Benign Neurogenic Amyotrophy in Klinefelter's Syndrome

64060oumnal of Neurology, Neurosurgery, and Psychiaty 1994;57:640-642

SHORT REPORT J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.5.640 on 1 May 1994. Downloaded from

Benign neurogenic amyotrophy in Klinefelter's syndrome

S Matsubara, M Yoshino, M Takamori

Abstract cm height and 43 kg weight. He responded Two cases of benign neurogenic amy- slowly but correctly to our questions on gen- otrophy associated with Klinefelter's eral knowledge. He had a mild degree of syndrome are reported. Both presented gynaecomastia and testicular atrophy. On with slowly progressive, diffuse neuro- neurological examination, the distal and genic muscle atrophy of juvenile onset. proximal limb muscles and trunk and facial Both had a karyotype of XXY. Ampli- muscles were atrophied (fig 1 a). The cranial fication, by the polymerase chain reac- nerves were normal apart from facial weak- tion, of a fragment of androgen receptor ness. Knee jerks were barely elicitable; the that was related to bulbospinal muscular other deep tendon reflexes were absent in all atrophy, showed no abnormality. Treat- four limbs. He had fine hand tremors of 10 ment with androgen in one case provided Hz. The plantar responses were flexor bilater- no benefit. Benign neurogenic amyotro- ally. His sensory system and coordination phy in the Klinefelter's syndrome is were normal. likely to be an independent type of motor Serum creatine kinase was raised to 518 neuron disease and suggests that the X IU/l (normal range for males 55-306 IU/1), chromosome plays an important part in of which 97-9% was MM isoenzyme, the rest the biology ofmotor neurons. MB. An oral glucose tolerance test was normal. EMG of the biceps brachii and other (7 Neurol Neurosurg Psychiatry 1994;57:640-642) muscles showed fibrillations at rest and giant neuromuscular units indicating active neurogenic atrophy. Motor nerve conduction Motor neuron disease is a group of con- velocities of the median, ulnar, tibial, and ditions, including amyotrophic lateral sclero- peroneal nerves were normal as were the

sis, that involve upper and lower motor sensory conduction velocities of the median, http://jnnp.bmj.com/ neurons. Besides studying amyotrophic lat- ulnar and sural nerves. Serum oestrone and eral sclerosis itself, it is important to identify oestradiol concentrations were 23-2 and 24-0 other conditions with motor neuron involve- pg/ml respectively and were both normal. ment, as they may enable us to gain new Serum testosterone concentration was 249 knowledge of the pathophysiology of the ng/dl, slightly lower than the normal range motor neurons. In this paper, two cases of (250-1100 ng/dl). Karyotype analysis benign neurogenic amyotrophy associated revealed the XXY pattern. with Klinefelter's syndrome are reported. He was treated each month with an on September 29, 2021 by guest. Protected copyright. Only one similar case has been described.' intramuscular injection of testosterone enanthate 125 mg for a year, but improve- ment in muscle strength did not occur. Case reports Case 1 A man of 46 had been thin since childhood. At school, he was the slowest at running and Department of never able to lift himself above a horizontal I.. Neurology, Kanazawa .,.j bar in the gymnasium. In his twenties and t. University School of :.a Medicine, Kanazawa, thirties, he was a manual worker and aware X Japan that despite being right handed, his right arm .{ffi S Matsubara M Yoshino was thinner than his left. At the age of 40, the M Takamori weakness of his right arm became worse and CZ t ..1 .'.¢e,.... :.. .- BE Correspondence to: caused him considerable handicap at work. .:. .:|- :: Dr S Matsubara, Then he began to have difficulty in climbing ..E -,....: Department ofNeurology, .R.: 2. o stairs. Weakness of the limbs became aggra- .: Kanazawa University School :. .. of Medicine, 13-1 o. vated in the subsequent years. After exercise : Takaramachi, Kanazawa B: he had painful stiffness of the legs. He . i- City, Ishikawa 920, Japan. __ w Received 23 December 1992 noticed fine tremors in his arms. Other mem- _}i'. and in final revised bers of his had no disease. form 22 June 1993. family neurological Accepted 5 July 1993 On examination, he was a- thin man of 162 Figure I (a) case 1; (b) case 2. J.- X.. ::-. s b ^: :.,:::: Benign neurogenic amyotrophy in Klinefelter's syndrome 641

Case 2 central nuclei. Hypertrophied fibres were fre- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.5.640 on 1 May 1994. Downloaded from A man of 29 had a waddling gait at the age of quent. NADH-TR activity showed fibre type 10. He was mentally retarded to a mild grouping and occasional target fibres. degree. At school, he was unable to run or Additional information was not obtained by jump. Aged 17 he started to fall and often electron microscopy. had cramps in his legs. Atrophy of the leg The sural nerve of case 2 showed no muscles was noted and he had an operation abnormality. The peroneal muscle of case 2 to elongate his left Achilles tendon. The showed occasional small angulated fibres and weakness and atrophy of the leg muscles pro- fibre type grouping, and a predominance of gressed gradually in the next 12 years. Before type 1 fibres (fig 2b). A histogram of fibre he attended our clinic, the neurologists at diameter, examined on sections stained with another hospital had made a diagnosis of myosin ATPase (pH 9 4) revealed atrophied amyotrophic lateral sclerosis. fibres of both types 1 and 2. He was a tall (height 179 cm), thin (weight 58 kg) man with a mild degree of gynaecomastia and testicular atrophy. His tongue was Molecular biological investigations: both not atrophied. The jaw jerk was normal. All cases the leg muscles were atrophied and weak (fig As the present cases had considerable similar- lb). There were no fasciculations. The legs ity with bulbospinal muscular atrophy,2 the were spastic and the knee and ankle jerks androgen receptor CAG repeat on the long brisk. The plantar responses were extensor arm of the X chromosome was amplified by bilaterally. There was no sensory deficit or the polymerase chain reaction.' Normal con- ataxia. On the Wechsler adult intelligence trols and cases 1 and 2 showed products with scale, his performance IQ was 93, verbal IQ a size of 405-450 base pairs, whereas cases 69, and total IQ 79, all in the borderline of bulbospinal muscular atrophy showed range. products of around 500 base pairs. Serum creatine kinase activity, testosterone concentration, and other blood and cere- brospinal fluid tests were normal. His kary- Discussion otype was XXY. The plain radiograph of the Patients with Klinefelter's syndrome are cervical vertebrae showed fusion of the verte- described as having long slender extremities bral bodies C2 and C3 without basilar with poorly developed musculature.' The pre- impression. Myelography followed by CT sent cases had weakness that disturbed their myelography did not show stenosis of the daily lives, clearly exceeding the mere ten- spinal canal or any other abnormality. dency to poor general physique. Klinefelter's The EMG of the anterior and posterior syndrome is associated with various neurolog- tibial muscles showed neuromuscular units of ical disturbances, including mental retarda- high amplitude and long duration indicating tion, epilepsy, and essential tremor. In terms neurogenic processes. Motor and sensory of neurogenic muscular atrophy, however, nerve conduction velocites were normal. only a few cases have been reported and not all of them were fully investigated.

Case 2 of Nielsen' was a man of 65 with http://jnnp.bmj.com/ Histological investigations: both cases diffuse muscle atrophy. The EMG and mus- Muscle biopsies were taken from both cases. cle biopsy showed neurogenic changes. Frozen sections of 8 ,um were cut. They were Jenkins and Ferriman4 described a man of 42 stained with haematoxylin-eosin, Gomori with peroneal muscular atrophy. The nature trichrome, NADH-TR, periodic acid-Schiff of the atrophy was not clear. reaction, and myosin ATPase (pH 4-2, 4-6, The present cases and Nielsen's case 2' and 9 4). Other portions of muscle were had much in common. They had Klinefelter's processed for electron microscopy. A sural syndrome and the karyotype XXY without on September 29, 2021 by guest. Protected copyright. nerve biopsy from case 2 was embedded in any familial stigmata of muscle atrophy. They epoxyresin and examined by light and elec- showed diffuse neurogenic muscular atrophy tron microscopy. that progressed slowly over many years. In the rectus femoris muscle of case 1, There were a few points, however, which dif- there were groups of small angulated fibres fered. Our case 2 had bilateral extensor plan- (fig 2a), which often harboured clusters of tar responses. The absence of cord compression on myelography does not pre- Figure 2 (a) Muscle clude the possibility that the Klippel-Feil biopsy of case 1. The rectus anomaly is responsible for it. Alternatively the femoris muscle showed upper and lower motor neurons may be large groups ofsmall angulatedfibres indicating affected by a common cause. Case 2 of neurogenic muscle atrophy. Nielsen' had a mild degree of sensory impair- HE (bar= 30,um). (b) ment in the legs. Peroneal muscle biopsy of The muscle in case 2. Fibre type grouping biopsies our cases showed with type 1 predominance changes typical of chronic neurogenic muscle was noted along with atrophy.5 They include clusters of small angu- occasional small angulated fibres. Myosin ATPase lated atrophic muscle fibres beside normal or activity (pH 9 4) (bar = often hypertrophic fibres. Fibre type grouping 100pm). may be a sole abnormality in an early stage of neurogenic muscular atrophy. 642 Matsubara, Yoshino, Takamori

Absence of abnormality in the nerve con- family history of motor neuron disease. These J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.57.5.640 on 1 May 1994. Downloaded from duction velocities and nerve biopsy and the points accord with out hypothesis that motor occurrence of brisk tendon reflexes in case 2 neuron disease is related to Klinefelter's are more in keeping with motor neuron syndrome. disease than peripheral neuropathy. Androgens prevent loss of motor neurons Both of our present cases resembled in rats.7 Whether the presence of an extra X bulbospinal muscular atrophy in regard to chromosome or androgen deficiency play a feminisation and neurogenic muscular part in the motor neuron involvement atrophy and case 1 in regard to hand tremors. remains to be elucidated. Bulbar symptoms, which are one of the hall- We are grateful to Dr WGP Mair who encouraged us and marks of bulbospinal muscular atrophy, were, kindly reviewed the English. however, absent. As all 20 Japanese cases of 1 Nielsen J. Klinefelter's syndrome in a neurological ward. bulbospinal muscular atrophy that we have Acta Neurol Scand 1965;41:197-214. 2 Kennedy WR, Alter M, Sung JH. Progressive proximal examined so far showed polymerase chain spinal and bulbar muscular atrophy of late onset. A sex- reaction products of abnormal length (un- linked recessive trait. Neurology 1968;18:671-80. 3 La Spada AR, Wilson EM, Lubahn DB, Harding AE, published data), the present cases are unlikely Fischbeck KH. Androgen receptor gene mutations in X- to have bulbospinal muscular atrophy. linked spinal and bulbar muscular atrophy. Nature 199 1;352:77-9. The clinical features of the present cases 4 Jenkins CO, Ferriman D. Klinefelter's syndrome associ- and the case of Nielsen suggest that the ated with peroneal muscular atrophy. 1Proc R Soc Med 1968;61:86. involvement of motor neurons in Klinefelter's 5 Matsubara S, Tanabe H. A clinico-pathological study of syndrome is a rare condition. It may be a for- chronic hereditary motor neuropathy. Acta Neuropathol (Berl) 1983;61:43-51. tuitous association of Klinefelter's syndrome 6 Harding AE. Inherited neuronal atrophy and degeneration and motor neuron disease. The clinical predominantly of lower motor neurons. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheral course of the present cases resembled that of neuropathy, Vol 2. Philadelphia: WB Saunders, 1984; hereditary motor neuron disease6 rather than 1537-56. 7 Yu W-HA. Sex difference in neuronal loss induced by sporadic amyotrophic lateral sclerosis, which axotomy in the rat brain stem motor nuclei. Exp Neurol is far commoner, yet none of our cases had a 1988;102:230-5. http://jnnp.bmj.com/ on September 29, 2021 by guest. Protected copyright.