Satoyoshi syndrome has antibody against brain and gastrointestinal tissue

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<ul><li><p>CASE OF THE MONTH ABSTRACT: Satoyoshi syndrome is a rare postnatal disorder with musclespasms, alopecia, and diarrhea of unknown etiology. Nutritional deciencyseems to inuence lifespan. We present a patient with this syndrome havinga unique mesh-like mucosal change radiographically and white granulesendoscopically in the gastrointestinal tract. A common antibody againstbrain, stomach, and duodenal tissue, according to Western blot analysis,was detected in the sera of two patients with this syndrome. These ndingssuggest that Satoyoshi syndrome is a systemic autoimmune disease involv-ing the nervous, endocrine, and gastrointestinal systems.</p><p>Muscle Nerve 36: 400403, 2007</p><p>SATOYOSHI SYNDROME HAS ANTIBODY AGAINSTBRAIN AND GASTROINTESTINAL TISSUE</p><p>EIJI MATSUURA, MD, PhD,1 WATARU MATSUYAMA, MD, PhD,2</p><p>TOMOYUKI SAMESHIMA, MD, PhD,3 and KIMIYOSHI ARIMURA, MD, PhD1</p><p>1 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medicaland Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan</p><p>2 Division of Respiratory Medicine, Kagoshima University Hospital, Kagoshima, Japan3 Division of Gastroenterology, Kagoshima University Hospital, Sakuragaoka, Kagoshima, Japan</p><p>Accepted 1 February 2007</p><p>Satoyoshi syndrome is a rare postnatal disorder ofunknown etiology characterized by progressive,painful, and intermittent muscle spasms of the wholebody, and by alopecia and diarrhea.13,14 Malabsorp-tion, amenorrhea, and skeletal abnormalities arealso frequent.5,8 Satoyoshi and Yamada rst reportedthis disorder in Japan in 1967,14 and it was calledgeneralized komuragaeri disease (komura,meaning calf, and gaeri, meaning spasm). To ourknowledge, 52 cases, including the present case,have been reported worldwide. In most cases, thedisease starts in the rst or second decade of life.The mean age of onset is 10.6 years (range, 436years). Patients are usually small in stature fromnutritional deciency and have a shorter lifespanattributed to this deciency. Satoyoshi syndrome isknown to occur in association with autoimmune dis-eases such as myasthenia gravis,12 idiopathic throm-bocytopenia,15 or nephritis. The dramatic effect ofimmunotherapy with glucocorticoids,3,10,11,15 intrave-nous immunoglobulins,2 and tacrolimus7 on musclespasms, alopecia, and gastrointestinal symptoms sug-</p><p>gests that Satoyoshi syndrome is an autoimmunedisease.</p><p>Although the gastrointestinal problem is a majordeterminant of outcome, this aspect has not beenthe subject of detailed study. We present a patientwith Satoyoshi syndrome in whom gastrointestinalimaging studies and duodenal biopsy disclosed ab-normalities unique to this syndrome.</p><p>CASE REPORT</p><p>A 17-year-old Japanese woman was admitted for di-agnostic evaluation of painful intermittent musclespasms, alopecia, diarrhea, and short stature. Shewas born to healthy, non-consanguineous parents.Family and prenatal histories were unremarkable. Atthe age of 2 years, she developed atopic dermatitisfollowed by bronchial asthma a few years later. Hergrowth and psychomotor development were normaluntil the age of 8 years, when she was diagnosed withpituitary dwarsm. Although she received growthhormone (GH) supplementation therapy, it was noteffective. At the age of 10 years, she noted progres-sive loss of eyebrows and scalp hair and painfulinvoluntary muscle contractions of the extremities.Within a year she had completely lost her eyebrowsand scalp hair. Since the age of 15 years she has hadrecurrent diarrhea and abdominal spasms. Thespasms became increasingly severe and spreadthroughout her body, which caused her to moveslowly to avoid precipitating cramps.</p><p>Abbreviations: EMG, electromyography; GH, growth hormone; SDS-PAGE, sodium dodecylsulfatepolyacrylamide gel electrophoresisKey words: alopecia; antibody; autoimmune disease; diarrhea; musclecramp; Satoyoshi syndromeCorrespondence to: K. Arimura; e-mail:</p><p> 2007 Wiley Periodicals, Inc.Published online 2 April 2007 in Wiley InterScience ( DOI 10.1002/mus.20773</p><p>400 Satoyoshi Syndrome MUSCLE &amp; NERVE September 2007</p></li><li><p>Physical examination revealed a girl of short stat-ure with a height of 128 cm and weight of 24 kg(weight appropriate for height). Other characteris-tics were as follows: body mass index, 14.6; bloodpressure, 95/58 mm Hg; pulse, regular at 72 beatsper minute; and body temperature, 36.2C. Hermental status was normal. Muscle spasms were notaccompanied by myokymia and fasciculations. Wedid not nd any other neurological abnormality. Shehad not begun to have menstrual periods or to de-velop secondary sexual characteristics. Bowel soundswere slightly hyperactive. She had clubbed ngers.Urination occurred ve or six times daily, and bowelmovement occurred four to seven times daily.</p><p>Pertinent laboratory ndings were as follows: he-moglobin, 8.5 g/dl; platelet count, 400,000/l; totalprotein, 5.2 g/dl (normal, 6.78.3); total choles-terol, 98 (128219) mg/dl; triglyceride, 79 (30149)mg/dl; potassium, 3.0 (3.64.9) mEq/L; Na and Cl,normal; iron, 10 (40158) g/dl; ferritin, 1 (1.0124.7) ng/ml; copper, 72 (80130) g/dl; calcium,5.7 (8.710.3) mg/dl; magnesium, 0.6 (1.72.6) mg/dl; zinc, 39 (59135) mg/dl; fasting blood sugar, 88mg/dl; vitamin A, 366 (4311041) ng/ml; vitamin E,0.43 (0.751.41) mg/dl; 1-25-vitamin D, 85 (2060) pg/ml; and creatine kinase, 454 (45163) U/L.Serum free T3 and T4, thyroid-stimulating hormone,follicle-stimulating hormone, luteinizing hormone,estradiol, cortisol, immunoglobulin (Ig)M, IgG, IgA,total complement activity, and C3 and C4 were nor-mal. Serum IgE was elevated at 2387 (3304) U/ml.Anti-RNP, anti-Sm, antiSS-A, antiSS-B, and rheu-matoid factor were negative. Acetylcholine receptorantibody was negative. d-Xylose absorption test was1.0 g (4.18.2 g) per 5 hours. Serum lactate was notelevated. All abnormal ndings were thought to becaused by malabsorption due to severe diarrhea.Nerve conduction studies of median, ulnar, tibial,peroneal, and sural nerve were normal. Needle elec-tromyography (EMG) of anterior tibial, bicepsbrachii, rst dorsal interossei, rectus femoris, andparaspinal (10th thoracic level) muscles showed noabnormality.</p><p>Radiographic Study of Intestine. A double-contrastbarium study of the duodenum revealed mild lumi-nal dilation and decrease of Kerckrings folds. Finegranular changes were observed in the upper part ofthe second portion of the duodenum and relativelylarge, granular, mesh-like mucosal changes werepresent in the lower part of the second and thirdportions. Unclear contour and occulation of bar-ium, suggesting malabsorption syndrome, were also</p><p>observed. These radiographic changes were attrib-uted to chronic inammatory damage (Fig. 1A, B).</p><p>Endoscopic Study of Upper Gastrointestinal Tract. Al-most the entire mucosa of the stomach was atrophic,and multiple ulcer scars were observed, mainly in thebody. Small white granules, speculated to be a typeof secretion, were observed from the rst to thesecond portion of the duodenum (Fig. 1C). Histo-pathology of the rst portion of the duodenumshowed mucosal inltration with inammatory cells(Fig. 1D). Helicobacter pylori was not present.</p><p>Western Blot. To determine whether antibodyagainst tissues other than brain were present in thepatients serum, we purchased human brain, spinalcord, stomach, duodenum, and uterine tissue lysates(Clontech, Mountain View, California) and per-formed Western blot analysis. Lysates were analyzedon 10% polyacrylamide gels by sodium dodecyl-sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) and transferred electrophoretically to nitro-cellulose membranes at 150 mA for 1 h. Themembranes were incubated with the patients serumand 10 control sera (normal controls and patientswith cerebrovascular dementia, essential tremor,hemifacial spasm, diabetic neuropathy, and head-ache), followed by sheep anti-human IgG coupledwith horseradish peroxidase (Amersham PharmaciaBiotech, Piscataway, New Jersey). Peroxidase activitywas visualized using an enhanced chemilumines-cence detection system (Amersham Pharmacia Bio-tech).</p><p>After incubation with control sera, no band wasdetected for human brain, spinal cord, stomach,duodenum, or uterine tissue lysates. In contrast, in-cubation with the patients serum showed a band atthe 90-kDa position for brain, stomach, and duode-num tissue lysates (Fig. 2) but not for spinal cordand uterine tissue lysates. We also examined theserum of another patient with typical Satoyoshi syn-drome at our hospital (a 36-year-old woman withgeneralized painful muscle cramps, primary amen-orrhea, alopecia, and diarrhea). Serum from thispatient also reacted against a 90-kDa protein in thesame tissue lysates as in the rst patient (Fig. 2).</p><p>DISCUSSION</p><p>Our study revealed abnormalities of the gastrointes-tinal tract that are not found in other neurologicaldiseases with muscle spasm such as stiff-person syn-drome or Issacs syndrome.1 The double-contrastbarium study revealed a decrease of the circular</p><p>Satoyoshi Syndrome MUSCLE &amp; NERVE September 2007 401</p></li><li><p>folds, mild luminal dilation, and relatively largegranular, mesh-like mucosal changes, which havenot previously been reported in Satoyoshi syndrome</p><p>or in other inammatory bowel diseases. Endoscopicstudy also revealed disseminated white granules inthe duodenum and diffuse mucosal atrophy as well</p><p>FIGURE 1. Radiographic and endoscopic ndings. (A, B) Fine granular change in the upper part of the second portion of the duodenumand relatively large, granular, mesh-like mucosal change (arrow) in the lower part of the second portion. (C) Small white granules wereobserved at the duodenal bulb. (D) Histopathological ndings of the rst portion of the duodenum show invasion of inammatory cells inthe mucosal layer.</p><p>FIGURE 2. Western blot. After incubation with patients sera, a band was detected at the 90-kDa position for human brain, humanstomach, and human duodenum lysates. The band was not detected for human uterus and human spinal cord lysates. No band wasdetected after incubation with normal control sera (St, stomach lysate; U, uterine tissue lysate; D, duodenal lysate; S, spinal cord lysate;B, brain lysate).</p><p>402 Satoyoshi Syndrome MUSCLE &amp; NERVE September 2007</p></li><li><p>as multiple ulcer scars in the stomach, as was alsodescribed in the original report9 and is thus animportant characteristic of Satoyoshi syndrome.</p><p>Several laboratory ndings were abnormal in ourcase secondary to malabsorption. However, obviousgastrointestinal symptoms are found in only half ofthe patients with Satoyoshi syndrome and often ap-pear some years after the onset of muscle spasms.Endo et al. reported that a 13-year-old girl withSatoyoshi syndrome had no gastrointestinal symp-toms but had an asymptomatic gastric ulcer.7 Wetherefore recommend that a thorough investigationof the gastrointestinal system be performed in sus-pected cases of Satoyoshi syndrome, even in thosewithout relevant symptoms.</p><p>Antinuclear antibody,2,15 acetylcholine receptorantibodies,7 antiglutamic acid decarboxylase anti-bodies,4 and antibodies to brain6 have already beenreported in this disease, leading to speculation of itsautoimmune nature. However, the specic antibodythat accounts for the pathogenesis of this syndromehas not been reported. In 2001, Endo et al.6 re-ported the presence of autoantibody against normalbrain tissue in a patient with Satoyoshi syndrome.Our Western blot detected an antibody at the 90-kDaposition against not only human brain but also stom-ach and duodenum in the sera of two patients withSatoyoshi syndrome, suggesting that the unique ap-pearance of stomach and duodenum are due to acommon autoimmune pathogenesis.</p><p>Despite the amenorrhea often seen in Satoyoshisyndrome, the same antibody was not detectedagainst the uterus. We suspect that amenorrhea maybe secondary to nutritional deciency.</p><p>Our ndings, which include an absence of familyhistory, the coexistence of various autoimmune dis-orders, and a dramatic efcacy of immunotherapyfor all symptoms, suggest that Satoyoshi syndrome isa systemic autoimmune disease.</p><p>We thank Prof. Eijirou Satoyoshi, Dr. Arlene R. Ng, and Dr. MoeMoe Aye for their critical reviews of the manuscript. This work wassupported in part by a Neuroimmunological Disease Research</p><p>Committee grant and a research grant (16B-1) for nervous andmental disorders from the Ministry of Health, Labour and Wel-fare.</p><p>REFERENCES</p><p>1. Arimura K. Isaacs syndrome, stiff person syndrome and Sa-toyoshi disease: pathomechanisms and treatment. RinshoShinkeigaku 2004;44:805807.</p><p>2. Arita J, Hamano S, Nara T, Maekawa K. Intravenous gamma-globulin therapy of Satoyoshi syndrome. Brain Dev 1996;18:409411.</p><p>3. Cecchin CR, Felix TM, Magalhaes RB, Furlanetto TW. Satoyo-shi syndrome in a Caucasian girl improved with glucocorti-coidsa clinical report. Am J Med Genet A 2003;118:5254.</p><p>4. Drost G, Verrips A, Hooijkaas H, Zwarts M. Glutamic aciddecarboxylase antibodies in Satoyoshi syndrome. Ann Neurol2004;55:450451.</p><p>5. Ehlayel MS, Lacassie Y. Satoyoshi syndrome: an unusual post-natal multisystemic disorder. Am J Med Genet 1995;57:620625.</p><p>6. Endo K, Kumagai T, Nakahara T, Nakamura K, Shimizu M,Watanabe A, et al. A novel autoantibody associated with Sa-toyoshi syndrome. Neuroimmunology (Tokyo) 2001;9:102103.</p><p>7. Endo K, Yamamoto T, Nakamura K, Hoshi A, Yamanoi T,Watanabe A, et al. Improvement of Satoyoshi syndrome withtacrolimus and corticosteroids. Neurology 2003;60:20142015.</p><p>8. Haymon M, Willis RB, Ehlayel MS, Lacassie Y. Radiologicaland orthopedic abnormalities in Satoyoshi syndrome. PediatrRadiol 1997;27:415418.</p><p>9. Itahara K, Oyama K, Ohara Y, Kobayashi K, Tsumuyara K,Iijima K, et al. Gastroscopic ndings of a patient with recur-rent muscle spasm of central origin (Satoyoshi). Shinkei Ken-kyu No Shimpo 1976;20:706708.</p><p>10. Kamat D, Petry L, Berry S. A case of Satoyoshi syndrome: amultisystem disorder. Clin Pediatr 2003;42:745748.</p><p>11. Kuru S, Riku S, Nakayabu M, Kobayashi Y, Ieda T. A case ofsyndrome of progressive muscle spasm, alopecia, and diar-rhea (Satoyoshi) treated with steroid pulse therapy. RinshoShinkeigaku 1992;32:612615.</p><p>12. Satoh A, Tsujihata M, Yoshimura T, Mori M, Nagataki S.Myasthenia gravis associated with Satoyoshi syndrome: musclecramps, alopecia, and diarrhea. Neurology 1983;33:12091211.</p><p>13. Satoyoshi E. A syndrome of progressive muscle spasm, alope-cia, and diarrhea. Neurology 1978;28:458471.</p><p>14. Satoyoshi E, Yamada K. Recurrent muscle spasms of centralorigin. A report of two cases. Arch Neurol 1967;16:254264.</p><p>15. Yamagata T, Miyao M, Momoi M, Matsumoto S, YanagisawaM. A case of generalized komuragaeri disease (Satoyoshi dis-ease) treated with glucocorticoid. Rinsho Shinkeigaku 1991;31:7983.</p><p>Satoyoshi Syndrome MUSCLE &amp; NERVE September 2007 403</p></li></ul>


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