26 Inherited metabolic disease

Inherited metabolic disease (IMD) may present at any age and the signs and symptoms may result from:

The commonest error in managing infants and children with IMD is a delay in diagnosis, and therefore a delay in starting treatment. Failure to recognize an IMD may occur because its clinical features are confusing because of:

A useful approach is to consider certain ‘syndromes’ and use this as a framework for investigation (Table 26.1).¹ This approach is widely used and should serve the purpose.

There are 7 presentations of IMD with neurological features.

Developmental delay is a common problem (see  pp.557, 562), but the features that warrant investigation for IMD include:

Causes include vitamin B₆ dependency; biotinidase deficiency; neuronal ceroid-lipofuscinosis; GM2 gangliosidosis; cherry-red spot–myoclonus syndrome (sialidosis type I); Leigh disease; Alper’s disease; MELAS (mitochondrial encephalopathy–lactic acidosis and stroke-like episodes syndrome).

Deterioration in level of consciousness resulting from IMD:

The likely causes are: hyperammonaemia (urea cycle;  p.964); amino acidopathy (  p.965); organic aciduria (  p.966); fatty acid oxidation defect (  p.970); mitochondrial defect (  p.971); hypoglycaemia (  p.96).

The IMD associated with stroke or stroke-like episodes are:

The causes include: dopamine β-hydroxylase deficiency; neurovisceral porphyrias; Fabry disease; MPS I–III; occipital horn syndrome; mitochondrial neurogastrointestinal encephalomyopathy.

The causes include the following:

The emergency care of acid–base problems is discussed on  p.104. Metabolic acidosis may occur as a result of:

These two states can be differentiated by calculating the anion gap (i.e. the difference between plasma [Na⁺] and the sum of plasma [Cl⁻] and [HCO₃  ⁻]). The normal anion gap is 10–15mmol/L.

When metabolic acidosis is due to bicarbonate loss from either the gut or kidney:

To distinguish bicarbonate loss from the gut or from the kidney:

IMDs associated with RTA include—galactosaemia; hereditary fructose intolerance; hepatorenal tyrosinaemia; cystinosis; glycogen storage disease I; Fanconi–Bickel syndrome; congenital lactic acidosis; Wilson disease; vitamin D dependency; osteopetrosis with RTA; Lowe syndrome.

When metabolic acidosis is due to accumulated organic anion:

The causes include the following:

The characteristic features of this storage dysmorphic syndrome are:

The characteristic features of the Zellweger phenotype are:

The initial investigation should include the following.

There are four possible ways in which IMD may present with hepatic involvement.

See  pp.130–131, 314–315

See  p.967. The liver enlargement associated with IMD is usually persistent and not tender. The causes include:

See  pp.96–97, 132, 412, 967

IMD with characteristic, severe liver involvement may present at different ages.

may be the dominant or only clinical problem in a variety of IMDs.

Pompe disease (GSD II)—presents in early infancy with marked skeletal myopathy, massive cardiomegaly (large QRS, left axis deviation, shortened PR, T-wave inversion).

Organic acidopathy (dilated cardiomyopathy) Propionic acidaemia— intermittent metabolic acidosis; ketosis; hyperammonaemia; neutropenia.

Fabry disease— chronic neuritis pain in hands and feet; angiokeratomata; corneal opacities; progressive renal failure; cardiac arrhythmias (intermittent SVT); cerebrovascular disease.

IMD-related cardiomyopathy may be complicated by arrhythmias including:

CAD occurs in Fabry disease, familial hyperlipidaemias, and familial hypercholesterolaemia (FH).

FH affects 1/500 individuals with the following effects.

Familial hyperlipidaemias causing premature CAD include the following.

The urea cycle disorders are a group of conditions in which enzyme defects result in the accumulation of nitrogen in the form of ammonia, which is a highly toxic substance causing irreversible brain damage. Clinical presentation may be in the first few days of life. Hyperammonaemia (usually severe) results in:

Clinical confusion with septicaemia is common. In the older child, patients may present with:

It is essential to monitor the blood ammonia in any patient with unexplained neurological symptoms.

Plasma concentrations of ammonia are elevated, glutamine and alanine (the major nitrogen-carrying amino acids) are usually high, and arginine is low. Specific urea cycle defects can be diagnosed by their characteristic plasma and urine amino acid profiles.

Management of dietary protein intake with essential amino acids and restriction of protein intake to suppress ammonia formation.

Due to defects either in the synthesis of (or the breakdown of) amino acids or in the body’s ability to transport amino acids into cells. Most are autosomal recessive. Diagnosis is established by detecting abnormal plasma and urinary amino acid profiles.

AR. Occurs in 1/10 000–15 000 live births. In its classical form it is due to a deficiency in phenylalanine hydroxylase. Untreated, brain development is impaired leading to progressive mental retardation and seizures, usually evident by 6–12mths of age. Many children have fair hair and blue eyes. In PKU phenylalanine accumulates and is converted into phenylketones, which are detected in the urine.

Due to deficiency in cystathionine beta-synthase, resulting in increased urinary homocystine and methionine excretion.

resemble those of Marfan’s syndrome (see  p.940).

with high-dose pyridoxine and low-methionine diet, supplemented with cysteine.

A large group of disorders characterized by a broad range of clinical symptoms and signs varying in seriousness from trivial to lethal. Includes developmental delay, poor growth, and episodic illnesses with vomiting and metabolic acidosis. Some of these may be precipitated by prolonged fasting or minor viral infection. May be associated with hypoglycaemia and ketosis or ketoacidosis.

Examples include the following.

Caused by methylmalonyl-CoA mutase deficiency. Commonly presents in the newborn period with:

May present in the newborn period with severe metabolic acidosis, poor feeding and vomiting, lethargy, altered level of consciousness, hypoglycaemia, and hyperammonaemia.

Autosomal recessive conditions. Often presenting with one or more of the following—episodic hypoglycaemia; lactic acidosis; poor growth and hypotonia; mental retardation/developmental delay; and vomiting; cramps, myoglobinuria, and muscle weakness.

Specific enzyme defects preventing mobilization of glucose from glycogen, and resulting in abnormal storage in liver and/or muscle (see Table 26.2).

Fructose-1-phosphate aldolase deficiency. Failure to thrive; hypoglycaemia; metabolic/lactic acidosis; vomiting; GI bleeding.

Galactose-1-phosphate uridyltransferase deficiency. Failure to thrive; cataracts; hepatomegaly; jaundice, vomiting and diarrhoea; mental retardation (if untreated). Treatment with galactose-free diet.

This is a heterogeneous group of disorders resulting in abnormalities of blood lipid profile. May predispose to cardiovascular disease (see  p.963).

See also  p.959. This is a large group of disorders due to defects in lysosomal function.

A group of IMD caused by deficiency in lysosomal enzymes needed to break down glycosaminoglycans (long chain carbohydrate molecules formerly called mucopolysaccharides). Affects bone, cartilage, tendons, eyes, skin, and connective tissue, leading to accumulation of glycosaminoglycans and progressive cellular and tissue damage.

Clinical features are not apparent at birth, but progress with time as storage of glycosaminoglycans impacts on tissues and organs. Typical features include:

Clinically the sphingolipidoses show variable severity. They cause progressive peripheral and CNS disease (psychomotor retardation, myoclonus, weakness, and spasticity).

Variants of Gaucher and Niemann–Pick disease that do not affect the nervous system are termed non-neuronopathic.

A heterogeneous group of disorders of glycoprotein storage. A spectrum of phenotypes include neurological deterioration, growth retardation, visceromegaly, and seizures. Also coarse facial features, angiokeratoma corporis diffusum, spasticity, and delayed development.

Disorders of fatty acid metabolism may be due to deficiency in the acyl dehydrogenase enzyme complex, deficiency in carnitine, or a defect in the carnitine transport process.

This is the commonest fatty acid oxidation disorder (1/13 000 births) and is due to mutations in the MCAD gene (1p31). Clinical presentation may vary from asymptomatic to fulminant. Newborn screening programs, utilizing neonatal blood spot collection methods, are now in place in many countries for the early detection and management of this condition.

Disorders of mitochondrial function result in a wide of clinical problems (see Box 24.1).

Relapsing acute encephalopathy; lactic acidosis; hypotonia; seizures; +/− cardiomyopathy; +/− hepatic or renal tubular dysfunction.

Failure to thrive; lactic acidosis; sideroblastic anaemia; hypoparathyroidism; diabetes mellitus.

Peroxisomes are ubiquitous cellular organelles that function to rid the cell of toxic material. They contain a number of oxidative enzymes and have an important role in the metabolism of fatty acid molecules. Peroxisomal disorders result in abnormalities of lipid metabolism.

The classic peroxisomal disorder, due to defect in peroxisome biogenesis. ‘Severe peroxisome phenotype’ (see  p.959); leads to death within few months of birth.

Severe peroxisome phenotype with retinal degeneration, decreased plasma cholesterol, increased plasma phytanate. Survival to early childhood.

A miscellaneous group of disorders characterized by abnormalities in enzymes responsible for metabolism and removal of the purine and pyrimidine components of proteins and amino acids.

X-linked recessive. Due to a deficiency in hypoxanthine–guanine phosphoribosyltransferase (HPRT) leading to the formation of excessive uric acid.

Children are normal at birth and symptoms and signs develop in the first few months. Classic clinical features include:

Biochemical analysis demonstrates increased plasma and urinary uric acid levels. Molecular genetic testing for mutations in the HPRT gene is available.

The porphyrins are the main precursors of haem, and essential constituents of haemoglobin, myoglobin, the respiratory and P450 liver cytochromes, and of other enzymes (catalases and peroxidases). Deficiency in porphyrin pathway leads to accumulation of precursors, which are toxic to tissues in high concentration. The chemical properties of these precursors determines the site of tissue accumulation, and whether they induce photosensitivity.

The porphyrias (Table 26.3) may be inherited or acquired. They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and main accumulation of the porphyrins. They manifest with either skin problems or with neurological complications (or occasionally both) and present either acutely or non-acutely.

Spectroscopic and biochemical analysis for abnormalities in porphyrin metabolite profile in urine and stools is required for diagnosis. In nearly all cases of acute porphyria syndromes, urinary porphobilinogen is markedly elevated (except in ALA dehydratase deficiency).

High carboydrate diet and avoidance of precipitating factors. Haemearginate (early in acute episode). Symptomatic treatment.

The skin rash that occurs in erythropoietic porphyrias generally requires use of sunscreens and avoidance of bright sunlight. Chloroquine may be used to increase porphyrin secretion.

Autosomal recessive (1/30,000 births); due to mutation in the ATP7B gene that encodes for a cell membrane ATP-sensitive copper pump. The condition results in a build-up of intracellular hepatic copper with subsequent hepatic dysfunction, neurological abnormalities, and haemolytic anaemia.

Usually develop from the age of 10yrs onwards (rare <5yrs). Half of patients first present with chronic active hepatitis (which may lead to cirrhosis), and half with neurological symptoms including mood disorder, psychosis, and features consistent with Parkinson’s disease. Haemolysis is usually present only in severe cases. Other features seen include renal tubular acidosis, renal stones, and cardiomyopathy.

X-linked recessive. Caused by mutation in the gene encoding Cu²⁺-transporting ATPase, alpha polypeptide. The disease is characterized by:

The phenotype also includes hypotonia, seizures, microcephaly, and osteoporosis. Predisposition to intracranial haemorrhage is also recognized.

Biochemical analysis reveals low plasma levels of caeruloplasmin and copper.

At least 4 inherited iron-overload disorders have been identified:

The clinical features of haemochromatosis are wide ranging and include:

Primary hepatocellular carcinoma complicating cirrhosis is responsible for about one-third of deaths in affected homozygotes.

Increased serum iron and ferritin levels. Liver biopsy.

Repeated therapeutic phlebotomy.