J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry, 1975, 38, 297-304

Myopathy in hypophosphataemic presenting in adult life

G. D. SCHOTT' AND M. R. WILLS From the Departments ofNeurology and Chemical Pathology, The Royal Free Hospital, London

SYNOPSIS Three cases of hypophosphataemic osteomalacia presenting in adult life, in which a myopathy was a prominent presenting feature, are described. In one, a nasopharyngeal haemangioma was also present. Possible mechanisms underlying the myopathy are discussed briefly.

Muscle weakness as a major or even the present- tendon reflexes are characteristically brisk. The ing symptom of metabolic disease has been degree of muscle weakness may be difficult to recognized for many years. Whistler (1645) in the assess because ofcoincidental bone . As well first clearly documented description of as the hypophosphataemia and relative hyper- referred among the Signa Diagnostica of this phosphaturia-that is, high renal phosphate Protected by copyright. disease to the profound weakness that occurs in clearance-investigations typically reveal ele- the limbs and trunk, and similar observations vated activity, radiological were made in the earliest account of osteo- changes of osteomalacia, and in some patients an malacia by the French surgeon Jean Louis Petit excess of glycine on urine amino-acid chromato- (1726). Since then, it has become apparent that graphy. The plasma concentrations are there exists an important group of myopathic consistently normal. In addition to the phos- disorders associated with osteomalacia and phaturia, renal glycosuria has been found in which are due to either a deficiency of D some cases, enabling the tubular defect to be or as a consequence of 'resistance' to its bio- classified as a type II osteomalacia (Dent, 1952). logical effects. In a few instances electromyography has been During the 1950s, a rare form of primary non- performed on affected muscles and myopathic familial osteomalacia presenting in adult life features noted (Smith and Stern, 1969; Dent and characterized by hypophosphataemia and high Stamp, 1971); nerve conduction studies have phosphate clearance was established. The syn- always proved normal. The relationship of drome was defined by Dent and Stamp (1971) tumours to this condition is discussed below, as http://jnnp.bmj.com/ who described in detail nine patients and are aspects of therapy. No familial case has yet reviewed all previously reported cases. The been described, contrasting with the much more essential clinical features of this unusual cause of common dominant, sex-linked, childhood-onset osteomalacia comprise an often prolonged history deficient rickets, in which myopathy of widespread bone , loss of stature from is absent (Williams and Winters, 1972). vertebral collapse, and muscular weakness. The Three adult patients with hypophosphataemic weakness predominantly affects proximal muscles osteomalacia are reported here in which a on October 1, 2021 by guest. and, since bony disorders of the spine and myopathy was the prominent presenting symp- frequently coexist, may markedly affect the tom. In all patients the myopathy responded to trunk and lead to a waddling gait. The muscles appropriate treatment for the osteomalacia. are painless, the limbs usually hypotonic, but the

1 Address for correspondence: Dr G. D. Schott, Department of CASE 1 Neurology, Royal Free Hospital, Pond Street, London, NW3 2QG. (Accepted 4 November 1974.) A 31 year old white woman, born in 1942, presented 297 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from 298 G. D. Schott and M. R. Wills here in May 1974 with a history of intermittent pain sounds and a diminished percussion note inferiorly around the rib cage particularly precipitated by over the left side of the chest. coughing and sneezing, which had developed over the Neurological abnormalities were confined to the preceding seven years. Three years before admission motor system. There was moderate diffuse wasting she had complained of episodes of acute pain in the of the shoulder and upper arm muscles, and moder- metatarsal area of both feet on walking, especially ate wasting ofthe leg muscles particularly proximally, in tight shoes, and of the feet at that sparing those of the feet; the muscles were not time revealed healing fractures of two metatarsal tender. The muscles of the face were normal, but heads. Also at that time she became aware of there was gross weakness of neck movements, muscular weakness, initially causing difficulty in especially flexion. Striking symmetrical weakness of climbing high steps and in manoeuvring her legs all shoulder movements was apparent, and elevation when getting into a car. The weakness of both thighs of the arms was impossible above 45°. There was subsequently progressed, and was associated with moderate weakness of elbow movements, but the intermittent hip and low back pain. She was investi- hands were normal. A similar distribution of pro- gated in another hospital one year before admission found proximal weakness was noted in the legs, with here, when proximal muscle weakness and a waddling sparing of ankle and toe movements. She was unable gait were noted, together with brisk tendon reflexes to turn over in bed, stand unaided, or sit up without and bone tenderness on palpation. An electromyo- much assistance; she could walk only a few yards gram performed at that time was normal, and the using a Zimmer frame. All the tendon reflexes were only significant abnormal investigation found was a very brisk, and the plantar responses were flexor. low renal threshold for glucose. The symptoms were Radiological examination of the skeleton showed considered to be hysterical and she was discharged. generalized, severe loss of with multiple Her weakness, however, became more profound, and fractures of the ribs, hands, and feet, and Looser

she had to pull herself upstairs, a task that became zones in both pubic rami; no tumours were de-Protected by copyright. increasingly difficult with the development of tected, and the lamina dura appeared intact. The proximal weakness in the arms, and for six months chest radiograph showed displacement of the before admission she had been unable to raise her normally orientated heart to the right, and a very arms above her shoulders. She was admitted at that high left hemidiaphragm consistent on radiographic time to a second hospital for investigation, and was screening with congenital eventration of the hemi- again thought to be psychoneurotic and no specific diaphragm. Radiography of the abdomen was therapy was prescribed. She continued to deteriorate, normal, as were an intravenous urogram and barium commenced walking with a Zimmer frame, and was meal and follow-through examinations. admitted to this hospital for further assessment. The fasting plasma calcium ranged from 9.2 to 9.4 On direct questioning, she had noted that her mg/dl, 0.7 to 1.3 mg/dl, and alkaline nails had become brittle, and that she had had a phosphatase 32 to 43 KA units per dl. On a normal tendency to vomit occasionally over the preceding 10 ward diet, 24-hour urinary calcium excretion ranged years. Her weight had fallen by about 13 kg over from 72 to 250 mg and urinary phosphorus 350 to four years, although she had always eaten an ade- 850 mg. Glycosuria was consistently present and was quate and normal diet. Her sister reported that the shown to be of renal origin; a urine amino-acid patient had 'shrunk' over the preceding two years. chromatogram showed an excess of glycine. Urine The patient's family have been in good health, and osmolality was 530 to 629 mOsmol/kg, and a 24- http://jnnp.bmj.com/ there is no consanguinity. hour urine pH was 5.8. Urine culture was sterile. The Examination revealed dry, scaly skin and dry following investigations were normal: blood picture, hair; her finger nails were brittle and cracked, and ESR, , serum folate, vitamin she had mildly carious teeth. There was bone B12, vitamin A, copper and caeruloplasmin, protein tenderness on palpation over the left chest wall, hips bound iodine, creatine phosphokinase and aldolase, and both tibiae. A marked thoracic was total protein, albumin, globulin and protein electro- present. Her skeletal measurements were: crown to phoresis, creatinine clearance, urine urea and electro- pubis 67.5 cm, pubis to heels 87.5 cm, span 85.5 cm, lyte excretion, and glucose and xylose tolerance on October 1, 2021 by guest. giving an estimated height loss of 16 to 20 cm. tests. Blood serological tests for syphilis were nega- Trousseau's and Chvostek's signs were absent, as tive. The plasma electrolytes were normal, although were corneal and Kayser-Fleischer the plasma bicarbonate was at the lower limit of rings, the latter observations being confirmed by slit- normal. An electrocardiogram and electroencephalo- lamp examination. Her apex beat and heart sounds gram were normal. Electromyography with con- were apparent to the right of the midline; the centric needle samplings of the right deltoid, triceps, trachea was central, but there were absent breath vastus medialis, and tibialis anterior muscles J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from Myopathy in hypophosphataemic osteomalacia presenting in adult life 299 demonstrated at all sites a proportion of brief, poly- the plantar responses were unobtainable because of phasic and low amplitude motor units consistent previous arthroplasty operations on both halluces. with a myopathy. A biopsy of the left triceps muscle Sensory examination was normal. showed randomly scattered, rather small angulated fibres, with evidence of non-specific fibre atrophy on INVESTIGATIONS Full blood picture, erythrocyte electron microscopy; histochemical examination sedimentation rate, plasma electrolytes, urea, revealed atrophy of type IIB fibres. phosphocreatine kinase, glutamic-oxaloacetic trans- In view of the investigations, which confirmed a aminase, and latex test for rheumatoid arthritis were myopathy associated with osteomalacia, the diagno- all normal; the blood Wassermann reaction was sis was made of adult presenting primary hypo- negative. Electromyography showed no abnormality. phosphataemic osteomalacia. She was also seen at A biopsy of the left triceps muscle showed some that time by Professor C. E. Dent who confirmed the variation of fibre diameter, and many fibres demon- diagnosis, and she was subsequently started on treat- strated an increase in subsarcolemmal nuclei, but ment with vitamin D2, 5 mg daily, disodium hydrogen there were no pathognomic features; histochemical phosphate, 10 g daily, and calcium supplements as stains, however, revealed type II fibre atrophy, con- bone meal, 8 g daily, together with physiotherapy. sistent with a myopathy. Radiographs of chest and Within a month the weakness had started to im- spine were normal, but skull films and subsequent prove: she was able to raise her arms above her head tomography showed opacification of the left frontal, and walk with less difficulty. Her also ethmoid, and maxillary sinuses and of the left nasal lessened considerably. Within a few months she was cavity. The walls of the ethmoid sinuses were not walking unaided and able to look after herself at visible and those of the maxillary sinuses were thin. A home. rounded filling defect protruding from the choanae into the nasopharynx was also visible. This defect was found to be due to a pedunculated growth of Protected by copyright. CASE 2 which as much as possible was removed surgically, A 56 year old woman, born in 1918, first developed although some polypoid material undoubtedly re- stiffness and heaviness in both legs at the age of 48 mained. The tumour proved histologically to be a years. Initially the weakness affected her when climb- haemangioma without evidence of malignancy. ing stairs or rising from a chair, but shortly after- She was readmitted in 1971 for further assessment. wards she became aware of weakness when raising Despite a course of steroids, over the intervening her arms above her head and a tendency for them to two years her weakness had not altered significantly; tire easily with prolonged use. At that time she was she required assistance to walk even a few steps and referred on two separate occasions to psychiatrists, spent most of her time in a wheelchair. Considerable since her condition was thought to be hysterical in proximal weakness was present in the arms as before. origin. The weakness gradually increased in severity However, she had also noted an increasing bony causing progressive difficulty in walking, and she was deformity with a depression of the upper end of the virtually confined to a wheelchair by the age of 50 sternum, and increasing bone pain over the chest years. She was admitted in 1969 to the National wall on coughing or sneezing. Since commencing Hospital, Queen Square. During the months before steroids, she had developed a dry, scaly erythema

her admission she had in addition developed inter- and tendency to bruise easily. On this admission, she http://jnnp.bmj.com/ mittent deep cramp and tenderness in the legs related was noted to have developed an appearance resemb- to movement, and this was followed by the develop- ling Cushing's syndrome, with the skin and skeletal ment ofthoracic and lumbar pain on bending quickly, deformities of which she had complained. The coughing, or sneezing. She had also complained of neurological signs were similar to those noted on her nasal obstruction of some months' duration with earlier admission. Investigations at that time added occasional purulent discharge from the left nostril. the following information: serum calcium 9.9 mg/dl, There was no significant family history. serum phosphorus 1.3 mg/dl, alkaline phosphatase

Examination in 1969 revealed slight bilateral 187 i.u./l; her serum phosphocreatine kinase re- on October 1, 2021 by guest. wasting of deltoid and quadriceps muscles and early mained normal. Radiological examination of the contractures of the hamstrings. There was weakness chest, cervical and thoracic spine, pelvis, hips, and of neck flexion and generalized but mainly proximal knees showed widespread bone rarefaction with weakness in the upper and lower limbs, but pain numerous pathological fractures. Looser zones were made accurate assessment of muscle strength diffi- present in the scapulae and right pubic ramus. cult. Weakness of a similar distribution was found in Electromyography performed on the right deltoid, the lower limbs which again was accompanied by biceps, triceps, and vastus medialis muscles showed considerable pain. Tendon reflexes were brisk, and in all muscles a large proportion of low amplitude J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from 300 G. D. Schott and M. R. Wills

motor unit action potentials of short duration; no , or of consanguinity. She had always spontaneous activity was seen, and there was no eaten a normal diet. excess of polyphasic potentials; a few motor unit On examination, there was a thoracolumbar potentials were above the normal amplitude at 6 mV. , wasting of the shoulder girdle The possibility of a myopathy in association with musculature, especially of both deltoids, with weak- osteomalacia was considered, and the patient re- ness of abduction at the hips. The tendon reflexes ferred to Professor C. E. Dent at University College were noted to be brisk, and the plantar responses Hospital. flexor. Sensory examination was normal. She was admitted under the care of Professor Dent Electromyography at that time was performed on in August 1971 for assessment of her metabolic state. the right supraspinatus, deltoid, triceps and biceps Additional findings were of tender ribs on palpation muscles, and the left deltoid muscle, and was re- and body proportions of: crown to pubis 66 cm, ported as normal. However, radiological assessment pubis to heel 76 cm on the right and 74 cm on the demonstrated widespread demineralization, Looser left, span 152 cm (confirming a height loss of 9 to 11 zones in both pubic rami and medial aspect of the cm). Trousseau's and Chvostek's signs were nega- right femur, and a diagnosis of osteomalacia was tive. Investigations confirmed the reduced plasma made. Further investigation revealed low serum phosphorus values and elevated alkaline phosphatase phosphorus values (1.5 to 2.4 mg/dl) in the presence activity, and showed in addition increased urinary of a normal urine phosphorus excretion (680 to glycine excretion and a 24-hour urinary excretion of 1 280 mg/day) and elevated alkaline phosphatase phosphorus of 252 mg and calcium 133 mg. A bone activity (21 to 48 KA units per dl). The plasma biopsy showed characteristic changes of osteo- calcium values were consistently normal. A blood malacia. count, erythrocyte sedimentation rate, plasma electro- lytes, urea, proteins, and liver function tests, and a The features of this case were Protected by copyright. considered to be barium meal and intravenous urogram were all consistent with adult presenting hypophosphataemic normal. No Bence osteomalacia, and she was treated with Jones proteins were found in the daily doses of urine and a urinary amino-acid chromatogram vitamin D3 5 mg, disodium hydrogen phosphate demonstrated 10 g, and bone meal (Ossopan) 8 g. Thereafter she normal amino-acid excretion. Glyco- made slow but steady progress, with relief both from suria was absent. bone pain and muscle A diagnosis of osteomalacia of unknown cause weakness. By the end of five was made and weeks, she was able to walk again with two sticks. treatment commenced with a high She has calcium diet, , and 50000 units subsequently been followed up at University vitamin D Within a College Hospital, and over the past three years her daily. month she was feeling vitamin D has been progressively reduced because of considerably better, and was asymptomatic apart impending intoxication, and she is from some minor stiffness in the left leg. This currently receiv- improvement was temporary, however, for within a ing 0.5 mg vitamin D3 daily. Bone meal was dis- few weeks continued after about a year and she has remained she complained of lumbar pain, general- on the same dose of ized muscular weakness, and required the aid of a phosphate. Her symptoms con- stick for walking, but refused further assessment and tinued to lessen, and she is now symptom free. These defaulted from changes have been associated with a return to normal follow-up on many occasions. of her alkaline phosphatase activity and complete In February 1971, she was admitted as an emer- http://jnnp.bmj.com/ healing of her osteomalacia as demonstrated radio- gency after a fall in which she sustained a fracture of logically; her serum phosphorus concentration is the right femoral shaft. Since her previous admission maintained at 1.5-3.0 she had developed widespread bone pain and more mg/dl. diffuse muscular weakness was evident. The fracture failed to unite and required temporary insertion of a CASE 3 pin and plate, a procedure that produced three other fractures nearby resulting from the extreme fri- Born in a 1927, 46 year old woman presented in ability of the bone. Further investigation of her on October 1, 2021 by guest. October 1968 with a nine month history of increasing underlying osteomalacia was undertaken, and the 'curvature of the spine' and several months' additional relevant results were of a normal ability inability to raise her arms above her head. She had to acidify her urine after an acid loading test with also noticed some lower back pain for many years ammonium chloride, normal faecal fat excretion, and and more recently a tendency to limp while walking. normal serum folate and vitamin B12 values. The Apart from a hysterectomy and oophorectomy for plasma calcium, phosphorus, and alkaline phospha- uterine fibroids, her previous health had been good. tase values found previously were confirmed; histo- There was no family history of neuromuscular or logical examination of a bone biopsy obtained from J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from Myopathy in hypophosphataemic osteomalacia presenting in adult life 301 around the fracture site showed the characteristic closely resemble the syndrome. . .'. Vicale's features of osteomalacia. In view of the clinical findings contrast with those of Smith and Stern features, biochemical, radiological, and histo- (1967), who in a retrospective study found logical findings and previous response to therapy, a definite muscle weakness in only six of 91 diagnosis of adult-onset hypophosphataemic osteo- malacia was made. She was started on phosphate patients with primary supplements (3.5 g daily as Phosphate-Sandoz) in (three of whom had osteomalacia), although addition to the (2 g daily of they confirmed the high incidence of weakness in Calcium-Sandoz) and high dose of vitamin D their patients with osteomalacia; similar findings (calciferol 50 000 u daily) she was already receiving. were obtained in their subsequent prospective Within a few weeks of commencing the phosphate study (Smith and Stern, 1969). supplement her fractures began to heal, her bone The weakness which may develop insidiously pain started to improve, and her strength gradually over many years results in severe disability, increased. She has been followed up since this time, although formal testing may not correlate well and has maintained this slow progress, now walking with the symptoms experienced. The apparent with the aid of a stick, remaining free from pain and in appearance and absence of muscle weakness. The plasma calcium, phosphorus, delay frequent and alkaline phosphatase values have remained very florid myopathic changes on electromyography, variable, and appear throughout to be unrelated to despite severe or even gross disability, is of her clinical condition: there has been a tendency for interest. Histological examination revealed little her hypophosphataemia and raised alkaline phospha- of significance in the patients reported here, as tase values to persist, despite continuation of therapy Smith and Stern (1969) found in their cases. The and her satisfactory symptomatic state. histochemical findings consistent with type II fibre atrophy in two of the present patients are Protected by copyright. compatible with a metabolic myopathy, but are of no diagnostic significance (Dubowitz and DISCUSSION Brooke, 1973). In all of the patients with this The aetiology of the hypophosphataemia in syndrome, the phosphocreatine kinase activity these cases of osteomalacia is unknown. Certain has either been normal or minimally elevated, features of the accompanying myopathy, how- and the activity of this enzyme in the plasma ever, pose some questions of relevance with clearly does not correlate with the degree of regard to muscle disease. weakness. There are many reports of myopathy associ- Calcium, phosphorus, and vitamin D may ated with osteomalacia from a variety of causes play an important part in the aetiology of the and these have recently been reviewed (McArdle, muscle weakness. The critical role of calcium in 1974; Pallis and Lewis, 1974). Vicale (1949) muscle function has been known since the studied 33 patients with primary hyperpara- classical experiments of Heilbrunn and Wier- thyroidism and three patients with osteomalacia cinski (1947), who using a micropipette injected associated with , and found calcium-containing Ringer solution into muscle http://jnnp.bmj.com/ muscular weakness affecting 21 patients in the fibres of the frog adductor magnus and observed former group and two in the latter. She also the ensuing contraction. It is recognized that described the salient features that occur in the both intra- and extracellular calcium concentra- myopathy of , and drew tions are of critical importance to muscle cell attention to its proximal distribution, the slow function, particularly contractility (Frank, 1965). waddling gait, the discomfort and pain that The plasma concentrations of calcium (and muscular effort produces, the very active phosphorus) are, however, unlikely to be the on October 1, 2021 by guest. reflexes that occur in the absence of pathological sole factors of importance in the genesis of reflexes, and the bone tenderness on pressure. muscle weakness occurring in several metabolic Vicale also differentiated between a number of bone diseases, a problem discussed by Henson diseases with which this myopathy could be con- (1966). For instance, in the present report there fused, and noted that 'the most difficult diagnos- was little correlation between the myopathy and tic differentiation is undoubtedly from the the plasma phosphorus concentration, and the neurotic muscular disorders which may clinically calcium concentration remained normal through- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from 302 G. D. Schott and M. R. Wills out. This lack of correlation between plasma whether obtained from the diet or by ultra- calcium concentration and the severity of myo- violet irradiation of 7-dehydrocholesterol in the pathy was noted by Prineas et al. (1965) in their skin, is converted to 25-hydroxycholecalciferol report of two myopathic patients, one with a in the liver, and thence in the kidney to di- parathyroid adenoma, osteomalacia, and osteo- hydroxy metabolites, of which 1 ,25-dihydroxy- sclerosis, and the other with osteomalacia is the most biologically active (see associated with idiopathic steatorrhoea. Smith Kodicek, 1974). The concentration and activity and Stern (1967; 1969) were also unable to of the various metaboJites of cholecalciferol establish any relationship between proximal have not been determined in hypophosphataemic myopathy and plasma calcium or phosphorus osteomalacia, but it is tempting to postulate that, values in their reviews of patients with metabolic since impaired renal tubular function, as shown bone diseases from a variety of causes. by the high renal phosphate clearance, appears The role of plasma phosphorus is also un- to be an important factor in this disease, another certain. It is clear that isolated hypophos- renal function-the final conversion of chole- phataemia induced iatrogenically (Baker et al., calciferol to its active di-hydroxy metabolite- 1974), by self-medication (Dent and Winter, could also be impaired. This proposal is sup- 1974) and in normal volunteers (Lotz et al., 1968) ported by the observation that the myopathy may produce muscle weakness together with associated with osteomalacia from renal failure myopathic changes on electromyography (Baker has been shown to improve after administration et al., 1974); the weakness responds rapidly to of small amounts of 1,25-dihydroxycholecalci- phosphate repletion, and in these instances it is ferol (Henderson et al., 1974). It is also pertinent reasonable to assume that the weakness is that in the recessively inherited vitamin D Protected by copyright. attributable to hypophosphataemia. Moreover, resistant rickets, recent findings point to a the myopathy associated with primary hypo- defect in the conversion of 25-hydroxycholecalci- phosphataemic osteomalacia has been success- ferol to 1,25-dihydroxycholecalciferol (Fraser et fully treated with phosphate replacement alone al., 1973) and again a defect in the kidney is (Nagant de Deuxchaisnes and Krane, 1967), likely to be implicated. although Dent and Stamp (1971) found the The action of vitamin D with regard to muscle greatest benefit using a combination of vitamin function remains at present unknown. Large D, phosphate, and calcium supplements. Per- doses of radioactive vitamin D given orally to haps surprisingly, symptomatic improvement in rats have been found to be localized to a zone adult-onset hypophosphataemic osteomalacia underneath the sarcolemma, and appear 'to sit does not appear to correlate with the plasma in or on the muscle membrane' (Kodicek, 1963). phosphorus concentration in the present cases In the present context it is perhaps no coinci- or in others reported. It is also recognized that dence that this vitamin was also located in the myopathy does not occur despite longstanding first third of the proximal renal tubule, where the hypophosphataemia in sex-linked familial hypo- active reabsorption of phosphate is known to http://jnnp.bmj.com/ phosphataemia. occur. The radioactive vitamin D available at It is possible that disordered metabolism of that time required very large doses to be given to vitamin D could play an important part in the enable intracellular localization to be detected. genesis of osteomalacic myopathy. Smith and However, later methods enabled Neville and Stern (1967) found low plasma vitamin D levels DeLuca (1966) to synthesize a biologically in three out of four patients in whom this was active vitamin D compound with high enough measured, but in their subsequent publication specific radioactivity to enable physiological on October 1, 2021 by guest. (1969) a definite correlation between myopathy doses to be given. By such a technique, tissue and low plasma vitamin D activity was not distribution was estimated in a variety of organs demonstrated. More recently, understanding of in rats: although muscle accumulated a high vitamin D metabolism has increased consider- percentage of the dose, the concentration was ably, and with it an appreciation of the number low when estimated as relative incorporation per of possible derangements which might occur. It weight of tissue. They considered, however, that, is apparent that vitamin D3 (cholecalciferol), if corrections for non-cellular elements were J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.38.3.297 on 1 March 1975. Downloaded from Myvopathy in hypophosphataemic osteomalacia presentinig in adult life 303

made, skeletal muscle and bone were the most The three patients reported here also illustrate radioactive. some aspects of more general interest. In the first It has recently been demonstrated that rachitic patient, the disorder had been diagnosed as rabbits have a diminished rate of calcium uptake hysterical and psychoneurotic, probably because by muscle sarcoplasmic reticulum, which is of the lack of abnormality on electromyography, independent of sarcoplasmic reticular magnes- which, as has been discussed, may prove mis- ium- and magnesium-calcium-stimulated adeno- leading. In the second patient, the possibility of sine triphosphatase activity (Curry et al., 1974), polymyositis was entertained, a diagnostic suggesting a link between vitamin D activity and difficulty that was pointed out by Vicale (1949); calcium uptake by muscle sarcoplasmic reticu- in this patient there was also the early mistaken lum. Such a link between vitamin D and calcium impression that the condition was hysterical. In may nevertheless not be an exclusive one. There the third patient, although osteomalacia was is now evidence possibly relevant to hypophos- recognized shortly after the patient had presented phataemic osteomalacia that the level of in- to hospital, her bone lesions and muscle weak- organic phosphorus within the renal tubule cell ness failed to improve until phosphate supple- may underlie the regulation of synthesis of ments were added to her treatment regimen. 1,25-dihydroxycholecalciferol, and both para- The importance of elucidation of the dis- thyroid hormone and calcitonin may exert their order underlying these myopathies need hardly effect via control of the cellular phosphorus be emphasized, since, at least in idiopathic and concentration (Tanaka and DeLuca, 1973). tumour-associated hypophosphataemic osteo- The defect in hypophosphataemic osteo- malacia presenting in adults, recovery with malacic myopathy may, however, be complex, treatment may be anticipated. Protected by copyright. or, alternatively, may comprise several different disorders. In the past few years, a few patients We wish to thank Dr J. Newsom Davis, Dr K. J. Zilkha, with hypophosphataemic osteomalacia associ- and Professor C. E. Dent, FRS, and Dr C. Symons for ated with usually benign skeletal or soft tissue permission to publish accounts of these patients who were tumours have been reported (see Stanbury, under their care. We are greatly indebted to Professor Dent and Dr Newsom Davis for their help with case 1, for 1972; Mankin, 1974). The features are similar to valuable discussion in producing this report, and for help- 'idiopathic' adult-onset cases, but the disease ful comments on the manuscript. Professor P. K. Thomas is generally reversible after the removal of the kindly performed the electrophysiological investigations tumour, suggesting that the tumours might be on case 1, and we are indebted to him and Dr R. H. M. producing an 'anti-vitamin D' substance, King for allowing us to publish the results of the muscle biopsy on this case. We are also particularly grateful to although such a substance has not yet been Dr J. Morgan-Hughes for making available the histo- isolated. In this context, the presence of the chemical findings in cases 1 and 2, and for drawing our nasopharyngeal haemangioma that was demon- attention to the latter case. strated in case 2 is likely to be of considerable significance. Since complete resection of the http://jnnp.bmj.com/ tumour was not feasible at the time, speculation REFERENCES remains whether complete removal would have Baker, L. R. I., Ackrill, P., Cattell, W. R., Stamp, T. C. B., resulted in 'cure' of the and Watson, L. (1974). latrogenic osteomalacia and hypophosphataemic myopathy due to phosphate depletion. British Medical osteomalacia. Naturally, speculation must re- Journal, 3, 150-152. main as to whether patients with 'primary' Curry, 0. B., Basten, J. 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