Inborn Errors of Metabolism (IEM) - An Indian Perspective
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《美国医学杂志》
Department of Pediatrics, KEM Hospital, Mumbai, Maharashtra, India
Abstract
The inborn errors of metabolism (IEM) constitute a diverse heterogeneous group of disorders with protean clinical manifestations presenting mainly in the pediatric population. Though individually rare, together they constitute a significant percentage of children seen in genetic and neurology clinics. This review focuses on selected IEMs and highlights those seen in the neonatal period. Data from Indian centers are presented. It also emphasizes principles of management in these difficult disorders in the context of a developing country.
Keywords: Inborn errors of metabolism; Neurometabolic; Childhood; India
There is an accelerating demographic switch from communicable diseases to genetic disorders. The expression of a genetic disease is the combined effect of genes and the environment. There are 24 million births in India annually; 780,000 are born with congenital malformation, 340,000 with G6PD, 20,800 with metabolic disorder, 21,000 with Down syndrome, 10,400 with congenital hypothyroidism, 9000 with thalassemia and 5200 with sickle cell anemia. In a hospital based study in India biochemical screening of 4400 cases of mental retardation revealed that 5.75 % (256 cases) were due to a metabolic disorder.[1],[2]
Mechanism of Metabolic Disorders
EAB is an enzyme converting A into B. EBC, the enzyme converting B into C, is absent and is the cause of the IEM. This leads to accumulation of substrate B to abnormal levels which then gets diverted to an abnormal metabolic pathway to yield a toxic metabolite D. B or D could be toxic. B & D could be detected and EAB can be estimated biochemically.
Neonatal IEM
Organic aciduria or urea cycle disorders are not uncommon and often present fulminantly. Early diagnosis is crucial for three reasons,[1] the condition is rapidly progressive and causes irreversible damage early in the course,[2] the treatment can often be effective if commenced early and long term outcome maybe improved[3] and correct early diagnosis helps in genetic counseling. Use of blood gases, electrolytes, ammonia, lactate, pyruvate, urine metabolic spot tests, gas chromatography mass spectroscopy (GCMS) or tandem mass spectrometry (TMS) for organic acids, amino acid chromatography, enzyme estimations in white cells, skin fibroblasts and other tissues have made diagnosis possible.
In neonatal IEM pregnancy, delivery is uneventful. The newborn baby with IEM is normal for the first three or four days after which the disorder presents due to intake of dietary protein etc. Neonates with IEM are misdiagnosed to have sepsis or other disorders. Sepsis often accompanies IEM and may confound diagnosis further. Pediatricians often think that neonatal IEM is rare. Though individual disorders may be uncommon these disorders are fairly common when considered together. Though IEM are usually recessive disorders they are very often occur in only one sib. The neonate has a limited response to illness and predominant symptoms & signs are poor feeding, lethargy, coma, failure to thrive, seizures, acidosis or ketosis. Emergency adequate laboratory facilities to diagnose neonatal IEM are scarce and lacking in India leading to delays in diagnosis, treatment and hence a poor prognosis in most cases.
A high index of suspicion is necessary when the following are present :
Parental consanguinity
Positive family history of a similar illness/death
Symptoms onset a few days after feeding (refusal to feed, lethargy, vomiting, hypotonia, coma, seizures)
Ketosis, acidosis, hypoglycemia
Unusual odour to the urine
Jaundice, visceromegaly
Dysmorphic features or coarse facies
Specific Features in Certain Neonatal IEM.
(1) Abnormal urine or body odour is characteristic of some IEM MSUD - maple syrup or burnt sugar smell, Isovaleric acidemia, Glutaric aciduria type II - sweaty feet smell, Phenylketonuria -mousy or mushy, b methyl crotonyl aciduria - tom cat urine, Methionine malabsorption - cabbage, Trimethyl aminuria - rotting fish, Tyrosinemia - rancid or fishy odour.
(2) Diarrhoea: (a) Severe watery diarrhoea - congenital chloride diarrhoea, galactosemia, primary lactase, sucrase, isomaltase deficiency. (b) Chronic diarrhoea- bile acid disorder,infantile Refsum disease, respiratory chain disorders associated with steatorrhoea , vitamin deficiency osteopenia, hypocholesterolemia (c) Diarrhoea, failure to thrive, hypotonia hepatomegaly - GSD I, Wolmans disease
(3) Cardiomyopathy, Cardiac Failure - Pompe's disease GSD II,respiratory chain disorder, fatty acid oxidation (FAO) defects
(4) Hepatomegaly - Tyrosinemia, galactosemia, fructosemia and alpha 1 antitrypsin deficiency, GSD. Hepatomegaly with splenomegaly consider mucolipidosis, Gaucher's disease Niemann-Pick type A
(5) Seizures - Nonketotic hyperglycinemia, pyridoxine dependency, and molybdenum co-factor deficiency. In most others seizures are associated with coma and hyperglycinemia
IEM has a "Characteristic"
1 Age of onset
2 Temporal profile i.e. evolution of the disease with characteristic symptom & sign as the disease advances; affected sibs usually show a similar temporal profile
3 IEM has a characteristic inheritance pattern eg. ornithine transcarbamylase deficiency (OTC), Fabry's disease, Menkes disease and Hunter's disease are X-linked recessive and most others are autosomal recessive.
4 Often there are characteristic triggers - environmental factors which precipitate the presentation of the IEM e.g. diet, infection, fasting, drugs (see below)
5 Age of neurological man ifestations and death
Triggering Factors Precipitating Iem0
1 Diet: Introduction of cane sugar - hereditary fructose intolerance, milk - galactosemia, proteins = urea cycle disorders (UCD), MSUD and other aminoacid disorders. carbohydrate - pyruvate dehydrogenase & respiratory chain disorders.
2 Infection, Fasting and Fever: FAO defects, certain aminoacid disorder and organic aciduria.
3 Anaesthesia - Homocystinuria
4 Drugs - Porphyria and G6 PD deficiency
Group 1- Aminoacidopathies: Neurologic Distress "Intoxication" Type With Ketosis
MSUD - Maple syrup urine disease - only amino acid disorder that presents acutely in the neonatal period.
It is a branch chain amino acid (BCAA) disorder i.e. leucine, isoleucine and valine. Deficiency of ketoacid dehydrogenase results in formation of ketoacids, which give a strongly positive urinary dipstick test for ketones. There is a strong smell of maple syrup to the urine. Initial 3 - 4 days after birth are normal; feeding difficulties start and gradually the neonate becomes comatose with episodic generalized hypertonia, dystonia, ophisthotonos and boxing / pedaling movements. Urine DNPH test is strongly positive and test for acetone is negative. Plasma amino acid chromatography displays elevation of branched chain aminoacids. Dialysis removes the branched chain aminoacids and should be instituted promptly. Treatment of cerebral oedema is mandatory and special f ormula feeding with low BCAA is the most important part of management. Liver transplant offers promising results. Prognosis is guarded. Intercurrent infections leads to severe ketoacidosis, cerebral oedema and death.
Group 2 - Organic acidopathies0 : Methylmalonic academia (MMA), Propionic academia (PA), Isovaleric academia (IVA) : Neurologic distress "intoxication" type with ketoacidosis and hyperammonemia
Infants present with recurrent vomiting, deep acidotic breathing and failure to thrive. They are acutely ill, dehydrated and hypothermic. There is truncal and peripheral hypotonia and coarse limb tremors. The blood bicarbonate is low with an increased anion gap Neutropenia and thrombocytopenia are also common, along with ketonuria. GCMS or tandem mass spectroscopy gives confirms the correct diagnosis and MMA, PA and IVA account for 90% of neonatal presenting organic acidopathies. Propionic acid is a potent inhibitor of mitochondrial function resulting in accumulation of lactic acid and ketones leading to metabolic acidosis. MMA sometimes responds to high doses of vitamin B12 while PA might respond to biotin.
Treatment: Dialysis is used to to remove the offending organic acid and elevated ammonia. Dietary protein restriction, avoidance of fasting and metronidazole therapy (to reduce organic acid production by gut flora) are other measures.
Differential diagnosis includes the adrenogenital syndrome with high potassium and low sodium, sepsis with neutropenia and thrombocytopenia and the UCD.
Group 3 - Primary Lactic Acidosis (PDH PC ETC def.) With Neurologic Distress; "Energy Deficiency" type
Enzyme defects in Kreb's cycle leads to respiratory chain deficiencies. The most common of these disorders are pyruvate dehydrogenase (PDH), pyruvate carboxylase (PC) and electron transport chain (ETC) deficiencies. PDH is an X-linked disorder. Boys present with severe metabolic and lactic acidosis in the neonatal period. Clinically the neonate is neurologically depressed and serum lactate is markedly elevated. There is an elevated anion gap because of the elevated lactate and ketosis. The ketogenic diet & dichloracetate 25 to 100 mg/kg orally or parentally may produce a response in 24 hours.Thiamine supplements may be tried. PC deficiency is an AR disorder with lactic acidosis and neurological dysfunction in the newborn period and intermittent ataxia in later life. PC deficiency in early life characteristically has an elevated lactate to pyruvate ratio, moderate citrullinemia, hyperammonemia and hyperlysinemia (type B) while in the later onset variant moderate lactic acidosis & developmental delay occur (type A). The other features are spasticity, severe psychomotor retardation and seizures. Holocarboxylase, synthase and biotinidase deficiencies present with rash, alopecia, lactic acidosis and will remain asymptomatic if biotin supplementation (5 to 20 mg/day) is started before brain damage occurs. This is possible after newborn screening. A trial of biotin is warranted in all patients with lactic acidosis
Though ETC deficiencies may respond to specific vitamins like riboflavin, L-carnitine and co-enzyme Q the response is usually less than satisfactory.
Group 4a - Urea Cycle Disorders (UCD): Neurologic Distress Due to "Intoxication"; Hyperammonemia Without Ketoacidosis
Transamination reactions in most amino acid catabolic pathways result in transfer of amino group to glutamine and glycine either of which might release ammonia into the urea cycle converting it to urea.
Proximal defects in this pathway result in severe accumulation of ammonia vis-à-vis distal defects.
Ammonia is toxic and causes cerebral oedema leading to drowsiness, lethargy, coma, seizures and early death. Ornithine transcarbamylase (OTC) deficiency is X-linked. All others are inherited as autosomal recessive. Measurement of plasma ammonia, plasma aminoacids and urinary amino and orotic acids are crucial to identify the specific defects in the UCD. Citrullinemia, argininosuccinic acidemia and argininemia are diagnosed by aminoacid chromatography, whereas OTC deficiency and carbamoylphosphate synthetase (CPS) deficiency being more proximal defects give deficiencies of citrulline or arginine. These latter two are differentiated on the basis of an elevated orotic acid excretion in the urine. The diagnosis is also confirmed by enzyme estimation in skin fibroblast or in the liver cells. Treatment of UCD involves dietary protein restriction, sodium benzoate and phenyl butyrate therapy. The more distal defects are more amenable to treatments with drugs. Prognosis depends heavily on the degree of the cerebral damage sustained prior to the diagnosis and treatment.
Group 4b - Nonketotic hyperglycinemia (NKH) : Neurologic distress due to "energy deficiency"; type without ketoacidosis and without hyperammonemia
This is characterized by poor feeding, failure to suck, lethargy hypotonia, coma, and myoclonic jerks appearing within few hours of birth in an infant with no history of perinatal insults. A burst suppression EEG pattern, elevated plasma glycine, elevated CSF to plasma glycine ratio constitutes the diagnosis of neonatal NKH.
Molybdenum co-factor deficiency / sulfite oxidase deficiency present similarly with hypotonia, seizures, dysmorphic features and cataracts. Diagnosis is suggested by a very low plasma uric acid and presence of sulfites in fresh urine while aminoacid chromatography shows high sulfite concentration in the form of sulfocystenine.
Group 4c - Lysosomal Storage Disorders Without Metabolic Disturbances
Few lysosomal disorders present in the neonatal period. These disorders are GM 1 ganglioidosis, Gaucher's disease, Niemann-Pick disease type C, MPS VII and sialiodosis.
Other disorders are glycogenosis (GSD) and gluconeogesis defects, fatty acid oxidation defects etc.
Selected IEMs presenting after the neonatal period
Neurometabolic/Neurodegenerative Disorders
These are genetically inherited disorders with progressive neurologic deterioration, having a demonstrable biochemical abnormality associated with enzyme defects. Heterozygote detection and prenatal diagnosis is possible. Most of them belong to the lysosomal storage disorders leading to neural, neurovisceral and musculo-skeletal manifestations. Simple molecular disease like amino acid, sugar, organic acids and UCD have a catastrophic presentation whereas complex molecular diseases have an insidious onset and a chronic cour
Disorders of copper metabolism
A total of 146 children were seen at the KEM with 142 being Wilson's disease and 4 being Menkes disease.
Wilson's disease is an inborn error of copper metabolism. It is an autosomal recessive disorder with an incidence 1 in 35,000 - 1,00,000; the gene is located at 13q 14 - 21. It is characterized by increased copper deposition in the liver, brain, kidneys and corneas. Classically, there are specific progressive neurological findings, chronic liver disease or cirrhosis, renal tubular dysfunction, sunflower cataract and pigmented corneal rings (Kayser - Fleischer rings). However, the variability of the disease is such that it should be suspected in any patient with unexplained neurologic or psychiatric dysfunction, hepatitis, hemolytic anemia, renal Fanconi syndrome or hematuria. The onset ranges from 4 to 50 years. An earlier age of onset is in general associated with liver disease often without neurological manifestation and not invariable K-F rings. Liver involvement may present with asymptomatic hepatomegaly, jaundice with edema and ascitis, hepatosplenomegaly with vague gastrointestinal symptoms or subacute viral hepatitis, fulminant hepatitis, chronic active hepatitis, juvenile cirrhosis, post-hepatic cirrhosis and cryptogenic cirrhosis. Neurological manifestations range from dystonia- Parkinsonism More Details, dysarrthria, drooling, scholastic deterioration/dementia and behavioural changes.
Clinical and laboratory investigations include peripheral blood for hemolytic anemia, liver function abnormalities, urinary abnormality suggestive of Fanconi syndrome, slit-lamp examination for K-F ring, low serum ceuroplasmin (< 20 mg/dl), increased urinary copper excretion (> 100 mcg/day) especially after D-penicillamine challenge (> 1000 mcg/day), increased liver copper (> 250 mcg/gm dry weight liver) and positive radioactive copper studies.
Untreated Wilson's disease is invariably fatal. The objective of treatment is to prevent copper from accumulating in the tissues. Intake should be decreased by restricting foods high in copper content (liver, cocoa, chocolate, mushroom, shellfish, nuts, dried fruits and vegetables) to less than 0.6 mg/day of copper. The mainstay of medical therapy is the use of copper binding agents like D-penicillamine. The usual starting dose is 10 mg/kg/day increased gradually over two weeks to 20 mg/kg/day for children under 10 years and 1 gm/day for those above 10 years. Children receiving this therapy require B6 supplementation, and monitoring for proteinuria and blood count abnormalities. If treatment is begun early the neurological and hepatic functions can be normalized and K-F rings can disappear. On the other hand, advanced disease may not be reversible. Further, there is a subgroup of patients who seem to worsen after initial treatment with D-penicillamine. Though these patients recover, they do not usually recover to pretreatment baseline. Side effects of D-penicillamine include early and late reactions including rash, leucopenia, immune-complex nephritis, Goodpasture syndrome, etc.
Other options for treatment are Trientene, Ammonium tetrathiomolybdate, and oral zinc sulfate or acetate at 75 - 150 mg of elemental zinc per day. Zinc is becoming the mainstay of maintenance treatment after the other agents achieve initial decoppering. Liver transplant is the only measure for patients with fulminant hepatic failure or with end stage hepatic disease.
Screening of all siblings is advised. Absence of symptoms or abnormalities on clinical examination does not exclude the possibility of Wilson's, which needs investigation. Haplotype analysis helps to diagnose carriers and asymptomatic patients where serum ceruloplasmin levels are inconclusive. Availability of molecular diagnosis aids prenatal diagnosis. At the moment these sophisticated tests pose a limitation in Indian conditions.
Disorders of Carbohydrate Metabolism
The commonest types are GSD3 and GSD1. GSD3 is debrancher enzyme deficiency. The symptoms of GSD3 are similar to GSD 1 but milder. Both of them have hepatomegaly and hypoglycemia .In GSD 1 there is hyperlipidemia ketoacidosis, hyperlactic acidemia and hyperuricemia. There is platelet dysfunction and prolonged bleeding time. Failure to thrive, doll-like facies, huge abdomen and early morning fasting hypoglycemia with or without seizures and xanthomas are clinical clues to the diagnosis. Liver biopsy reveals PAS positive and diastase sensitive material and liver enzyme analysis reveals glucose 6 phosphates deficiency. In GSD 3 profound hypoglycemia and extreme hyperlipidemia is rare. Prognosis is fair to good.
Galactosemia presents with milk-triggered symptoms of vomiting, diarrhoea, hypoglycemia, jaundice and the later development of cirrhosis, mental retardation and cataract. Reducing substances are present in the urine on Benedicts test while glucostix are negative suggesting that the sugar is other than glucose. Sugar chromatography confirms the diagnosis. Treatment is avoiding milk containing lactose and giving soy milk.
MANAGEMENT OF INBORN ERRORs OF METABOLISM (IEM)
Basic Principles of Therapy
(a) Prevention of the accumulation of toxic levels of the precursor substance. Restrict offending substrate in the diet.
(b) Stimulation of elimination of a toxic substrate / precursor by an alternative pathway
(c) Supply the deficient product.
(d) Enhance the activity of the deficient enzyme by providing co-factors e.g. vitamins (see below).
(e) Supply essential nutrients / disease specific diet after the diagnosis is established, sometimes specific synthetic medical formulae are ideal
In majority of aminoacid disorders human breast milk provides least protein load e.g.1gm%. Breast milk is relatively safe to give except in galactosemia Animal milk is unsafe because of high lactose concentration.
Emergency Management - General Principles
1. Minimize intake of substrates that produce toxic metabolite viz. protein in aminoacidopathies lactose in galactosemia, sugar in hereditary fructose intolerance, fats in fatty acid oxidation disorders. Administer high carbohydrate IV fluids (10% dextrose), maintainence fluid requirement 1.5 times to promote diuresis and to avoid overload. As the child improves, increase protein intake gradually from 0.5 gm/kg/day to 1gm/kg/day. Avoid trigger factors mentioned above.
2. Treat hypoglycemia, metabolic acidosis, electrolyte imbalance, infections and coagulopathies using conventional treatments.
3. Dialysis for sever hyperammonemia and resistant life-threatening metabolic acidosis; peritonial dialysis is slower but less technologically/ hemodynamically demanding than haemodialysis
4. Pharmacological agents to detoxify and accelerate the excretion of toxic metabolites.
5. Vitamin co-factor therapy to increase residual enzyme activity ( see below ).
6. Secondary carnitine deficiency occurs in many IEMs and oral carnitine should be supplemented (100 mg/kg/day). In critical cases collect enough blood - separate plasma and RBCS collect 50-100 ml urine and freeze it at -20 C. This could come useful for diagnosis and genetic counseling. The importance of diagnosis is underestimated. Once the samples are collected one can start the treatment.
VITAMINS & CO-FACTORS
Vitamins which act as cofactors give striking improvement in many simple molecular diseases.
Recommended readings
The Metabolic and Molecular Basis of Inherited Disease. CR Scriver, AL Beaudet, WS Sly, D Valle, eds. 7th edn (1995) McGraw Hill, Newyork.
Clinical Biochemistry and The Sick Child. BE Clayton, JM. Round. 2nd edn (1994), Blackwell Scientific Publications, Oxford.
A Clinical Guide to Inherited Metabolic Diseases. JTR Clarke 1996 Cambridge University Press, Cambridge
Burton BK. Inborn errors of metabolism in infancy : a guide to diagnosis. Pediatrics 1998; 102: 6.
Neurology of Hereditary Metabolic Diseases of Children; Gilles Lyon; Raymond D Adams Edwin H Kolodny. McGraw-Hill; 2nd edn.
References
1. Verma IC. Burden of genetic disease in India. Indian J Pediatr 2000; 67 (12) : 893-898.
2. ICMR Collaborating centres & central coordinating unit. Multicentric study on genetic causes of mental retardation in India. Indian J Med Res (B) 1991; 94 : 161-169.
3. Muranjan M. Personal communication analysis of data on Inborn Errors of Metabolism seen over a period from 1979 to 2004 at the Genetic clinic PRL, KEM Hospital Mumbai.(Kumta NB)
Abstract
The inborn errors of metabolism (IEM) constitute a diverse heterogeneous group of disorders with protean clinical manifestations presenting mainly in the pediatric population. Though individually rare, together they constitute a significant percentage of children seen in genetic and neurology clinics. This review focuses on selected IEMs and highlights those seen in the neonatal period. Data from Indian centers are presented. It also emphasizes principles of management in these difficult disorders in the context of a developing country.
Keywords: Inborn errors of metabolism; Neurometabolic; Childhood; India
There is an accelerating demographic switch from communicable diseases to genetic disorders. The expression of a genetic disease is the combined effect of genes and the environment. There are 24 million births in India annually; 780,000 are born with congenital malformation, 340,000 with G6PD, 20,800 with metabolic disorder, 21,000 with Down syndrome, 10,400 with congenital hypothyroidism, 9000 with thalassemia and 5200 with sickle cell anemia. In a hospital based study in India biochemical screening of 4400 cases of mental retardation revealed that 5.75 % (256 cases) were due to a metabolic disorder.[1],[2]
Mechanism of Metabolic Disorders
EAB is an enzyme converting A into B. EBC, the enzyme converting B into C, is absent and is the cause of the IEM. This leads to accumulation of substrate B to abnormal levels which then gets diverted to an abnormal metabolic pathway to yield a toxic metabolite D. B or D could be toxic. B & D could be detected and EAB can be estimated biochemically.
Neonatal IEM
Organic aciduria or urea cycle disorders are not uncommon and often present fulminantly. Early diagnosis is crucial for three reasons,[1] the condition is rapidly progressive and causes irreversible damage early in the course,[2] the treatment can often be effective if commenced early and long term outcome maybe improved[3] and correct early diagnosis helps in genetic counseling. Use of blood gases, electrolytes, ammonia, lactate, pyruvate, urine metabolic spot tests, gas chromatography mass spectroscopy (GCMS) or tandem mass spectrometry (TMS) for organic acids, amino acid chromatography, enzyme estimations in white cells, skin fibroblasts and other tissues have made diagnosis possible.
In neonatal IEM pregnancy, delivery is uneventful. The newborn baby with IEM is normal for the first three or four days after which the disorder presents due to intake of dietary protein etc. Neonates with IEM are misdiagnosed to have sepsis or other disorders. Sepsis often accompanies IEM and may confound diagnosis further. Pediatricians often think that neonatal IEM is rare. Though individual disorders may be uncommon these disorders are fairly common when considered together. Though IEM are usually recessive disorders they are very often occur in only one sib. The neonate has a limited response to illness and predominant symptoms & signs are poor feeding, lethargy, coma, failure to thrive, seizures, acidosis or ketosis. Emergency adequate laboratory facilities to diagnose neonatal IEM are scarce and lacking in India leading to delays in diagnosis, treatment and hence a poor prognosis in most cases.
A high index of suspicion is necessary when the following are present :
Parental consanguinity
Positive family history of a similar illness/death
Symptoms onset a few days after feeding (refusal to feed, lethargy, vomiting, hypotonia, coma, seizures)
Ketosis, acidosis, hypoglycemia
Unusual odour to the urine
Jaundice, visceromegaly
Dysmorphic features or coarse facies
Specific Features in Certain Neonatal IEM.
(1) Abnormal urine or body odour is characteristic of some IEM MSUD - maple syrup or burnt sugar smell, Isovaleric acidemia, Glutaric aciduria type II - sweaty feet smell, Phenylketonuria -mousy or mushy, b methyl crotonyl aciduria - tom cat urine, Methionine malabsorption - cabbage, Trimethyl aminuria - rotting fish, Tyrosinemia - rancid or fishy odour.
(2) Diarrhoea: (a) Severe watery diarrhoea - congenital chloride diarrhoea, galactosemia, primary lactase, sucrase, isomaltase deficiency. (b) Chronic diarrhoea- bile acid disorder,infantile Refsum disease, respiratory chain disorders associated with steatorrhoea , vitamin deficiency osteopenia, hypocholesterolemia (c) Diarrhoea, failure to thrive, hypotonia hepatomegaly - GSD I, Wolmans disease
(3) Cardiomyopathy, Cardiac Failure - Pompe's disease GSD II,respiratory chain disorder, fatty acid oxidation (FAO) defects
(4) Hepatomegaly - Tyrosinemia, galactosemia, fructosemia and alpha 1 antitrypsin deficiency, GSD. Hepatomegaly with splenomegaly consider mucolipidosis, Gaucher's disease Niemann-Pick type A
(5) Seizures - Nonketotic hyperglycinemia, pyridoxine dependency, and molybdenum co-factor deficiency. In most others seizures are associated with coma and hyperglycinemia
IEM has a "Characteristic"
1 Age of onset
2 Temporal profile i.e. evolution of the disease with characteristic symptom & sign as the disease advances; affected sibs usually show a similar temporal profile
3 IEM has a characteristic inheritance pattern eg. ornithine transcarbamylase deficiency (OTC), Fabry's disease, Menkes disease and Hunter's disease are X-linked recessive and most others are autosomal recessive.
4 Often there are characteristic triggers - environmental factors which precipitate the presentation of the IEM e.g. diet, infection, fasting, drugs (see below)
5 Age of neurological man ifestations and death
Triggering Factors Precipitating Iem0
1 Diet: Introduction of cane sugar - hereditary fructose intolerance, milk - galactosemia, proteins = urea cycle disorders (UCD), MSUD and other aminoacid disorders. carbohydrate - pyruvate dehydrogenase & respiratory chain disorders.
2 Infection, Fasting and Fever: FAO defects, certain aminoacid disorder and organic aciduria.
3 Anaesthesia - Homocystinuria
4 Drugs - Porphyria and G6 PD deficiency
Group 1- Aminoacidopathies: Neurologic Distress "Intoxication" Type With Ketosis
MSUD - Maple syrup urine disease - only amino acid disorder that presents acutely in the neonatal period.
It is a branch chain amino acid (BCAA) disorder i.e. leucine, isoleucine and valine. Deficiency of ketoacid dehydrogenase results in formation of ketoacids, which give a strongly positive urinary dipstick test for ketones. There is a strong smell of maple syrup to the urine. Initial 3 - 4 days after birth are normal; feeding difficulties start and gradually the neonate becomes comatose with episodic generalized hypertonia, dystonia, ophisthotonos and boxing / pedaling movements. Urine DNPH test is strongly positive and test for acetone is negative. Plasma amino acid chromatography displays elevation of branched chain aminoacids. Dialysis removes the branched chain aminoacids and should be instituted promptly. Treatment of cerebral oedema is mandatory and special f ormula feeding with low BCAA is the most important part of management. Liver transplant offers promising results. Prognosis is guarded. Intercurrent infections leads to severe ketoacidosis, cerebral oedema and death.
Group 2 - Organic acidopathies0 : Methylmalonic academia (MMA), Propionic academia (PA), Isovaleric academia (IVA) : Neurologic distress "intoxication" type with ketoacidosis and hyperammonemia
Infants present with recurrent vomiting, deep acidotic breathing and failure to thrive. They are acutely ill, dehydrated and hypothermic. There is truncal and peripheral hypotonia and coarse limb tremors. The blood bicarbonate is low with an increased anion gap Neutropenia and thrombocytopenia are also common, along with ketonuria. GCMS or tandem mass spectroscopy gives confirms the correct diagnosis and MMA, PA and IVA account for 90% of neonatal presenting organic acidopathies. Propionic acid is a potent inhibitor of mitochondrial function resulting in accumulation of lactic acid and ketones leading to metabolic acidosis. MMA sometimes responds to high doses of vitamin B12 while PA might respond to biotin.
Treatment: Dialysis is used to to remove the offending organic acid and elevated ammonia. Dietary protein restriction, avoidance of fasting and metronidazole therapy (to reduce organic acid production by gut flora) are other measures.
Differential diagnosis includes the adrenogenital syndrome with high potassium and low sodium, sepsis with neutropenia and thrombocytopenia and the UCD.
Group 3 - Primary Lactic Acidosis (PDH PC ETC def.) With Neurologic Distress; "Energy Deficiency" type
Enzyme defects in Kreb's cycle leads to respiratory chain deficiencies. The most common of these disorders are pyruvate dehydrogenase (PDH), pyruvate carboxylase (PC) and electron transport chain (ETC) deficiencies. PDH is an X-linked disorder. Boys present with severe metabolic and lactic acidosis in the neonatal period. Clinically the neonate is neurologically depressed and serum lactate is markedly elevated. There is an elevated anion gap because of the elevated lactate and ketosis. The ketogenic diet & dichloracetate 25 to 100 mg/kg orally or parentally may produce a response in 24 hours.Thiamine supplements may be tried. PC deficiency is an AR disorder with lactic acidosis and neurological dysfunction in the newborn period and intermittent ataxia in later life. PC deficiency in early life characteristically has an elevated lactate to pyruvate ratio, moderate citrullinemia, hyperammonemia and hyperlysinemia (type B) while in the later onset variant moderate lactic acidosis & developmental delay occur (type A). The other features are spasticity, severe psychomotor retardation and seizures. Holocarboxylase, synthase and biotinidase deficiencies present with rash, alopecia, lactic acidosis and will remain asymptomatic if biotin supplementation (5 to 20 mg/day) is started before brain damage occurs. This is possible after newborn screening. A trial of biotin is warranted in all patients with lactic acidosis
Though ETC deficiencies may respond to specific vitamins like riboflavin, L-carnitine and co-enzyme Q the response is usually less than satisfactory.
Group 4a - Urea Cycle Disorders (UCD): Neurologic Distress Due to "Intoxication"; Hyperammonemia Without Ketoacidosis
Transamination reactions in most amino acid catabolic pathways result in transfer of amino group to glutamine and glycine either of which might release ammonia into the urea cycle converting it to urea.
Proximal defects in this pathway result in severe accumulation of ammonia vis-à-vis distal defects.
Ammonia is toxic and causes cerebral oedema leading to drowsiness, lethargy, coma, seizures and early death. Ornithine transcarbamylase (OTC) deficiency is X-linked. All others are inherited as autosomal recessive. Measurement of plasma ammonia, plasma aminoacids and urinary amino and orotic acids are crucial to identify the specific defects in the UCD. Citrullinemia, argininosuccinic acidemia and argininemia are diagnosed by aminoacid chromatography, whereas OTC deficiency and carbamoylphosphate synthetase (CPS) deficiency being more proximal defects give deficiencies of citrulline or arginine. These latter two are differentiated on the basis of an elevated orotic acid excretion in the urine. The diagnosis is also confirmed by enzyme estimation in skin fibroblast or in the liver cells. Treatment of UCD involves dietary protein restriction, sodium benzoate and phenyl butyrate therapy. The more distal defects are more amenable to treatments with drugs. Prognosis depends heavily on the degree of the cerebral damage sustained prior to the diagnosis and treatment.
Group 4b - Nonketotic hyperglycinemia (NKH) : Neurologic distress due to "energy deficiency"; type without ketoacidosis and without hyperammonemia
This is characterized by poor feeding, failure to suck, lethargy hypotonia, coma, and myoclonic jerks appearing within few hours of birth in an infant with no history of perinatal insults. A burst suppression EEG pattern, elevated plasma glycine, elevated CSF to plasma glycine ratio constitutes the diagnosis of neonatal NKH.
Molybdenum co-factor deficiency / sulfite oxidase deficiency present similarly with hypotonia, seizures, dysmorphic features and cataracts. Diagnosis is suggested by a very low plasma uric acid and presence of sulfites in fresh urine while aminoacid chromatography shows high sulfite concentration in the form of sulfocystenine.
Group 4c - Lysosomal Storage Disorders Without Metabolic Disturbances
Few lysosomal disorders present in the neonatal period. These disorders are GM 1 ganglioidosis, Gaucher's disease, Niemann-Pick disease type C, MPS VII and sialiodosis.
Other disorders are glycogenosis (GSD) and gluconeogesis defects, fatty acid oxidation defects etc.
Selected IEMs presenting after the neonatal period
Neurometabolic/Neurodegenerative Disorders
These are genetically inherited disorders with progressive neurologic deterioration, having a demonstrable biochemical abnormality associated with enzyme defects. Heterozygote detection and prenatal diagnosis is possible. Most of them belong to the lysosomal storage disorders leading to neural, neurovisceral and musculo-skeletal manifestations. Simple molecular disease like amino acid, sugar, organic acids and UCD have a catastrophic presentation whereas complex molecular diseases have an insidious onset and a chronic cour
Disorders of copper metabolism
A total of 146 children were seen at the KEM with 142 being Wilson's disease and 4 being Menkes disease.
Wilson's disease is an inborn error of copper metabolism. It is an autosomal recessive disorder with an incidence 1 in 35,000 - 1,00,000; the gene is located at 13q 14 - 21. It is characterized by increased copper deposition in the liver, brain, kidneys and corneas. Classically, there are specific progressive neurological findings, chronic liver disease or cirrhosis, renal tubular dysfunction, sunflower cataract and pigmented corneal rings (Kayser - Fleischer rings). However, the variability of the disease is such that it should be suspected in any patient with unexplained neurologic or psychiatric dysfunction, hepatitis, hemolytic anemia, renal Fanconi syndrome or hematuria. The onset ranges from 4 to 50 years. An earlier age of onset is in general associated with liver disease often without neurological manifestation and not invariable K-F rings. Liver involvement may present with asymptomatic hepatomegaly, jaundice with edema and ascitis, hepatosplenomegaly with vague gastrointestinal symptoms or subacute viral hepatitis, fulminant hepatitis, chronic active hepatitis, juvenile cirrhosis, post-hepatic cirrhosis and cryptogenic cirrhosis. Neurological manifestations range from dystonia- Parkinsonism More Details, dysarrthria, drooling, scholastic deterioration/dementia and behavioural changes.
Clinical and laboratory investigations include peripheral blood for hemolytic anemia, liver function abnormalities, urinary abnormality suggestive of Fanconi syndrome, slit-lamp examination for K-F ring, low serum ceuroplasmin (< 20 mg/dl), increased urinary copper excretion (> 100 mcg/day) especially after D-penicillamine challenge (> 1000 mcg/day), increased liver copper (> 250 mcg/gm dry weight liver) and positive radioactive copper studies.
Untreated Wilson's disease is invariably fatal. The objective of treatment is to prevent copper from accumulating in the tissues. Intake should be decreased by restricting foods high in copper content (liver, cocoa, chocolate, mushroom, shellfish, nuts, dried fruits and vegetables) to less than 0.6 mg/day of copper. The mainstay of medical therapy is the use of copper binding agents like D-penicillamine. The usual starting dose is 10 mg/kg/day increased gradually over two weeks to 20 mg/kg/day for children under 10 years and 1 gm/day for those above 10 years. Children receiving this therapy require B6 supplementation, and monitoring for proteinuria and blood count abnormalities. If treatment is begun early the neurological and hepatic functions can be normalized and K-F rings can disappear. On the other hand, advanced disease may not be reversible. Further, there is a subgroup of patients who seem to worsen after initial treatment with D-penicillamine. Though these patients recover, they do not usually recover to pretreatment baseline. Side effects of D-penicillamine include early and late reactions including rash, leucopenia, immune-complex nephritis, Goodpasture syndrome, etc.
Other options for treatment are Trientene, Ammonium tetrathiomolybdate, and oral zinc sulfate or acetate at 75 - 150 mg of elemental zinc per day. Zinc is becoming the mainstay of maintenance treatment after the other agents achieve initial decoppering. Liver transplant is the only measure for patients with fulminant hepatic failure or with end stage hepatic disease.
Screening of all siblings is advised. Absence of symptoms or abnormalities on clinical examination does not exclude the possibility of Wilson's, which needs investigation. Haplotype analysis helps to diagnose carriers and asymptomatic patients where serum ceruloplasmin levels are inconclusive. Availability of molecular diagnosis aids prenatal diagnosis. At the moment these sophisticated tests pose a limitation in Indian conditions.
Disorders of Carbohydrate Metabolism
The commonest types are GSD3 and GSD1. GSD3 is debrancher enzyme deficiency. The symptoms of GSD3 are similar to GSD 1 but milder. Both of them have hepatomegaly and hypoglycemia .In GSD 1 there is hyperlipidemia ketoacidosis, hyperlactic acidemia and hyperuricemia. There is platelet dysfunction and prolonged bleeding time. Failure to thrive, doll-like facies, huge abdomen and early morning fasting hypoglycemia with or without seizures and xanthomas are clinical clues to the diagnosis. Liver biopsy reveals PAS positive and diastase sensitive material and liver enzyme analysis reveals glucose 6 phosphates deficiency. In GSD 3 profound hypoglycemia and extreme hyperlipidemia is rare. Prognosis is fair to good.
Galactosemia presents with milk-triggered symptoms of vomiting, diarrhoea, hypoglycemia, jaundice and the later development of cirrhosis, mental retardation and cataract. Reducing substances are present in the urine on Benedicts test while glucostix are negative suggesting that the sugar is other than glucose. Sugar chromatography confirms the diagnosis. Treatment is avoiding milk containing lactose and giving soy milk.
MANAGEMENT OF INBORN ERRORs OF METABOLISM (IEM)
Basic Principles of Therapy
(a) Prevention of the accumulation of toxic levels of the precursor substance. Restrict offending substrate in the diet.
(b) Stimulation of elimination of a toxic substrate / precursor by an alternative pathway
(c) Supply the deficient product.
(d) Enhance the activity of the deficient enzyme by providing co-factors e.g. vitamins (see below).
(e) Supply essential nutrients / disease specific diet after the diagnosis is established, sometimes specific synthetic medical formulae are ideal
In majority of aminoacid disorders human breast milk provides least protein load e.g.1gm%. Breast milk is relatively safe to give except in galactosemia Animal milk is unsafe because of high lactose concentration.
Emergency Management - General Principles
1. Minimize intake of substrates that produce toxic metabolite viz. protein in aminoacidopathies lactose in galactosemia, sugar in hereditary fructose intolerance, fats in fatty acid oxidation disorders. Administer high carbohydrate IV fluids (10% dextrose), maintainence fluid requirement 1.5 times to promote diuresis and to avoid overload. As the child improves, increase protein intake gradually from 0.5 gm/kg/day to 1gm/kg/day. Avoid trigger factors mentioned above.
2. Treat hypoglycemia, metabolic acidosis, electrolyte imbalance, infections and coagulopathies using conventional treatments.
3. Dialysis for sever hyperammonemia and resistant life-threatening metabolic acidosis; peritonial dialysis is slower but less technologically/ hemodynamically demanding than haemodialysis
4. Pharmacological agents to detoxify and accelerate the excretion of toxic metabolites.
5. Vitamin co-factor therapy to increase residual enzyme activity ( see below ).
6. Secondary carnitine deficiency occurs in many IEMs and oral carnitine should be supplemented (100 mg/kg/day). In critical cases collect enough blood - separate plasma and RBCS collect 50-100 ml urine and freeze it at -20 C. This could come useful for diagnosis and genetic counseling. The importance of diagnosis is underestimated. Once the samples are collected one can start the treatment.
VITAMINS & CO-FACTORS
Vitamins which act as cofactors give striking improvement in many simple molecular diseases.
Recommended readings
The Metabolic and Molecular Basis of Inherited Disease. CR Scriver, AL Beaudet, WS Sly, D Valle, eds. 7th edn (1995) McGraw Hill, Newyork.
Clinical Biochemistry and The Sick Child. BE Clayton, JM. Round. 2nd edn (1994), Blackwell Scientific Publications, Oxford.
A Clinical Guide to Inherited Metabolic Diseases. JTR Clarke 1996 Cambridge University Press, Cambridge
Burton BK. Inborn errors of metabolism in infancy : a guide to diagnosis. Pediatrics 1998; 102: 6.
Neurology of Hereditary Metabolic Diseases of Children; Gilles Lyon; Raymond D Adams Edwin H Kolodny. McGraw-Hill; 2nd edn.
References
1. Verma IC. Burden of genetic disease in India. Indian J Pediatr 2000; 67 (12) : 893-898.
2. ICMR Collaborating centres & central coordinating unit. Multicentric study on genetic causes of mental retardation in India. Indian J Med Res (B) 1991; 94 : 161-169.
3. Muranjan M. Personal communication analysis of data on Inborn Errors of Metabolism seen over a period from 1979 to 2004 at the Genetic clinic PRL, KEM Hospital Mumbai.(Kumta NB)