I Tangier Disease in a Black Patient: An Unusual Clinical Presentation WARREN D. Lo, M.D., HOWARD R. SLOAN,M.D., Ph.D., BRIANP. FAHEY,~6, JANEF. DONAT,M.D., COCKS, ohio, WOLFGANG STROBL,M.D., D.Phil.,JOSEFR. PATSCH,M.D., ANTONIOM. GOTTO,Jr., M.D., WOLFGANG PATSCH,M.D., HOUSTON, Texas
angier disease is a rare autosomal recessive disorT der marked by very low plasma levels of apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL) cholesterol [1,2] and by an accumulation of cholesteryl esters in a variety of cells and tissues [2]. Peripheral neuropathy, a common feature of this disease, is present in about half of the patients [3]. The abnormality usually presents in one of three forms: a relapsing and asymmetric process; a progressive symmetric polyneuropathy; or an asymmetric syringomyelic syndrome [3,4]. In no reported case has the disorder presented as a plexopathy. We report a case of Tangier disease in a 14-year-old black boy, who presented with the symptoms of a progressive lumbosacral plexopathy and a cornea1 interstitial keratitis. The patient had markedly depressed levels of apoA-I, a finding consistent with the diagnosis of Tangier disease; the apoA-I, however, was structurally normal as judged by two-dimensional electrophoresis. The disorder has been reported in a worldwide distribution of whites [3,5-81, but involvement of other races has not been previously reported.
CASE REPORT A 14-year-old, mentally retarded black boy presented with a 4-month history of left leg weakness, pain, and numbness that had begun suddenly and had increased in severity. The patient could not accurately describe his pain and numbness except that they involved the left leg. His adoptive mother said that he had always been clumsy and that he always had a left ptosis. Because he was adopted at age 5 months, his family and early medical history are unknown. His full-scale intelligence quotient was 50, as assessed by the Wechsler Intelligence Scale for Children-revised version [9]. At age 9 years, his tonsils were removed because of recurring pharyngitis and otitis. Presurgical evaluation detected sickle cell trait, an enlarged spleen, stomatocytosis, and cornea1 scarring. Physical examination showed cornea1 opacities, orange nodular accretions on the posterior pharynx, and an enlarged spleen. The patient had a left ptosis and left leg weakness that affected the distal more than the proximal muscles. He could not elevate his left leg against gravity and could barely extend his foot against gravity. His strength in the other limbs was normal. The deep tendon reflexes of the left knee,
From the Departments of Pediatrics and Neurology, Ohio State University. Columbus, Ohio, and Baylor College of Medicine and The Methodist Hospital, Houston, Texas. Dr. Lo was supported fn part by a Clinfcal Investigator Development Award from the National Institute of Neurological Diseases and Stroke (l-KO8-NS-01235-OlAl). Requests for reprints should be addressed to Warren D. Lo. M.D., W-203 Children’s Hospital, 700 Children’s Drive, Columbus, Ohfo 43205. Manuscript submitted June 8, 1989. and accepted in rewed form February 12. 1990.
medial hamstring, and ankle were absent. Deep tendon reflexes were hypoactive in the right leg, but normal in both arms. Pain and temperature sensations were decreased in the fourth lumbar through first sacral dermatomes on the left. Light touch, position, and vibration perceptions were normal. The patient’s gait was abnormal because of a left foot drop and external rotation of the left hip. The consulting ophthalmologist found a deep interstitial keratitis in both corneas. A marked 360’ vascular infiltrate involved the periphery of both corneas, but spared the central area. Lipid infiltration and corneal opacities related to the vascular infiltration were noted. A retrospective review of the tonsillectomy sections revealed aggregates of large, foamy histiocytes in the perifollicular and sinusoidal areas, consistent with the diagnosis of Tangier disease (Figure 1, top and bottom).
METHODS Venous blood was collected into tubes containing 1.5 mg/mL EDTA, and plasma was separated by centrifugation. Cholesterol and triglyceride in plasma and isolated lipoprotein fractions were determined by enzymatic methods [lO,ll]. HDL cholesterol was measured after precipitation of apolipoprotein B (apoB)containing lipoproteins [12]. ApoA-I and apoB were determined by radioimmunoassay [13,14]. Major lipoprotein classes were isolated by zonal ultracentrifugation [15] and analyzed for free ,cholesterol, esterified cholesterol [10,16], triglyceride [ll], lipid phosphorus [17], and protein [18]. ApoA-I isoproteins were studied by isoelectric focusing and two-dimensional sodium dodecyl sulfate (SDS) gel electrophoresis [19] as previously described [20]. Whole plasma, after incubation with decylsulfate and @-mercaptoethanol, was focused on 7.5% polyacrylamide slab gels containing 6 M urea in a pH gradient from pH 4 to 6. Molecular weight was determined by second-dimension SDS gel electrophoresis [21]. The immunologic identity of the apoA-I isoforms was established by immunoblotting. Proteins separated by isoelectric focusing or two-dimensional SDS gel electrophoresis were transferred to nitrocellulose membranes for 3 hours at 4°C and 55 V [22]. Nonspecific binding sites were blocked by incubation of the membranes in 0.02 M TRIS HCl, pH 7.4, 0.9% sodium azide, 3% dry skim milk (weight/volume) for 2 hours at 37°C. Membranes were then incubated with rabbit antihuman HDL antiserum overnight at 37OC. The membranes were then washed 5 times for 15 minutes in 0.9% sodium chloride and incubated with 1 X lo6 cpm/mL of goat antirabbit IgG iodinated with lz51 by the chloramine T method [23]. The filters were washed as just described, air dried, and exposed to x-ray film.
July 1990
The American
Journal
of Medicine
Volume
89
105
TANGIER DISEASE IN A BLACK PATIENT / LO ET AL TABLE I Plasma lipid and Apolipoprotein Analysis Concentration*
lipid or Apolipoprotein Total cholesterol
25 (129-195y
Triglyceride Apo B HDL-cholesterol Apo A-l
98 (25-88)t 38(51-106)t
angier disease is a rare autosomal recessive disorT der marked by very low plasma levels of apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL) cholesterol [1,2] and by an accumulation of cholesteryl esters in a variety of cells and tissues [2]. Peripheral neuropathy, a common feature of this disease, is present in about half of the patients [3]. The abnormality usually presents in one of three forms: a relapsing and asymmetric process; a progressive symmetric polyneuropathy; or an asymmetric syringomyelic syndrome [3,4]. In no reported case has the disorder presented as a plexopathy. We report a case of Tangier disease in a 14-year-old black boy, who presented with the symptoms of a progressive lumbosacral plexopathy and a cornea1 interstitial keratitis. The patient had markedly depressed levels of apoA-I, a finding consistent with the diagnosis of Tangier disease; the apoA-I, however, was structurally normal as judged by two-dimensional electrophoresis. The disorder has been reported in a worldwide distribution of whites [3,5-81, but involvement of other races has not been previously reported.
CASE REPORT A 14-year-old, mentally retarded black boy presented with a 4-month history of left leg weakness, pain, and numbness that had begun suddenly and had increased in severity. The patient could not accurately describe his pain and numbness except that they involved the left leg. His adoptive mother said that he had always been clumsy and that he always had a left ptosis. Because he was adopted at age 5 months, his family and early medical history are unknown. His full-scale intelligence quotient was 50, as assessed by the Wechsler Intelligence Scale for Children-revised version [9]. At age 9 years, his tonsils were removed because of recurring pharyngitis and otitis. Presurgical evaluation detected sickle cell trait, an enlarged spleen, stomatocytosis, and cornea1 scarring. Physical examination showed cornea1 opacities, orange nodular accretions on the posterior pharynx, and an enlarged spleen. The patient had a left ptosis and left leg weakness that affected the distal more than the proximal muscles. He could not elevate his left leg against gravity and could barely extend his foot against gravity. His strength in the other limbs was normal. The deep tendon reflexes of the left knee,
From the Departments of Pediatrics and Neurology, Ohio State University. Columbus, Ohio, and Baylor College of Medicine and The Methodist Hospital, Houston, Texas. Dr. Lo was supported fn part by a Clinfcal Investigator Development Award from the National Institute of Neurological Diseases and Stroke (l-KO8-NS-01235-OlAl). Requests for reprints should be addressed to Warren D. Lo. M.D., W-203 Children’s Hospital, 700 Children’s Drive, Columbus, Ohfo 43205. Manuscript submitted June 8, 1989. and accepted in rewed form February 12. 1990.
medial hamstring, and ankle were absent. Deep tendon reflexes were hypoactive in the right leg, but normal in both arms. Pain and temperature sensations were decreased in the fourth lumbar through first sacral dermatomes on the left. Light touch, position, and vibration perceptions were normal. The patient’s gait was abnormal because of a left foot drop and external rotation of the left hip. The consulting ophthalmologist found a deep interstitial keratitis in both corneas. A marked 360’ vascular infiltrate involved the periphery of both corneas, but spared the central area. Lipid infiltration and corneal opacities related to the vascular infiltration were noted. A retrospective review of the tonsillectomy sections revealed aggregates of large, foamy histiocytes in the perifollicular and sinusoidal areas, consistent with the diagnosis of Tangier disease (Figure 1, top and bottom).
METHODS Venous blood was collected into tubes containing 1.5 mg/mL EDTA, and plasma was separated by centrifugation. Cholesterol and triglyceride in plasma and isolated lipoprotein fractions were determined by enzymatic methods [lO,ll]. HDL cholesterol was measured after precipitation of apolipoprotein B (apoB)containing lipoproteins [12]. ApoA-I and apoB were determined by radioimmunoassay [13,14]. Major lipoprotein classes were isolated by zonal ultracentrifugation [15] and analyzed for free ,cholesterol, esterified cholesterol [10,16], triglyceride [ll], lipid phosphorus [17], and protein [18]. ApoA-I isoproteins were studied by isoelectric focusing and two-dimensional sodium dodecyl sulfate (SDS) gel electrophoresis [19] as previously described [20]. Whole plasma, after incubation with decylsulfate and @-mercaptoethanol, was focused on 7.5% polyacrylamide slab gels containing 6 M urea in a pH gradient from pH 4 to 6. Molecular weight was determined by second-dimension SDS gel electrophoresis [21]. The immunologic identity of the apoA-I isoforms was established by immunoblotting. Proteins separated by isoelectric focusing or two-dimensional SDS gel electrophoresis were transferred to nitrocellulose membranes for 3 hours at 4°C and 55 V [22]. Nonspecific binding sites were blocked by incubation of the membranes in 0.02 M TRIS HCl, pH 7.4, 0.9% sodium azide, 3% dry skim milk (weight/volume) for 2 hours at 37°C. Membranes were then incubated with rabbit antihuman HDL antiserum overnight at 37OC. The membranes were then washed 5 times for 15 minutes in 0.9% sodium chloride and incubated with 1 X lo6 cpm/mL of goat antirabbit IgG iodinated with lz51 by the chloramine T method [23]. The filters were washed as just described, air dried, and exposed to x-ray film.
July 1990
The American
Journal
of Medicine
Volume
89
105
TANGIER DISEASE IN A BLACK PATIENT / LO ET AL TABLE I Plasma lipid and Apolipoprotein Analysis Concentration*
lipid or Apolipoprotein Total cholesterol
25 (129-195y
Triglyceride Apo B HDL-cholesterol Apo A-l
98 (25-88)t 38(51-106)t
