October 1994, Volume 44, Issue 10

Original Article

Inherited Metabolic Disorders in Pakistan: Presentation, Diagnosis and Outcome of Congenital Hyperammonemias

Perween Multi  ( Department of Paediatrics, Aga Khan University Hospital, Karachi. )
Iqbal Ahmed  ( Department of Paediatrics, Aga Khan University Hospital, Karachi. )

Abstract

A total of 21 patients were admitted to Aga Khan University Hospital with suspected congenital hyperam­monemias during the period 1989 to 1992. There were 11 patients with acidosis and 10 patients were without acidosis. Prominent clinical manifestations included positive family history (76%), onset in the first week of life (67%) and neurological manifestations (76%). Of patients with hyperammonemia and acidosis, 4 had severe metabolic acidosis with anion gap of 3OmEq/L and above. Of patients with hyperammonemia without acidosis, 4 had ammonia level ranging from 1600-2000 mg/dl. Diagnosis was confirmed in only 1 patient and that was also done abroad. Overall mortality was 71%. In conclusion, these disorders are not uncommon in our country and should be suspected in all infants with above clinical or biochemical abnormalities (JPMA 44: 229,1994).

Introduction

In born errors of metabolism are group of disorders which result from partial or complete absence of enzymes involved in biochemical reactions within the cells. This leads to both abnormal synthesis as well as ketabolism of metabo­lites. Most of these metabolites are neurotoxic and may cause death in early neonatal period or severe neurological disabil­ity. There are about 60 inherited metabolic disorders which can present in the neonatal period1,9. Number of these can be treated successfully if suspected and diagnosed early. Galac­tosemia2, pheny lketonuria3, homocystinuria4,8. methylmalo­nic aciduria5,8 and congenital hyperammonemia6,7,11 are groups of disorders for which treatment is available. The incidence of each of these conditions is rare, but as a group they are not infrequent cause of disease in neonatal period. Since most of inborn errors of metabolism are inherited as autosomal recessive traits, incidence is expected to be high in Pakistan because of increased frequency of consanguinity in muslim couples. Over the last 7 years we have seen a number of inherited metabolic disorders. Though the facilities for diagnosis are limited, it has been possible for us to suspect disorders of hyperammonemia with or without metabolic acidosis on clinical and biochemical evaluation. The present study will focus on this particular group of disease. Our objectives are to describe different types of disor­ders with hyperammonemia, to evaluate their clinical mani­festation and outcome at this hospital and increase awareness of this problem among the pediatricians in this country.

Methodology

A review of charts was conducted from January, 1989 to December, 1992 (Table 1).


All infants whose laboratory evaluation or clinical manifestation were suggestive of congenital hyperainmonemias were included in the study.

Clinical manifestations which helped to suspect and diagnose are shown in Appendix A1,9,12. Step wise approach was used for laboratory evaluation, (Appendix B)10,12,13.

Results

There were total of 21 patients suspected of having hyperammonemia with and without metabolic acidosis (Table II).

There were 11 patients with acidosis and 10 without acidosis.

Patients with isovaleric acidemia and non-ketotic hyperglycinemia were diagnosed elsewhere but were fol­lowed at AKU. All infants were admitted to neonatal intensive care unitlintensive care unit. Appendix C6,7,11,12,14,15 shows the overall treatment given to infants with congenital hyperam­monemia.

Table III shows major clinical manifestation. Prominent features included positive family history (76%), onset in the first week of life (67%) and neurological manifestation (76%). Tables IV and V show laboratory evaluations of patients with hyperammonemia. All 3 patients suspected of having There were total of 21 patients suspected of having hyperammonemia with and without metabolic acidosis (Table II). There were 11 patients with acidosis and 10 without acidosis. Patients with isovaleric acidemia and non-ketotic hyperglycinemia were diagnosed elsewhere but were fol­lowed at AKU. All infants were admitted to neonatal intensive care unitlintensive care unit. Appendix C6,7,11,12,14,15 shows the overall treatment given to infants with congenital hyperam­monemia. Table III shows major clinical manifestation. Prominent features included positive family history (76%), onset in the first week of life (67%) and neurological manifestation (76%).


Tables IV and V show laboratory evaluations of patients with hyperammonemia. All 3 patients suspected of having Maple syrup urine disease (MSUD) had abnonnal excretion of isoleucine. 1/3 infants also bad Maple syrup body odour. Ammonia level was normal in 2/3 infants. Of 6 patients suspected of organic acidemia, five died. Four had severe metabolic acidosis with Anion gap of >30mEq/L. Patient #7 was included in the study because there was strong family history of sibling deaths, compensated metabolic acidosis and high ammonia level. He also had Klebsiella sepsis. This infant is alive and thriving. Urinary chromatography was not helpful in any of these cases. Among infants with hyperammonemia without acidosis, 4 had ammonia level ranging from 1600-nearly 2000 mg/dl. One of these infants also had tenninal metabolic acidosis with pH of 6.9 and and anion gap of 25 mEq/L (Patients # 14, 16, 17,21). Patient #21 was first seen at 8 months of age with recurrent episodes of intermittent vomitingand drowsiness andthenatoneyearofage. This time his drowsiness progressed to coma. Ammonia level prior to death was 727 ug/dl. We suspected urea cycle defect in all 5 infants. The other 4 infants were also suspected of having urea cycle defect. Patient # 13 was twin brother of Patient# 16. He died at 2 months of age in a comatosed state. Unfortunately NH3 level was not documented at this time. Patient # 18 presented to us with failure to thrive, vomiting and diarrhoea. His weight was 1.9 kg at 2 months of age. This child was lost to follow up. Patient# 19 developed seizures at 1 month of age.
Three of her siblints died of similar complaints. Patient # 14 was an older child of 4 years of age who had intermittent episodes of unconsciousness. This child was also lost to follow-up. Infant with non-ketotic hyperglycinemia was 2 years old female who presented to ER with hypoglycemic coma. She died on the same day of admission.

Table VI shows the outcome. 15/21(7 1%) infants died. Three infants were lost to followup.

Discussion

This is undoubtedly large group of patients with congenital hyperam.monemia seen at AKU which is one of the largest teaching hospitals in this country. One of the major problems we encountered here was confirmation of diagnosis which could not be done because of non existence of diagnostic facilities needed for this purpose. However, inspite of this, these conditions were suspected on clinical symptom and tests described in Appendix B. Overall mortality was extremely high. In patients with less severe clinical presenta­tion proper management led to improvement. We feel that because of consanguineous marriages in this country these problems are not uncommon and there is a great need of establishing diagnostic facilities to confirm diagnosis, insti­tute early treatment for better outcome and counselling parents. It is important to make the diagnosis for the sake of parents who have every right to know why their in fant had died and for the purpose of genetic counselling.

References

1. Burton, B.K. and Nadleç H.L. Clinical diagnosis of the inborn errors of metabolism in the neonatal period. Pediatrics, 1978;61:398-405.
2. Donnell, ON., Koch, R. and Bergren, WIt Observations on reaulta of management of galactosemicpatienta, in Hsia DYY (ed): Galactoaemia. Springfield, Charles C. Thomas Publisher, 1969,pp.247-75.
3. Clayton, B. Moncrieff, A. and Roberta, G.E. Dietary treatment of phenylketonuria: A followup study. Br. Med. 3., 1967;3: 133-36.
4. Gaull, G.E. and Stunnan, J.A. Vitamin B6 dependency in homocystinuria. Br. Med. J., 1971;3:532-33.
5. Hsia, YE., Liiljeqvist, A-Ch. and Rosenberg. L.E. VItamin B12 dependent methylinalo­nicaciduria amrnoaridtoxicity,longchainketonuria and protective effect of Vitamin B12. Paediatrics, 1970;46:497-507.
6. Batahaw, M.L., Bruaiow, S., Waber, L. et al. Treatment of inborn errors of urea syntbeais.Activation of alternative pathways of waste Nitrogen synthesis and excrelion N. Engi. J. Med., 1982;306:1387-92.
7. Bathabaw, M. L. and Bruaiow, SW. Treatment of hyperammonemic cores caused by inbornerrors of urea synthesis. J. Pediatr., 1980;97:893-900.
8. Rosenberg, L. E. inherited aminoacidopathies demonstrating Vitamin dependency. N. Engl. J. Med., 1969;281:145-152.
9. Burton, BK. Inborn errors of metabolism: The clinical diagnosis in early infancy. Pediatrics, 1987;79:359-369.
10. Green, A. and Hall, SM. Investigation of metabolic disorders resembling Reye’s Syndrome. Arch. Dis. Child., 1992;67: 1313-17.
11. Brusiow, SW., Danney, M., Weber, L.J. et al. Treatment of episodic hyperammonemia in children withinborn errors of urea synthesis. N. EngL J. Med., 1984;3 10:1630-4.
12. Wraith, I.E. Diagnosis and management of inborn errors of metabolism. Arch. Dis. Child., 1989;64:1410-15.
13. Kronjck, J.B., Sceiver, C.R., Goodyer, P.R. et al. A perimortem protocol for suspected genetic disease. Pediatrics, 1983;71:960- 963.
14. Dixon, MA. and Leonard, J.V. Intercurrent illness in inborn errors of intermediary metabolism. Arch. dis. Child., 1992;67: 1387-1391.
15. Naglak, M., Salvo, R., Madsen, K. et al. The treatment of isovaleric acidemia with Glycine supplement. Pediatr. Res., 1988;24:9-13.

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