INBORN ERRORS OF METABOLISM

Question 1

What are IEM?

Answer 1

IEM are genetically determined biochemical disorders in which a specific enzyme defect produces a metabolic block that may have pathologic consequences at birth or in later life.
The clinical and biochemical abnormalities observed in a given inherited metabolic disease reflect the mutation of a specific gene. Most of the inherited metabolic disorders (inborn errors of metabolism) are due to the defective synthesis of a single protein or peptide which normally functions as an enzyme or as a transport system.

Question 2

What are some effects of metabolib block?

Answer 2

1. Accumulation of enzyme substrate (A): e.g., phenylalanine in phenylketonuria (PKU), glycogen in glucose-6-phosphatase deficiency.
2. Conversion of enzyme substrate to other metabolites (C) by an alternative pathway, e.g. phenylalanine to phenylpyruvate in PKU.
3. Lack of formation of end products (B) subsequent to the block, e.g., melanin in phenylketonuria, cortisol in CAH.

Question 3

Effects of a metabolic block in PKU

Answer 3

1. Accumulation of the enzyme substrate -→ phenylalanine
2. Conversion of enzyme substrate to other metabolites by an alternative pathway→ phenylalanine to phenylpyruvate
3. Lack of formation of end products subsequent to the block -→ melanin

• If the accumulated products are soluble they will accumulate in the body fluids and excreted in urine (e.g., phenylpyruvate in PKU)

*if insoluble they may be stored in cells (e.g., glycogen in glycogen storage diseases) or excreted in faeces (e.g., coproporphyrins & protoporphyrins in certain porphyrias).

Question 4

What are the Types of inheritance?

Answer 4

• Autosomal inheritance –
  Autosomal Dominant (AD) or
  Autosomal recessive(AR)

*Sex linked inheritance
X-linked recessive
X-linked dominant

*Other inheritance
Maternal (Mitochondrial) inheritance
Others

Question 5

Discuss potency and it’s effect on genetic expression

Answer 5

The expression of the gene depends on its potency. Dominant genes produce effects in both homozygous & heterozygous individuals; recessive genes only produce effects in homozygous subjects.
However, the terms are relative & dominance may not be absolute. E.g.
A dominant gene may show incomplete penetrance in that it may skip a generation, or it may vary in degree of potency & produce a lesser effect.
Sometimes a recessive gene which normally only produces its effect in the homozygous patient may be of sufficient potency to produce minor effects in the heterozygote.

Question 6

Discuss Maternal (Mitochondrial) inheritance

Answer 6

Maternal (Mitochondrial) inheritance: a maternal mode of inheritance, in which all the offspring of an affected mother are affected, but none of an affected father

Question 6

Discuss Sex linked inheritance

Answer 6

Sex linked inheritance: Some abnormal genes are carried on the sex chromosomes (XX in females, XY in males), mostly on the X chromosome.
X-linked recessive: A recessive gene on an X chromosome will manifest if:
it is combined with a Y chromosome, i.e., in the male, or
the female is homozygous for it, having inherited one abnormal gene from her father & one from her mother.
X-linked dominant: In this situation both males & females will be affected. E.g. Familial hypophosphataemia.

Question 7

Classification of IEM

Answer 7

1. Disorders of amino acid metabolism
2. Organic acidurias
3. Disorders of carbohydrate metabolism
4. Urea cycle disorders
5. Lysosomal storage defects
6. Disorders of lipid metabolism
7. Mitochondrial disorders
8. Peroxisomal disorders
9. Abnormalities of drug metabolism
10. Miscellaneous causes

Question 8

Discuss DISORDERS OF AMINO ACID METABOLISM (AMINOACIDURIAS) and the types

Answer 8

2. They can be due to a transport defect (inherited disorders of amino acid transport mechanisms) e.g.
   the dibasic amino acids (with two amino groups) cystine, ornithine, arginine and lysine (cystinuria)
   neutral amino acids (with one amino and one carboxyl group) (Hartnup’s dx)
   the imino acids proline and hydroxyproline, which probably share a pathway with glycine (familial iminoglycinuria).
3. an overflow type of disorder resulting from excess production of amino acids or their metabolites due to an enzyme deficiency, e.g., PKU, alkaptonuria, maple syrup urine dx, homocysteinuria, tyrosinaemia, albinism, histidinaemia

Question 9

Discuss Cystinuria as an Inherited disorders of amino acid transport mechanisms
What are it’s 2 reconized phenotypes?

Answer 9

Cystinuria: is the commonest inborn error of amino acid transport and is due to failure of the renal tubular and gut transport mechanisms concerned with absorption of the dibasic amino acids; cystine, ornithine, arginine, and lysine (COAL).
This results in cystinuria and often the formation of cystine renal stones (but usually asymptomatic).

There are 2 recognized phenotypes:
Type 1 or recessive cystinuria where there is increased renal excretion of all four dibasic amino acids and commonly associated with stone formation.
Type 2 which is incompletely recessive and associated with increased urinary levels of cystine and lysine only (stone formation is rare).

Question 10

Diagnosis and management of cystinuria?

Answer 10

Diagnosis is made by demonstrating excessive urinary excretion of the characteristic amino acids. A useful screening test is the cyanide-nitroprusside reaction with cystine.

The management of cystinuria aims to prevent calculi (stone) formation by reducing urinary concentration.
drink plenty of fluid.

Alkalinizing the urine increases the solubility of cystine.

If these measures prove inadequate, D-penicillamine may be given; this forms a chelate, which is more soluble than cystine alone.

Question 11

Discuss Hartnup’s disease as an Inherited disorders of amino acid transport mechanisms

Answer 11

Hartnup’s disease: a rare recessive disorder where there is a renal & gut transport defect involving the neutral amino acids including tryptophan, an essential amino acid. It may present with a pellagra-type rash, mental confusion, and ataxia which may be due to tryptophan deficiency

(tryptophan is a precursor of nicotinic acid/vitamin B2, which causes pellagra when deficient). The metabolic defect is diagnosed by demonstrating the characteristic excess of neutral amino acids in the urine.

Question 12

Hartnup’s disease is also known as:

Answer 12

Blue diaper syndrome/Drummond’s syndrome

Question 13

Discuss Familial iminoglycinuria as an Inherited disorders of amino acid transport mechanism

Answer 13

Familial iminoglycinuria: Increased urinary excretion of the imino acids; proline, hydroxyproline and glycine, despite normal plasma concentrations, is due to a transport defect for these 3 compounds. The condition is inherited as AR trait. It is apparently harmless, but must be differentiated from other more serious causes of iminoglycinuria, such as the defect of proline metabolism, hyperprolinaemia.

Question 14

Discuss cycstinosis as an Inherited disorders of amino acid transport mechanism

Answer 14

Cystinosis: A very rare but serious disorder of cystine metabolism, characterized by intracellular (lysosomal) accumulation & storage of cystine in the cornea, bone marrow, kidney, leucocytes and other tissues. Inherited in an AR manner. It must be distinguished from cystinuria, a relatively harmless condition.
The most severe form is nephropathic cystinosis with impaired renal function and the Fanconi syndrome. Growth may be retarded and vitamin D resistant rickets may develop.
RX = renal transplantation; cystine does not accumulate in the transplant. Amino aciduria is non-specific and of renal origin. Affected individuals may die young

Question 15

Discuss Overflow aminoaciduria - Phenylketonuria (PKU)

Answer 15

PKU is an AR disorder caused primarily by a deficiency of phenylalanine hydroxylase (converts phenylalanine to tyrosine).
In about 3% of cases, the biochemical defect is in enzymes that synthesize cofactors for phenylalanine hydroxylase (phenylalanine hydroxylase requires tetrahydrobiopterin as a cofactor which in turn depends on the enzymes dihydropteridine reductase and dihydropteridine synthetase for maintenance; deficiency of either enzyme will cause the disorder).
There is accumulation of phenylalanine in the blood (and urine) and reduced tyrosine formation. Activation of alternate pathways of metabolism leads to formation of phenylalanine derivatives such as phenyllactate, phenylacetate, and phenylpyruvate which are produced in excess & appear in the urine.

Question 16

Clinical features, diagnosis and treatment of PKU

Answer 16

The CFs are initially irritability, feeding problems/vomiting, seizures, and a tendency to reduced melanin formation resulting in a pale skin, fair hair, and blue eyes. Mental retardation develops later at 3-6 months.

Diagnosis: high plasma phenylalanine levels.

Guthrie test (a screening test) was used to assay phenylalanine, but chromatography methods or tandem mass spectroscopy are used.

In the newborn, and especially preterm infants, the enzyme system may not be fully developed and false-positive results are likely if the test is performed too early. If a positive result is found, the test should be repeated later, to allow time for development of enzyme.

Urinary phenylpyruvate can also be detected by the ferric chloride reaction, e.g., Phenistix.
Heterozygotes may be clinically normal, but can be detected by biochemical tests.
Rx - maintenance on a low-phenylalanine diet

Question 17

Discuss Overflow aminoaciduria - Alkaptonuria

Answer 17

is an AR disorder associated with a deficiency of homogentisic acid oxidase (HGA). This leads to a build-up of HGA, an intermediate compound in the metabolism of tyrosine.
In infancy and childhood, the only sign is darkening of the urine, which occurs when the urine stands in an alkaline pH or is exposed to air. The disease is usually detected by mothers who notice dark stains on diapers.
The conversion of HGA to alkapton is accelerated in alkaline conditions, and sometimes the most obvious abnormality in alkaptonuria is darkening of the urine as it becomes more alkaline on standing. HGA, a reducing substance, reacts with Clinitest tablets

Question 18

Discuss CF and treatment of alkaptonuria

Answer 18

Clinical symptoms begin in adulthood = degenerative arthritis & dark pigmentation of cartilage (ochronosis) caused by binding of HGA and its metabolites to collagen in the connective tissues and cartilage.
Rx - No completely satisfactory treatment yet. If detected early, dietary restriction of tyrosine and phenylalanine may be beneficial. Vitamin C therapy is also used (VitC is said to be required for maximal HGA oxidase activity)

Question 19

Homocystinuria

Answer 19

An AR disorder due to deficiency of cystathionine synthase.

Partial or complete lack of cystathionine synthase, resulting in increased levels of methionine, homocystine, and other sulphur-containing amino acids in body fluids.

Patients may show progressive central nervous system (CNS) dysfunction, thrombotic disease, eye disease, including cataracts, and cardiovascular problems.

The diagnosis is based on the presence of raised urinary and plasma homocysteine with low plasma methionine concentrations.

The defective enzyme can be assayed in cultured skin fibroblasts.

Question 20

Discuss Overflow aminoaciduria - Tyrosinaemia

Answer 20

presents with renal tubular dysfunction, hypoglycaemia and severe liver disease with very raised plasma ALP concentration. The defect is due to abnormal fumarylacetoacetase leading to raised tyrosine, succinylacetone & hydroxyphenylpyruvate.

Diagnosis = raised urinary succinylacetone concentration and assay of fumarylacetoacetase in cultured leucocytes or fibroblasts.

Rx can be dietary, by liver transplantation or by nitro-trifluoromethylbenzoyl cyclohexanedione

Question 21

Discuss Overflow aminoaciduria- Histidinaemia

Answer 21

Histidinaemia is associated with deficiency of histidinase, an enzyme needed for normal histidine metabolism, and is probably inherited as an AR trait. Some individuals may have intellectual disabilities and speech defects, but others may be normal.

The diagnosis is made by demonstrating raised plasma levels of histidine, and by finding histidine and the metabolite imidazole pyruvic acid in the urine.

Question 21

Overflow aminoaciduria - Albinism

Answer 21

A deficiency of tyrosinase in melanocytes causes a severe form of albinism (oculocutaneous albinism type 1, OCA1 Type)
it is inherited as an AR disorder.

Pigmentation of the skin, hair and iris is reduced and the eyes may appear pink. Reduced pigmentation of the iris causes photosensitivity, and decreased skin pigmentation is associated with an increased incidence of certain skin cancers.

Question 22

What are ORGANIC ACIDURIAS (ACIDAEMIAS)?
What is the most common cause and common type of disorder?

Answer 22

A diverse group of disorders which result in accumulation of organic acids in blood & urine. They occur in a wide variety of diseases affecting intermediary metabolism, particularly that of the branched-chain amino acids, the fatty acids, and pyruvate.

They are individually rare, but collectively have an incidence of about 1 in 12,000 births, similar to that of PKU. They may present in the neonatal period with life-threatening metabolic acidosis, vomiting and hypotonia, or in early infancy with failure to thrive, a Reye-like syndrome and convulsions associated with profound hypoglycaemia. They may also be a cause of sudden infant death.

The diagnosis is suggested by the clinical findings and supported by initial tests demonstrating a metabolic acidosis and sometimes hyperammonaemia, with or without ketosis.

It is confirmed by measuring urinary organic acid excretion and subsequent enzyme analysis, performed in specialized laboratories.

The common causes of organic acidurias involve the branched-chain amino acids (leucine, isoleucine, valine), methionine & threonine.

The commonest of these disorders are maple syrup urine disease (MSUD) and methylmalonic aciduria.

Question 23

Consider organic aciduria when an acutely ill child presents with one or more of the following features:

Answer 23

1. vomiting, convulsions, coma of uncertain aetiology
2. unexplained metabolic acidosis
3. hypoglycaemia or ketosis of dubious origin
4. unexplained hyperammonaemia
5. unresolved CNS disorders

Question 24

What is Maple Syrup Disease?

Answer 24

An AR condition, with deficient decarboxylation (branched chain ketoacid decarboxylase) of the oxoacids resulting from deamination of the 3 branched-chain amino acids, leucine, isoleucine and valine.

These amino acids accumulate in the plasma and are excreted in the urine with their corresponding oxoacids. The sweet smell of the urine is like that of maple syrup, hence the condition’s name.

CFs = anorexia, failure to thrive, mild mental retardation, which can progress (especially after a protein load) to severe keto-acidosis, hypoglycaemia, coma, and death. The dx presents during the 1st wk of life and, if not treated, severe neurological lesions develop which cause death within a few wks or mths.

Question 25

Diagnosis and treatment of Maple Syrup Disease

Answer 25

The diagnosis of maple syrup urine disease is made by demonstrating raised concentrations of branched-chain amino acids in plasma and urine and low plasma alanine concentration. It may be confirmed by demonstrating the enzyme defect in leucocytes.

Rx = diet deficient in the branched chain amino acids. Thiamine is effective in some cases.

Question 26

What is Methylmalonic aciduria?

Answer 26

This AR disorder, the commonest of the organic acidurias, is due to either a deficiency of methylmalonyl CoA mutase, or a defect in the metabolism of adenosylcobalamin, a cofactor for the enzyme. The disorder also occurs in severe vitamin B12 deficiency.

The characteristic features include metabolic acidosis, ketosis, hypoglycaemia and hyperammonaemia. Those with the cofactor defect may also have homocystinuria (methylcobalamin is required in homocystine metabolism) and may not have overt ketosis.

Question 27

Discuss carbohydrate disorders and their classification

Answer 27

The 2 commonest disorders of CHO metabolism, other than DM, are Galactosaemia & von Gierke’s dx, both of which may be associated with hypoglycaemia.

Classification:
Disorders of sugars (Galactosaemia, Hereditary fructose intolerance)
Glycogen storage disorders (Types I-X) and
Inborn errors of gluconeogenesis

Question 28

What is galactosemia?

Answer 28

Galactosaemia: refers to either of 2 inborn errors of galactose metabolism: galactose-1-phosphate uridyl transferase deficiency and galactokinase deficiency. These enzymes, together with UDP-galactose-4-epimerase, catalyse the conversion of galactose to glucose-1-phosphate.

Both are transmitted as AR traits. Heterozygotes have half-normal enzyme activities but are asymptomatic.
Diagnosis is made by demonstrating the deficiency of the relevant enzyme in red cells, the clinical picture, and the finding of galactose (reducing sugar) in the urine.

Question 29

What is the cause of galatosaemia, clinical syndrome and treatment?

Answer 29

Deficiency of galactose-1-phosphate uridyl transferase (converts galactose-1-phosphate to glucose-1-phosphate) is the cause of the classical type of galactosaemia.

The clinical syndrome, which only occurs after milk has been added to the diet, is due to toxic effects of accumulated galactose-1-phosphate. In addition to galactosaemia and galactosuria, infants afflicted with this disorder develop diarrhoea and vomiting and hypoglycaemia after meals containing galactose.

The accumulation of galactose in tissues results in liver damage with jaundice, the Fanconi syndrome, and hepatomegaly.

If Rx with a galactose-free diet is not instituted early on, mental deficiency and cataracts will develop.

Answer 30

Galactose kinase deficiency leads primarily to cataract formation. In this condition galactose accumulates in the blood and tissues; in the optic lens galactose is reduced to galactitol, a sugar to which the lens is impermeable and this causes cataract formation.

Question 31

Hereditary fructose intolerance:

Answer 31

This is caused by a deficiency in fructose bisphosphate aldolase, a key enzyme in fructose metabolism.
Normally, the 2 triose phosphates, dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, can be converted to glucose (gluconeogenesis) or to pyruvate (glycolysis).

≈ is characterised by hypoglycaemia and vomiting following a fructose-rich feed. The clinical manifestations are due to the accumulation of fructose-1-phosphate, the immediate precursor of the enzyme blockade, and include hepatomegaly, jaundice, and aminoaciduria. Hypoglycaemia is due to depression of glycogenolysis (inhibition of liver phosphorylase) and gluconeogenesis (the causal enzyme deficiency).

Generally the affected individuals learn to avoid fructose-containing foods, and thus limit the adverse effects.

Diagnosis is based on the clinical picture, the finding of fructose (reducing sugar) in urine & estimation of the aldolase activity in liver biopsy material.

Question 32

What is GSD?

Answer 32

Glycogen storage diseases (GSD)
The GSDs are disorders of glycogen mobilisation associated with enzyme defects of the glycogenolysis. They have been classified according to the particular enzyme deficiency involved:

Question 33

Type of GSD

Answer 33

Type I: glucose-6-phosphatase deficiency in liver (von Gierke’s dx)
Type II: lysosomal α-l, 4-glucosidase deficiency (Pompe’s dx)
Type III: amylo-I, 6-glucosidase deficiency (Forbes-Cori’s’ dx???)
Type IV: amylo-I, 6-glucosyltransferase deficiency (Anderson’s dx)
Type V: muscle phosphorylase deficiency (McArdle’s dx)
Type VI: liver phosphorylase deficiency (Hers’ dx)
Type VII: muscle phosphofructokinase deficiency
Types VIII, IX, X: variants of Type VI

Question 34

Glycogen storage diseases - Pathogenesis

Answer 34

The breakdown of glycogen (glycogenolysis) is brought about by the coordinated activities of several glycogenolytic enzymes: glycogen phosphorylase, debrancher enzyme (with dual catalytic activities; a glucosyltransferase activity and an amylo-1,6-glucosidase activity).

The end-products of their combined action are glucose-1-phosphate (≈90%) & free glucose residues (7-10%). In the liver, glucose-1-phosphate is converted to glucose-6-phosphate (phosphoglucomutase) and then to glucose (glucose-6-phosphatase). Muscle tissue does not have glucose-6-phosphatase activity; hence is unable to produce free glucose from glycogen.

Deficiency in any of these enzymes will lead to GSD.

Answer 35

Type I: von Gierke’s disease and is a deficiency of glucose-6-phosphatase. Pts may display lactic acidosis, hypoglycaemia, hyperuricaemia & hypertriglyceridaemia.
Type II: Pompe’s disease or maltase (α-1,4- glucosidase) deficiency is a lysosomal defect. It is associated with skeletal myopathy, including muscular hypotonia and cardiomyopathy.
Type III: This is a defect of debranching enzyme and is known as Forbes–Cori disease. Abnormal glycogen with short external branches accumulates in skeletal muscle, heart and liver. This can result in growth retardation, muscular weakness and cardiomyopathy.
Type IV: This is a defect of glycogen branching enzyme and is also called Andersen’s dx. There is hepatosplenomegaly, cardiac & skeletal muscle defects.
Type V: McArdle’s disease is a deficiency of muscle phosphorylase. Muscle cramps and fatigue occur on heavy exertion. The urine may be burgundy-red in colour due to myoglobin from muscle breakdown.
Type VI: Hers’ disease is due to hepatic phosphorylase deficiency. Symptoms may be mild, although growth retardation may occur.
Type VII: Tarui’s disease is due to phosphofructokinase deficiency. The symptoms are similar to those of type V.
Types VIII, IX, X: variants of Type VI.

Question 36

GSD diagnosis and treatment

Answer 36

Diagnosis is based on the clinical picture and biochemical features and the response to glucagon (no increase in plasma glucose concentration).
Rx - frequent feeding to maintain the blood glucose level.

Question 37

CHO DISORDERS - Inborn errors of gluconeogenesis

Answer 37

Gluconeogenesis - formation of glucose from non-CHO precursors (lactate, pyruvate, glycerol & amino acids).
Occurs exclusively in liver & kidney.

The gluconeogenic pathway is a partial reversal of the glycolytic pathway, sharing all but 3 of the rxns of glycolysis.

Affected subjects with deficiencies of the above enzymes present with fasting hypoglycaemia, lactic acidosis, ketosis, and hyperalaninaemia.

Glucose-6-phosphatase deficiency also results in liver glycogen accumulation (the reaction it catalyses is common to both glycolysis and glycogenolysis).

Pyruvate carboxylase deficiency produces severe mental retardation and causes early death.

Question 38

What are UREA CYCLE DISORDERS?

Answer 38

Urea cycle defects are an important cause of hyperammonaemia and there may also be raised urinary orotic acid concentration (an intermediate metabolite of pyrimidine synthesis derived from carbamyl phosphate).

The urea cycle defects can present not only with severe hyperammonaemia, but also with a respiratory alkalosis and low plasma urea concentration.

Carbamyl phosphate synthetase deficiency is a urea cycle disorder in which, unlike other defects in this pathway, urinary orotic acid is not raised.

Ornithine transcarbamylase deficiency is probably the most common urea cycle defect and is sex linked.

Question 39

TYPES of UREA CYCLE DISORDERS

Answer 39

Ornithine transcarbamylase deficiency (OTC)
Carbamyl phosphate synthase deficiency (CPS)
Argininosuccinate synthase deficiency or citrullinaemia (ASS)
Argininosuccinate lyase deficiency (ASL)
Arginase deficiency
N-acetyl glutamate synthase deficiency (NAG)

Question 40

LYSOSOMAL DISORDERS

Answer 40

Consist of:
Mucopolysaccharidoses (MPS): rare conditions caused by defects of the enzymes that hydrolyse mucopolysaccharides (glycosaminoglycans), which therefore accumulate in tissues such as the liver, spleen, eyes, CNS, cartilage and bone.

E.g.; Hurler, Hunter, Morquio syndromes
Lipid storage disorders (Lipoidoses): deficiency of a lysosomal hydrolase is inherited, resulting in the accumulation of sphingolipids.
E.g.; Gaucher’s, Niemann-Pick, Fabry, Tay-Sachs diseases
Most have are AR inheritance except a few like Hunter’s syndrome (MPS II, sex recessive) and Fabry disease.

Question 41

The mucopolysaccharidoses (MPS)

Answer 41

Hurler’s syndrome (MPS IH) is the least rare, and is inherited as an AR disorder. Pts present in infancy or early childhood with the characteristic coarse features, short stature, intellectual disabilities and clouding of the cornea. They usually die young of cardiorespiratory disease.

Scheie’s syndrome (MPS IS) is difficult to distinguish clinically from Hurler’s syndrome at the time of diagnosis, but has a much better prognosis; there is little intellectual disability.

Hunter’s syndrome (MPS II), in contrast to all the other MPSs, is inherited as a sex-linked recessive trait.

Other MPSs include Sanfilippo’s syndrome, which manifests severe CNS abnormalities, and Morquio’s syndrome, which is associated with short stature, barrel chest, genu valgum and other skeletal abnormalities.

The MPSs can initially be diagnosed biochemically by demonstrating increased urinary excretion of sulphated glycosaminoglycans (e.g. dermatan, heparan and keratan sulphates); the excretion pattern being characteristic of each syndrome. The diagnosis should be confirmed by direct enzyme assay and gene tests with family studies.

Rx - There is current research looking at enzyme therapy.

Question 42

LYSOSOMAL DISORDERS - Lipid storage disorders (Lipoidoses)

Answer 42

GM1 gangliosidosis → β-galactosidase deficiency
GM2 gangliosidosis e.g. Tay–Sachs disease → hexosaminidase deficiency
Gaucher’s disease → β-glucosidase (glucocerebrosidase) deficiency
Niemann–Pick disease → sphingomyelinase deficiency,
Fabry’s disease → α-galactosidase A deficiency (sex-linked recessive)
Metachromic leucodystrophy → arylsulphatase deficiency.
CFs of these conditions may include organomegaly, skeletal abnormalities, pulmonary infiltration and cherry-red macular spot on ophthalmologic examination.

Question 43

MITOCHONDRIAL DISORDERS

Answer 43

Mitochondrial DNA (mtDNA) is derived from the mother. This differs from nuclear DNA in that there are no introns & replication of mtDNA lacks proofreading, and the mutation rate is thus about 10–100 times greater than that of nuclear DNA. Mitochondria lack an adequate DNA repair mechanism.
CFs may include neuropathy, intellectual disabilities, lactic acidosis, myopathy, ocular defects, diabetes mellitus, anaemia & hearing loss.

Question 44

MITOCHONDRIAL DISORDERS

Answer 44

Examples include:

Leigh’s syndrome,
MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke),
Kearns–Sayre syndrome,
NARP syndrome (neuropathy, ataxia, retinitis pigmentosa) and
LHON syndrome (Leber’s hereditary optic neuropathy).

The arterial or venous lactate to pyruvate ratio may be high (more than 50:1), which suggests a metabolic block in the respiratory chain system. There is often a high plasma lactate at rest. Plasma creatine kinase activity may be raised and rhabdomyolysis can occur with myoglobinuria. Specialized muscle histology may be useful with genetic tests & family studies

Question 45

LIPID DISORDERS

Answer 45

Discussed under disorders of lipid metabolism (primary hyperlipoproteinaemia and hypolipoproteinaemia).

Organic acids derived from the metabolism of lipids are often detectable in the urine; others accumulate if there is an enzyme deficiency in a specific metabolic pathway resulting in some types of organic acidurias.

Question 46

What are PEROXISOMAL DISORDERS?

Answer 46

There is either a deficiency of a peroxisomal enzyme or a defect in forming intact peroxisomes. Peroxisomes are involved in a number of metabolic processes.

Examples: defects of phytanic acid oxidation (Refsum’s disease), dihydroxyacetone phosphate acyltransferase abnormality (Zellweger’s syndrome), catalase defects (neonatal adrenoleucodystrophy), and abnormal plasmalogen biosynthesis (rhizomelic chondrodysplasia punctata).

CFs include dysmorphia, cataracts, liver disease, retinitis pigmentosa, adrenal insufficiency, peripheral neuropathy, deafness and ataxia.

Question 47

What are DRUGS AND INHERITED METABOLIC DISORDERS?

Answer 47

The variation in individual response to drugs may be partly due to genetic variation. There are a number of well-defined inherited disorders that are aggravated by, or which become apparent only after, the administration of certain drugs. These disorders may be classified into 2 groups.

1. Disorders resulting in deficient metabolism of a drug: The muscle relaxant suxamethonium (scoline) normally has a very brief action because it is rapidly broken down by plasma cholinesterase. In suxamethonium sensitivity, a cholinesterase variant of low biological activity impairs the breakdown of the drug, and prolonged post-operative respiratory paralysis may result (‘scoline apnoea’).

Two other inherited disorders are characterized by defective metabolism of the drugs isoniazid and phenytoin. In both, toxic effects occur more frequently, and at lower dosages, than in normal individuals. There are genetic differences in the metabolism of azathioprine.

2. Disorders resulting in an abnormal response to a drug: Deficiency of glucose-6-phosphate dehydrogenase (G6PD) may cause haemolytic anaemia. It is X-linked. G6PD catalyses the 1st step in the hexose monophosphate pathway and is needed for the formation of NADP, which is important for the maintenance of intact red cell membranes. Haemolysis may be precipitated by certain antimalarial drugs (e.g. primaquine) & by sulphonamides.
   In the inherited hepatic porphyrias, acute attacks may be precipitated by drugs such as barbiturates.
   Some people react to general anaesthetics (most commonly halothane with suxamethonium) with a rapidly rising temperature, muscular rigidity & acidosis (malignant hyperpyrexia), which is associated with high mortality.

Question 48

CLINICAL IMPORTANCE OF IEM

Answer 48

Early recognition of any IEM is an important part of clinical medicine bcos, although many are completely harmless, a number of them are potentially dangerous but may be successfully treated if recognised early. Others may express themselves later in life in response to some precipitating factor and knowledge of their existence is thus vital. Yet others, which are completely harmless, may be misdiagnosed and lead to inappropriate mgt.
1. Early diagnosis and treatment may prevent irreversible damage in: PKU, Galactosaemia, MSUD, congenital hypothyroidism
2. Disorders that respond to some precipitating factor and thus should be sought amongst blood relatives of an affected individuals are: cystinuria, cholinesterase variants, Wilson’s disease, haemochromatosis, porphyrias
3. Disorders that are harmless but may be confused for more serious conditions are: alkaptonuria, Gilbert’s syndrome, renal glycosuria
4. Clinical features that can suggest an inherited disorder in infants are:

Question 49

Some clinical features that can suggest an inherited disorder in infants are:

Answer 49

failure to thrive, poor feeding, persistent vomiting
hypoglycaemia
persistent jaundice, hepatosplenomegaly
neurological problems (convulsions, spasticity), mental retardation
unexplained metabolic acidosis, ketosis,
lethargy

Question 50

When to suspect an IEM?

Answer 50

The possibility of an inherited metabolic defect should be considered if there are
unusual, unexplained CFs
abnormal laboratory findings: hypoglycemia, H+ disorders- Met acidosis & Resp alkalosis, abnormal LFTs
in infancy or early childhood
especially if more than one infant in the family has been affected or there has been a consanguineous marriage

Question 51

Laboratory investigation of a suspected IEM

Answer 51

Specimens
The following specimens should be considered:
blood collected in lithium heparin tubes for amino acids and acyl carnitines (plasma)
blood collected in EDTA tubes for DNA analysis
urine for organic acids and amino acids
CSF for lactate, pyruvate, amino acids
skin biopsy for fibroblast culture

Question 52

Newborn Screening

Answer 52

Detection of disease before it manifests clinically
Prenatal, in neonatal period or later
Criteria for selection of disorders for screening
Condition either fatal or leads to severe morbidity if untreated
Effective and acceptable treatment is available
Condition is relatively common in the population to be screened
Screening method is reliable (high sensitivity & acceptable specificity) and cost-efficient
Confirmatory diagnostic tests available
Resource implications not prohibitive

Question 53

PRENATAL SCREENING

Answer 53

Counsel patient depending on
Family risk factors
Fetal risk from sampling
Maternal risk from sampling
Clinical validity of test
Disease burden
Phenotypic variability of disease
Demonstrating metabolic defect in cultured fetal fibroblasts obtained by amniocentesis early in second trimester or by chorionic villous sampling during the first trimester.

Question 54

NEONATAL SCREENING & OTHERS

Answer 54

Neonatal screening – sampling on 2nd day. A Guthrie test testing infants for PKU can be done a few days after birth.
Neonatal screening samples for IEM can be analysed using electrophoresis, immunophoresis or tandem mass spectrometry or high performance liquid chromatography.
Symptomatic screening – collect both blood and urine and use same methods as for neonatal screening
Postmortem screening – can be done for suspected infants or adults with sudden death. Collect spot blood, bile, liver and skin samples

Question 55

PRINCIPLES OF TREATMENT OF IEM

Answer 55

1. Substrate reduction e.g., limiting dietary intake of precursors in the affected metabolic pathway, such as phenylalanine in PKU or lactose in galactosaemia.
2. Correcting the product deficiency i.e., supplying the missing metabolic product, such as cortisol in congenital adrenal hyperplasia.
3. Decreasing toxicity of metabolites, i.e., removing or reducing the accumulated product, such as ammonia in urea cycle disorders.
4. Stimulating residual enzymes via vitamins or drugs.
5. Experimental treatments may be tried for some disorders with particularly poor prognoses e.g. replacement of organ, enzyme or gene.
6. Genetic counselling