LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES

Dominantly Inherited Hypertrophic Neuropathy

S. K. MONGIA, Q. GHANEM, D. PRESTON, A. J. LEWIS, AND E. A. ATACK

SUMMARY: Clinical, electrophysiolog­ shoulder girdle muscles was seen in 13 Charcot and Marie (1886) and ical, and histopathological studies of patients. Four patients gave a history of Tooth (1886) first described an some members of a family with domin­ trigeminal neuralgia. Motor nerve con­ hereditary neuropathy, now called antly inherited hypertrophic neuropathy duction velocities were markedly im­ after their names, Charcot-Marie- are presented. Twenty-five members paired in all the clinically affected mem­ Tooth disease (CMT disease). A were studied. Seventeen were abnormal bers. These studies were normal in the 8 similar disorder was described by on clinical examination. Their ages var­ unaffected members. Motor conduction ied from 2lA to 78 years. Age at onset in velocities of the proximal segment of the Dejerine and Sottas (1893). Some of 14 of the 17 varied between 2 Vi and 56 ulnar nerve were slower compared to the the other hereditary neuropathies years. Pes cavus and palpable nerve distal segment in almost all the affected are Refsum's disease (Refsum, 1946) thickening were present in more than members. There was no significant cor­ hereditary sensory radicular half of the affected individuals. All pa­ relation between the degree of clinical neuropathy (Denny-Brown, 1951), tients had areflexia. Fifteen of the 17 had disability and the extent of impairment in Roussy-Levy syndrome (Roussy distal motor weakness as well as mild to the motor nerve conduction velocities. and Levy, 1926), Roussy-Cornil type moderate sensory impairment. Motor Sural nerve biopsies were studied. These of late onset (Roussy and Cornil, weakness affecting the proximal hip and observations are discussed. 1919), neuropathy of Friedreich's ataxia (McLeod, 1971), amyloid neuropathy (Bradley, 1974a) neuropathies of Bassen-Kornzweig RESUME: Nous presentons les aspects la hanche et aux epaules. 4 patients av­ disease (Farquhar and Ways, 1966), cliniques, electrophysiologiques et his- aient deja souffert de nevralgie du tri- Tangier's disease (Kocen, Lloyd topathologiques des divers membres jumeau. La vitesse de conduction ner- and Lascelles, 1967), porphyria d'une famille avec neuropathie hyper- veuse dans les nerfs moteurs etait net- (Cavanagh and Mellick, 1965) and trophique a heredite dominante. Des 25 tement diminuee chez tous les sujets at­ membres de cette famille examines, 17 teints, alors qu'elle se situait dans les leukodystrophies (Bradley, 1974b). semblaient atteints. Les ages variaient limites normales chez les sujets juges Metabolic abnormalities have been de 2V2 a 78 ans. L'age de debut deter­ normaux cliniquement. La vitesse de recognized in some of these and it is mine chez 14 patients variait egale- conduction motrice du segment proximal possible that a metabolic defect ex­ ment de 2Vi a 56 ans. Un pes cavus du nerf cubital etait nettement plus lente ists in the others. Hypertrophy of et une hypertrophic palpable du nerf se que celle du segment distal, chez pres- the peripheral nerves, thought to be retrouvaient chez plus de la moitie des que tous les sujets atteints. Cependant il characteristic of Dejerine-Sottas individus atteints. Tous etaient n'existait aucune correlation entre le neuropathy (also called hypertrophic areflexiques. Des 17 patients, 15 degre d'atteinte clinique et celui du ralentissement de la conduction dans les interstitial neuropathy), is seen in presentaient une faiblesse motrice dis- many chronic neuropathies and sig­ tale ainsi quune atteinte sensitive nerfs moteurs. Des biopsies surales moderee. De plus 13 patients avaient furent egalement faites. nifies recurrent demyelination and aussi une faiblesse motrice proximate a remyelination of the nerves (Thomas and Lascelles, 1967; Pleasure and Towfighi, 1972). It is seen in Dejerine-Sottas neuropathy, CMT disease, Refsum's disease, amyloid neuropathy (Dyck and Lambert, 1968 a and b), diabetic neuropathy (Thomas and Lascelles, 1967), re­ lapsing neuropathy (Austin, 1958), multifocal enlargement of peripheral From the Division of Neurology, Faculty of nerves (Adams, Asbury and Michel- Medicine, University of Ottawa and The Ottawa son, 1965). The neuropathy of ac­ Civic Hospital. romegaly (Stewart, 1966), neurofib­ Presented at the Canadian Congress of Neurologi­ romatosis (Bielschowski, 1922; cal Sciences, London, Ontario, June 1975. Bailey and Herman, 1938), and am­ Reprint requests to: Dr. E. A. A tack. Ottawa putation neuromas (Krucke, 1949) Civic Hospital, 1053 Carling Avenue, Ottawa, On­ tario, K1Y4E9, Canada. are other examples. Dejerine-Sottas

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TABLE 1 clinical, electrophysiological and histopathological studies are re­ Age and Sex Distribution ported.

METHOD OF STUDY Age Group No. Males Females This family has thirty-nine mem­ bers over four generations. Twenty- five of these members were ex­ Clin cally Clinically amined by one or more of us. Infor­ Normal Affected Normal Affected mation was obtained about other members, but the data is restricted < 10 years 3 1 2 to those who were examined. Of these 25 members, 17 were 11-20 years 10 2 5 2 1 found to be abnormal (Table 1). These patients were divided into 21-30 years 4 1 1 2 four groups, depending upon the 31-40 years 4 2 2 severity of their clinical deficits (Table 2). 41-50 years 3 1 1 Motor nerve conduction velocities of the distal (elbow to wrist) and y 50 years 1 1 proximal (axilla to elbow) segments of the ulnar nerve and the knee to ankle segment of the lateral popliteal TOTAL 25 5 9 3 8 nerve were studied by conventional methods (Lambert, 1956). These studies were performed in 13 of the 17 abnormal and 6 of the 8 normal individuals (Table 3). Their ages var­ Table 2 ied from 11 to 50 years. Motor nerve conduction velocities of 45 m/sec or Grading of Neurological Deficit over for the lateral popliteal nerve were considered normal. Nerve conduction velocities in the affected Grade Description fo. of Patients members were classified into grades I-III as shown in Table 4. A decrease of 10 m/sec of conduction velocity I Areflexia with no motor or 2 separated one grade from the other. sensory impairment The grading of nerve conduction velocities and the clinical deficits II Mild weakness (4/5) with 8 was designed arbitrarily. mild sensory impairment plus areflexia Sural nerve biopsy was available from patients Bl, B4, C10, Cll, III Moderate weakness (2-3/5) 5 C12, and C13 as shown in Figure 1. with moderate sensory impair­ Gastrocnemius muscle biopsies ment plus areflexia were available from patients Bl and CI3. All specimens were picked up IV Marked weakness (0-1/5) with 2 immediately and prepared for teas­ moderate sensory impairment ing (of nerves), frozen section, plus areflexia paraffin section and electronmicros- copy. Standard techniques used for nerve and muscle included qualita­ tive histochemistry and enzyme his­ neuropathy and CMT disease may cessively inherited hypertrophic tochemistry. be inherited as dominant, recessive neuropathies rather than by All patients were subjected to the or sex-linked traits (Bell, 1935; Au­ eponyms. following hematological and stin, 1956; Thomas and Lascelles, This communication deals with biochemical studies: total and diffe­ 1967; Dyck and Lambert, 1968a). It the prospective study of a family rential blood cell counts; hemoglo­ is suggested these disorders might be with dominantly inherited hyper­ bin; erythrocytic sedimentation rate; better classified as dominantly or re- trophic neuropathy (Fig. 1). Detailed serum levels of sodium, potassium,

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AGE OF ONSET

,2 -

-.4 *.__ o- -oo ooo ©- BOD 66 C-IO C-lt C-12 C-IJ C-14 -I- -r f r/A -I— I 5 10 15 20 25 56 ©0 AGE OF ONSET Clinically affected Not available for study 3 Patients asymptomatic yet clinically affected. Figure /—Family pedigree showing both female and male indi­ Figure 2—The dots indicate the number of cases as they started viduals that were normal, clinically affected, or not available their symptoms at a particular age in years. Three patients for study. were asymptomatic but clinically affected and are not included in this figure.

chloride, calcium, phosphorus, al­ showed tremor, pupillary abnor­ feature of all the patients. Distal kaline phosphatase, SGOT SGPT, malities, nystagmus, cerebellar or weakness of the lower extremities fasting and post-prandial blood long tract signs. Pes cavus and palp­ was seen in 15 patients. Thirteen of sugar. Serum electrophoresis for able nerve thickening were found in these 15 had weakness of the distal proteins and lipoproteins and more than half of the patients. muscles of the upper extremities. serological tests for syphilis were Mild to marked motor and moder­ Thirteen of the 15 patients had performed. Blood levels of arsenic, ate sensory deficits were seen in 15 significant proximal weakness, lead, mercury, and phytanic acid of the 17 patients. The other two pa­ mostly in the lower limbs. The pro- were assessed and X-rays of spine tients had no weakness, although were taken in some of the patients. they were areflexic and showed ab­ normal nerve conduction velocities. 70- OBSERVATIONS Absent deep tendon reflexes was a Of the 17 abnormal members, 9 ^ 60-

were males (Table 1). The disorder COMPARISON OF PWOX1MAL ft OISTAL ULNAR NERVE CONDUCTION VELOCITIES was inherited as an autosomal do­ minant trait (Fig. 1). No sex pre­ 50- dominance was seen. Two members of the family, B-5 40- and B-6 in Fig. 1, a male and a female, were twins. Both of them 30- had moderate peripheral I neuropathy. Motor nerve conduc­ tion velocities were slow in one of ^ 20- them (B-6) and she had transmitted the disease to one of her two chil­ 10- dren. This was confirmed by clinical and nerve conduction studies. Figure 3 — Comparison of the proximal At the time of the examination, and distal ulnar nerve conduction norm, grade I I III isr their ages varied from 2V2 to 78 years velocities (N.C.V.) in meters per sec­ Neurological Status (Table 1). Twelve of the 14 patients ond (M/sec) in affected individuals. Figure 4 — Motor nerve conduction vel­ had the onset of illness some time The dots indicate distal nerve con: ocities of ulnar nerve, as indicated by before 20 years of age. Of these, five duction velocity as shown on the the black dots, are correlated to the neurological status in normal (norm) began at 2lk to 5 years of age. There horizontal line and the proximal nerve conduction velocity as plotted and affected individuals. The were two patients who had their first on the vertical line in the same indi­ neurological status of affected mem­ symptoms at 25 and 56 years of age vidual. In 9 of the 12 patients, the bers was graded I-IV (please see the (Fig. 2). motor nerve conduction velocity of text). There is some tendency for the Examination of intellectual func­ the proximal segment was lower nerve conduction velocities to show a tions and cranial nerves revealed no compared to that of the distal seg­ lower value in more severely affected abnormalities. None of the patients ment. members.

Mongia et at. MAY 1978 - 241

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ximal weakness affected the lower material. Occasionally, segmental or extremities in six, the lower and the paranodal demyelination could be upper extremities in another six, and recognized. only the upper extremities in one Electronmicroscopy confirmed (Fig. 3). The proximal weakness in­ seveje reduction in numbers of volved predominantly the hip flexors myelin sheaths. Most of the remain­ and the shoulder abductors. Fascicu- ing sheaths were thin, and showed lations were seen in the proximal morphological abnormalities, includ­ arm muscles in one patient while, ing vesiculation at the minor dense subjectively, the fasciculations were line, distorted and separated lamel­ felt in the proximal muscles by four lae especially in the inner part of the other patients. sheath, and areas of irregular thick­ Sensory examination showed mild ening. Large axons, presumably to moderate impairment of distal demyelinated, appeared normal. vibration and position sense of the Small fibers were plentiful, and ap­ lower and upper extremities. Pain peared morphologically normal. A and temperature modalities were not few empty Schwann cell profiles, affected. with occasionally collagen pockets, Four patients, including the prop­ were present. Onion bodies with 3 to ositus, had a history of trigeminal 6 concentric lamellae of Schwann neuralgia. Two of these had nerve cell cytoplasm were present (Fig. 7), blocks to relieve their pain. The the lamellae being interspersed with other two had medical treatment for and surrounded by large numbers of variable periods. Figure 5 — Transverse section of two collagen fibers. Redundant base­ fasciculae, showing clumps of thick­ Motor nerve conduction studies ment membrane material was some­ ened endoneurium but normal times seen. were performed in 19 members of perineurium (Masson's trichrome, x the family. Clinically, 13 of the 19 400) The other three biopsies showed were affected, while six had no similar changes, but in lesser degree. neurological deficit (Table 3). The 13 In C12 and C13, there was moderate affected members had abnormal fected nerves (Bl, B4, and Cll) endoneurial thickening, but few motor nerve conduction velocities, showed almost complete loss of well-formed onion bulbs. Teased while the six healthy members had myelin with moderate reduction of preparations showed more myeli­ normal nerve conduction velocities. large axons. The endoneurial con­ nated axons, with areas of consecu­ In the affected group, areflexia was tent of collagen (trichrome stain) and tive segmental demyelination. In the only abnormality in two. basement membrane material (re- CIO, changes were minimal except Motor conduction velocities of the ticulin stain) was markedly in­ for some segmental demyelination in distal and proximal segments of the creased, and there was a moderate the teased preparations. No Renaut ulnar nerve were compared in 11 pa­ increase in Schwann cell nuclei. On bodes were seen in any biopsy. tients. In eight of the 11 the proximal transverse section the increased en­ Both muscle biopsies showed de­ segment showed lower conduction doneurial tissue formed small clus­ nervation atrophy. In Bl, there was velocity compared to the distal seg­ ters (Fig. 6), but onion bulb forma­ advanced muscle fiber loss with ment. tion was not clearly visible under fibro-fatty replacement; the remain­ An attempt was made to correlate light microscopy. There was no ac­ ing small muscle fibers (less than the nerve conduction velocities with cumulation of myelin breakdown \5\x ) could not be typed, since they the severity of the neurological de­ products (ORO-positive or PAS- all showed well-marked oxidative ficit (Fig. 5). Only motor nerve con­ positive material). In one case (B4) activity with variable levels of AT- duction velocities of the ulnar nerve there were apparently "empty" Pase and phosophorylase. In C13, were used for this correlation. The spaces in the endoneurium, which there was less advanced atrophy normal members had normal nerve contained finely granular selectively involving type I fibers, conduction velocities. In the af­ mucopolysaccharide (Alcian Blue). most of which were less than 30^i in fected members the motor conduc­ Teased preparation (Fig. 7) diameter, but no stromal changes. tion velocities were reduced in all showed a marked increase in longi­ There was no type grouping, hyper­ grades of neurological deficit and the tudinally orientated collagen fibers trophy, or other evidence of re- reduction was approximately pro­ and bundles, and very few continu­ innervation. portional to the grade of the disease. ous myelin sheaths. Most of these None of the hematological or were thin and palely stained com­ DISCUSSION biochemical studies was abnormal. pared with control material. Some Hypertrophic neuropathies of the Sural nerve biopsies showed no fibers showed multisegmental de- type known as CMT disease and changes in epineurium, perineurium myelination with or without ellipsoi­ Dejerine-Sottas disease have been or vessels. The most severely af- dal accumulations of osmiophilic classified into five types by Bradley

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•i\

i l\ I [ \ V V t Figure 6—Representative teased nerve fibers, showing pre­ Figure 7—An onion-bulb with two Schwann cell nuclearouni d a served original myelin in often incomplete segments, ovoids of thinly myelinated (? re-myelinated), but otherwise normal. abnormally formed myelin, extensive thin remyelination, and axon (x 17,750). endoneurial fibrosis (onion bulbs). (Osmium tetroxide, x 900).

(1974a). Mode of inheritance, age of patients of Dyck and Lambert (1968 bers, and in detecting the carriers of onset, and progression of the disease a) had either. These signs, therefore, the gene, who have not yet man­ were some of the main differentiat­ are not helpful in separating CMT ifested the disease (Lambert et al., ing features. In our cases, the age of disease from Dejerine-Sottas 1958; Dycket al., 1963). onset varied from 2V2 to 56 years." neuropathy. In the present series, the impair­ Progression of the disease was also Sensory loss, although described ment of deep tendon reflexes, with variable. For example, the proposi­ as most severe in Dejerine-Sottas or without other clinical signs, was tus became aware of his disability disease, is predominant for the mod­ as sensitive an indicator of the dis­ at 15-20 years of age. He was con­ alities of light touch, vibration and ease as the abnormalities on nerve fined to a wheelchair several years position sense (Dyck and Lambert, conduction studies. Those members before he died, of an unrelated prob­ 1968a). Similar predominance for with impairment of deep tendon re­ lem, at the age of 50. He had five these modalities is seen in CMT dis­ flexes also showed abnormal motor affected siblings. Their symptoms ease. Severe sensory impairment for nerve conduction velocities. The started at ages 5-15 years and were pain and other sensations, including velocities were normal in those with only moderately disabling in the next trophic disturbances, have been de­ normal deep tendon reflexes. 20-30 years. A similar variability in scribed in CMT disease by England Pathological examination is of lit­ the progression was seen in other af­ and Denny-Brown (1952). tle assistance in the classification of fected members. Apparently, age of Hypertrophy of the peripheral familial or sporadic hypertrophic onset and speed of progression are nerves is not exclusive to Dejerine- neuropathies, all of which show not reliable classifying features. Sottas disease. This finding has been similar changes exemplified by the Nystagmus, tremor, miosis, and described in many other present cases (Thomas and Lascel- cerebellar or long tract signs were neuropathies. les, 1967; Dyck and Lambert, not seen in any of our patients. Nys­ Nerve conduction velocities are 1968b). These include loss of myelin tagmus and miosis described in generally low in the hereditary by segmental demyelination fre­ Dejerine-Sottas neuropathy is not a neuropathies. These studies have quently accompanied by remyelina­ consistent feature. None of the five been utilized in the affected mem­ tion, variable loss of large axons but

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TABLE 3 sumably neuropathic. Subjective and objective fasciculations in some Nerve Conduction Velocities: Clinically Normal and Affected Members. of the patients and relatively slower motor nerve conduction velocities in Clinical Status NO. Motor Nerve Conduction Velocities the proximal compared to the distal of Individuals Not Done Normal Abnormal segment of the ulnar nerve support this contention.

Clinically Four of our 17 patients com­ Normal Members 8 2 6 0 plained of trigeminal neuralgic pains. Kimura (1971) found elec­ trophysiological evidence of facial Clinically and trigeminal nerve involvement in Affected CMT disease. Kalynanaraman et al Members 17 4 0 13 (1974) reported a case of hereditary hypertrophic neuropathy with facial and trigeminal nerve involvement. This patient had trigeminal neuralgic TABLE 4 pains and facial hemispasms. Elec- Nerve Conduction Velocities: Clinically Affected Members trophysiologically, the facial nerve was found to have reduced conduc­ Nerv e Conduction Vel ocities tion time. This isolated patient was presumed to have autosomal reces­ Nerve No. of Normal Grade I Grade II Grade III Patients 44 m/sec. 35-44 m/sec. 25-34 m/sec. 25 m/sec. sive inheritance and was diagnosed as a case of Dejerine-Sottas neuropathy. They found similarities Distal Ulnar 13 0 0 3 10 between their case and the cases de­ scribed by Hellsing (1930) and later Proximal restudied by Lundberg and Wester- Ulnar 12 0 0 0 12 berg (1968). The cases described by the latter authors had facial spasms, optic atrophy, Argyll-Robertson Nerve No. of Normal Grade I Grade II Grade III pupils, disturbed eye movements, 30-39 m/sec. 20-29 m/sec. 20 m/sec. Patients '40 m/sec. diminished or absent deep tendon re­ flexes, slight to moderate peripheral Lateral Popliteal weakness in the legs and elec­ Nerve 9 0 0 0 9 trophysiological evidence of motor I . I peripheral neuropathy. Two of their patients were said to have trigeminal neuralgia. These workers confirmed usually normal small axons, prolifif-­ either dominantly inherited hyper- the dominant inheritance of the syn­ eration of Schwann cells with thhe trophic neuropathy or recessively drome and concluded that Hellsing's formation of onion bulbs, markeed inherited hypertrophic neuropathy, cases represented a unique syn­ increase in endoneurial collagen fib­b- Thirteen of the 17 clinically af- drome of hereditary neuropathy. ers, and variable accumulation of fected individuals in the present The case described by Kalyanara- acid mucopolysaccharide in the disis­- study had mild-moderate weakness man et al. (1974) was believed to tended ground substance. Micros>s­- of the hip and shoulder girdle mus- have recessive inheritance, while the copy may assist in the exclusion of cles. This was distinct from the dis- cases described as Hellsing's syn­ somewhat similar conditions, succh tal weakness in both the upper and drome had a dominant inheritance. as Refsum's disease (Fardeau anrid lower extremities. For example, We agree with the suggestion that Engel, 1969). Fabry's diseasse many of these patients showed the cases described by Hellsing, (Kocen and Thomas, 1970; Ohnish;hi weakness of the dorsiflexors and Kalyanaraman et al, as well as our and Dyck, 1974), or Tangier diseasse everters of the feet and some weak- patients, represent hereditary hyper­ (Kocen, King, Thomas and Haasis, ness of the hip flexors, with com- trophic neuropathy with cranial 1973), in which lipid inclusions of paratively preserved strength of the nerve involvement and other atypi­ more or less specific nature maay knee flexors and extensors. The cal features. Our cases had the un­ occur in well-defined situations. proximal weakness of both lower usual feature of proximal muscle The mode of inheritance seems to and upper extremities has not been weakness, not emphasized in the lit­ be the most useful guide for differen:n­- described in cases of CMT or erature. tiating these various types of Dejerine-Sottas disease. This prox- hereditary neuropathy, calling the;m imal motor involvement was pre­ The pathogenesis of these

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hereditary neuropathies is not clear. the presence of relatively intact la nevrite interstitielle hypertrophique et A metabolic error has been eluci­ motor and sensory functions, as progressive de 1'enfance. Comptes Rendus, dated in cases of Refsum's disease. seen in some of our cases and stres­ des Seances oe la Societe de Biologie et de Phytanic acid, a free fatty acid, is sed by earlier workers (Lambert et ses Filiales (Paris), 45, 63-96. increased in the blood and elsewhere al., 1958; Dyck et al., 1963), would DENNY-BROWN, D. (1951). Hereditary sensory radicular neuropathy. Journal of (Klenke and Kahlke, 1963). Dyck et be difficult to explain on the basis of Neurology, Neurosurgery and Psychiatry, al. (1970) found evidence of an ab­ a primary neuronal degeneration. A 14, 237-252. normal metabolism of ceramide slowly progressive disorder of DYCK, P. J., LAMBERT, E. A. and MUL­ hexosides and ceramide hexoside myelin would seem more reasona­ DER, D. W. (1963). Charcot-Marie-Tooth sulphates in recessively inherited ble. disease: nerve conduction and clinical hypertrophic neuropathy (Dejerine- studies of a large kinship. Neurology (Min­ Sottas neuropathy). A metabolic ab­ neapolis). 13. 1-11. normality of genetic type is almost DYCK, P. J. and LAMBERT, E. H. (1968a). REFERENCES Lower motor and primary sensory neurone certainly involved in cases of do­ diseases with peroneal muscular atrophy. I. minantly inherited hypertrophic ADAMS, R. D., ASBURY, A. K. and Neurologic, genetic and electrophysiologic neuropathy. A dominant inheritance MICHELSEN, J. J. (1965). Multifocal findings in hereditary polyneuropathies. with high penetrance is evident from pseudohypertrophic neuropathy. Transac­ Archives of Neurology (Chicago), 18, our cases (Fig. 1). This is also sug­ tions of the American Neurological Associ­ 603-618. gested by the fact that two of our ation (New York), 90, 30-32. DYCK, P. J. and LAMBERT. E. H. (1968b). AUSTIN, J. H. (1956). 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