Six members originating from two families with hereditary motor and sensory neuropathy (hypertrophic and neuronal types) were noted to have enlarged calf muscles. Muscle computed tomography revealed that muscle enlargement in the propositus of the family with the hypertrophic type of HMSN was due to an increase in muscle and/or connective tissue. Computed tomography of the legs of the propositus of the family with the neuronal type of HMSN showed infiltration of the medial head of the gastrocnemius muscle by adipose tissue. Key words: hereditary motor and sensory neuropathy computed tomography calf enlargement MUSCLE & NERVE 13:40-46 1990
CALF ENLARGEMENT IN HEREDITARY MOTOR AND SENSORY NEUROPATHY MARIANNE DE VISSER, MD, JESSICA E. HOOGENDIJK, MD, BRAM W. ONGERBOER DE VISSER, MD, and BERNHARD J. VERBEETEN Jr., MD
peroneal muscular atrophy, or hereditary motor and sensory neuropathy (HMSN), is characterized by familial occurrence and slowly progressive distal limb weakness and atrophy, due to a denervating process, initially involving the feet and lower legs and later the hands and forearms.’ Two main types are distinguished, the hypertrophic and the neuronal type, each one of them displaying specific electrophysiological and neuropathological
feature^.^'^'^ This report describes two families in which clinical, electrophysiological, and histopathological findings were consistent with the diagnosis of HMSN. However, an unusual feature was the enlargement of the calf muscles in several affected family members.
From the Departments of Neurology (Drs. de Visser and Hoogendijk), Clinicai Neurophysiology (Dr. Ongerboer de Visser), and Diagnostic Radiology (Dr. Verbeeten), Academic Medical Center, University of Amsterdam, The Netherlands. Acknowledgments: The authors thank Prof. F.G.I. Jennekens for carrying out the nerve biopsy examinations, the Prinses Beatrix Fonds, the Hague, for financial support, Dr. J.W.H.H. Dammers and Dr. J.C. Gauw for referring the index patients, and Mrs. Joke van Gulik for secretarial assistance. Address reprint requests to Dr. de Visser at the Department of Neurology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
CASE REPORTS Family 1. Thirteen affected and unaffected individuals, as shown in Fig. 1, were evaluated by neurological and electrophysiological examination. The propositus (11-6), a 36-year-old woman, had been noted to have weakness of the legs since infancy. Frequent falling in childhood was ascribed to bilateral recurrent hip dislocation. On examination, she showed slight atrophy of the hand muscles. Claw toes, hypertrophic calves, and hyperflexibility of the finger joints were seen. There was marked distal weakness of the legs and slight weakness of the hip and thigh muscles. Sensory loss was tactile and confined to hands and feet. Both tricipital reflexes and the right ankle jerk were absent. Other reflexes were present. Electroneurography revealed motor nerve conduction velocities (MNCVs) well below the normal range of the median nerve (29 m/sec) and of the peroneal nerve (14 m/sec). Sensory nerve conduction velocity (SNCV) of the sural nerve was markedly reduced (22 m/sec). Light microscopic examination of a sural nerve biopsy showed a mild reduction in the number of myelinated fibers. The majority of myelinated fibers was surrounded by onion-bulb formations. Computed tomographic (CT) examination of the legs showed an increase in size of the medial head of the gastrocnemius muscles without definite signs of lower attenuation (Fig. 2).
Accepted for publication January 31, 1989 CCC 0148-639X/90/01040-07 $04.00 0 1990 John Wiley & Sons, Inc.
40
Calf Enlargement in HMSN
An abnormality of gait was reported by patients 11-5 (since the age of 35),
Other Family Members.
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I
I1 I
/
/
/
I11
0 male
0 female @ ;;fgpby Qcieceased
L
spontaneous abortion
h
affected by examination propositus
FIGURE 1. Pedigree of family 1; key to the pedigrees.
111-6,111-7,and 111-8 (since childhood). Recurrent dislocation of the patellae occurred in two patients (11-4 and 111-8). Dislocation of the shoulder was mentioned by two nonaffected individuals (111-5 and 111-10).Three patients were asymptomatic (114,11-8, and 11-11). The results of the clinical and electrophysiological evaluation are summarized in Table 1. Hyperflexibility of the fingerjoints was encountered not only in all patients but also in two nonaffected individuals (11-7 and 111-5). All pa-
tients were ambulatory at the time of examination. Nerve enlargement was not detected in any patient. Neurophysiological examination consisted only of assessment of MNCVs and SNCVs. Family 2 (pedigree in Fig. 3). The propositus (IV-l),a 40-year-old man, was aware of having high foot arches and firm calves all his life, but he had no other neurological symptoms. Clinical examination revealed mild atrophy and weakness of the
FIGURE 2. CT scan of the lower legs of the propositus of family 1, showing an increase in size of the medial head of both gastrocnemius muscles (GCmh).
Calf Enlargement in HMSN
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Table 1. Results of clinical and electrophysiological evaluation of family 1. ~~
Signs Pedigree no. 11-2 11-4 11-5 11-6 11-7 11-8 11-11 111-5 111-6 111-7 111-8 111-9 Ill-10
SexJage (years)
Pes c a w s
-
MI41 MI39 Fl38 F136 MI35 F133 MI23 Fl13 MI9 F17 MI14 FA1 Fl7
+ + + + -
+ + -
EMG
-
Calf hypertrophy
Leg weakness
Hand weakness
-
-
-
-
Refused clinical examination
+ + +
+ +
-
+ -
+ + -
-
+ -
Hypo- or areflexia
Sensory loss
-
-
+ + +
+ + +
+ +
+
-
-
-
-
Hyperflex.
-
NC Abn.
-
+ + + + + + + +
+ + + -
+ + + + +
-
-
Note: i= presence of abnormaiity, - = absence, Hyperflex. = hypeiflexibility of the fingerjoints,NC Abn. = nerve conduction abnormality.
intrinsic hand muscles. In contrast, the calf muscles were markedly enlarged (Fig. 4). There was moderate weakness of the foot and toe extensors and the peroneal muscles. Bilateral pes cavus and clawed toes were present. Sensory examination showed decreased response to vibration in the legs up to the ankles. The ankle jerks were absent, the other myotatic reflexes were normal. Electromyography (EMG) disclosed signs of reinnervation, including large polyphasic motor unit potentials (MUPs), and MUPs increased in amplitude and in duration in various hand and leg muscles. Nerve conduction studies showed absent potentials in sural nerves, and no potentials could be evoked from the left extensor digitorum brevis muscle. MNCV of the right ulnar nerve was 45 m/sec, of the right peroneal nerve 28 d s e c , and of the right tibia1 nerve 22 m/sec. Computed tomographic (CT) examination of the lower legs showed a decrease in attenuation of the tibialis anterior, toe extensors, and peroneal muscles, but
I
I1
I
IY
&itB
'1
2
FIGURE 3. Pedigree of family 2.
42
Calf Enlargement in HMSN
.-
..
also of the medial head of the gastrocnemius, especially on the right side (Fig. 5). Light microscopic examination of a fascicular biopsy of the left sural nerve showed a fiber density within the normal range (8089/mm2). The histogram of the fiber diameter revealed a reduction in the number of myelinated fibers, mostly affecting the large fibers. T h e myelin sheath of fibers above 4 pm was disproportionately thin in relation to the axon caliber. In addition, there were signs of axonal degeneration and clusters of small myelinated fibers. Few small onion-bulb formations were encountered. One axon was found to have a swollen appearance and was densely packed with organelles (Fig. 6A). Electron microscopic examination showed that this thinly myelinated axon contained large mitochondria, membranous structures, and neurofilaments (Fig. 6B). An electrocardiogram showed no abnormalities. Serum CK activity was normal. His brother (IV-2), a 39-year-old man, was asymptomatic. However, on clinical examination, he was found to have enlarged calf and thigh muscles (Fig. 4), bilateral pes cavus, and clawed toes. There was slight weakness of the tibialis anterior muscles, toe extensors, and peroneal muscles. Sensory examination showed a decreased response to vibration in the legs u p to the ankles. Myotatic reflexes were all present. EMG revealed signs of reinnervation in various hand and leg muscles. MNCV of the right peroneal nerve was 37 m/sec, of the left peroneal nerve 28 m/sec, and of the right median nerve 43 m/sec. SNCV of the right median nerve was 37 m/sec. An electrocardiogram was normal.
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FIGURE 4. Photograph of the legs of the propositus (left) of family 2 and his brother (right) showing enlargement of the calf muscles.
The 74-year-old mother of the propositus (III3 ) was asymptomatic. However, she was aware of the occurrence of high arched feet and “weak ankles’’ in the family (her father and father’s mother and sister were affected). Clinical examination showed bilateral pes cavus, enlarged calf muscles, and mild weakness of the opponens digiti quinti and peroneal muscles. There were no sensory symptoms. T h e ankle jerks were absent; the other myotatic reflexes were normal. EMG revealed signs of reinnervation in various hand and leg muscles. The MNCV of the right peroneal nerve was 49 m/sec, of the left peroneal nerve 50 m/sec, of the right median nerve 40 m/sec, and of the right ulnar nerve 43 m/sec. The SNCV of the right sural nerve was 27 m/sec. DISCUSSION
The affected members of both families reported were found to have autosomal-dominantly inherited polyneuropathy, predominantly involving the lower legs, known as HMSN.’ The electrophysio-
Calf Enlargement in HMSN
logical and histological features observed in family I were in agreement with a diagnosis of the hypertrophic type of HMSN.’ T h e disorder of family 2 was classified as the neuronal type of HMSN, based on MNCVs of the median nerve above 38 m/secYand nerve biopsy findings, showing axonal degeneration with regeneration and little evidence of onion bulb formation. The significance of the single axon swelling containing mitochondria, membranous structures, and neurofilaments in the sural nerve tissue of the propositus of family 2 is unclear. The occurrence of the occasional axonal swelling containing stacks of mitochondria, myelin-like figures, glycogen vacuoles, and hyperplastic agranular endoplasmatic reticulum in the neuronal type of HMSN was observed by Joosten.” Recently, Vogel et a1.“ reported on a German kinship with the neuronal type of HMSN, where sural nerve biopsies showed infrequent giant axuns with neurofilament accumulations. The authors raised the question of whether one was dealing with a new disorder or
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FIGURE 5. CT scan of the lower legs of the propositus of family 2, revealing a decrease in attenuation of the medial head of the gastrocnemius muscle (GCmh), especially on the right side. In addition, a decrease in attenuation of the tibialis anterior (TA), toe extensors (E), and peroneal muscles (P) on both sides is observed.
FIGURE 6. (A) One micrometer semithin transverse section of epon-embeddedmaterial of the sural nerve of the propositus of family 2. Bar = 10 pm. Myelin sheaths are thin. There are a few small clusters of myelinated axons. One axon (arrow) is enlarged in diameter. (6) Electronmicrographof enlarged axon. Bar = 100 nm. The myelin sheath is thin. Membraneous structures are accumulated in the axon. Neurofilaments are present in a shallow zone immediately beneath the myelin sheath (asterisk).
44
Calf Enlargement in HMSN
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rather with a new finding in the neuronal type of HMSN. A conspicuous feature that appears to be atypical for HMSN is the enlargement of the calf muscles in several affected members of both families. A CT scan of the lower legs of the patient with the hypertrophic type of HMSN showed an increase in size of the medial head of the gastrocnemius muscles. Whether the enlargement is solely due to muscle hypertrophy or also caused by an increase in connective tissue is not elucidated since a muscle biopsy was not performed. The CT scan of the propositus of the family with the neuronal type of HMSN revealed that the right medial head of the gastrocnemius muscle was diffusely infiltrated by fat, whereas the left medial head showed fewer density changes. Muscle enlargement is rare in neurogenic disorders but has been reported in some patients with spinal muscular atrophies, 1,4,15221 radiculo athies,2+’2-14,16,19 and peripheral neuro athies 1,17,18 and in postpoliomyelitis patients. This phenomenon is termed “denervation hypertrophy,” caused by work hypertrophy andlor “stretch” hypertrophy.2 There are only three reports on patients with muscle hy ertrophy and n e u r ~ p a t h y . ” ~ ’ ~Korczyn ,’~ et al.“ described a patient with distal muscle weakness and atrophy, hypertrophy of the thenar and hypothenar mus-
P
8;
cles and the calves, sustained spasms, and thickened nerves. Electrophysiological studies and sural nerve biopsy examination showed demyelinating peripheral neuropathy. An unusual histological feature was the occurrence of large vacuoles within Schwann cells. Valenstein et al.” reported on a patient with chronic recurrent demyelinating polyneuropathy showing distal muscle weakness, hypertrophy of the thenar muscles and the right calf, myokymia caused by continuous motor unit activity (CMUA), and prolonged contraction in response to muscle percussion. Since the propositus’ half-brother was also found to have distal weakness and decreased MNCVs, the possibility of an unusual form of familial demyelinating neuropathy was considered. Another patient with CMUA, muscle hypertrophy, and peripheral neuropathy has been described by Vasilescu et a1.I8 Histopathological and electrophysiological findings revealed a mixed process of axonal degeneration with secondary demyelination and remyelination. It was presumed that the patient had the neuronal form of HMSN, since a maternal aunt was said to have a similar clinical picture. However, the authors do not mention the presence of muscle hypertrophy in the latter. The present report clearly demonstrates that calf enlargement may be encountered in both types of HMSN.
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cramps and fasciculations after poliomyelitis or myelitis. Ann Neurol. 1982;11:423-427. 9. Harding AE, Thomas PK: The clinical features of hereditary motor and sensory ncuropathy types I and 11. Bruin. 1980;103:259- 280. 10. Joosten EMG: De syndromen van Charcot-Marie-Tooth en van Dejerine-Sottas. Thesis, Krips Repro Meppel, 1982, p 169. 11. Korczyn AD, Kuritsky A, Sandbank V: Muscle hypcrtrophy with neuropathy.J Neurol Sci. 1978;36:399-408. 12. Lapresle J, Fardeau M, Said G: L’hypertrophie musculaire vraie secondaire a une atteinte nerveuse peripherique. Reu Neurol 1973; 128: 153- 160. 13. Mielkc U, Ricker K, Emser W, Boxler K: Unilateral calf enlargement following S 1 radiculopathy. Muscle Nerve. 1982;5:434-438. 14. Montagna P, Martinclli P, Rasi F, Cirignotta F, Govoni E, Lugaresi E: Muscular hypertrophy after chronic radiculopathy. Arch Neurol. 1984;41:397-398. 15. Pearn J, Hudgson P: Anterior horn cell degeneration and gross calf hypertrophy with adolescent onset. Lancet 1978;l: 1059- 1061. 16. Ricker K, Rohkamm R, Moxley R T 111: Hypertrophy of the calf with S-1 radiculopathy. Arch Neurol. 1988;45:660664. 17. Valenstein E, Watson RT, Parker JL: Myokymia, muscle hypertrophy and percussion “myotonia” in chronic recurrent polyneuropathy. Neurology. 1978;28:1130- 1134.
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18. Vqsilescu C, Alexianu M, Dau A: Neuronal type of Charcot-Marie-Tooth disease with a syndrome of continuous motor unit activity.J Neural Sci. 1984;63: 11-25. 19. Visser M de, Verbeeten B Jr, Lyppens KCH: Pseudohypertrophy of the calf following S 1 radiulopathy. Neurorudzology. 1986;28:279-280. 20. Vogel P, Gabriel M, Goebel HH, Dyck PJ: Hereditary mo-
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tor sensory neuropathy type I1 with neurofilament accumulation: new finding or new disorder? Ann Neural 1985; 17:445-461. 21. Yamada M, Kano M, Chida K, Furukawa T, Tsukagoshi H: Asymptomatic benign familial spinal muscular atrophy with hypertrophy of the calves and high creatine kinase levels. J Neural Neurosurg Psychiatry. 1988;51:452-453.
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