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Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood
Journal of the Neurological Sciences, 1981, 51 : 181-197
181
Elsevier/North-Holland Biomedical Press
HEREDITARY MOTOR AND SENSORY NEUROPATHY OF NEURONAL TYPE WITH ONSET IN EARLY CHILDHOOD
R. A. OUVRIER, J. G. McLEOD, G. J. MORGAN, G. A. WISE and T. E. CONCHIN
Department of Medicine, University of Sydney, The Childrens Medical Research Foundation of the Royal Alexandra Hospital for Children, and the Prince of Wales Childrens Hospital, Sydney, New South Wales (Australia) (Received 31 December, 1980) (Accepted 19 January, 1981)
SUMMARY
Eleven cases of a severe neuropathy with onset in early childhood are described. The condition commences with distal weakness and wasting of the lower limbs and subsequently involves the hands, causing severe paralysis of the hands and feet towards the end of the second decade. Sensory changes are common but are usually only mild. The peripheral nerves are not enlarged. Claw hand, scoliosis and other orthopaedic deformities are seen in the later stages. CSF protein is not elevated and there is only mild slowing of motor conduction velocities. The pathological changes in sural nerve biopsies are those of axonal degeneration affecting myelinated and unmyelinated fibres. Family studies suggested autosomal recessive inheritance in two kindreds and dominant inheritance in another. Five cases were sporadic. The condition is clinically more severe and of earlier onset than hereditary motor and sensory neuropathy (HMSN) type II and differs electrophysiologically and pathologically from D6jerine-Sottas disease.
INTRODUCTION
The chronic hereditary polyneuropathies that affect motor and sensory nerves (HMSN) have been classified and distinguished from one another on clinical, genetic, electrophysiological and histological grounds (Dyck 1975; Dyck and
This work was supported by a grant from the Children's Medical Research Foundation of the Royal Alexandra Hospital for Children. Reprint requests to: J.G. McLeod, Department of Medicine, University of Sydney, Sydney, NSW 2006, Australia. 0022-510X/81/0000-0000/$2.50 © Elsevier/North-Holland Biomedical Press
182 Lambert 1968a,b; Harding and Thomas 1980a,b). They include the hypertrophic and neuronal forms of peroneal muscular atrophy or Charcot Marie-Tooth disease (HMSN type I and II) which are usually transmitted by autosomal dominant inheritance, although autosomal recessive inheritance is also described; D6jerine Sottas disease (HMSN type Ill) which has a recessive inheritance; Refsum's disease (HMSN type IV); and certain forms of neuropathy associated with distinctive central nervous system involvement (HMSN types V -VII). In the course of a review of childhood peripheral nerve disease, we have encountered 11 cases of a severe form of motor and sensory neuropathy of the neuronal type, commencing in early childhood and resulting in moderately severe disability in the second decade. It differs clinically and pathologically from D6jerine-Sottas disease and hypertrophic Charcot Marie-Tooth disease, which may also present in early childhood. This form of neuropathy is not specifically included in Dyck's (1975) classification, yet there is evidence to suggest that it is a distinct form of childhood neuropathy and that it has a genetic basis. PATIENTS AND METHODS
Patients Six of the 11 patients were studied in the course of a clinical and electrophysiological review of 104 patients on whom sural nerve biopsy was performed for investigation of chronic peripheral neuropathy in childhood. Two other patients were affected siblings but did not undergo sural nerve biopsy. A further patient was seen in consultation after thorough investigation at another hospital and review of the physiological and histological data. Two other patients were included in the series as they suffered from an apparently identical neuropathy to the other cases, but differed in that inheritance was autosomal dominant.
Electrophysiological techniques Techniques, which are standard in our laboratory, have been reported elsewhere (Walsh and McLeod 1970). Motor conduction velocity was measured in the median, ulnar and lateral popliteal nerves, using either concentric needle or surface electrodes. Sensory action potentials were recorded from the median and ulnar nerves at the wrist.
Histological techniques The techniques have been fully described elsewhere (Walsh and McLeod 1970; Low et al. 1978). Whole sural nerve biopsy was performed at the level of the lateral malleolus under local anaesthesia. The nerve was divided into 3-5 portions, each about 1 cm in length and the segments were splinted on cards. One piece of nerve was fixed in Flemming's solution for 24 h, dehydrated in alcohol, embedded in paraffin wax, and cut transversely in serial sections of 5 #m thickness. The sections were stained with Kultschitzsky's haematoxylin and counterstained with Van Gieson stain.
183 A second piece was stained for 24 h in 1~o osmic acid, macerated in glycerol and teased apart under a dissecting microscope in order to isolate single nerve fibres. A third piece of nerve was fixed in cold 2.5~o glutaraldehyde in 0.1 M cacodylate buffer for 3 h followed by Dalton's chrome-osmium for 90 min. The tissue was dehydrated in graded concentrations of ethanol, passed through acetone and embedded in Spurr's medium. Sections were cut with glass or diamond knives and stained with uranyl acetate and lead citrate and examined in a Philips 200 or 201 electron microscope. In most biopsies additional portions of nerve were also obtained. One portion was fixed immediately in Dalton's chrome-osmium and then processed as described for glutaraldehyde-fixed tissue. Another piece of each nerve was fixed in picric acid, embedded in paraffin and cut transversely and longitudinally in sections of 5/~m thickness. The sections were stained with haematoxylin and eosin, and with Congo red. QUANTITATIVE STUDIES
(1) Myelinated fibre density Photomicrographs of portions of fascicles selected according to the methods described by Dyck et al. (1979) were printed on photographic paper at an enlargement of × 1 100. The external diameter of all myelinated fibres not undergoing active degeneration was measured with a Zeiss TGZ3 particle size analyser set on the linear mode and the total number of fibres was counted. The endoneurial area of the fascicles was measured with a digitizer attachment (HP 9864 A) of a HewletW Packard 9815 A programmable calculator. The fibre density was calculated as the number of fibres/mm2 of intra-perineurial area. Histograms of fibre diameter distribution were drawn with a plotter (HP 9862 A).
(2) Unmyelinatedfibre density Axons of unmyelinated fibres were counted and their diameters measured as described above, with a Zeiss TGZ3 particle size analyser set in the linear mode on prints at a final magnification of × 8 544. The numbers of denervated Schwann cell subunits and collagen pockets were counted on the prints used in the measurement of unmyelinated fibres. RESULTS
Summary of clinical features The clinical features of the 11 cases reported in this study are summarised in Table 1. Full details are given in the Appendix. In no case was there a history of exposure to toxins and in all cases the onset of weakness was at or before the age of 5 years. One patient was noticed to have "limp" feet at birth but all patients walked by the age of 2 years. Often the gait was clumsy and associated with frequent falls. Orthopaedic surgery was sometimes
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Fig. 1. Case 9, aged 6 years, showing distal muscle wasting, claw hands, and contractures.
performed in the first few years of life before the correct diagnosis of a peripheral neuropathy had been made. Ambulation continued late in the first decade often with the assistance of braces and crutches but none of the patients over 12 years of age was still ambulant with the exception of an 18-year-old boy who was less severely affected than his sister. By the late teens, there was near or complete paralysis of the hands and feet. Pes cavus and claw feet deformities were uncommon. Wasting of the lower limbs was apparent early, particularly in the muscles below the knee (Fig. 1). It was difficult to determine when weakness of the hands was first apparent, but it was certainly present in all patients early in the second decade and in some from infancy. Proximal weakness of the arms was sometimes present but was never very significant. Much more marked weakness developed proximally in the lower limbs but generally it occurred after the patient was no longer independently ambulant. It may therefore mainly represent a form of disuse atrophy rather than a direct effect of the underlying pathological changes. Spinal deformity was seen in only 2 patients, both seriously affected. The cranial nerves were generally not involved except for a disturbance of
186 convergence with questionable optic disc pallor and visual field constriction in Case 5, and nystagmus in Cases 6, 8 and 9. Facial weakness was observed in one case. Ankle jerks were absent in all except one case. Of the 7 patients over the age of 10 years, all tendon reflexes were absent in 5, but in two patients sluggish biceps and triceps jerks could be elicited. Ataxia was not apparent within the limits of the examination with the exception of Case 5 in whom there was some truncal ataxia while seated and Case 6 in whom there was an intention tremor of the upper limbs. Sensory changes were clinically evident in 9 of the 11 cases. All modalities of sensation were affected in 2 patients; in 2 patients there was sparing of pain sensation and in 3 there was loss of vibration and joint position sense only. In 3 patients there were hyperpat.hic and delayed responses to pain on stimulation on the feet. One patient had normal sensation except for decreased two-point discrimination on the dorsum of the feet. In general, sensory changes were more prominent with increasing age of the patient, starting with loss of two-point discrimination, then affecting joint position, vibration and touch sensation and finally, pain sensitivity. The peripheral nerves were not definitely thickened in any of the patients but in 2 patients the cervical nerves were easily visible and in one of these there was questionable thickening of the median and ulnar nerves in the arms. Cerebro-spinal fluid protein was normal in 3 patients in whom it was measured, There was no clinical evidence of diabetes or renal failure in any patient and when determined, blood glucose and urea estimations were normal. Lipid profiles were examined in 3 patients and were normal. Immunoglobulins were normal in 2 patients. Creatine phosphokinase (CPK) estimation was normal in the 3 patients on whom it was performed.
Family studies The 11 patients were members of 8 families. Autosomal recessive inheritance seemed likely in 2 families in which siblings were affected (Cases 1 and 2; Cases 3 and 4) since the parents were clinically normal and had normal nerve conduction studies. Autosomal dominant inheritance was likely in the family of patients 10 and 11, where a father and daughter were affected. The child's mother was clinically normal. The father's parents were unavailable for testing but were reported to be clinically normal. The remaining 5 patients were sporadic cases. Nine of the 10 parents and 8 of the 10 available siblings were examined clinically and neurophysiologically and found to be normal. The father of Case 8 was not available for examination.
Electrophysiological studies The results of electrophysiological studies are summarized in Table 2. Electromyography in 5 patients was suggestive of denervation with spontaneous fibrillation
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188 and positive sharp waves present in one patient, and large polyphasic potentials firing in relative isolation in all 5 cases. Recording of sensory action potenti;tls from the median nerve at the wrist was attempted in all 11 patients. They were absent in 7 cases, reduced in amplitude in 2 cases, and normal in the remaining 2 patients. Ulnar nerve sensory action potentials were absent from 6 of the 7 patients tested and borderline in one case. The sural nerve sensory action potential was absent in all 5 patients in whom recordings were attempted. An attempt was made to stimulate the c o m m o n peroneal nerve in 9 of the 11 patients, but no muscle action potential was evoked from the extensor digitorum brevis in any of these. Conduction velocities in the upper limbs were unobtainable in 5 cases, and in the others they were normal or only mildly slowed. In no case did the measured conduction velocities fall below 35 m/s.
Sural nerve biopsy No abnormality was seen in the blood vessels or connective tissue in sections stained with haematoxylin and eosin. In the sections fixed in Flemming's solution it was apparent that in all nerves there was a reduction in the density of myelinated fibres. In some cases (e.g. Cases 3 and 11) the fibres were grossly reduced in number (Figs. 2 and 3; Table 3). Large diameter fibres were affected to a greater extent than small diameter fibres (Fig. 3). There was no evidence of demyelination or onion bulb formations in the osmic stains or in thin sections stained with toluidine blue. Single fibres were teased from all the nerves. There was no evidence of segmental demyelination nor of active axonal degeneration. On electron microscopy the" reduction in numbers of myelinated fibres was confirmed. The myelin sheath appeared normal in the surviving fibres and there were no onion bulb formations. In some nerves (Cases 3 and 8) myelin debris was seen in the cytoplasm of some
TABLE 3 M Y E L I N A T E D FIBRES IN S U R A L NERVES OF PATIENTS Case No.
Sex
1
M
3 5 6 8 9 11
F F F M M M
Age (yr)
13 16 12 14 7 4 31
Density
Density of fibres >/8/am
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0
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Control range: 3.81-6.42 x 103/ram 2 (mean: 4.57; SD: 0.89) (Low et al. 1978).
189
Fig. 2. Photomicrographs of transverse sections o f sural nerve of A, control subject; B, Case 6; C, Case 8 : D, Case 1 I. F l e m m i n g - K u l t s c h i t z s k ~ V a n Gieson.
Schwann cells. In the nerves of Cases 8 and 9 clusters were seen suggesting regeneration following axonal degeneration (Fig. 4a). In some nerves there appeared to be loss of unmyelinated fibres evidenced by increase in Schwann cell subunits and collagen pockets (Cases 3, 5 and 11) (Fig. 4b). On morphometric analysis of 5 nerves the density of unmyelinated fibres ranged from 23.8 to 58.7 x 103/mm 2 (mean: 38.7; SD: 16.6), which did not differ significantly from that of 24.7 to 51.5 × 103/mm 2 (mean: 38.0; SD: 9.5) in adult control nerves (Low et al. 1978) or from the density in the sural nerves of 3 children aged 2, 9 and 13 years (Table 4). In 2 cases (Cases 5 and 6) there was an increase in the proportion of small
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TABLE 4 U N M Y E L I N A T E D FIBRES IN S U R A L NERVES OF PATIENTS A N D CONTROLS Case No.
Sex
Age (yr)
Density (103 fibre/ram 2)
Denervated Schwann cell density (103/ram 2)
Collagen pocket density (103/mm2)
3 5 6 8 11
F F F M M
16 12 14 7 31
23.8 31.3 58.7 54.4 25.5
19.0 12.9 4.1 2.9 10.5
4.8 5.1 7.9 1.7 6.l
Control 1 Control II Control III
M M F
2 13 9
93.5 30.8 49.9
0 0 0.09
0.25 0.92 1.22
191
Fig. 4. a: Case 9. There are well developed cluster formations (C). Bar = 0.5 ,am. b: Case 11. Collagen pockets (arrows) and multilamellated Schwann cell subunits devoid of axons (M) are prominent. Bar = I ,am.
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DIAMETER ( ~ M ) Fig. 5. Percentagedistributionsof unmyelinatedfibre diameters. unmyelinated fibres (0.2-0.6 #m) compared with controls (Fig. 5). The density of denervated Schwann cell subunits ranged from 2.9 to 19.0 x 103/mm: (mean: 9.9; SD: 6.6), which was greater than that of 1.8 to 5.5 × 103/mm2 (mean: 4.3; SD: 1.5) in control subjects aged 12-54 years (Low et al. 1978) (P < 0.10) and considerably greater than that in 3 controls aged 2, 9 and 13 (Table 4). The density of collagen pockets ranged from 1.7 to 7.9 x 103/mm~ (mean: 5.1; SD: 2.3) which did not differ significantly from that of 3.5 to 9.1 × 103/mm: (mean: 5.7; SD: 2.2) in adult controls (Low et al. 1978), but was considerably greater than that of 0.25 to 1.22 x 103/mm2 in 3 controls of comparable age (Table 4). in summary, the appearances on light and electron microscopy are those of chronic axonal degeneration affecting both myelinated and unmyelinated fibres. DISCUSSION The 11 cases described in this report suffer from a chronically progressive neuropathy commencing in earlv childhood and resulting in moderately severe disability in the second decade. Ihe mild degree of slowing of motor conduction velocity in the majority of cases and the fact that it was never recorded below 35 m/s in the upper limbs of any of the patients, is consistent with the underlying pathology of axonal degeneration (Gilliatt 1966; McLeod et al. 1973). There was a pronounced loss of myelinated fibres in the sural nerve, particularly those of large diameter, and on electron microscopy and teased nerve fibre studies there was no evidence of segmental demyelination or onion bulb formation. In some cases, the increase in density of small unmyelinated fibres (0.2-0.6 #m), and the increase in density of collagen pockets and empty Schwann cell subunits indicated damage to unmyelinated fibres (Thomas 1973). Most of the cases appear to be sporadic or to have an autosomal recessive mode of inheritance but in one family there was a pattern of dominant inheritance.
193 The present cases do not fit satisfactorily into the classification of neuropathies described by Dyck (1975), and are clearly of greater severity and of earlier onset than those classified as HMSN type II (neuronal form ofperoneal muscular atrophy) (Dyck 1975; Harding and Thomas 1980a). In the latter condition, the onset of the symptoms is generally after the second decade and may be delayed into middle-age. Apart from absent ankle jerks, tendon reflexes tend to be retained and sensory findings are mild. Furthermore, the condition usually has an autosomal dominant mode of inheritance (Dyck 1975), only 2 patients with an autosomal recessive pattern of inheritance having been reported (Harding and Thomas 1980a,b). Although the pathological changes in HMSN type II are those of axonal degeneration (Dyck 1975; McLeod and Low 1977), the sural nerve biopsies of the patients in the present study differed from those described in that condition. There was a considerably greater reduction of myelinated fibre density and involvement of unmyelinated fibres than has been reported in HMSN type II (Dyck 1975 ; McLeod and Low 1977). Cases with autosomal recessive inheritance similar to those in the present report have been described clinically in the earlier literature, although the pathological features were not reported. Bell (1948) refers to several families reported by previous authors in which there was autosomal recessive inheritance of a moderately severe neuropathy commencing in early childhood and resulting in significant disability in the second decade. Cases 2 and 3 in the original report of Charcot and Marie (1886) showed probable recessive inheritance. These 2 boys aged 11 and 7 years, respectively, had the commencement of weakness in the lower limbs at the age of 3 years, progressing to considerable weakness and deformity of the distal limbs by the age of 11 in the older boy. The father was stated to be neurologically normal except for mental defect. No details of the mother's examination were given. Harding and Thomas (1980b) reported 2 families with HMSN II with autosomal recessive inheritance. However, the age of onset was later than that in our cases; in 2 members of one family it was 11 and 12 years, respectively, and 13 years in a single member of another family. The age of onset of autosomal dominant HMSN II is usually in the second decade or later, and tends to be later than that of HMSN 1 (Harding and Thomas 1980a). The siblings reported by Kalyanaraman et al. (1970) suffered from a condition which appears clinically identical with that described in the present report. However, these authors interpreted the histological findings as being suggestive of a hypertrophic type of neuropathy. The condition bears some clinical similarities to HMSN type III (D6jerine-Sottas disease) but can be distinguished by the electrophysiological and pathological features. Although it is probable that all the present cases are genetically determined, until a specific biochemical defect can be found sporadic cases must be viewed for diagnostic purposes as being possibly secondary to some other recognisable underlying disorder. In the present study, there was no evidence to implicate toxins and none of the patients suffered from diabetes, porphyria, vascular disease or malignant disorder. The present condition appears to run a progressive course resulting in severe
194 disability by the late teens. None of the patients is older than 35 years, so that the long-term prognosis cannot yet be confidently stated. Case 7, in the present series, was given steroids on several occasions for a period of some months. No clinical or electrophysiological benefit was observed. Furthermore, the surgical procedures which were performed on some patients appeared to be of no long-term benefit. In view of the fact that proximal weakness seemed to develop after the patients ceased walking, ambulation should be encouraged for as long as possible. Once walking is no longer possible, a programme of swimming or other active exercise to encourage use of the proximal muscles would appear desirable. These measures might have helped prevent the spinal complications seen in 2 of the present cases. In reviewing these cases, it initially appeared that the condition was transmitted by an autosomal recessive gene. However, Cases 10 and 11 were subsequently encountered, illustrating that an almost identical clinical phenotype can be inherited in either a dominant or recessive mode. Accurate genetic counselling in sporadic cases is therefore difficult, ACKNOWLEDGEMENT
The authors gratefully acknowledge the receipt of software used in the morphometric evaluation of peripheral nerve from Dr. Peter James Dyck, Mayo Clinic, Rochester, MN, U.S.A. APPENDIX Case l (T.R., male, born 1954, brother of Case 2)
Pregnancy and birth were normal but his feet were noted to be "limp". He walked clumsily at 13 months, had difficulty fitting shoes and wore calipers from ages 2-7 years. Corrective surgery to the feet was performed at age 5. He could run a little at age 5 but by age 17 he could no longer walk. The hands were always weak. On examination at age 24, the cranial nerves were intact. There was marked distal muscle atrophy but no fasciculations, Peripheral nerves were not enlarged. There was mild weakness of shoulder and hip girdles; the biceps a n d triceps were able to overcome gravity and slight resistance. Knee flexion and extension were almost totally paralysed and there were no voluntary movements of wrists, hands, ankles or feet. Tendon reflexes were all absent. There was some loss of vibration and proprioception in the feet and there were hyperpathic delayed pain responses in legs and feet. C P K was normal. CSF was not examined. Both parents are clinically and electrophysiologically normal. Two older siblings, one of w h o m was examined, are normal but the younger brother is similarly affected (Case 2). Case 2 (L.R., male, born 1958, brother of Case 1)
Pregnancy and delivery were normal. He walked at 18 m o n t h s but was unable to continue walking after the age of 13. Physical examination at the age of 20 was very similar to that of Case 1, except that there was still a flicker of m o v e m e n t in the fingers. Muscle and sural nerve biopsies were not performed. Case 3 (M.A., female, born 1959, sister of Case 4)
Pregnancy and delivery were normal. She walked at 13 m o n t h s but never normally, a n d was referred to an orthopaedic surgeon at age 2 and subsequently had numerous operative procedures on hands and feet. She fell frequently and was unable to walk after 15 years. The hands began t o claw at age 13, but had obviously been previously weak.
195 On examination at the age of 18, she was obese. There were bilateral claw hands, mild pes cavus, and distal wasting of upper a n d lower limbs. The nerves were not palpably enlarged. Proximal muscle strength was almost normal, but there was moderate weakness at the wrists and very marked weakness at the ankles a n d of the intrinsic muscles of the hands and feet. Tendon reflexes were absent. There was distal loss of all modalities of sensation with hyperpathic pain sensation on the feet. CSF examination was not performed. Both parents were clinically normal with normal nerve conduction studies. The only sibling is Case 4. Case 4 (K.A., male, born 1961, brother of Case 3) Pregnancy a n d delivery were normal. He walked at age 10 m o n t h s and nothing was noted to be abnormal until age 5 when he commenced to have frequent falls. An orthopaedic surgeon performed several operations on the feet between the ages of 5 and 6. The hands started to claw at age 13. At age 17 he was still able to walk and to move the hands. On examination at age 17, the cranial nerves were intact except for a small patch o f chorioretinitis in the left fundus. Fasciculations were not seen. There was very mild proximal weakness of the arms and legs. The wrists could flex and extend against gravity and mild resistance but there was marked weakness of the intrinsic muscles of the hands and feet and of ankle dorsiflexion and eversion. Biceps a n d triceps jerks could still be elicited, but the other tendon reflexes were absent. Sensation appeared normal. Case 5 (G.H., female, born 1958) Except for a 24-h illness with vomiting at 3 m o n t h ' s gestation, the mother's pregnancy and delivery were normal. Early development was normal until she began walking at the age of 18 m o n t h s when a slow gait was noted. At 2½years, a muscle biopsy was performed and a diagnosis of CharcotMarie Tooth disease was made. By 3 or 4 years, weakness of the hands was noted and she had difficulty in running. By 8 years, she could still walk short distances but was confined to a wheelchair by 15 years. On examination at age 20, the cranial nerves were normal except for inability to converge the eyes, slight disc pallor and questionable constriction of the visual fields. The subcutaneous nerves were visible in the neck and felt slightly thick in the arms. Scoliosis, hip and knee flexion contractures as well as marked clawing of the fingers were present. The feet were flat. There was gross muscle wasting below the upper third of the thigh and below the elbows. Proximal strength was good in arms but there was marked weakness of the wrists and fingers. Both the proximal and distal muscles o f the legs were very weak. All tendon reflexes were absent. There was some apparent truncal ataxia in the seated position. It was difficult to evaluate limb ataxia because of the weakness present. There was marked loss of all modalities of sensation below the ankles with definite diminution of vibration and joint position sense in the hands. C P K was normal. A muscle biopsy showed neurogenic atrophy. Both parents and one male sibling, aged 24 years, are clinically well, and their nerve conduction studies are normal. There is no history of consanguinity between the parents and no family history o f neuromuscular disease. The child's paternal great grandmothers were sisters. Case 6 (K.T., female, born 1959) Pregnancy and delivery were normal. At 9 months, she had difficulty sitting. By the age of 2 she was walking but appeared ataxic and the feet dragged. At age 5 years, she could walk a mile. By the age of 8 years, she could still run a little but when aged 9 years, because of her frequent falls, she was made to use a wheelchair at a special school a n d has never walked since. Scoliosis and slight facial weakness were apparent by the age o f 9 years. Weakness of the h a n d s had been noted from the age of 2 years. On examination, at age 20, there was a tremor of the tongue and chin. There was marked thoracic scoliosis with flexion contractures o f the knees and hips, severe distal muscle atrophy and bilateral claw hands. There was slight horizontal nystagmus and left exotropia. There was mild proximal weakness in the arms and legs, moderate weakness of the wrists and profound weakness of the ankles and intrinsic muscles of the hands. Tendon reflexes were absent. Touch, two-point discrimination, vibration and joint position sense were all impaired in the upper and lower limbs, but pain sensation was intact. CSF protein was less than 10 mg/100 ml. E C G and C P K were normal. Clinical and electrophysiological studies o f both parents and one brother were normal. Another sister is reported to be normal but was not available for examination. There is no family history of consanguinity or neuromuscular disease.
196 Case 7 (M.M., female, born 1967)
The pregnancy and delivery were normal. She sat early, crawled at 5 m o n t h s and ~xalked al 10 m o n t h s but always tip-toed. She lost the ability to run in the second year, and began to I~dl frequently. She was seen by a neurologist at age 3 years and 6 m o n t h s when peripheral neuropathy was diagnosed. Steroids were administered for 6 m o n t h s without obvious improvement. She was still ambulant at 10 years with braces and crutches. Weakness of the hands was first noted at age 7. On examination at age 10 years, the cranial nerves were normal. There were bilateral claw hands and marked distal atrophy of forearms, thighs and calves with small feet and hands and wasting of intrinsic muscles. There was good proximal strength in the arms, but moderate weakness of wrists and severe weakness of the intrinsic muscles of the hands and of all the lower limb muscles. The tendon reflexes were sluggish in the arms and absent in the legs. There was mild loss of touch, vibration and joint position sense in the feet. Peripheral nerves were not thickened. Glucose tolerance test, serum lipoprotein and phytanic acid levels, urinary porphyrin and lead estimations were normal. CSF protein was 3 mg/100 ml. Muscle biopsy at age 3 showed marked muscle fibre atrophy considered to be due to denervation. The parents and only sister of the patient are clinically and electrophysiologically normal. There was no family history o f consanguinity or of neuromuscular disease. Case 8 (S.G., male, born 1969)
Pregnancy and delivery were normal. He walked at 13 m o n t h s and was apparently normal until the age of 5 years when he began to walk with an abnormal gait affecting mainly the left foot. Slow deterioration occurred over the next few years, and by the age of 8 years he was walking with a complete left foot drop, but could still run a little by the time the h a n d s had noticeably become affected. On examination at age 8, the cranial nerves were normal apart from slight horizontal nystagmus. Peripheral nerves were not palpably thickened, There was bilateral pes planus with a valgoid left foot and marked distal atrophy in the legs. There was only mild distal upper limb weakness but moderate weakness of the right foot and severe weakness of the left foot. Deep tendon reflexes were all preserved and sensation was intact. The CSF was not examined. The mother, one brother and 2 sisters were clinically and electrophysiologieally normal. The father was not examined but was said to be normal. There was no family history of consanguinity or of neuromuscular disease. Case 9 (E.S., male, born 1972)
Pregnancy and delivery were normal. He walked at 14 months. By the age of 2 years and 6 months, the feet were turned-in and flat a n d he could not walk as far nor as fast as before. An operation on the feet was performed at age 3 and the feet were noted to be wasted after removal of plasters. The hands were noted to be weak by the age 5 years. By age 6 years, he could still walk a mile or more without aids, but fell frequently. On examination at the age of 6 years, he was able to run a little, there was slight horizontal nystagmus, and marked wasting o f calves, forearms and hands. Early claw h a n d s a n d flexion contractures of Achilles' tendons were present. There was good preservation of proximal strength of the limbs but marked weakness of intrinsic muscles of the hands and of the ankles and feet. The tendon reflexes were present except for the ankle jerks. Sensation was intact except for some diminution of two-point discrimination over the feet. Blood urea, cholesterol, triglycerides, a n d glucose were all normal. CSF protein was 20 mg/100 ml. Muscle biopsy showed evidence of chronic denervation and reinnervation. Clinical and electrophysiological examination of the parents and 2 male siblings were normal. There was no family history o f consanguinity or of neuromuscular disease. Case 10 (P.P., female, born 1975, daughter of Case 11)
Pregnancy and delivery were normal. She sat alone at 6 months, walked at 13 m o n t h s but tended to throw the right foot and never seemed to walk straight. On examination at age 3, the cranial nerves were normal. There was slight wasting of the calves. The upper limbs appeared normal in strength but there was marked weakness of the ankles and feet. The biceps and triceps jerks were sluggish and the other tendon reflexes were absent. There was some loss of vibration and joint position sense in the feet. The nerves were not thickened; Blood film, serum cholesterol and triglycerides, immunoglobulins, blood urea and glucose were normal. Case 11 (J.P., male, born 1944, father of Case 10)
He was born in 1944 after a normal pregnancy and delivery. He sat, crawled and walked at a normal age but tended to fall easily. In the third year, there was an increasing tendency of the feet to
197 turn inward and he had manipulations of the feet and elongation of the Achilles' tendons. At the age of 3 years he was diagnosed by an orthopaedic surgeon as having peroneal muscular atrophy. By 10 years, he had no active ankle movements and had some weakness of the hands. On examination at the age of 27 years, the cranial nerves were normal. There was some weakness of the abdominal musculature. In the upper limbs, distal muscles were functionless except that he could move his thumbs a very small amount. Biceps and triceps muscles were weak. There was minimal weakness of the shoulder girdles. Distal muscles in the lower limbs were functionless and quadriceps and hamstrings were incapable of moving the knee joints against gravity. Sensation was impaired with decreased vibration, joint position, two-point discrimination and pain sensation in the distal extremities. The nerves were not palpably thickened. REFERENCES Bell, J. (1948) On the peroneal type of progressive muscular atrophy. In: The Treasury of Human Inheritance, Vol. 9, Cambridge University Press, London, pp. 69-140. Charcot, J.-M. and P. Marie (1886) Sur une forme particuli6re d'atrophie musculaire progressive souvent familiale, d+butante par les pieds et les jambes, et atteignant plus tard les mains, Rev. Med. (Paris), 6: 97-138. Dyck, P. J. (1975) Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In : P. J. Dyck, P. K. Thomas and E. H. Lambert (Eds.), Peripheral Neuropathy, Saunders, Philadelphia, PA, pp. 825-867. Dyck, P. J. and E. H. Lambert (1968a) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy, Part 1 (Neurologic, genetic and electrophysiologic findings in hereditary polyneuropathy), Arch. Neurol. (Chic.), 18: 603-618. Dyck, P. J. and E. H. Lambert (1968b) Lower motor and primary sensory diseases with peroneal muscular atrophy, Part 2 (Neurologic, genetic and electrophysiologic findings in various neuronal degenerations), Arch. Neurol. (Chic.), 18: 619~25. Dyck, P. J., H. Jedrezejowska, J. Karnes, Y. Kawamura, P. A. Low, P. C. O'Brien, K. Offord, A. Ohnishi, M. Ohta, M. Pollock and J.C. Stevens (1979) Reconstruction of motor, sensory and autonomic neurons based on morphometric study of sampled levels, Muscle and Nerve, 2 : 399~105. Gilliatt, R. W. (1966) Nerve conduction in human and experimental neuropathies, Proc. roy. Soc. Med., 59:989 993. Harding, A. E. and P. K. Thomas (1980a)The clinical features of hereditary motor and sensory neuropathy types I and II, Brain, 103: 259-280. Harding, A. E. and P. K. Thomas (1980b) Autosomal recessive forms of hereditary motor and sensory neuropathy, J. Neurol. Neurosurg. Psychiat., 43: 669~578. Kalyanaraman, K., P.A. Cancilla, T. Munsat and C.M. Pearson (1970) Hereditary hypertrophic neuropathy, Bull. Los Angeles neurol. Soc., 35 : 58-68. Low, P. A., J. G. McLeod and J. W. Prineas (1978) Hypertrophic Charcot-Marie Tooth disease - - Light and electron microscope studies of the sural nerve, J. neurol. Sci., 35:93 115. McLeod, J. G. and P.A. Low (1977) Peroneal muscular atrophy with autosomal dominant inheritance, Clin. exp. Neurol., 14: 142-153. McLeod, J. G., J. W. Prineas and J. C. Walsh (1973) The relationship of conduction velocity to pathology in peripheral nerves. In : J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 2, Karger, Basel, pp. 248-258. Thomas, P. K. (1973) The ultrastructural pathology of unmyelinated nerve fibres. In: J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 2, Karger, Basel, pp. 227-239. Walsh, J. C. and J. G. McLeod (1970) Alcoholic neuropathy - - An electrophysiological and histological study, J. neurol. Sci., 10: 457~,69.
181
Elsevier/North-Holland Biomedical Press
HEREDITARY MOTOR AND SENSORY NEUROPATHY OF NEURONAL TYPE WITH ONSET IN EARLY CHILDHOOD
R. A. OUVRIER, J. G. McLEOD, G. J. MORGAN, G. A. WISE and T. E. CONCHIN
Department of Medicine, University of Sydney, The Childrens Medical Research Foundation of the Royal Alexandra Hospital for Children, and the Prince of Wales Childrens Hospital, Sydney, New South Wales (Australia) (Received 31 December, 1980) (Accepted 19 January, 1981)
SUMMARY
Eleven cases of a severe neuropathy with onset in early childhood are described. The condition commences with distal weakness and wasting of the lower limbs and subsequently involves the hands, causing severe paralysis of the hands and feet towards the end of the second decade. Sensory changes are common but are usually only mild. The peripheral nerves are not enlarged. Claw hand, scoliosis and other orthopaedic deformities are seen in the later stages. CSF protein is not elevated and there is only mild slowing of motor conduction velocities. The pathological changes in sural nerve biopsies are those of axonal degeneration affecting myelinated and unmyelinated fibres. Family studies suggested autosomal recessive inheritance in two kindreds and dominant inheritance in another. Five cases were sporadic. The condition is clinically more severe and of earlier onset than hereditary motor and sensory neuropathy (HMSN) type II and differs electrophysiologically and pathologically from D6jerine-Sottas disease.
INTRODUCTION
The chronic hereditary polyneuropathies that affect motor and sensory nerves (HMSN) have been classified and distinguished from one another on clinical, genetic, electrophysiological and histological grounds (Dyck 1975; Dyck and
This work was supported by a grant from the Children's Medical Research Foundation of the Royal Alexandra Hospital for Children. Reprint requests to: J.G. McLeod, Department of Medicine, University of Sydney, Sydney, NSW 2006, Australia. 0022-510X/81/0000-0000/$2.50 © Elsevier/North-Holland Biomedical Press
182 Lambert 1968a,b; Harding and Thomas 1980a,b). They include the hypertrophic and neuronal forms of peroneal muscular atrophy or Charcot Marie-Tooth disease (HMSN type I and II) which are usually transmitted by autosomal dominant inheritance, although autosomal recessive inheritance is also described; D6jerine Sottas disease (HMSN type Ill) which has a recessive inheritance; Refsum's disease (HMSN type IV); and certain forms of neuropathy associated with distinctive central nervous system involvement (HMSN types V -VII). In the course of a review of childhood peripheral nerve disease, we have encountered 11 cases of a severe form of motor and sensory neuropathy of the neuronal type, commencing in early childhood and resulting in moderately severe disability in the second decade. It differs clinically and pathologically from D6jerine-Sottas disease and hypertrophic Charcot Marie-Tooth disease, which may also present in early childhood. This form of neuropathy is not specifically included in Dyck's (1975) classification, yet there is evidence to suggest that it is a distinct form of childhood neuropathy and that it has a genetic basis. PATIENTS AND METHODS
Patients Six of the 11 patients were studied in the course of a clinical and electrophysiological review of 104 patients on whom sural nerve biopsy was performed for investigation of chronic peripheral neuropathy in childhood. Two other patients were affected siblings but did not undergo sural nerve biopsy. A further patient was seen in consultation after thorough investigation at another hospital and review of the physiological and histological data. Two other patients were included in the series as they suffered from an apparently identical neuropathy to the other cases, but differed in that inheritance was autosomal dominant.
Electrophysiological techniques Techniques, which are standard in our laboratory, have been reported elsewhere (Walsh and McLeod 1970). Motor conduction velocity was measured in the median, ulnar and lateral popliteal nerves, using either concentric needle or surface electrodes. Sensory action potentials were recorded from the median and ulnar nerves at the wrist.
Histological techniques The techniques have been fully described elsewhere (Walsh and McLeod 1970; Low et al. 1978). Whole sural nerve biopsy was performed at the level of the lateral malleolus under local anaesthesia. The nerve was divided into 3-5 portions, each about 1 cm in length and the segments were splinted on cards. One piece of nerve was fixed in Flemming's solution for 24 h, dehydrated in alcohol, embedded in paraffin wax, and cut transversely in serial sections of 5 #m thickness. The sections were stained with Kultschitzsky's haematoxylin and counterstained with Van Gieson stain.
183 A second piece was stained for 24 h in 1~o osmic acid, macerated in glycerol and teased apart under a dissecting microscope in order to isolate single nerve fibres. A third piece of nerve was fixed in cold 2.5~o glutaraldehyde in 0.1 M cacodylate buffer for 3 h followed by Dalton's chrome-osmium for 90 min. The tissue was dehydrated in graded concentrations of ethanol, passed through acetone and embedded in Spurr's medium. Sections were cut with glass or diamond knives and stained with uranyl acetate and lead citrate and examined in a Philips 200 or 201 electron microscope. In most biopsies additional portions of nerve were also obtained. One portion was fixed immediately in Dalton's chrome-osmium and then processed as described for glutaraldehyde-fixed tissue. Another piece of each nerve was fixed in picric acid, embedded in paraffin and cut transversely and longitudinally in sections of 5/~m thickness. The sections were stained with haematoxylin and eosin, and with Congo red. QUANTITATIVE STUDIES
(1) Myelinated fibre density Photomicrographs of portions of fascicles selected according to the methods described by Dyck et al. (1979) were printed on photographic paper at an enlargement of × 1 100. The external diameter of all myelinated fibres not undergoing active degeneration was measured with a Zeiss TGZ3 particle size analyser set on the linear mode and the total number of fibres was counted. The endoneurial area of the fascicles was measured with a digitizer attachment (HP 9864 A) of a HewletW Packard 9815 A programmable calculator. The fibre density was calculated as the number of fibres/mm2 of intra-perineurial area. Histograms of fibre diameter distribution were drawn with a plotter (HP 9862 A).
(2) Unmyelinatedfibre density Axons of unmyelinated fibres were counted and their diameters measured as described above, with a Zeiss TGZ3 particle size analyser set in the linear mode on prints at a final magnification of × 8 544. The numbers of denervated Schwann cell subunits and collagen pockets were counted on the prints used in the measurement of unmyelinated fibres. RESULTS
Summary of clinical features The clinical features of the 11 cases reported in this study are summarised in Table 1. Full details are given in the Appendix. In no case was there a history of exposure to toxins and in all cases the onset of weakness was at or before the age of 5 years. One patient was noticed to have "limp" feet at birth but all patients walked by the age of 2 years. Often the gait was clumsy and associated with frequent falls. Orthopaedic surgery was sometimes
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performed in the first few years of life before the correct diagnosis of a peripheral neuropathy had been made. Ambulation continued late in the first decade often with the assistance of braces and crutches but none of the patients over 12 years of age was still ambulant with the exception of an 18-year-old boy who was less severely affected than his sister. By the late teens, there was near or complete paralysis of the hands and feet. Pes cavus and claw feet deformities were uncommon. Wasting of the lower limbs was apparent early, particularly in the muscles below the knee (Fig. 1). It was difficult to determine when weakness of the hands was first apparent, but it was certainly present in all patients early in the second decade and in some from infancy. Proximal weakness of the arms was sometimes present but was never very significant. Much more marked weakness developed proximally in the lower limbs but generally it occurred after the patient was no longer independently ambulant. It may therefore mainly represent a form of disuse atrophy rather than a direct effect of the underlying pathological changes. Spinal deformity was seen in only 2 patients, both seriously affected. The cranial nerves were generally not involved except for a disturbance of
186 convergence with questionable optic disc pallor and visual field constriction in Case 5, and nystagmus in Cases 6, 8 and 9. Facial weakness was observed in one case. Ankle jerks were absent in all except one case. Of the 7 patients over the age of 10 years, all tendon reflexes were absent in 5, but in two patients sluggish biceps and triceps jerks could be elicited. Ataxia was not apparent within the limits of the examination with the exception of Case 5 in whom there was some truncal ataxia while seated and Case 6 in whom there was an intention tremor of the upper limbs. Sensory changes were clinically evident in 9 of the 11 cases. All modalities of sensation were affected in 2 patients; in 2 patients there was sparing of pain sensation and in 3 there was loss of vibration and joint position sense only. In 3 patients there were hyperpat.hic and delayed responses to pain on stimulation on the feet. One patient had normal sensation except for decreased two-point discrimination on the dorsum of the feet. In general, sensory changes were more prominent with increasing age of the patient, starting with loss of two-point discrimination, then affecting joint position, vibration and touch sensation and finally, pain sensitivity. The peripheral nerves were not definitely thickened in any of the patients but in 2 patients the cervical nerves were easily visible and in one of these there was questionable thickening of the median and ulnar nerves in the arms. Cerebro-spinal fluid protein was normal in 3 patients in whom it was measured, There was no clinical evidence of diabetes or renal failure in any patient and when determined, blood glucose and urea estimations were normal. Lipid profiles were examined in 3 patients and were normal. Immunoglobulins were normal in 2 patients. Creatine phosphokinase (CPK) estimation was normal in the 3 patients on whom it was performed.
Family studies The 11 patients were members of 8 families. Autosomal recessive inheritance seemed likely in 2 families in which siblings were affected (Cases 1 and 2; Cases 3 and 4) since the parents were clinically normal and had normal nerve conduction studies. Autosomal dominant inheritance was likely in the family of patients 10 and 11, where a father and daughter were affected. The child's mother was clinically normal. The father's parents were unavailable for testing but were reported to be clinically normal. The remaining 5 patients were sporadic cases. Nine of the 10 parents and 8 of the 10 available siblings were examined clinically and neurophysiologically and found to be normal. The father of Case 8 was not available for examination.
Electrophysiological studies The results of electrophysiological studies are summarized in Table 2. Electromyography in 5 patients was suggestive of denervation with spontaneous fibrillation
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188 and positive sharp waves present in one patient, and large polyphasic potentials firing in relative isolation in all 5 cases. Recording of sensory action potenti;tls from the median nerve at the wrist was attempted in all 11 patients. They were absent in 7 cases, reduced in amplitude in 2 cases, and normal in the remaining 2 patients. Ulnar nerve sensory action potentials were absent from 6 of the 7 patients tested and borderline in one case. The sural nerve sensory action potential was absent in all 5 patients in whom recordings were attempted. An attempt was made to stimulate the c o m m o n peroneal nerve in 9 of the 11 patients, but no muscle action potential was evoked from the extensor digitorum brevis in any of these. Conduction velocities in the upper limbs were unobtainable in 5 cases, and in the others they were normal or only mildly slowed. In no case did the measured conduction velocities fall below 35 m/s.
Sural nerve biopsy No abnormality was seen in the blood vessels or connective tissue in sections stained with haematoxylin and eosin. In the sections fixed in Flemming's solution it was apparent that in all nerves there was a reduction in the density of myelinated fibres. In some cases (e.g. Cases 3 and 11) the fibres were grossly reduced in number (Figs. 2 and 3; Table 3). Large diameter fibres were affected to a greater extent than small diameter fibres (Fig. 3). There was no evidence of demyelination or onion bulb formations in the osmic stains or in thin sections stained with toluidine blue. Single fibres were teased from all the nerves. There was no evidence of segmental demyelination nor of active axonal degeneration. On electron microscopy the" reduction in numbers of myelinated fibres was confirmed. The myelin sheath appeared normal in the surviving fibres and there were no onion bulb formations. In some nerves (Cases 3 and 8) myelin debris was seen in the cytoplasm of some
TABLE 3 M Y E L I N A T E D FIBRES IN S U R A L NERVES OF PATIENTS Case No.
Sex
1
M
3 5 6 8 9 11
F F F M M M
Age (yr)
13 16 12 14 7 4 31
Density
Density of fibres >/8/am
(103/mm 2)
(103/mm 2)
(%)
2.14 0.93 1.92 2.23 3.18 3.70 0.49
0
0
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Control range: 3.81-6.42 x 103/ram 2 (mean: 4.57; SD: 0.89) (Low et al. 1978).
189
Fig. 2. Photomicrographs of transverse sections o f sural nerve of A, control subject; B, Case 6; C, Case 8 : D, Case 1 I. F l e m m i n g - K u l t s c h i t z s k ~ V a n Gieson.
Schwann cells. In the nerves of Cases 8 and 9 clusters were seen suggesting regeneration following axonal degeneration (Fig. 4a). In some nerves there appeared to be loss of unmyelinated fibres evidenced by increase in Schwann cell subunits and collagen pockets (Cases 3, 5 and 11) (Fig. 4b). On morphometric analysis of 5 nerves the density of unmyelinated fibres ranged from 23.8 to 58.7 x 103/mm 2 (mean: 38.7; SD: 16.6), which did not differ significantly from that of 24.7 to 51.5 × 103/mm 2 (mean: 38.0; SD: 9.5) in adult control nerves (Low et al. 1978) or from the density in the sural nerves of 3 children aged 2, 9 and 13 years (Table 4). In 2 cases (Cases 5 and 6) there was an increase in the proportion of small
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TABLE 4 U N M Y E L I N A T E D FIBRES IN S U R A L NERVES OF PATIENTS A N D CONTROLS Case No.
Sex
Age (yr)
Density (103 fibre/ram 2)
Denervated Schwann cell density (103/ram 2)
Collagen pocket density (103/mm2)
3 5 6 8 11
F F F M M
16 12 14 7 31
23.8 31.3 58.7 54.4 25.5
19.0 12.9 4.1 2.9 10.5
4.8 5.1 7.9 1.7 6.l
Control 1 Control II Control III
M M F
2 13 9
93.5 30.8 49.9
0 0 0.09
0.25 0.92 1.22
191
Fig. 4. a: Case 9. There are well developed cluster formations (C). Bar = 0.5 ,am. b: Case 11. Collagen pockets (arrows) and multilamellated Schwann cell subunits devoid of axons (M) are prominent. Bar = I ,am.
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DIAMETER ( ~ M ) Fig. 5. Percentagedistributionsof unmyelinatedfibre diameters. unmyelinated fibres (0.2-0.6 #m) compared with controls (Fig. 5). The density of denervated Schwann cell subunits ranged from 2.9 to 19.0 x 103/mm: (mean: 9.9; SD: 6.6), which was greater than that of 1.8 to 5.5 × 103/mm2 (mean: 4.3; SD: 1.5) in control subjects aged 12-54 years (Low et al. 1978) (P < 0.10) and considerably greater than that in 3 controls aged 2, 9 and 13 (Table 4). The density of collagen pockets ranged from 1.7 to 7.9 x 103/mm~ (mean: 5.1; SD: 2.3) which did not differ significantly from that of 3.5 to 9.1 × 103/mm: (mean: 5.7; SD: 2.2) in adult controls (Low et al. 1978), but was considerably greater than that of 0.25 to 1.22 x 103/mm2 in 3 controls of comparable age (Table 4). in summary, the appearances on light and electron microscopy are those of chronic axonal degeneration affecting both myelinated and unmyelinated fibres. DISCUSSION The 11 cases described in this report suffer from a chronically progressive neuropathy commencing in earlv childhood and resulting in moderately severe disability in the second decade. Ihe mild degree of slowing of motor conduction velocity in the majority of cases and the fact that it was never recorded below 35 m/s in the upper limbs of any of the patients, is consistent with the underlying pathology of axonal degeneration (Gilliatt 1966; McLeod et al. 1973). There was a pronounced loss of myelinated fibres in the sural nerve, particularly those of large diameter, and on electron microscopy and teased nerve fibre studies there was no evidence of segmental demyelination or onion bulb formation. In some cases, the increase in density of small unmyelinated fibres (0.2-0.6 #m), and the increase in density of collagen pockets and empty Schwann cell subunits indicated damage to unmyelinated fibres (Thomas 1973). Most of the cases appear to be sporadic or to have an autosomal recessive mode of inheritance but in one family there was a pattern of dominant inheritance.
193 The present cases do not fit satisfactorily into the classification of neuropathies described by Dyck (1975), and are clearly of greater severity and of earlier onset than those classified as HMSN type II (neuronal form ofperoneal muscular atrophy) (Dyck 1975; Harding and Thomas 1980a). In the latter condition, the onset of the symptoms is generally after the second decade and may be delayed into middle-age. Apart from absent ankle jerks, tendon reflexes tend to be retained and sensory findings are mild. Furthermore, the condition usually has an autosomal dominant mode of inheritance (Dyck 1975), only 2 patients with an autosomal recessive pattern of inheritance having been reported (Harding and Thomas 1980a,b). Although the pathological changes in HMSN type II are those of axonal degeneration (Dyck 1975; McLeod and Low 1977), the sural nerve biopsies of the patients in the present study differed from those described in that condition. There was a considerably greater reduction of myelinated fibre density and involvement of unmyelinated fibres than has been reported in HMSN type II (Dyck 1975 ; McLeod and Low 1977). Cases with autosomal recessive inheritance similar to those in the present report have been described clinically in the earlier literature, although the pathological features were not reported. Bell (1948) refers to several families reported by previous authors in which there was autosomal recessive inheritance of a moderately severe neuropathy commencing in early childhood and resulting in significant disability in the second decade. Cases 2 and 3 in the original report of Charcot and Marie (1886) showed probable recessive inheritance. These 2 boys aged 11 and 7 years, respectively, had the commencement of weakness in the lower limbs at the age of 3 years, progressing to considerable weakness and deformity of the distal limbs by the age of 11 in the older boy. The father was stated to be neurologically normal except for mental defect. No details of the mother's examination were given. Harding and Thomas (1980b) reported 2 families with HMSN II with autosomal recessive inheritance. However, the age of onset was later than that in our cases; in 2 members of one family it was 11 and 12 years, respectively, and 13 years in a single member of another family. The age of onset of autosomal dominant HMSN II is usually in the second decade or later, and tends to be later than that of HMSN 1 (Harding and Thomas 1980a). The siblings reported by Kalyanaraman et al. (1970) suffered from a condition which appears clinically identical with that described in the present report. However, these authors interpreted the histological findings as being suggestive of a hypertrophic type of neuropathy. The condition bears some clinical similarities to HMSN type III (D6jerine-Sottas disease) but can be distinguished by the electrophysiological and pathological features. Although it is probable that all the present cases are genetically determined, until a specific biochemical defect can be found sporadic cases must be viewed for diagnostic purposes as being possibly secondary to some other recognisable underlying disorder. In the present study, there was no evidence to implicate toxins and none of the patients suffered from diabetes, porphyria, vascular disease or malignant disorder. The present condition appears to run a progressive course resulting in severe
194 disability by the late teens. None of the patients is older than 35 years, so that the long-term prognosis cannot yet be confidently stated. Case 7, in the present series, was given steroids on several occasions for a period of some months. No clinical or electrophysiological benefit was observed. Furthermore, the surgical procedures which were performed on some patients appeared to be of no long-term benefit. In view of the fact that proximal weakness seemed to develop after the patients ceased walking, ambulation should be encouraged for as long as possible. Once walking is no longer possible, a programme of swimming or other active exercise to encourage use of the proximal muscles would appear desirable. These measures might have helped prevent the spinal complications seen in 2 of the present cases. In reviewing these cases, it initially appeared that the condition was transmitted by an autosomal recessive gene. However, Cases 10 and 11 were subsequently encountered, illustrating that an almost identical clinical phenotype can be inherited in either a dominant or recessive mode. Accurate genetic counselling in sporadic cases is therefore difficult, ACKNOWLEDGEMENT
The authors gratefully acknowledge the receipt of software used in the morphometric evaluation of peripheral nerve from Dr. Peter James Dyck, Mayo Clinic, Rochester, MN, U.S.A. APPENDIX Case l (T.R., male, born 1954, brother of Case 2)
Pregnancy and birth were normal but his feet were noted to be "limp". He walked clumsily at 13 months, had difficulty fitting shoes and wore calipers from ages 2-7 years. Corrective surgery to the feet was performed at age 5. He could run a little at age 5 but by age 17 he could no longer walk. The hands were always weak. On examination at age 24, the cranial nerves were intact. There was marked distal muscle atrophy but no fasciculations, Peripheral nerves were not enlarged. There was mild weakness of shoulder and hip girdles; the biceps a n d triceps were able to overcome gravity and slight resistance. Knee flexion and extension were almost totally paralysed and there were no voluntary movements of wrists, hands, ankles or feet. Tendon reflexes were all absent. There was some loss of vibration and proprioception in the feet and there were hyperpathic delayed pain responses in legs and feet. C P K was normal. CSF was not examined. Both parents are clinically and electrophysiologically normal. Two older siblings, one of w h o m was examined, are normal but the younger brother is similarly affected (Case 2). Case 2 (L.R., male, born 1958, brother of Case 1)
Pregnancy and delivery were normal. He walked at 18 m o n t h s but was unable to continue walking after the age of 13. Physical examination at the age of 20 was very similar to that of Case 1, except that there was still a flicker of m o v e m e n t in the fingers. Muscle and sural nerve biopsies were not performed. Case 3 (M.A., female, born 1959, sister of Case 4)
Pregnancy and delivery were normal. She walked at 13 m o n t h s but never normally, a n d was referred to an orthopaedic surgeon at age 2 and subsequently had numerous operative procedures on hands and feet. She fell frequently and was unable to walk after 15 years. The hands began t o claw at age 13, but had obviously been previously weak.
195 On examination at the age of 18, she was obese. There were bilateral claw hands, mild pes cavus, and distal wasting of upper a n d lower limbs. The nerves were not palpably enlarged. Proximal muscle strength was almost normal, but there was moderate weakness at the wrists and very marked weakness at the ankles a n d of the intrinsic muscles of the hands and feet. Tendon reflexes were absent. There was distal loss of all modalities of sensation with hyperpathic pain sensation on the feet. CSF examination was not performed. Both parents were clinically normal with normal nerve conduction studies. The only sibling is Case 4. Case 4 (K.A., male, born 1961, brother of Case 3) Pregnancy a n d delivery were normal. He walked at age 10 m o n t h s and nothing was noted to be abnormal until age 5 when he commenced to have frequent falls. An orthopaedic surgeon performed several operations on the feet between the ages of 5 and 6. The hands started to claw at age 13. At age 17 he was still able to walk and to move the hands. On examination at age 17, the cranial nerves were intact except for a small patch o f chorioretinitis in the left fundus. Fasciculations were not seen. There was very mild proximal weakness of the arms and legs. The wrists could flex and extend against gravity and mild resistance but there was marked weakness of the intrinsic muscles of the hands and feet and of ankle dorsiflexion and eversion. Biceps a n d triceps jerks could still be elicited, but the other tendon reflexes were absent. Sensation appeared normal. Case 5 (G.H., female, born 1958) Except for a 24-h illness with vomiting at 3 m o n t h ' s gestation, the mother's pregnancy and delivery were normal. Early development was normal until she began walking at the age of 18 m o n t h s when a slow gait was noted. At 2½years, a muscle biopsy was performed and a diagnosis of CharcotMarie Tooth disease was made. By 3 or 4 years, weakness of the hands was noted and she had difficulty in running. By 8 years, she could still walk short distances but was confined to a wheelchair by 15 years. On examination at age 20, the cranial nerves were normal except for inability to converge the eyes, slight disc pallor and questionable constriction of the visual fields. The subcutaneous nerves were visible in the neck and felt slightly thick in the arms. Scoliosis, hip and knee flexion contractures as well as marked clawing of the fingers were present. The feet were flat. There was gross muscle wasting below the upper third of the thigh and below the elbows. Proximal strength was good in arms but there was marked weakness of the wrists and fingers. Both the proximal and distal muscles o f the legs were very weak. All tendon reflexes were absent. There was some apparent truncal ataxia in the seated position. It was difficult to evaluate limb ataxia because of the weakness present. There was marked loss of all modalities of sensation below the ankles with definite diminution of vibration and joint position sense in the hands. C P K was normal. A muscle biopsy showed neurogenic atrophy. Both parents and one male sibling, aged 24 years, are clinically well, and their nerve conduction studies are normal. There is no history of consanguinity between the parents and no family history o f neuromuscular disease. The child's paternal great grandmothers were sisters. Case 6 (K.T., female, born 1959) Pregnancy and delivery were normal. At 9 months, she had difficulty sitting. By the age of 2 she was walking but appeared ataxic and the feet dragged. At age 5 years, she could walk a mile. By the age of 8 years, she could still run a little but when aged 9 years, because of her frequent falls, she was made to use a wheelchair at a special school a n d has never walked since. Scoliosis and slight facial weakness were apparent by the age o f 9 years. Weakness of the h a n d s had been noted from the age of 2 years. On examination, at age 20, there was a tremor of the tongue and chin. There was marked thoracic scoliosis with flexion contractures o f the knees and hips, severe distal muscle atrophy and bilateral claw hands. There was slight horizontal nystagmus and left exotropia. There was mild proximal weakness in the arms and legs, moderate weakness of the wrists and profound weakness of the ankles and intrinsic muscles of the hands. Tendon reflexes were absent. Touch, two-point discrimination, vibration and joint position sense were all impaired in the upper and lower limbs, but pain sensation was intact. CSF protein was less than 10 mg/100 ml. E C G and C P K were normal. Clinical and electrophysiological studies o f both parents and one brother were normal. Another sister is reported to be normal but was not available for examination. There is no family history of consanguinity or neuromuscular disease.
196 Case 7 (M.M., female, born 1967)
The pregnancy and delivery were normal. She sat early, crawled at 5 m o n t h s and ~xalked al 10 m o n t h s but always tip-toed. She lost the ability to run in the second year, and began to I~dl frequently. She was seen by a neurologist at age 3 years and 6 m o n t h s when peripheral neuropathy was diagnosed. Steroids were administered for 6 m o n t h s without obvious improvement. She was still ambulant at 10 years with braces and crutches. Weakness of the hands was first noted at age 7. On examination at age 10 years, the cranial nerves were normal. There were bilateral claw hands and marked distal atrophy of forearms, thighs and calves with small feet and hands and wasting of intrinsic muscles. There was good proximal strength in the arms, but moderate weakness of wrists and severe weakness of the intrinsic muscles of the hands and of all the lower limb muscles. The tendon reflexes were sluggish in the arms and absent in the legs. There was mild loss of touch, vibration and joint position sense in the feet. Peripheral nerves were not thickened. Glucose tolerance test, serum lipoprotein and phytanic acid levels, urinary porphyrin and lead estimations were normal. CSF protein was 3 mg/100 ml. Muscle biopsy at age 3 showed marked muscle fibre atrophy considered to be due to denervation. The parents and only sister of the patient are clinically and electrophysiologically normal. There was no family history o f consanguinity or of neuromuscular disease. Case 8 (S.G., male, born 1969)
Pregnancy and delivery were normal. He walked at 13 m o n t h s and was apparently normal until the age of 5 years when he began to walk with an abnormal gait affecting mainly the left foot. Slow deterioration occurred over the next few years, and by the age of 8 years he was walking with a complete left foot drop, but could still run a little by the time the h a n d s had noticeably become affected. On examination at age 8, the cranial nerves were normal apart from slight horizontal nystagmus. Peripheral nerves were not palpably thickened, There was bilateral pes planus with a valgoid left foot and marked distal atrophy in the legs. There was only mild distal upper limb weakness but moderate weakness of the right foot and severe weakness of the left foot. Deep tendon reflexes were all preserved and sensation was intact. The CSF was not examined. The mother, one brother and 2 sisters were clinically and electrophysiologieally normal. The father was not examined but was said to be normal. There was no family history of consanguinity or of neuromuscular disease. Case 9 (E.S., male, born 1972)
Pregnancy and delivery were normal. He walked at 14 months. By the age of 2 years and 6 months, the feet were turned-in and flat a n d he could not walk as far nor as fast as before. An operation on the feet was performed at age 3 and the feet were noted to be wasted after removal of plasters. The hands were noted to be weak by the age 5 years. By age 6 years, he could still walk a mile or more without aids, but fell frequently. On examination at the age of 6 years, he was able to run a little, there was slight horizontal nystagmus, and marked wasting o f calves, forearms and hands. Early claw h a n d s a n d flexion contractures of Achilles' tendons were present. There was good preservation of proximal strength of the limbs but marked weakness of intrinsic muscles of the hands and of the ankles and feet. The tendon reflexes were present except for the ankle jerks. Sensation was intact except for some diminution of two-point discrimination over the feet. Blood urea, cholesterol, triglycerides, a n d glucose were all normal. CSF protein was 20 mg/100 ml. Muscle biopsy showed evidence of chronic denervation and reinnervation. Clinical and electrophysiological examination of the parents and 2 male siblings were normal. There was no family history o f consanguinity or of neuromuscular disease. Case 10 (P.P., female, born 1975, daughter of Case 11)
Pregnancy and delivery were normal. She sat alone at 6 months, walked at 13 m o n t h s but tended to throw the right foot and never seemed to walk straight. On examination at age 3, the cranial nerves were normal. There was slight wasting of the calves. The upper limbs appeared normal in strength but there was marked weakness of the ankles and feet. The biceps and triceps jerks were sluggish and the other tendon reflexes were absent. There was some loss of vibration and joint position sense in the feet. The nerves were not thickened; Blood film, serum cholesterol and triglycerides, immunoglobulins, blood urea and glucose were normal. Case 11 (J.P., male, born 1944, father of Case 10)
He was born in 1944 after a normal pregnancy and delivery. He sat, crawled and walked at a normal age but tended to fall easily. In the third year, there was an increasing tendency of the feet to
197 turn inward and he had manipulations of the feet and elongation of the Achilles' tendons. At the age of 3 years he was diagnosed by an orthopaedic surgeon as having peroneal muscular atrophy. By 10 years, he had no active ankle movements and had some weakness of the hands. On examination at the age of 27 years, the cranial nerves were normal. There was some weakness of the abdominal musculature. In the upper limbs, distal muscles were functionless except that he could move his thumbs a very small amount. Biceps and triceps muscles were weak. There was minimal weakness of the shoulder girdles. Distal muscles in the lower limbs were functionless and quadriceps and hamstrings were incapable of moving the knee joints against gravity. Sensation was impaired with decreased vibration, joint position, two-point discrimination and pain sensation in the distal extremities. The nerves were not palpably thickened. REFERENCES Bell, J. (1948) On the peroneal type of progressive muscular atrophy. In: The Treasury of Human Inheritance, Vol. 9, Cambridge University Press, London, pp. 69-140. Charcot, J.-M. and P. Marie (1886) Sur une forme particuli6re d'atrophie musculaire progressive souvent familiale, d+butante par les pieds et les jambes, et atteignant plus tard les mains, Rev. Med. (Paris), 6: 97-138. Dyck, P. J. (1975) Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In : P. J. Dyck, P. K. Thomas and E. H. Lambert (Eds.), Peripheral Neuropathy, Saunders, Philadelphia, PA, pp. 825-867. Dyck, P. J. and E. H. Lambert (1968a) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy, Part 1 (Neurologic, genetic and electrophysiologic findings in hereditary polyneuropathy), Arch. Neurol. (Chic.), 18: 603-618. Dyck, P. J. and E. H. Lambert (1968b) Lower motor and primary sensory diseases with peroneal muscular atrophy, Part 2 (Neurologic, genetic and electrophysiologic findings in various neuronal degenerations), Arch. Neurol. (Chic.), 18: 619~25. Dyck, P. J., H. Jedrezejowska, J. Karnes, Y. Kawamura, P. A. Low, P. C. O'Brien, K. Offord, A. Ohnishi, M. Ohta, M. Pollock and J.C. Stevens (1979) Reconstruction of motor, sensory and autonomic neurons based on morphometric study of sampled levels, Muscle and Nerve, 2 : 399~105. Gilliatt, R. W. (1966) Nerve conduction in human and experimental neuropathies, Proc. roy. Soc. Med., 59:989 993. Harding, A. E. and P. K. Thomas (1980a)The clinical features of hereditary motor and sensory neuropathy types I and II, Brain, 103: 259-280. Harding, A. E. and P. K. Thomas (1980b) Autosomal recessive forms of hereditary motor and sensory neuropathy, J. Neurol. Neurosurg. Psychiat., 43: 669~578. Kalyanaraman, K., P.A. Cancilla, T. Munsat and C.M. Pearson (1970) Hereditary hypertrophic neuropathy, Bull. Los Angeles neurol. Soc., 35 : 58-68. Low, P. A., J. G. McLeod and J. W. Prineas (1978) Hypertrophic Charcot-Marie Tooth disease - - Light and electron microscope studies of the sural nerve, J. neurol. Sci., 35:93 115. McLeod, J. G. and P.A. Low (1977) Peroneal muscular atrophy with autosomal dominant inheritance, Clin. exp. Neurol., 14: 142-153. McLeod, J. G., J. W. Prineas and J. C. Walsh (1973) The relationship of conduction velocity to pathology in peripheral nerves. In : J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 2, Karger, Basel, pp. 248-258. Thomas, P. K. (1973) The ultrastructural pathology of unmyelinated nerve fibres. In: J. E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 2, Karger, Basel, pp. 227-239. Walsh, J. C. and J. G. McLeod (1970) Alcoholic neuropathy - - An electrophysiological and histological study, J. neurol. Sci., 10: 457~,69.