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Phenotypic variability in biotinidasedeficiency
964
Editorial correspondence
The majority of immunosuppressed patients who have developed disease due to cryptosporidiosis have been adults with acquired immune deficiency syndrome (AIDS)? .+ The mortality in patients with immunodeficiency and cryptosporidios!s is >70%. 4 Our patient was possibly immunosuppressed by anticancer chemotherapy, but recovered whiie anticancer chemotherapy was continued; metronidazole did not appear to affect the clinical course. Numerous agents have been used to treat severe cryptosporidiosis, without clinical or mierobiologic response, although spiramycin may be beneficial in patients with AIDS? More information is needed about the epidemiology, pathogenesis, and treatment ol~ this organism in both immunocompromised and noncompromised hosts. Sung Hee Oh, M.D. Norman Jaffe, M.D. Victor Fainstein, M.D. Larr), K. Picketing, M.D. University of Texas System Cancer Center M. D. Anderson llospital University of Texas Medical School at Houston ilouston, TX 77025
The Journal of Pediatrics June 1984
seen in patients with AIDS, in whom spontaneous resolution has not been observed. The disease syndromes manifested both by this patient and the one reported by Oh et al. appear to fit into a "gray area" between the previously recognized extremes. Patients with this intermediate syndrome have mildly deranged host immunity, and develop a moderately severe diarrheal illness that persists for 4 to 8 weeks and then slowly resolves with eradication of the oocysts from the stool despite persistence of the immunodeficiencY. Recognition of this variant syndrome is important because of its relatively favorable prognosis. Unfortunately, the factors that determine whether a patient falls into this group or into the group with intractable diarrhea are unknown, so we continue to recommend that immunosuppressive medications be discontinued, if possible, in patients with cryptosporidiosis. Richard A. Miller, M.D. .,lcting Assistant Professor Infectious Diseases Division Pacific Medical Center Seattle. IYA 98144
REFERENCES 1.
2. 3.
4.
5.
Miller RA, Holmberg RE Jr, Clausen CR: Life-threa!ening diarrhea caused by Cryptosporidium in a child undergoing therapy for acute lymphocytic leukemia. J PEDIArR 103:256, i983. Tzipori S: Cryptosporidium in animals and humans. Microbiol Rev 47:84, 1983. Current WL, Reese NC, Ernst JV, et al: Human cryptosporidiosis in immunocompetent and immunodeficient persons. N Engl J Med 308:1252, 1983. pitl!k SD, Fainstein V, Garza D, et al: Human cryptosporidiosis: Spectrum of disease. Report of six cases and review of literature. ,~rch Intern Med 143:2269; 1983. Centers for Disease Control: Update: Treatment ofcryptosporidiosis in patients with acquired immunodeficiency syndrome (AIDS). MMWR 33:117, 1984.
Reply To the Editor The patient we reported had a more fulminant illness and a lower white blood cell count, but it is conceivable that her infection would have cleared even if chemotherapy had been continued. As more cases of cryptosporidiosis are reported, the division of the clinical syndromes into mild gastroenteritis in normal hosts and severe, intractable diarrhea in immunocompromised hosts is proving inadequate. We have observed one case of cryptosporidiosis in a homosexual male, with chronic generalized lymphadenopathy and afiergy, that spontaneously cleared after a course significantly longer and more severe than that seen in normal hosts; it is unlikely that his recovery from cryptosporidiosis coincided with an improvement in his immune status. Nonetheless, the fact of his recovery distinguishes his disease from that
Phenotypic variability in biotinidase deficiency To the Editor: Wolf et al? and Swick and Kien z recently stressed phenotypic variability in blotlnldase deficiency, independently reporting several patients with neurologic and cutaneous symptoms but without ketoacidosis and organic aciduria. It was suggested by Wolf that neurologic and dermatoiogic findings result from mild to moderate depletion of biotin at a time when the residual carboxylase activities are still adequate to ensure a normal metabolic balance. We examined a 2-year-old girl who showed, from the age of 14 months, psychomotor regression, marked hypotonia, truncal ataxin, mild optic atrophy, an d hyperpnea with laryngeal stridor. No conjunctival or cutaneous lesions were found. After demonstration of a characteristic urinary organic acid pattern, the carboxylase activities were found to be normal in cultured fibroblasts,* but a marked deficiency in biotinidase activity, as determined by the bioiinyI-PABA cleavage assay, ~was found in the patient's plasma (1.2% of controls).i Gas chromatography-mass spectrometry of organic acids in the cercbrospinal fluid revealed the presence of the same metabolites found in urine, although in the CSF, lactate levels were very increased, and isovalerate and propionate were present only in trace amounts. In our opinion, these results, besides indicating a pathogenetically predominant role of pyruvate carboxylase deficiency in the central nervous system, may suggest a different sensitivity of the biotin-dependent carboxylases in different organs. It might be *Carboxylase assays performed by Drs. L. Sweetman and F. Swcctman. San Diego. l"Biotinidascassay performed by Dr. Baumgartner, Basel.
Volume 104 Number 6
interesting to verify the CSF organic acid pattern in those patients who show neurologic features in the absence of organic aciduria.
Finally, we wish to point out another element of phenotypic variation: the absence of cutaneous findings, usually reported as a prominent feature of biotinidase deficiency. In our patient this absence was misleading in clinical differential diagnosis. Maja Di Rocco, M.D. A. Superti-Furga, S.M.S. Daniela Caprino. $LD. N. Oddino, M.D. 3rd Department of Pediatrics lstituto G. Gaslini 16148 Genova-Quarto, Italy REFERENCES 1.
Wolf B, Grier RE, Allen R J, Goodman SI, Kien CL, Parker WD, Howell DM, Hurst DL: Phenotypic variation in biotinidase deficiency. J PVDIA'ra 103:233, 1983. 2. Swick HM, Kien L: Biotin deficiency with neurologic and cutaneous manifestation but without organic aciduria. J PEDIATR 103:265, 1983. 3. Knappe J, Brunner W, Bederbick KH: Reinigung und Eigenschaften der Biotinidase aus Schweinenieren und Laetobacillus Casei. Biochem Zeitschrift 338:599, 1963. 4. Di Rocco M, Superti-Furga A, Durand P, Cerone R, Romano C, Bachmann C, Baumgartner R: Different organic acid pattern in urine and cerebrospinal fluid in a patient with biotinidase deficiency. J Inher Metab Dis (In press.)
To the Editor: In their paper on the phenotypic variation of biotinidase deficiency, Wolf et al. 1 include some of the children with multiple carboxylase deficiency that we have reported, but there are some errors.
Patient 9 of Wolf et al. t does not have biotinidase deficiency, but late-onset holocarboxylase synthetase deficiency, which has been fully documented. 24 She presented at the age of 14 months in coma with metabolic acidosis. Patient 10 of Wolf et al. I appears to be the child described by Keeton and Moosa ~ (Wolf et al. reference 31). No details of this child were given by us in the other reference cited ~ (Wolf et al. reference 32), and we do not know the precise diagnosis. Of the cases that we have published with our colleagues, we have now shown that patient 4 of Leonard et al) and the child described by Charles et al? have biotinidase deficiency. 7 We conclude that late-onset multiple carboxylase deficiency should not be designated as biotinidase deficiency, and that some of the "'phenotypic variation" may be spurious because the patients do not all have the same inborn error. K. Bartlett, M.D. Senior Lecturer in Clinical Biochemistry University of Newcastle J. V. Leonard, M.D. Senior Lecturer in Child Health Institute of Child Health 30 Guilford St. London WCIN IEH. England
Editorial correspondence
965
REFERENCES 1. Wolf B, Grier RE, Allen R J, Goodman SI, Kien CL, Parker WD, et al: Phenotypic variation in biotinidase deficiency. J PemA'ra 103:233, 1983. 2. Bartlett K, Ng H, Leonard JV: A combined defect of three mitochondrial carboxylases presenting as biotin-responsive 3-methyl erotonyl glycinuria and 3-hydroxy isovaleric aciduria. Clin Chim Acta 100:183, 1980. 3. Leonard JV, Seakins JWT, Bartlett K, Hyde JC, Wilson J, Clayton BE: Inherited disorders of 3-methyl crotonyl CoA carboxylation. 56:53, 1982. 4. Ghneim HK, Bartlett K: Mechanism of biotin-responsive combined earboxylase deficiency. Lancet 1:1187, 1982. 5. Keeton BR, Moosa A: Organic aciduria: Treatable cause of floppy infant syndrome. Arch Dis Child 51:636, 1979. 6. Charles BM, Hosking G, Green A, Pollitt R, Bartlett K, Taitz LS: Biotin responsive alopecia and developmental regression. Lancet 2:118, 1979. 7. Bartlett K, Wastell H J, Stirk JH, Bennett M, Leonard JV, Taitz LS, Saudubray JM: A new sensitive fluorimetric assay for biotinidase and its application to the elucidation of the primary defect in some patients with combined carboxylase defect. Poster Presentation (P4). Society for the Study of Inborn Errors of Metabolism, Annual Meeting 1983, Lyon, France.
Reply To the Editor: The observation of DiRocco et al. of a disproportionate increase in lactate conccntration as compared with the other abnormal metabolites in the cerebrospinal fluid of a patient with biotinidase deficiency is very interesting. These results suggest that pyruvate carboxylase activity is preferentially affected in the brain of biotinidase-deficient individuals. Previous studies using human fibroblastsL2 and livers from biotin-deficient rats 3 demonstrate that the activity of pyruvate carboxylase is indeed decreased more than that of the other carboxylases. In addition, we have found the same relative decrease of activities in the brains of biotin-deficient rats? Therefore it is possible that a localized increase in lactate concentration in the brain is responsible for neurologic symptoms prior to the appearance of organic aciduria. We appreciate Bartlett and Leonard providing clarification and the definitive diagnoses of some of the patients who were included in the Table in our paper. However, we reiterate that among the six patients we described, four newly diagnosed individuals, and the patient described by DiRicco et al. there is considerable vari.ability in the clinical expression of this disorder. Our recent studies have suggested that biotinidase may be important in the processing of dietary protein-bound biotin, and affected individuals are probably unable to use this source of the vitamin? Differences in the quantities of free and protein-bound biotin in the diets of these patients may partially explain the variation in the age of onset and severity of disease. We agree that the designations neonatal or early-onset and juvenile or late-onset multiple carboxylase deficiency are no longer applicable. Therefore, patients with multiple carboxylase deficiency should be designated as having biotin holocarboxylase
Editorial correspondence
The majority of immunosuppressed patients who have developed disease due to cryptosporidiosis have been adults with acquired immune deficiency syndrome (AIDS)? .+ The mortality in patients with immunodeficiency and cryptosporidios!s is >70%. 4 Our patient was possibly immunosuppressed by anticancer chemotherapy, but recovered whiie anticancer chemotherapy was continued; metronidazole did not appear to affect the clinical course. Numerous agents have been used to treat severe cryptosporidiosis, without clinical or mierobiologic response, although spiramycin may be beneficial in patients with AIDS? More information is needed about the epidemiology, pathogenesis, and treatment ol~ this organism in both immunocompromised and noncompromised hosts. Sung Hee Oh, M.D. Norman Jaffe, M.D. Victor Fainstein, M.D. Larr), K. Picketing, M.D. University of Texas System Cancer Center M. D. Anderson llospital University of Texas Medical School at Houston ilouston, TX 77025
The Journal of Pediatrics June 1984
seen in patients with AIDS, in whom spontaneous resolution has not been observed. The disease syndromes manifested both by this patient and the one reported by Oh et al. appear to fit into a "gray area" between the previously recognized extremes. Patients with this intermediate syndrome have mildly deranged host immunity, and develop a moderately severe diarrheal illness that persists for 4 to 8 weeks and then slowly resolves with eradication of the oocysts from the stool despite persistence of the immunodeficiencY. Recognition of this variant syndrome is important because of its relatively favorable prognosis. Unfortunately, the factors that determine whether a patient falls into this group or into the group with intractable diarrhea are unknown, so we continue to recommend that immunosuppressive medications be discontinued, if possible, in patients with cryptosporidiosis. Richard A. Miller, M.D. .,lcting Assistant Professor Infectious Diseases Division Pacific Medical Center Seattle. IYA 98144
REFERENCES 1.
2. 3.
4.
5.
Miller RA, Holmberg RE Jr, Clausen CR: Life-threa!ening diarrhea caused by Cryptosporidium in a child undergoing therapy for acute lymphocytic leukemia. J PEDIArR 103:256, i983. Tzipori S: Cryptosporidium in animals and humans. Microbiol Rev 47:84, 1983. Current WL, Reese NC, Ernst JV, et al: Human cryptosporidiosis in immunocompetent and immunodeficient persons. N Engl J Med 308:1252, 1983. pitl!k SD, Fainstein V, Garza D, et al: Human cryptosporidiosis: Spectrum of disease. Report of six cases and review of literature. ,~rch Intern Med 143:2269; 1983. Centers for Disease Control: Update: Treatment ofcryptosporidiosis in patients with acquired immunodeficiency syndrome (AIDS). MMWR 33:117, 1984.
Reply To the Editor The patient we reported had a more fulminant illness and a lower white blood cell count, but it is conceivable that her infection would have cleared even if chemotherapy had been continued. As more cases of cryptosporidiosis are reported, the division of the clinical syndromes into mild gastroenteritis in normal hosts and severe, intractable diarrhea in immunocompromised hosts is proving inadequate. We have observed one case of cryptosporidiosis in a homosexual male, with chronic generalized lymphadenopathy and afiergy, that spontaneously cleared after a course significantly longer and more severe than that seen in normal hosts; it is unlikely that his recovery from cryptosporidiosis coincided with an improvement in his immune status. Nonetheless, the fact of his recovery distinguishes his disease from that
Phenotypic variability in biotinidase deficiency To the Editor: Wolf et al? and Swick and Kien z recently stressed phenotypic variability in blotlnldase deficiency, independently reporting several patients with neurologic and cutaneous symptoms but without ketoacidosis and organic aciduria. It was suggested by Wolf that neurologic and dermatoiogic findings result from mild to moderate depletion of biotin at a time when the residual carboxylase activities are still adequate to ensure a normal metabolic balance. We examined a 2-year-old girl who showed, from the age of 14 months, psychomotor regression, marked hypotonia, truncal ataxin, mild optic atrophy, an d hyperpnea with laryngeal stridor. No conjunctival or cutaneous lesions were found. After demonstration of a characteristic urinary organic acid pattern, the carboxylase activities were found to be normal in cultured fibroblasts,* but a marked deficiency in biotinidase activity, as determined by the bioiinyI-PABA cleavage assay, ~was found in the patient's plasma (1.2% of controls).i Gas chromatography-mass spectrometry of organic acids in the cercbrospinal fluid revealed the presence of the same metabolites found in urine, although in the CSF, lactate levels were very increased, and isovalerate and propionate were present only in trace amounts. In our opinion, these results, besides indicating a pathogenetically predominant role of pyruvate carboxylase deficiency in the central nervous system, may suggest a different sensitivity of the biotin-dependent carboxylases in different organs. It might be *Carboxylase assays performed by Drs. L. Sweetman and F. Swcctman. San Diego. l"Biotinidascassay performed by Dr. Baumgartner, Basel.
Volume 104 Number 6
interesting to verify the CSF organic acid pattern in those patients who show neurologic features in the absence of organic aciduria.
Finally, we wish to point out another element of phenotypic variation: the absence of cutaneous findings, usually reported as a prominent feature of biotinidase deficiency. In our patient this absence was misleading in clinical differential diagnosis. Maja Di Rocco, M.D. A. Superti-Furga, S.M.S. Daniela Caprino. $LD. N. Oddino, M.D. 3rd Department of Pediatrics lstituto G. Gaslini 16148 Genova-Quarto, Italy REFERENCES 1.
Wolf B, Grier RE, Allen R J, Goodman SI, Kien CL, Parker WD, Howell DM, Hurst DL: Phenotypic variation in biotinidase deficiency. J PVDIA'ra 103:233, 1983. 2. Swick HM, Kien L: Biotin deficiency with neurologic and cutaneous manifestation but without organic aciduria. J PEDIATR 103:265, 1983. 3. Knappe J, Brunner W, Bederbick KH: Reinigung und Eigenschaften der Biotinidase aus Schweinenieren und Laetobacillus Casei. Biochem Zeitschrift 338:599, 1963. 4. Di Rocco M, Superti-Furga A, Durand P, Cerone R, Romano C, Bachmann C, Baumgartner R: Different organic acid pattern in urine and cerebrospinal fluid in a patient with biotinidase deficiency. J Inher Metab Dis (In press.)
To the Editor: In their paper on the phenotypic variation of biotinidase deficiency, Wolf et al. 1 include some of the children with multiple carboxylase deficiency that we have reported, but there are some errors.
Patient 9 of Wolf et al. t does not have biotinidase deficiency, but late-onset holocarboxylase synthetase deficiency, which has been fully documented. 24 She presented at the age of 14 months in coma with metabolic acidosis. Patient 10 of Wolf et al. I appears to be the child described by Keeton and Moosa ~ (Wolf et al. reference 31). No details of this child were given by us in the other reference cited ~ (Wolf et al. reference 32), and we do not know the precise diagnosis. Of the cases that we have published with our colleagues, we have now shown that patient 4 of Leonard et al) and the child described by Charles et al? have biotinidase deficiency. 7 We conclude that late-onset multiple carboxylase deficiency should not be designated as biotinidase deficiency, and that some of the "'phenotypic variation" may be spurious because the patients do not all have the same inborn error. K. Bartlett, M.D. Senior Lecturer in Clinical Biochemistry University of Newcastle J. V. Leonard, M.D. Senior Lecturer in Child Health Institute of Child Health 30 Guilford St. London WCIN IEH. England
Editorial correspondence
965
REFERENCES 1. Wolf B, Grier RE, Allen R J, Goodman SI, Kien CL, Parker WD, et al: Phenotypic variation in biotinidase deficiency. J PemA'ra 103:233, 1983. 2. Bartlett K, Ng H, Leonard JV: A combined defect of three mitochondrial carboxylases presenting as biotin-responsive 3-methyl erotonyl glycinuria and 3-hydroxy isovaleric aciduria. Clin Chim Acta 100:183, 1980. 3. Leonard JV, Seakins JWT, Bartlett K, Hyde JC, Wilson J, Clayton BE: Inherited disorders of 3-methyl crotonyl CoA carboxylation. 56:53, 1982. 4. Ghneim HK, Bartlett K: Mechanism of biotin-responsive combined earboxylase deficiency. Lancet 1:1187, 1982. 5. Keeton BR, Moosa A: Organic aciduria: Treatable cause of floppy infant syndrome. Arch Dis Child 51:636, 1979. 6. Charles BM, Hosking G, Green A, Pollitt R, Bartlett K, Taitz LS: Biotin responsive alopecia and developmental regression. Lancet 2:118, 1979. 7. Bartlett K, Wastell H J, Stirk JH, Bennett M, Leonard JV, Taitz LS, Saudubray JM: A new sensitive fluorimetric assay for biotinidase and its application to the elucidation of the primary defect in some patients with combined carboxylase defect. Poster Presentation (P4). Society for the Study of Inborn Errors of Metabolism, Annual Meeting 1983, Lyon, France.
Reply To the Editor: The observation of DiRocco et al. of a disproportionate increase in lactate conccntration as compared with the other abnormal metabolites in the cerebrospinal fluid of a patient with biotinidase deficiency is very interesting. These results suggest that pyruvate carboxylase activity is preferentially affected in the brain of biotinidase-deficient individuals. Previous studies using human fibroblastsL2 and livers from biotin-deficient rats 3 demonstrate that the activity of pyruvate carboxylase is indeed decreased more than that of the other carboxylases. In addition, we have found the same relative decrease of activities in the brains of biotin-deficient rats? Therefore it is possible that a localized increase in lactate concentration in the brain is responsible for neurologic symptoms prior to the appearance of organic aciduria. We appreciate Bartlett and Leonard providing clarification and the definitive diagnoses of some of the patients who were included in the Table in our paper. However, we reiterate that among the six patients we described, four newly diagnosed individuals, and the patient described by DiRicco et al. there is considerable vari.ability in the clinical expression of this disorder. Our recent studies have suggested that biotinidase may be important in the processing of dietary protein-bound biotin, and affected individuals are probably unable to use this source of the vitamin? Differences in the quantities of free and protein-bound biotin in the diets of these patients may partially explain the variation in the age of onset and severity of disease. We agree that the designations neonatal or early-onset and juvenile or late-onset multiple carboxylase deficiency are no longer applicable. Therefore, patients with multiple carboxylase deficiency should be designated as having biotin holocarboxylase