- Email: [email protected]
RENAL HYPOPHOSPHATAEMIA HAS SEVERAL MENDELIAN FORMS
918 cases and the results (4 positive, 6 negative) agreed with the histological findings. The results yet again show correlation between C pylori infection and histological chronic gastritis. The population of obese patients we studied can be considered a control population for C pylori infection, and like Langenberg et at,4 we found a high percentage of C pylori positive patients, all with abnormal histology, in such an asymptomatic group. Although our surgery was different from that of Lee et al,l we found no evidence to suggest that gastric manipulation (via vertical banded gastroplasty) or simple endoscopic examination was responsible for dissemination of C pylori or a change in its natural history.
Departments of Pathology, Gastroenterology, and Surgery, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex HA1 3UJ
J-F. FLEJOU A. B. PRICE A. C. SMITH E. R. T. C. OWEN
A, Carrick J, Borody TJ Campylobacter pyloridis Infection as possible complication of weight loss therapy. Lancet 1986; ii: 1343 2. Burnett JA, Brown IL, Findlay J. Cresyl fast violet staining method for Campylobacter like organisms. J Clin Pathol 1987; 40: 353 3 Whitehead R. Mucosal biopsy of the gastrointestinal tract. 2nd ed. Philadelphia: Saunders, 1985. 33-58. 4. Langenberg M-L, Tytgat GNJ, Schipper MEI, Rietra PJGM, Zanen HC. Campylobacter-like organisms in the stomach of patients and healthy individuals. 1. Lee
Lancet
1984; i: 1348.
RENAL HYPOPHOSPHATAEMIA HAS SEVERAL MENDELIAN FORMS
SiR,-Several mendelian forms of hypophosphataemia are associated with a primary impairment of renal phosphate reabsorption. The most recent to attract notice is hereditary hypophosphataemic rickets with hypercalciuria (HHRH);’ an autosomal phenotype (McKusick catalogue MIM 24153). Affected patients have the homozygous phenotype; heterozygotes have a form of idiopathic hypercalciuria with slightly abnormal values for
age-dependent serum inorganic phosphorus (low), TmP/GFR (low), urine calcium/creatinine (mg/mg) ratio (high), and plasma
1 a,25(OH)ZD (high). There is another autosomal form of hypophosphataemia inherited hypophosphataemic bone disease [HBD]; MIM 14635). Howard Rasmussen and Harriet S. Tenenhouse (personal communication) speculate that HBD might be the heterozygous form of HHRH. We give evidence here against that proposal. In untreated HBD, the plasma lst,25(OH)D is not raised,3 nor is the urine calcium value (calcium/creatinine ratio 0’01-0-28, n=12 in 5 probands, normal value below 030;
(dominantly
unpublished data). The number of genes coding for renal phosphate transport or components thereof, made manifest by variant phenotypes is now much larger than was once suspected. Besides the aforementioned variants, there are other mutations associated with their own particular phenotypes. These mutations may be alleles at recognised loci, or they may indicate additional loci. Disorders such as autosomal dominant vitamin-D-resistant rickets (MIM 19310) and autosomal recessive vitamin-D-resistant rickets’ may represent alleles at HHRH and HBD loci or they may indicate other autosomal genes controlling renal phosphate transport. Two X-linked loci determine renal phosphate transport in mammals. X-linked hypophosphataemia in man (MIM 30780) has a mouse counterpart in which the mutation maps to the Hyp locus. A second locus on the mouse X-chromosome (Gy) (MIM 30781) has recently been identified and it appears to have a human
systems,
counterparts The mendelian hypophosphataemias constitute the best evidence for heterogeneity of renal phosphate transport systems; physiological evidence6 corroborates the genetic evidence. However, the latter does not yet reveal how autosomal and X-linked gene products are distributed in the nephron nor why some forms of mendelian hypophosphataemia are associated with an adaptive increase in vitamin D hormone synthesis and others are not.1 Characterisation of genetic hypophosphataemias is not an
esoteric exercise since it influences associated disease. deBelle Laboratory for Biochemical Genetics, Montreal Children’s Hospital, Montreal, Quebec H3H 1P3, Canada
diagnosis and treatment of the CHARLES R. SCRIVER THERESA M. READE
M, Modai D, Samuel R, et al. Hereditary hypophosphatemic rickets with hypercalciuria N Engl J Med 1985, 312: 611-17. 2. Tieder M, Modai D, Shaked U, et al. "Idiopathic" hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med 1987; 316: 125-29. 3. Scnver CR, Reade TM, Deluca HF, Hamstra AJ. Serum 1,25-dihydroxyvitamin D levels m normal subjects and m patients with hereditary nckets or bone disease. N Engl J Med 1978; 299: 976-79. 4. Stamp TCB, Baker LRI. Recessive hypophosphataemic rickets, and possible aetiology of the vitamin D-resistant syndrome. Arch Dis Child 1976; 51: 360-65. 1. Tieder
CR, Rishikof E. Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse. Am J Med Genet (in press) 6. Gmaj P, Murer H. Cellular mechanisms of inorganic transport in kidney. Physiol Rev 1986; 66: 36-70. 5. Boneh A, Reade TM, Scriver
PATHOPHYSIOLOGY OF MYALGIC ENCEPHALITIS and
colleagues (Aug 8, p 328) report morphology in patients with myalgic encephalomyelitis (ME). Although the electron microscopic SiR,—Dr Mukherjee
abnormal red-blood-cell
demonstration of deformation of red-blood-cell membranes in two of seven cases of myalgic encephalomyelitis is interesting, we question the significance in such a small number of patients. It would be interesting to know if the aetiology of these patients’ postviral syndrome was different from that of patients who did not have this deformation, and if other peripheral blood cells had a similar membrane deformation. If the red-blood-cell abnormalities demonstrated by Mukherjee and colleagues are significant, this may represent a generalised membrane abnormality in patients with this disease. Postexercise fatigue is the major symptom of patients with ME. The pathophysiological basis of this fatigue is unclear. Muscle enzymes and standard electromyography are usually normal, and muscle biopsies have not revealed specific pathological changes. Jamal et all reported abnormal single fibre electromyography in 30 of 40 patients with a postviral syndrome. These patients had increased jitter without impulse blocking. This pattern of electrophysiological abnormality is also seen in patients with acute viral illness, even when they do not have associated myalgias, but is not seen in normal adults.3 The finding of increased jitter without impulse blocking is consistent with disturbed muscle-fibre conduction. Nuclear magnetic resonance (NMR) techniques have demonstrated excessive early intracellular acidosis in the exercised muscles of a patient with ME.’ Such acidosis may result from ultrastructural damage to the muscle-fibre membrane, causing impaired acid extrusion from the cell. These observations, and those of Mukherjee et al, indicate that membrane abnormalities may be important in the pathogenesis of ME. The symptoms of patients with ME are similar to side-effects in patients treated with intravenous lymphokines, such as interferon. These side-effects are believed to be due to the lymphokine itself, rather than impurities in the preparation or the underlying disease state.5 Such inflammatory mediators may be responsible for most symptoms of patients with viral and other infections, and may therefore be responsible for the muscular and neuropsychiatric manifestations of ME. Low-grade persistent intracellular infection with Epstein-Barr virus (EBV) or other microorganisms may elicit a lymphokine response by activated immune cells (T cells and macrophages), with interferon or other factors such as tumour necrosis factor (TNF) being episodically or continuously released. (t is possible that in ME the local cell-mediated immune response to intracellular pathogens in muscle and neural cells may elicit ncreased local interferon activity without producing a detectable :hange in circulating interferon levels. Increased levels of (2-5)Oligo-adenylate synthetase, a cellular enzyme specifically induced ?y interferon, have been demonstrated in patients with chronic BV infection.6,7 Such a local lymphokine response could be :orrelated with the reported electrophysiological and NMR tbnormalities. Lymphokines such as TNF have been shown to nduce alterations to skeletal muscle-cell membrane potentials8 and
Departments of Pathology, Gastroenterology, and Surgery, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex HA1 3UJ
J-F. FLEJOU A. B. PRICE A. C. SMITH E. R. T. C. OWEN
A, Carrick J, Borody TJ Campylobacter pyloridis Infection as possible complication of weight loss therapy. Lancet 1986; ii: 1343 2. Burnett JA, Brown IL, Findlay J. Cresyl fast violet staining method for Campylobacter like organisms. J Clin Pathol 1987; 40: 353 3 Whitehead R. Mucosal biopsy of the gastrointestinal tract. 2nd ed. Philadelphia: Saunders, 1985. 33-58. 4. Langenberg M-L, Tytgat GNJ, Schipper MEI, Rietra PJGM, Zanen HC. Campylobacter-like organisms in the stomach of patients and healthy individuals. 1. Lee
Lancet
1984; i: 1348.
RENAL HYPOPHOSPHATAEMIA HAS SEVERAL MENDELIAN FORMS
SiR,-Several mendelian forms of hypophosphataemia are associated with a primary impairment of renal phosphate reabsorption. The most recent to attract notice is hereditary hypophosphataemic rickets with hypercalciuria (HHRH);’ an autosomal phenotype (McKusick catalogue MIM 24153). Affected patients have the homozygous phenotype; heterozygotes have a form of idiopathic hypercalciuria with slightly abnormal values for
age-dependent serum inorganic phosphorus (low), TmP/GFR (low), urine calcium/creatinine (mg/mg) ratio (high), and plasma
1 a,25(OH)ZD (high). There is another autosomal form of hypophosphataemia inherited hypophosphataemic bone disease [HBD]; MIM 14635). Howard Rasmussen and Harriet S. Tenenhouse (personal communication) speculate that HBD might be the heterozygous form of HHRH. We give evidence here against that proposal. In untreated HBD, the plasma lst,25(OH)D is not raised,3 nor is the urine calcium value (calcium/creatinine ratio 0’01-0-28, n=12 in 5 probands, normal value below 030;
(dominantly
unpublished data). The number of genes coding for renal phosphate transport or components thereof, made manifest by variant phenotypes is now much larger than was once suspected. Besides the aforementioned variants, there are other mutations associated with their own particular phenotypes. These mutations may be alleles at recognised loci, or they may indicate additional loci. Disorders such as autosomal dominant vitamin-D-resistant rickets (MIM 19310) and autosomal recessive vitamin-D-resistant rickets’ may represent alleles at HHRH and HBD loci or they may indicate other autosomal genes controlling renal phosphate transport. Two X-linked loci determine renal phosphate transport in mammals. X-linked hypophosphataemia in man (MIM 30780) has a mouse counterpart in which the mutation maps to the Hyp locus. A second locus on the mouse X-chromosome (Gy) (MIM 30781) has recently been identified and it appears to have a human
systems,
counterparts The mendelian hypophosphataemias constitute the best evidence for heterogeneity of renal phosphate transport systems; physiological evidence6 corroborates the genetic evidence. However, the latter does not yet reveal how autosomal and X-linked gene products are distributed in the nephron nor why some forms of mendelian hypophosphataemia are associated with an adaptive increase in vitamin D hormone synthesis and others are not.1 Characterisation of genetic hypophosphataemias is not an
esoteric exercise since it influences associated disease. deBelle Laboratory for Biochemical Genetics, Montreal Children’s Hospital, Montreal, Quebec H3H 1P3, Canada
diagnosis and treatment of the CHARLES R. SCRIVER THERESA M. READE
M, Modai D, Samuel R, et al. Hereditary hypophosphatemic rickets with hypercalciuria N Engl J Med 1985, 312: 611-17. 2. Tieder M, Modai D, Shaked U, et al. "Idiopathic" hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med 1987; 316: 125-29. 3. Scnver CR, Reade TM, Deluca HF, Hamstra AJ. Serum 1,25-dihydroxyvitamin D levels m normal subjects and m patients with hereditary nckets or bone disease. N Engl J Med 1978; 299: 976-79. 4. Stamp TCB, Baker LRI. Recessive hypophosphataemic rickets, and possible aetiology of the vitamin D-resistant syndrome. Arch Dis Child 1976; 51: 360-65. 1. Tieder
CR, Rishikof E. Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse. Am J Med Genet (in press) 6. Gmaj P, Murer H. Cellular mechanisms of inorganic transport in kidney. Physiol Rev 1986; 66: 36-70. 5. Boneh A, Reade TM, Scriver
PATHOPHYSIOLOGY OF MYALGIC ENCEPHALITIS and
colleagues (Aug 8, p 328) report morphology in patients with myalgic encephalomyelitis (ME). Although the electron microscopic SiR,—Dr Mukherjee
abnormal red-blood-cell
demonstration of deformation of red-blood-cell membranes in two of seven cases of myalgic encephalomyelitis is interesting, we question the significance in such a small number of patients. It would be interesting to know if the aetiology of these patients’ postviral syndrome was different from that of patients who did not have this deformation, and if other peripheral blood cells had a similar membrane deformation. If the red-blood-cell abnormalities demonstrated by Mukherjee and colleagues are significant, this may represent a generalised membrane abnormality in patients with this disease. Postexercise fatigue is the major symptom of patients with ME. The pathophysiological basis of this fatigue is unclear. Muscle enzymes and standard electromyography are usually normal, and muscle biopsies have not revealed specific pathological changes. Jamal et all reported abnormal single fibre electromyography in 30 of 40 patients with a postviral syndrome. These patients had increased jitter without impulse blocking. This pattern of electrophysiological abnormality is also seen in patients with acute viral illness, even when they do not have associated myalgias, but is not seen in normal adults.3 The finding of increased jitter without impulse blocking is consistent with disturbed muscle-fibre conduction. Nuclear magnetic resonance (NMR) techniques have demonstrated excessive early intracellular acidosis in the exercised muscles of a patient with ME.’ Such acidosis may result from ultrastructural damage to the muscle-fibre membrane, causing impaired acid extrusion from the cell. These observations, and those of Mukherjee et al, indicate that membrane abnormalities may be important in the pathogenesis of ME. The symptoms of patients with ME are similar to side-effects in patients treated with intravenous lymphokines, such as interferon. These side-effects are believed to be due to the lymphokine itself, rather than impurities in the preparation or the underlying disease state.5 Such inflammatory mediators may be responsible for most symptoms of patients with viral and other infections, and may therefore be responsible for the muscular and neuropsychiatric manifestations of ME. Low-grade persistent intracellular infection with Epstein-Barr virus (EBV) or other microorganisms may elicit a lymphokine response by activated immune cells (T cells and macrophages), with interferon or other factors such as tumour necrosis factor (TNF) being episodically or continuously released. (t is possible that in ME the local cell-mediated immune response to intracellular pathogens in muscle and neural cells may elicit ncreased local interferon activity without producing a detectable :hange in circulating interferon levels. Increased levels of (2-5)Oligo-adenylate synthetase, a cellular enzyme specifically induced ?y interferon, have been demonstrated in patients with chronic BV infection.6,7 Such a local lymphokine response could be :orrelated with the reported electrophysiological and NMR tbnormalities. Lymphokines such as TNF have been shown to nduce alterations to skeletal muscle-cell membrane potentials8 and