752
Clinical and laboratory observations
6. Poh-Fitzpatrick MB, Masullo AS, Grossman ME. Porphyria cutanea tarda associated with chronic renal disease and hemodialysis. Arch Dermatol 1980;116:191-5. 7. Zeier M, Doss M, Ziegler T, Ritz E, Rambausek M. Pseudoporphyria cutanea tarda and non-A, non-B hepatitis in a CAPD patient. Perit Dial Bull 1987;7:231-3. 8. Grossman ME, Poh-Fitzpatrick MB. Porphyria cutanea tarda: diagnosis and management. Med Clin North Am 1980;64:80727. 9. Lever WG, Schaumberg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:462-6. 10. Poh-Fitzpatrick MB, Sosin AE, Bemis J. Porphyrin levels in plasma and erythrocytes of chronic dialysis patients. J Am Acad Dermatol 1982;7:100-4.
The Journal of Pediatrics November 1992
11. Seubert S, Seubert A, Rumpf KW, Kiffe H. A porphyria cutanea tarda-like distribution pattern of porphyrins in plasma, hemodialysate, hemofiltrate and urine of patients on chronic hemodialysis. J Invest Dermatol 1985;85:107-9. 12. Levy ML, Barron KS, Eichenfield A, Honig PJ. Naproxen-induced pseudoporphyria: a distinctive photodermatitis. J PEDIATR 1990;117:660-4. 13. Anderson KE, Goeger DE, Carson RW, Lee SMK, Stead RB. Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis. N Engl J Med 1990; 322:315-7. 14. Canadian Pharmaceutical Association. Compendium of pharmaceuticals and specialties. Toronto: CK Productions, 1991:222, 1191.
Variability of clinical presentation in fumarate hydratase deficiency Orly N. E l p e l e g , MD, N a o m i Amir, MD, a n d Ernst Christensen, PhD From the Metabolic and Neuropediatric Units,Shaare-Zedek Medical Center, Jerusalem, Israel, and the Metabolic Laboratory, Rigshospitalet, Copenhagen, Denmark
A 5-year-old girl with a previous diagnosis of cerebral palsy, nonprogressive psychomotor retardation, and hypotonia was found to excrete excessive fumaric acid in urine. Fumarate hydratase activity in skin fibroblasts was 10% of the control value. This case underscores the clinical heterogeneity of neurometabolic disorders and the importance of organic acid analysis in the diagnosis of static encephalopathy. (J PEDIATR1992;121:752-4) F u m a r i c aciduria is a rare inborn error of metabolism resuiting from decreased activity of f u m a r a t e hydratase. Deficiency of F H has been d e m o n s t r a t e d in five of the seven reported p a t i e n t s ) -6 T h r e e of t h e m died in infancy after neurologic deterioration, a n d two had a subacute, chronic course characterized mainly by m e n t a l r e t a r d a t i o n and dysarthria. W e report a girl with F H deficiency, static encephalopathy with psychomotor retardation, and generalized hypo-
tonia. CASE REPORT A 5-year-old girl was admitted to the hospital for evaluation of severe congenital hypotonia and psychomotor retardation. She was the third child of nonconsanguineous pa~ents of Ashkenazi-Jewish Submitted for publication May 7, 1992; accepted June 9, 1992. Reprint requests: Orly N. Elpeleg, MD, Metabolic Unit, ShaareZedek Medical Center, Jerusalem 91031, Israel. 9/22/40188
extraction. Two older sisters, 15 and 17 years of age, were healthy. She was born at term after an uneventful pregnancy. Birth weight was 3450 gm. A dislocated left hip was identified. The first few months were marked by excessive crying; at 6 months, failure to thrive and motgypdelay were noted. Cranial computed tomography revealed mild diffuse cortical atrophy with slight enlargement of FH S-Ado SAICAR
Fumarate hydratase Succinyladenosine Succinylaminoimidazole carboxamide ribotide
I [
I
the lateral ventricles, especially on the left. On the basis of the static nature of the child's neurologic deficit and the neuroradiologic findings, the diagnosis of cerebral palsy was made at 1 year of age. She never had seizures, vomiting, or metabolic crises. On admission, the patient was alert and cooperative. Her weight was 14.5 kg and head circumference 48 cm (both at the 3rd percentile). She had marked hypotonia and could not actively sit up or crawl but could sit unsupported. When helped to stand, she had dystonic posturing of her legs. There were no involuntary movements. Deep tendon reflexes were hyperactive. There were no
Volume 121 Number 5, Part I
pathologic reflexes. Results of ophthalmoscopy and slit-lamp examination were normal. Speech was extremely dysarthric and limited to a few single words; language comprehension was restricted to the simplest commands. The electroencephalogram showed diffusely slow background activity with no epileptiform components. Cranial computed tomography scan was similar to the one obtained at 6 months of age. Electrophysiologicstudies revealed reduced conduction velocity of the median nerve (39 m/sec; normal, 45 m/sec) and of the tibial nerve (35 m/sec; normal, 39 m/sec) consistent with a demyelinating and axonal peripheral neuropathy. Permission for nerve and muscle biopsy was refused. Complete blood cell count, e~ectrolyte values, and results of liver and renal function tests were normal, as were blood gas and plasma carnitine values. METHODS While the patient was on a regular diet, urine for organic acid analysis and determination of purine metabolites was collected for 5 to 8 hours on 5 different days. An oral protein load (1.1 gm/kg body weight) was given twice on different days. Blood ammonia levels were determined every 30 minutes for a total of 3 hours. Urine was collected for 8 hours and kept frozen at - 2 0 ~ C for analysis of amino and organic acids. Oral glucose load (2 gm/kg body weight) was administered twice on different days. The blood lactate level was measured every 45 minutes for a total of 3 hours, and urine was collected during a 7-hour period and kept frozen for organic acid analysis. For the analysis of organic acids, urine samples were acidified after the addition of internal standard (2-phenylbutyric acid), saturated with sodium chloride, and subsequently extracted twice by 5 volumes of ethylacetate. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was then treated with bis(trimethylsilyl)trifluoroacetamide with 1% trimethyl ehlorosilane for 30 minutes at 80 ~ C. The trimethylsilyl derivatives were injected into a Hewlett-Packard model 5890 serial II gas chromatograph equipped with Ultra-1 cross-linked methyl silicone gum phase (25 m x 0.2 mm x 0.33 /~m) column. Compounds were identified by using a HewlettPackard model 5970 mass-selective detector. Fumaric and succinic acids were quantitated by electron impact-selective ion monitoring. Amino acids in urine were quantitated by high-performance liquid chromatography as previously described. 7 An attempt was made to detect succinylaminoimidazole carboxamide ribotide and snccinyladenosine in urine by using thin-layer chromatography of monosaccharides8 (Dr. J. Jaeken, Louvain, Belgium). The activity of FH was determined in cultured skin fibroblasts of the patient and her parents according to a method modified from Hatch. 9
Clinical and laboratory observations
75 3
T a b l e . Urinary organic acid excretion Patient
Fumaric acid* Succinic acid* Fumaric acidt Suceinic acid1Fumaric acid:~ Succinic acid:~
38-137 (96.4 _4- 38.9) 15-95 (46.2 _+ 25.8) 73, 116 46, 48 36, 136 22, 138
Control value
0-10 22-90
Values are expressedas millimolesper molecreatinine.Numbersin parenthesis representmean _+SD. *Basal excretion. rAfter proteinloading. ~:Afterglucoseloading.
RESULTS The concentrations of fumaric and succinic acids in the basal state and after protein and glucose loading are presented in the Table. Neither SAICAR nor S-Ado was detected in the urine. After oral protein loading, blood ammonia levels remained within the control range, with the peak ammonia level being 52 ~mol/L. Urinary amino acid concentrations were within the normal range, as was the orotic acid concentration (2.86 rag/gin creatinine). Succinylacetone was undetectable in these samples. After oral glucose loading, the peak blood lactate level was 1.6 mmol/L (normal,
Clinical and laboratory observations
6. Poh-Fitzpatrick MB, Masullo AS, Grossman ME. Porphyria cutanea tarda associated with chronic renal disease and hemodialysis. Arch Dermatol 1980;116:191-5. 7. Zeier M, Doss M, Ziegler T, Ritz E, Rambausek M. Pseudoporphyria cutanea tarda and non-A, non-B hepatitis in a CAPD patient. Perit Dial Bull 1987;7:231-3. 8. Grossman ME, Poh-Fitzpatrick MB. Porphyria cutanea tarda: diagnosis and management. Med Clin North Am 1980;64:80727. 9. Lever WG, Schaumberg-Lever G. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990:462-6. 10. Poh-Fitzpatrick MB, Sosin AE, Bemis J. Porphyrin levels in plasma and erythrocytes of chronic dialysis patients. J Am Acad Dermatol 1982;7:100-4.
The Journal of Pediatrics November 1992
11. Seubert S, Seubert A, Rumpf KW, Kiffe H. A porphyria cutanea tarda-like distribution pattern of porphyrins in plasma, hemodialysate, hemofiltrate and urine of patients on chronic hemodialysis. J Invest Dermatol 1985;85:107-9. 12. Levy ML, Barron KS, Eichenfield A, Honig PJ. Naproxen-induced pseudoporphyria: a distinctive photodermatitis. J PEDIATR 1990;117:660-4. 13. Anderson KE, Goeger DE, Carson RW, Lee SMK, Stead RB. Erythropoietin for the treatment of porphyria cutanea tarda in a patient on long-term hemodialysis. N Engl J Med 1990; 322:315-7. 14. Canadian Pharmaceutical Association. Compendium of pharmaceuticals and specialties. Toronto: CK Productions, 1991:222, 1191.
Variability of clinical presentation in fumarate hydratase deficiency Orly N. E l p e l e g , MD, N a o m i Amir, MD, a n d Ernst Christensen, PhD From the Metabolic and Neuropediatric Units,Shaare-Zedek Medical Center, Jerusalem, Israel, and the Metabolic Laboratory, Rigshospitalet, Copenhagen, Denmark
A 5-year-old girl with a previous diagnosis of cerebral palsy, nonprogressive psychomotor retardation, and hypotonia was found to excrete excessive fumaric acid in urine. Fumarate hydratase activity in skin fibroblasts was 10% of the control value. This case underscores the clinical heterogeneity of neurometabolic disorders and the importance of organic acid analysis in the diagnosis of static encephalopathy. (J PEDIATR1992;121:752-4) F u m a r i c aciduria is a rare inborn error of metabolism resuiting from decreased activity of f u m a r a t e hydratase. Deficiency of F H has been d e m o n s t r a t e d in five of the seven reported p a t i e n t s ) -6 T h r e e of t h e m died in infancy after neurologic deterioration, a n d two had a subacute, chronic course characterized mainly by m e n t a l r e t a r d a t i o n and dysarthria. W e report a girl with F H deficiency, static encephalopathy with psychomotor retardation, and generalized hypo-
tonia. CASE REPORT A 5-year-old girl was admitted to the hospital for evaluation of severe congenital hypotonia and psychomotor retardation. She was the third child of nonconsanguineous pa~ents of Ashkenazi-Jewish Submitted for publication May 7, 1992; accepted June 9, 1992. Reprint requests: Orly N. Elpeleg, MD, Metabolic Unit, ShaareZedek Medical Center, Jerusalem 91031, Israel. 9/22/40188
extraction. Two older sisters, 15 and 17 years of age, were healthy. She was born at term after an uneventful pregnancy. Birth weight was 3450 gm. A dislocated left hip was identified. The first few months were marked by excessive crying; at 6 months, failure to thrive and motgypdelay were noted. Cranial computed tomography revealed mild diffuse cortical atrophy with slight enlargement of FH S-Ado SAICAR
Fumarate hydratase Succinyladenosine Succinylaminoimidazole carboxamide ribotide
I [
I
the lateral ventricles, especially on the left. On the basis of the static nature of the child's neurologic deficit and the neuroradiologic findings, the diagnosis of cerebral palsy was made at 1 year of age. She never had seizures, vomiting, or metabolic crises. On admission, the patient was alert and cooperative. Her weight was 14.5 kg and head circumference 48 cm (both at the 3rd percentile). She had marked hypotonia and could not actively sit up or crawl but could sit unsupported. When helped to stand, she had dystonic posturing of her legs. There were no involuntary movements. Deep tendon reflexes were hyperactive. There were no
Volume 121 Number 5, Part I
pathologic reflexes. Results of ophthalmoscopy and slit-lamp examination were normal. Speech was extremely dysarthric and limited to a few single words; language comprehension was restricted to the simplest commands. The electroencephalogram showed diffusely slow background activity with no epileptiform components. Cranial computed tomography scan was similar to the one obtained at 6 months of age. Electrophysiologicstudies revealed reduced conduction velocity of the median nerve (39 m/sec; normal, 45 m/sec) and of the tibial nerve (35 m/sec; normal, 39 m/sec) consistent with a demyelinating and axonal peripheral neuropathy. Permission for nerve and muscle biopsy was refused. Complete blood cell count, e~ectrolyte values, and results of liver and renal function tests were normal, as were blood gas and plasma carnitine values. METHODS While the patient was on a regular diet, urine for organic acid analysis and determination of purine metabolites was collected for 5 to 8 hours on 5 different days. An oral protein load (1.1 gm/kg body weight) was given twice on different days. Blood ammonia levels were determined every 30 minutes for a total of 3 hours. Urine was collected for 8 hours and kept frozen at - 2 0 ~ C for analysis of amino and organic acids. Oral glucose load (2 gm/kg body weight) was administered twice on different days. The blood lactate level was measured every 45 minutes for a total of 3 hours, and urine was collected during a 7-hour period and kept frozen for organic acid analysis. For the analysis of organic acids, urine samples were acidified after the addition of internal standard (2-phenylbutyric acid), saturated with sodium chloride, and subsequently extracted twice by 5 volumes of ethylacetate. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was then treated with bis(trimethylsilyl)trifluoroacetamide with 1% trimethyl ehlorosilane for 30 minutes at 80 ~ C. The trimethylsilyl derivatives were injected into a Hewlett-Packard model 5890 serial II gas chromatograph equipped with Ultra-1 cross-linked methyl silicone gum phase (25 m x 0.2 mm x 0.33 /~m) column. Compounds were identified by using a HewlettPackard model 5970 mass-selective detector. Fumaric and succinic acids were quantitated by electron impact-selective ion monitoring. Amino acids in urine were quantitated by high-performance liquid chromatography as previously described. 7 An attempt was made to detect succinylaminoimidazole carboxamide ribotide and snccinyladenosine in urine by using thin-layer chromatography of monosaccharides8 (Dr. J. Jaeken, Louvain, Belgium). The activity of FH was determined in cultured skin fibroblasts of the patient and her parents according to a method modified from Hatch. 9
Clinical and laboratory observations
75 3
T a b l e . Urinary organic acid excretion Patient
Fumaric acid* Succinic acid* Fumaric acidt Suceinic acid1Fumaric acid:~ Succinic acid:~
38-137 (96.4 _4- 38.9) 15-95 (46.2 _+ 25.8) 73, 116 46, 48 36, 136 22, 138
Control value
0-10 22-90
Values are expressedas millimolesper molecreatinine.Numbersin parenthesis representmean _+SD. *Basal excretion. rAfter proteinloading. ~:Afterglucoseloading.
RESULTS The concentrations of fumaric and succinic acids in the basal state and after protein and glucose loading are presented in the Table. Neither SAICAR nor S-Ado was detected in the urine. After oral protein loading, blood ammonia levels remained within the control range, with the peak ammonia level being 52 ~mol/L. Urinary amino acid concentrations were within the normal range, as was the orotic acid concentration (2.86 rag/gin creatinine). Succinylacetone was undetectable in these samples. After oral glucose loading, the peak blood lactate level was 1.6 mmol/L (normal,
