<p>Inborn errors of metabolism are disorders in which there is block at some point in the normal metabolic pathway caused by a genetic defect of a specific enzyme. There are over 300 such genetic disorders known. Neurometabolic disorders (NMD) are inborn errors of metabolism (IEM) with neurologic manifestations. Most of these are inherited in autosomal recessive manner but few are X-linked. The past three decades have witnessed impressive progress in our understanding of inherited neurometabolic diseases, promoted by the rapid development and application of molecular genetic strategies. Such progress has required the juxtaposition of clinical evaluations and basic science techniques. The central role of careful and complete assessment of affected children cannot be overemphasized and in no way has been diminished by technological advances. The need for early diagnosis accrues from the benefit of specific therapy, prognostication and genetic counseling for the family. Prenatal diagnosis is possible for many enzyme defects based on measurement of enzyme activity or metabolites in chorionic villi, amniotic fluid or cultured amniotic cells like in arginosuccinic aciduria, methylmalonic acidemia, propionic acidemia, homocystinuria to name a few.</p></sec><sec id="sec002"><title>Extent of the problem

Estimated burden of IEM is 3-4/1000 live births (multinational survey). Upto 20% of acute illnesses in newborn infants in developed countries belong to this category (1). 4.9% of genetic causes of mental retardation are due to IEM (ICMR multicentric study) (2). In various studies in India 0.5-2.4% of mentally retarded children have been reported to have an aminoacid metabolism disorder. (3, 4). In a study at AIIMS - 2560 cases were screened for inborn errors of metabolism; 49 (1.9%) had amino acid disorders. The four commonest disorders were homocystinuria, alcaptonuria, maple syrup urine disease and non ketotic hyperglycinemia. (5). The data on newborn screening available from India is detailed below in Table 1. Table 1

New born screening for inborn errors of metabolism

	India (112,369)*		AIIMS (270)**

Disorder	Detected	1 in	N	%

Phenylketonuria (PKU)	6	18,728	2	0.74
MSUD	11	10,215	2	0.74
Tyrosinemia	18	6,234	5	1.85
Glycinemia	73	26,053	16	5.93
Histidinemia	70	37,456	–	–
Generalised aminoacidemia	1	1,605	4	1.48
Methioninemia	–	1,12,369	–	–
Citrullinemia	–	–	4	1.48
Galactosemia	–	–	4	1.48
Alkaptonuria	–	–	1	0.37
Arginosuccinic aciduria	–	–	1	0.37

*(6)	**(7)

Most common neurometabolic disorders are organic acidurias and aminoacidopathies followed by urea cycle disorders, congenital lactic acidosis, peroxisomal disorders and less frequently sphingolipidoses, mucopolysaccharidoses, glycoprotein degradation disorders, fatty acid oxidation disorders and neuronal ceroid lipofuscinoses (8). Maple syrup urine disease, organic acidurias, urea cycle defects and nonketotic hyperglycinemia constitute over 65% of IEM (9). Distribution of neurometabolic disorders by broad disease category is indicated in the Table 2. Table 2

Spectrum Of Neurometabolic Disorders In Clinical Practice

	Saudubray et al (%) (1968-1987)	Mckusick V (Estimated number)

Aminoacidopathies	31.3	20
Organic acidurias	27.0	50
Hyperammonemias	20.8	5
Respiratory chain/hyperlacticacidemias	12.0	6
Glycogen storage disorders	8.3	–
Fatty acid oxidation	8.3	9
Peroxisomal disorders	4.6	6
Neuronal ceroid lipofuscinoses	–	3
Lysosomal storage diseases	–	20

The following clinical classification gives an insight into the manifestations and pathogenesis of NMDs (Table 3). As evident from this classification the neurological deterioration can be of intoxication energy deficiency type. Manifestations may differ in these two types of diseases. Table 3

Clinical classification of inherited neurometabolic disorders

Clinical Features	Acute Encephalopathy	Chronic (Progressive) Encephalopathy

Age at presentation	Neonatal or early infancy	Late infancy, childhood, or adolescence
Initial central nervous system symptoms	Gray matter	White matter
	Cognitive impairment	Spasticity
	Seizures	Ataxia
	Vision impairment	Hyper reflexia
Metabolite	Small-molecule	Large-molecule (storage)
Clinical course	Intoxication	Energy deficiency or intoxication
	Vomiting	Liver dysfunction
	Lethargy or coma	Cardiomyopathy
	Abnormal respirations	Weakness

Their may be intermittent presentation precipitated by diet, stress, infection and starvation. It includes disorders like methylmalonic acidurias, propionic aciduria, isovaleric aciduria, multiple carboxylase deficiency and urea cycle disorders.

Intoxication: Initial symptom free interval; poor feeding usually first reported; unexplained coma; respiratory abnormalities, hiccups, apnea, bradycardia and hypothermia; changes in muscle tone and involuntary movements; hypertonia, opisthotonus, axial hypotonia and limb hypertonia, myoclonic jerks.

Energy deficiency type: More variable, less dramatic features; May not have initial symptom free interval; hypotonia; cardiac signs, malformations, dysmorphism, organomegaly

Investigations for Neurometabolic disorders: Routine tests such as blood glucose, serum calcium, liver function tests and blood counts, urine metabolic screen, four simple tests particularly useful in detecting and broadly classifying neurometabolic disorders are– arterial blood gases (ABG), blood lactate, blood ammonia, urinary ketones, plasma and urinary aminoacidogram. (Table 4). Table 4

Four simple tests useful for broadly classifying neurometabolic disorders

Acidosis (arterial pH < 7.2, SBE > −5)	Ketosis (urinary ketones positive)	Arterial lactate (> 18 mg/dl)*	Ammonia (> 18 µg/dl)**	Diagnosis

±	+	−	−	Maple syrup urine disease
+	+	±	±	Organic acidurias
+	+	+	±	Lactic acidosis
−	−	−	+	Urea cycle disorders
−	−	−	−	Non ketotic Hyperglycinemia; Peroxisomal Disorders

*Obtain sample after 3 hrs fasting		,* Process immediately

Biochemical autopsy : In a severely ill child, near death, where a metabolic disease is suspected but not diagnosed, parents should be convinced about the need for a biochemical autopsy which includes : Blood :- 5-10ml; frozen at −20°C; preferably plasma (heparin) & leukocytes (EDTA) separately; Urine :- 20°C, as much as possible (may be taken by supra pubic aspiration);CSF;Skin biopsy :- including dermis in culture medium or saline with glucose;Liver, muscle, kidney or heart biopsy should be done and tissue must be frozen; Clinical photograph for dysmorphism; Infantogram Management

Principles of therapy for IEM (<xref ref-type="bibr" rid="bib010">10</xref>, <xref ref-type="bibr" rid="bib011">11</xref>)

Treatment may have to be instituted empirically without a specific diagnosis. Reduce the formation of toxic metabolites by decreasing substrate availability (by stopping feeds and preventing endogenous catabolism). Provide adequate calories. Enhance excretion of toxic metabolites. Institute co-factor therapy for specific disease and also empirically if diagnosis not established.

Immediate steps (For acutely ill child)

Stop oral feeds, process/store blood and urine samples before stopping feeds. Start parenteral fluids (appropriate for age). Correct dehydration, acidosis and dyselectrolytemias. Start specific therapy if any (e.g. sodium benzoate for hyperammonemic states).Monitor and maintain vitals, BS, pH, electrolytes. Transfer to a tertiary center.

Further management at a tertiary care center

Cardiorespiratory support (mechanical ventilation if needed). In case of non response/worsening with previous therapy/peritoneal dialysis, hemodialysis, exchange transfusion may be done to get rid of toxic metabolites.

Hyperammonemic states (organic acidemias, urea cycle defects)

Appropriate dietary restriction of protein (0.5-1.0 gm/kg/day), special diets. Sodium benzoate: 250 mg/kg/day in 4-6 doses orally (IV preparation not available in our country.

It conjugates with NH3 and forms a nontoxic metabolite that is easily excreted. Sodium phenylacetate (250-500 mg/kg/day) and arginine 200-800 mg/kg/day are also effective. Carnitine supplementation has also been recommended with phenylacetate and benzoate.

Catabolic states triggering hyper-ammonemia should be avoided.

General principles of dietary management

The fate of dietary protein is detailed in Fig. 1.

Dietary reduction of substrates frequently protein or amino-acids, associated with formation of the toxic metabolities. e.g. phenylalanine in PKU, protein restriction in urea cycle defects, galactose/lactose in galactossemia.

Replacement of essential nutrients that are deficient as a result of the metabolic block e.g. cystein in homocystinuria HCU.

Co-factor therapy: Pharmacological doses (upto 100 times the nutrient requirement) of specific vitamins to induce nonfunctional enzyme activity.

Enhancement of excretion or product utilization to form nontoxic metabolite like sodium benzoate in urea cycle disorders.

The choice of therapy depends on the enzyme defect and its consequences but must be constructed to allow the child to grow and develop normally.

Dietary therapy should be started as early as possible as during the initial years the developing brain is most susceptible to the toxic effects of substrate and the by products.

In most situations dietary therapy has to be continued through out life.

The requirement of protein and essential aminoacids must normally be provided in the diet. Total nitrogen requirement may be lower than normal for infants with organic acidemias and urea cycle defects. Non essential aminoacids should be provided ideally in the same proportion as in human milk.

Frequent measurements of plasma aminoacids and other metabolites is essential for monitoring deficiencies and control of the disorder. Table 5

Cofactor/limiting amino acid therapy

Disorders	Vitamin/cofactor	Dose (mg/d)	Aminoacid supplement

Phenylketonuria	–	–	Tyrosine
Neonatal tyrosinemia	Vit. C	50–100	–
Classical	Pyridoxine+	100–500	Cystine
homocystinuria	folic acid	10–20	(those needing methionine diet)
Hartnup with pellagra	Niacin	100–250	–
Maple syrup urine disease	Thiamine	1000	–
Methylmalonic acidemia	B–12	1–3	Bicarbonate Carnitine
Multiple carboxylase	Biotin	10–20	(100 mg/kg/d)
Isovaleric acidemia	–	–	Glycine ; Carnitine
Hawkinsuria	Vit. C	1000	–
Mitochondrial disorders	Riboflavin	100	–
	Coenzyme Q10	120
	Idebenone

Figure 1Fate of dietary protein

The various cofactors and limiting aminoacids are detailed in Table 5

As the diagnostic facilities are not easily available in our country one may occasionally resort to megavitamin therapy in unexplained situation as given below in Table 6: Table 6

Megavitamin therapy mg/day (when specific diagnosis not established)

Thiamine	50 (10-3000)
Riboflavin	50 (50-400)
Nicotinamide	600
Pyridoxine	100 (50-500)
Biotin	10 (5-50)
Vit B 12	1 (1-10)
Folic acid	15
Vit C	3000 (up to 5000)
Vit E	200-400
Carnitine	50-100 mg/kg/day

Few disorders are discussed in detail belowAminoacid disorders (<xref ref-type="bibr" rid="bib011">11</xref>)Alteration of aminoacid pattern of diet

This type of diet is used when the plasma aminoacid pattern is specifically altered by the inborn error. The elevated aminoacid is restricted e.g. low phenylalanine in PKU, low leucine, isoleucine and valine in MSUD. Limiting aminoacid is supplied by dietary protein supplements. Intake of protein is titrated against the plasma aminoacid levels. The specifically manufactured diets have proteins supplemented with aminoacids in the form of protein substitutes specific for the disorder and have a reduced content of the aminoacids which can not be metabolised.

Low Protein Diets

IEMS of the catabolism of aminoacids which lead to the accumulation of toxic metabolites such as ammonia but not of specific amino acid require restriction in dietary protein along with high energy intake. These patients will usually tolerate the amount of protein which is just adequate for growth. In these situations an arbitrary protein intake is prescribed and fine control is usually difficult. Alterative means of removing toxic metabolites is to be considered (Benzoate in urea cycle disorders). Protein should normally provide 6% of total dietary energy except during relapses. In severe forms adequate protein supplementation may be difficult.

Combined low protein diet with supplementary aminoacids

Certain disorders require limitation of total nitrogen intake but need supplementation of aminoacids which become essential as a result of metabolic block. e.g. arginine in urea cycle defects.

Practical Aspects to be kept in mind. In low protein diets, protein should be of high biological value but dietary variety should be kept in mind. In infancy human milk or whey based infant formulae are ideal protein sources. Later other foods such as cereals, pulses, milk etc. are introduced. Protein substitutes are available for specific IEMS but essential fatty acids, energy and conventional food are to be supplemented. Fruits and vegetables are permitted without measurement mostly except in few disorders like classical MSUD. Protein cannot be utilized for growth unless adequate dietary energy is available. Protein restricted diets are frequently low in energy. Energy can be provided by measured quantity of natural protein food, low protein or negligible protein food - sugar, fats, butter, fruits, vegetables and other low protein preparations. Glucose polymers and fat emulsions are at times necessary.When natural food is restricted vitamin deficiencies may result. A complete supplement of all natural vitamins may be given. Vitamins may have to be used as cofactor therapy in various diseases. A number of minerals and trace elements may have to be supplemented. Ready made preparations are available but not in India. Can be supplemented by using vegetable oils.

In case of acute illness and metabolic relapse: Precipitating event should be managed and specific management according to the disease should be done. Temporary omission of protein (or very low 0.25 - 0.5 gm/kg/day) is recommended along with high energy supplements through oral or parenteral route. We have found hepatic coma diet to be useful during these episodes.

Phenylketonuria

PKU is managed by using a controlled low phenylalanine diet. The recommended intake of nutrients (except phenyl alanine and tyrosine) are similar to normal infants. Protein free energy, all vitamins, minerals and trace elements are supplemented. Regular estimates of blood phenylalanine levels is essential. The levels must be maintained between 3-15 mg/dl. Several low phenylalanine diets are available in the west. None of these are available in India but can be imported. These special diets are very expensive and most parents have problem of affordability. Based on the phenylalanine content of some common products used in India dietary exchanges can be calculated and diet can be charted in situations when commercial diet cannot be procured (12), though the management is suboptimal and unsatisfactory. The patient is usually given 1/3 to 1/10th of normal phenylalanine content. The phenylalanine intake varies at different age groups and has to be titrated according to phenylalanine levels. There can be some relaxation in rigid dietary, restriction after 3 years of age but some restriction has to continue throughout life. A very strict control in PKU diet in girls during pregnancy is mandatory.

Maple syrup urine disease

In MSUD the intake of leucine, isoleucine and valine has to be restricted. It is a very difficult disorder to manage, and more so without availability of commercial diet. A modified Indian diet can be prescribed but there are no long term experiences available. The intakes should vary at different age groups and diet needs modification accordingly.

Homocystinuria (<xref ref-type="bibr" rid="bib013">13</xref>)

A low methionine and high cysteine diet helps in maintaining intellectual development. Introduction of dietary therapy is worthwhile at any age, but is very costly for the Indian patient, as the commercially produced low methionine and high cysteine formulas are not available and need to be imported. Therefore, most of the times, one has to plan a special diet for patients, using locally available foods. These diets aim to provide 25-45 mg/kg/day of methionine in infants and 8-10 mg/kg/day of methionine in teenagers. Since wheat and pulses are to be restricted, the caloric density of the diet can be increased by mixing sago or arrowroot powder in wheat flour. It is difficult to increase the cystine content of this diet without inadvertently increasing its methionine content. Therefore, these diets are not as effective as the commercial diets.

Trial of treatment with Pyridoxine and folic acid is worthwhile in all the cases. Treatment with betaine (trimethylglycine; 6-9 g/d) which serves as a methyl group donor, produces clinical improvement in patients unresponsive to pyridoxine.

Galactosemia

Classical form of galactossemia is caused by galactose 1 phosphate uridyl transferase deficiency. Other forms are due to galactokinase and epimerase deficiency. Dietary exclusion of galactose and lactose (from which galactose is derived) is necessary almost through out childhood and major sources should probably be omitted through out life (14). A nutritionally adequate galactose/lactose free milk substitute should be used during infancy and later as a suppliment to diet. In later childhood occasional lactose free milk and calcium and vitamin suppliments may suffice. The monitoring should ideally be done by measurement of galactose 1-phosphate levels in RBC’S. Fortunately lactose free formula are available in our country and this disorder can be managed with relative ease. Some people also recommend restriction of plant foods (pulses, beans, peas spinach) during infancy and early childhood due to presence of galactosides and nucleoproteins which are potential source of galactose but opinions differ (15, 16).

Glycogen storage diseases

These disorders principally affect the liver and have nine different types depending on the enzymes involved. As carbohydrate metabolism in liver is responsible for glucose homeostasis this group of disorders presents typically with hypoglycemia & hepatomegaly (not in all types). Treatment is designed mainly to maintain normoglycemia and is achieved by continous nasogastric infusion of glucose or oral uncooked starch. Uncooked starch acts as a slow release form of glucose (17) This is specially useful in Type I, III & VI but most demanding in Type I.

In some situations one is faced with a newborn baby whose previous sib(s) had a suspected NMD but diagnosis was not confirmed. The following flow chart gives an approach to such newborn (Fig 2). Figure 2Suspected neurometabolic disease in a new born infant

Management Issues in Inborn Errors of Metabolism