis (present family)Recessively inherited sensory neuropathy with spastic paraplegia (Cavanagh et al., 1979)

X-linked recessive inheritanceX-linked recessive sensory neuropathy (Jestico et al., 1985)

Uncertain statusHereditary sensory neuropathy with dysautonomia (Nordborg et al., 1981)Congenital sensory neuropathy with selective loss of small myelinated fibres (Low et al., 1978;

Dyck et al., 1983) (HSAN V*)

* Classification of Dyck et al. (1983)



Ben Hamida et al., 1981). One such family was described by Thomas et al. (1974)in whom an earlier diagnosis of 'lumbosacral syringomyelia' was revised to domi-nantly inherited type I hereditary motor and sensory neuropathy (HMSN). Theprominence of the motor signs in such cases makes it more satisfactory for themto be classified as HMSN. Whether families with severe sensory loss are geneticallydistinct is so far not established. Linkage studies have not yet been reported.

Autosomal dominant forms. The main disorder in this category is the formfirst adequately described by Denny-Brown (1951). It comprises a distal sensoryneuropathy with an onset most commonly in the second or third decades. Sensoryloss initially affects mainly pain and temperature appreciation. Dyck et al. (1971)and Dyck (1984) found loss of myelinated axons of all diameters and of unmyelin-ated axons. This was least for large myelinated fibres, intermediate for smallmyelinated axons and greatest for unmyelinated axons. Spontaneous pain is oftena feature. This form has been designated type I hereditary sensory neuropathy byOhta etal. (1973).

Cavanagh et al. (1979) reported the occurrence of a sensory neuropathy ac-companied by a spastic paraplegia of probable autosomal dominant inheritance.As the salient clinical feature was the sensory neuropathy and the accompanyingmutilating acropathy rather than the spastic paraplegia, it is appropriate for thiscondition to be included amongst the hereditary sensory neuropathies.

Autosomal recessive forms. The most important disorder in this category consistsof those cases described as congenital sensory neuropathy (Murray, 1973), pro-gressive sensory neuropathy of childhood (Johnson and Spalding, 1964) or type IIhereditary sensory neuropathy (HSN) (Ohta et al., 1973). Recessive inheritancehas been suggested by the involvement of more than one individual in a sibshipwith normal parents and, at times, parental consanguinity. Similar isolated casesare likely to represent the same condition (Linarelli and Prichard, 1970; Barry etal., 1974; Person et al., 1977; Nukada et al., 1982). In some cases the sensory lossis clearly present from birth or early life (e.g., Wadia and Dastur, 1960; Winkel-mann et al., 1962; Johnson and Spalding, 1964; Haddow et al., 1970; Linarelli andPrichard, 1970; Murray, 1973; Barry et al., 1974; Person et al., 1977). All sensorymodalities are affected. Because of the preservation of motor function and theearly age of onset, distal mutilation tends to be particularly severe. Not all havesymptoms from infancy. In some cases given this designation (Nukada et al.,1982) or with otherwise similar clinical features (Adams et al., 1973), diseasemanifestations have not appeared until the third decade. Ataxia rather thanthe occurrence of cutaneous sensory loss has at times been the initial feature(Nukada et al., 1982). Minor autonomic involvement occurs, including im-potence and disturbances of bladder function (Murray, 1973; Nukada et al.,1982). Nerve biopsies show severe loss of myelinated nerve fibres of all sizes andsome reduction in the number of unmyelinated axons (Ohta et al., 1973; Nukadaetal., 1982).

The question of progression in recessively inherited sensory neuropathy has



given rise to discussion. Murray (1973) considered that in his cases, the congenitalneurological disorder was static, the advance in the mutilations that they showedmerely being the result of persisting sensory loss. Other patients undoubtedly showprogression of neurological signs; moreover, increasing severity of fibre loss ofconsecutive biopsies has been demonstrated (Nukada et al., 1982). Tamari et al.(1980) have suggested that two forms exist: (1) a congenital nonprogressive form,including the cases of Haddow et al. (1970) and Murray (1973); (2) a progressiveform with an onset later in childhood, including the cases in the 3 families thatthey described and those of Johnson and Spalding (1964), Schoene et al. (1970),Ohta et al. (1973) and Jedrzejowska and Milczarek (1976). Not all published casesfall easily into one or other of these subdivisions. Nevertheless, in general, theavailable evidence makes this possibility worthy of further consideration.

The second clearly identifiable autosomal recessive form is sensory neuropathywith anhidrosis (Swanson, 1963; Brown and Podosin, 1966; Pinsky and DiGeorge,1966; Vassella et al., 1968) or type IV HSN (Dyck and Ohta, 1975). Affectedindividuals show congenital insensitivity to pain, loss of sweating and mild mentalretardation. There is a virtual absence of unmyelinated axons in the peripheralsensory nerves (Bischoff and Curti, 1977; Goebel et al., 1980), absence of smallneurons in the primary sensory ganglia and a reduction in the size of Lissauer'stract (Swanson et al., 1965).

A third distinct condition is the Riley-Day syndrome (familial dysautonomia,Riley et al., 1949). Although autonomic manifestations are the predominantfeature, individuals affected with this autosomal recessive disorder also displaycongenital insensitivity to pain. Aguayo et al. (1971), from a nerve biopsy study,demonstrated that there is a severe reduction in the number of unmyelinated axonsand a lack of myelinated fibres of largest diameter. There are also reduced numbersof neurons in sympathetic, dorsal root and trigeminal ganglia (Pearson et al.,1971). Nordborg et al. (1981) described 3 sporadic cases of a nonprogressivecongenital sensory neuropathy and dysautonomia with clinical features that diff-ered in a number of respects from the Riley-Day syndrome. Nerve biopsy showedan almost total loss of myelinated axons and a reduction in the number of unmyel-inated axons, this pattern more closely resembling that of type II HSN. It wasconsidered that they probably represented a separate entity, distinct from theRiley-Day syndrome.

Finally, Cavanagh et al. (1979) described a sensory neuropathy associated withspastic paraplegia of probable autosomal recessive inheritance, the manifestationsbeing more severe than in the autosomal dominant disorder that they also reported.A further family of this type has recently been identified (G. D. Schott and P. K.Thomas, unpublished).

X-linked recessive sensory neuropathy. There has been a single report of a sensoryneuropathy with symptoms that developed during the second decade with possibleX-linked recessive inheritance (Jestico et al., 1985). The clinical manifestationsresembled those of dominantly inherited sensory neuropathy. Nerve biopsy



revealed a generalized loss of myelinated fibres, but particularly those of smallerdiameter. Unmyelinated axons were present in normal numbers.

Pathological Basis for Hereditary Sensory NeuropathyIn dominantly inherited sensory neuropathy a progressive loss of dorsal root

ganglion cells is assumed to occur (Denny-Brown, 1951). Whether there is a preced-ing distal axonal degeneration ('dying-back' neuropathy) is not established but thiswas suggested by the observations of Dyck et al. (1971) and Dyck (1984). The'hyperplastic myelinopathy' affecting myelinated nerve fibres of medium or largecalibre found in nerve biopsies from patients in a family with autosomal dominantinsensitivity to pain (Comings and Amromin, 1974) represents artefactual myelindamage.

In recessively inherited sensory neuropathy, as already discussed, there is pos-sible clinical evidence for genetic heterogeneity with both a congenital nonprogres-sive form, and a progressive form, usually with a later onset in childhood (Tamariet al., 1980). Nukada et al. (1982) have provided nerve biopsy evidence of continuedfibre loss in the latter form.

The sensory neuropathy in the Riley-Day syndrome is probably nonprogressive.In this condition Aguayo et al. (1971) postulated a selective developmental arrestfor both unmyelinated and large myelinated axons. This they related to interferencewith the second neuronal migration from the neural crest which gives rise both tosmall and large neurons. No evidence of degeneration of fibres in the nerve biopsyfrom their case was detected and thus a developmental failure was assumed.

A further possibility to be considered has been raised by Chimelli and Scaravilli(1986) in the rat mutant 'mutilated foot' (mf), which consists of a congenitalsensory neuropathy. Here it has been shown that the pathological basis consistsof a massive degeneration of dorsal root ganglion cells in the later fetal periodwhich continues for a short time postnatally. It resembles, in excessive form, the'programmed cell death' that occurs as a normal feature during development.Observations at the appropriate stage are so far not available in congenitalsensory neuropathy in man to establish whether this could be the basis. In Case 1of the series reported by Dyck et al. (1983), nerve biopsy at the age of 26 monthsshowed no evidence of acute fibre breakdown, but it was not stated whetherthere was an excess of denervated Schwann cells to suggest previous fibre degenera-tion.

In Case IV.4 from the present study, the nerve biopsy appearances indicated apossible mild degree of continuing nerve fibre degeneration and regeneration.Surprisingly few denervated Schwann cells were present in relation to the magni-tude of the depletion of small myelinated axons. However, if the fibre loss hadoccurred at an early age, the denervated Schwann cells may have disappeared(Weinberg and Spencer, 1978). The overall pattern suggests either a failure ofdevelopment (aplasia) of the neurons giving rise to small myelinated axons, or apredominantly prenatal neuronal degeneration.


H E R E D I T A R Y SENSORY N E U R O P A T H Y . 579

Congenital Indifference to Pain

Earlier descriptions refer to cases with congenital indifference to pain (Arbuseet al, 1949; Boyd and Nie, 1949; Westlake, 1952; Critchley, 1956; Fanconi andFerrazzini, 1957; Silverman and Gilden, 1959), congenital universal insensitivityto pain (Ford and Wilkins, 1938; McMurray, 1950; Baxter and Olszewski, 1960),congenital pure analgesia (Dearborn, 1932) and asymbolia for pain (Schilder andStengel, 1931). Such patients were stated to be able to distinguish sharp from bluntbut not to recognize noxious stimuli as painful anywhere in their bodies, did notexhibit the usual physiological reactions to pain and retained their tendon reflexes(Ogden et al., 1959; Winkelmann et al., 1962). An agnosia for pain was postulated(Jewsbury, 1951).

Occasional cases were the product of consanguinous marriages (Durand andBelotti, 1957; Fanconi and Ferrazzini, 1957) or affected several siblings with normalparents (Thrush, 1973). Autosomal recessive inheritance might thus be suspected.Pathological changes were not recognized in the peripheral nerves, spinal cord orbrain (Moffie, 1951; Feindel, 1953; Ogden et al., 1959; Baxter and Olszewski, 1960).These reports are now difficult to analyse and it is not clear whether indifferenceor asymbolia for pain remains an acceptable entity. No cases have been describedin recent years which, after adequate study of the peripheral nerves, have provednot to have a sensory neuropathy. In the family reported by Thrush (1973), thesite of .the disturbance was considered to be in the CNS. The PNS was believed tobe 'relatively intact'. Nerve biopsy was reported as showing some loss of largemyelinated fibres with regenerative activity, but morphometry was not undertaken.Retention of the tendon reflexes, as in our cases, is typical of a 'small fibre'neuropathy; it does not exclude peripheral nerve disorder. Likewise, sensory nerveaction potentials, which reflect conduction in large myelinated nerve fibres, maybe preserved. Dyck et al. (1983) pointed out that their Case 1 and that of Low etal. (1978) would have been accepted as having normal peripheral nerve histologywithout morphometric study. The same is true of the present Case IV.4.

ACKNOWLEDGEMENTS

We wish to thank Miss Jane Workman for technical assistance and the Friedreich's Ataxia Groupfor financial support. The image analysis equipment was obtained with the aid of grants fromCiba Geigy Ltd., Basel, and the Central Equipment Fund of London University, and the electronmicroscope was provided by the Medical Research Council.

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{Received June 13,1986. Accepted August 8, 1986)


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