Purine, pyrimidine and porphyria disorders

Chapter 6
Purine, pyrimidine and porphyria
disorders
A purine is any of a group of organic compounds that are found in tissues, the two
major purines being adenine and guanine. Others include uric acid, xanthine and
hypoxanthine.
A pyrimidine is any of a group of organic compounds that are found in certain
coenzymes and in tissues, the three major pyrimidines being thymine, uracil and
cytosine.
Both purines and pyrimidines are components of DNA. They are involved in a
number of processes, each of which is catalysed by a di€erent enzyme. When there is a
de®ciency of one of these enzymes it causes disorders that can a€ect many of the body
systems, particularly the kidneys.
Porphyrias
The porphyrias are a group of seven disorders. These are as follows:
 acute intermittent porphyria (AIP)
 aminolevulinate dehydratase deficiency porphyria (ADP)
 congenital porphyria (CP)
 cutanea tarda porphyria (PCT)
 erythropoietic protoporphyria (EEP)
 hereditary coproporphyria (HCP)
 variegate porphyria (VP).
Many of the porphyrias are inherited, and a number of them are acquired. Each is
caused by a defect in a gene that codes for one of the seven enzymes that convert
aminolevulinic acid (ALA) into haem. Haem is used in molecules that carry oxygen
for use in the cells (e.g. haemoglobin in the red blood cells). In each type of porphyria a
speci®c enzyme is de®cient, and this causes the porphyrins to accumulate.
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84 Inherited metabolic diseases
Acute intermittent porphyria
Other names for this condition
 AIP
 Swedish porphyria
This disorder belongs to a group of conditions known as the porphyrias. In this
particular disorder there is a de®ciency of the enzyme porphobilinogen deaminase,
which slows the conversion into haem and leads to a build-up of aminolevulinic acid
(ALA) and porphobilinogen (PBG), the latter being produced directly from ALA. This
can cause acute attacks that a€ect the nervous system.
Acute intermittent porphyria does not cause any skin symptoms in sunlight, unlike
most of the other porphyrias.
The disorder is inherited in an autosomal dominant fashion.
A€ected individuals usually develop symptoms after they have reached puberty.
However, many people who inherit the gene for this condition do not display any
symptoms at all.
The main symptom of an acute attack is abdominal pain (or sometimes back pain),
and this can be accompanied by nausea, vomiting, constipation, confusion and
hallucinations. The urine may be red or brownish (particularly if left to stand for
testing), due to an excess of porphyrins. The salt content of the blood may fall
(hyponatraemia), and a blood test is needed to check whether this needs to be treated.
There may also be pain in the arms and legs, a rapid heartbeat, increased blood
pressure, muscle weakness and possibly seizures. Usually glucose therapy is given at
the start of an attack, with saline if there is hyponatraemia, but it is advisable to give
Normosang1 (haem arginate) as soon as possible, as this treatment is far more
reliable.
Precautions should be taken to avoid the stimuli that can lead to acute attacks,
even if the person has never had an attack. This means not drinking alcohol, only
taking drugs that are known to be safe, and eating regular meals with a high
carbohydrate content. This is particularly important for women, as the changes
during the menstrual cycle can provoke attacks. The wearing of a MedicAlert bracelet
is advisable for patients who have acute attacks, to ensure that in an emergency all
medical sta€ are aware of the individual's condition. A printable safe drugs list is
available from the Welsh Medicines Agency, via a link on the British Porphyria
Association website (www.porphyria.org.uk). This is updated regularly.
Reviewed by Mr and Mrs J Chamberlayne

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Purine, pyrimidine and porphyria disorders 85
Adenosine deaminase de®ciency
Other names for this condition
 ADA deficiency
 Adenosine aminohydrolase deficiency
 Severe combined immunodeficiency due to adenosine deaminase deficiency
Adenosine deaminase de®ciency is a complex disorder with variable phenotypes. In
this condition there is a de®ciency or an absence of the enzyme adenosine deaminase.
In some cases there may be a partial de®ciency of the enzyme. Adenosine deaminase
is responsible for promoting certain reactions in the immune cells, and a de®ciency of
the enzyme leads to a build-up of chemicals that either destroy these cells or prevent
them from working properly. The specialised immune cells are types of white blood
cells called B-cells that are formed in the bone marrow, and also T-cells that are
formed in the thymus gland. Individuals with adenosine deaminase de®ciency lack
the body's normal protection against di€erent types of infections.
The disorder is genetically inherited from the parents in an autosomal recessive
fashion.
This disorder generally presents within the ®rst 2 years of life. Symptoms that
commonly occur include diarrhoea and failure to grow and gain weight (failure to
thrive). A€ected individuals are highly susceptible to repeated severe infections (viral,
fungal, bacterial and protozoal), and may also experience persistent thrush (candi-
diasis). These infections can be very serious in an individual with this disorder, and
may be life threatening. The severity of the symptoms can vary, as some individuals
have a milder form that often presents later in childhood.
The possibility of adenosine deaminase de®ciency should be considered in any child
with candidiasis, especially when there is evidence of autosomal recessive inheri-
tance. This disorder is diagnosed by measuring the enzyme activity in red blood cells.
Prenatal diagnosis is available by chorionic villus sampling and amniocentesis.
Treatment of this disorder can involve enzyme replacement therapy using bovine
adenosine deaminase (bovine ADA), joined to a chemical called polyethylene glycol
(PEG) to form PEG±ADA. It is given in the form of an injection every 1 to 2 weeks, and
it restores the immune response. The ultimate treatment is a bone-marrow transplant
from a suitable donor. This is usually a sibling who has a matched tissue type, because
the immune system is so vulnerable that there can be a higher rate of rejection.
Reviewed by Dr MJ Henderson

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86 Inherited metabolic diseases
Adenylosuccinate lyase de®ciency
Other names for this condition
 Adenylosuccinase deficiency
 ADSL deficiency
 Succinylpurinemic autism
Adenylosuccinate lyase de®ciency is a rare disorder characterised by a de®ciency or
an absence of the enzyme adenylosuccinate lyase. This enzyme catalyses two
separate steps in the pathways of purine nucleotide synthesis. ADSL de®ciency results
in a blockage in these pathways and the build-up of two unusual chemical
compounds, succinylaminoimidazole carboxamide riboside (SAICAR) and adenylo-
succinic acid (AMPS), in the body. Both have a toxic e€ect on the brain and cause the
symptoms of this condition. There are four forms of this disorder.
This disorder is genetically inherited from the parents in an autosomal recessive
fashion.
Symptoms of this disorder usually appear during the ®rst 2 years of life, and may
include a delay in physical and mental development, epileptic seizures, growth delays,
muscle weakness and behavioural diculties similar to those seen in autism, such as
failure to make eye contact, repetitive behaviour and temper tantrums. Other
symptoms include low muscle tone (except in the hands and feet, where there is
high muscle tone), feeding problems, a squint (strabismus), muscle wasting and
twitching of the muscles. The range and severity of symptoms vary from one
individual to another. The prognosis for those a€ected by this disorder is poor.
Most people with adenylosuccinate lyase de®ciency have the type I disorder, which is
characterised by a severe delay in mental development, autistic features, epilepsy and
low muscle tone. Many of these individuals die in early infancy. Type II is
characterised by hearing diculties and a delay in mental and visual development.
The delay in mental development is less severe than that in Type I. This form has a
more positive prognosis, with some individuals reaching their twenties or thirties.
Type III is characterised by severe growth problems, severe delays in mental
development and muscle wasting. Type IV is a mixture of type I and type II.
Adenylosuccinate lyase de®ciency can be diagnosed by newborn screening pro-
grammes, and the diagnosis can be con®rmed by a urine test. Prenatal diagnosis is
available in some cases. Treatment for individuals with this disease aims to provide
relief of any symptoms and support in the care of the individual. Anti-epileptic drugs
may be used to treat seizures. Genetic counselling may be of bene®t to individuals
a€ected by this disorder.
Reviewed by Dr A Simmonds

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Purine, pyrimidine and porphyria disorders 87
Dihydropyrimidine dehydrogenase de®ciency
Other names for this condition
 Combined uraciluria±thyminuria
In this disorder there is a de®ciency or an absence of an enzyme called dihydropyr-
imidine dehydrogenase. This enzyme is required to break down uracil into dihy-
drouracil, and to break down thymine into dihydrothymine. The enzyme de®ciency
leads to a build-up of uracil and dihydrouracil, which causes the symptoms of the
condition. Uracil and thymine are important for the function of DNA. There are two
forms of this condition:
 an infantile form in which symptoms appear in early infancy
 a later-onset form in which symptoms present later in life.
This disorder is genetically inherited from the parents in an autosomal recessive
fashion.
In the infantile form, symptoms may include seizures, a delay in physical and
mental development, including growth and speech development, an increase in the
tone of the muscles, causing muscle rigidity and tension (hypertonia), heightened
re¯ex responses (hyperre¯exia) and a small-sized head (microcephaly). The severity
and range of symptoms vary form one individual to another. Those with a complete
absence of the enzyme may have a large number of the above symptoms, whereas
individuals with a milder de®ciency may present with seizures alone.
The later-onset form is also known as the pharmacogenic form. This is because
symptoms occur following exposure to 5-¯uorouracil, which is a chemotherapeutic
agent used in the treatment of some cancers. This can lead to a range of symptoms,
including severe diarrhoea, swelling, irritation, and ulceration of the mucosal cells
that line the digestive tract (mucositis), a de®ciency of one or more of the di€erent
types of blood cells (cytopenia), an inability to coordinate muscle movements (ataxia),
and muscle weakness. In this form of the disorder, the de®ciency of dihydropyrimi-
dine dehydrogenase is only partial.
Treatment for individuals with the early-onset form of the disorder aims to relieve
any symptoms and provide support in the care of the individual. Symptoms are
commonly non-progressive, so usually remain the same. However, a few deaths have
been documented in children who have been severely a€ected. In the adult-onset
form, cancer symptoms have slowly resolved after the discontinuation of chemother-
apeutic agents containing 5-¯uorouracil.
Reviewed by Dr G Besley

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88 Inherited metabolic diseases
Lesch±Nyhan disease
Other names for this condition
 Hereditary hyperuricaemia and choreoathetosis syndrome
 HGPRT, absence of
 HPRT, absence of
 Hyperuricaemia, choreoathetosis, self-mutilation syndrome
 Hyperuricaemia±oligophrenia
 Hypoxanthine±guanine phosphoribosyltranferase deficiency (complete
absence of HPRT)
 Juvenile gout, choreoathetosis, and mental retardation syndrome
 Lesch±Nyhan syndrome
This disorder belongs to a group of conditions known as purine metabolic disorders. It
is a rare and devastating genetic disorder associated with an almost complete absence
of the enzyme hypoxanthine±guanine phosphoribosyltransferase (HGPRT), which
metabolises hypoxanthine and guanine to uric acid, the nucleotides IMP and GMP.
The disorder is characterised by increased levels of uric acid in the blood and urine
and by the absence of the enzyme HPRT.
This disorder may occur spontaneously, but is usually inherited by a method called
X-linked inheritance.
Symptoms usually begin to appear between the ages of 3 and 6 months. Often the
®rst symptom is the presence of orange crystal-like deposits in the nappies of a€ected
infants. The deposits are uric acid (also known as urate) crystals, and are caused by
increased levels of uric acid in the urine. High uric acid levels in the circulation may
also cause sodium urate crystals to form in the joints, kidneys, central nervous system
and other tissues of the body. Other symptoms include kidney stones, impaired kidney
function, renal disease and blood in the urine. Individuals with this disorder are
irritable and display uncontrolled aggression.
Symptoms may include purposeless repetitive movements such as shoulder raising
and facial grimacing, destructive chewing of ®ngertips or lips, compulsive self-injury,
head banging, leg banging, rubbing the body until it is raw, and kicking and head
butting others, followed by repeated apologies for this behaviour. Behaviour problems
may escalate as the child gets older. Self-injury may be related to abnormalities in the
metabolism of the neurotransmitters serotonin or dopamine. Those a€ected by this
disorder may have diculty in swallowing (dysphagia) and eating, delayed motor
development followed by unusual movements and increased deep tendon re¯exes,
gout-like swelling of the joints, movement disorder, speech impairment, exaggerated
re¯exes (hyperre¯exia), vomiting, and a combination of slow writhing involuntary
movements and fast jerky movements (choreoathetoid movements). Severe and
progressive disability is likely.
No treatment exists for this condition. Haloperidol has been tried, and although it
decreases the uric acid levels, it does not improve the neurological outcome. Some
symptoms may be relieved by giving carbidopa/levodopa, diazepam, phenobarbital or
haloperidol. The patient's teeth may have been removed in the past to limit self-

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Purine, pyrimidine and porphyria disorders 89
destructive behaviour, but the use of mouth-guards should be tried ®rst. Treatment
for individuals with this disease aims to relieve any symptoms and to provide support
in the care of the individual. A€ected individuals become fearful and upset when left
unrestrained or unprotected. In the past the outcome was likely to be poor, but it has
been improved by the encouragement of dedicated parents. Genetic counselling may
be of bene®t to the families of individuals a€ected by this disorder.
Reviewed by Dr A Simmonds

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90 Inherited metabolic diseases
Myoadenylate deaminase de®ciency
Other names for this condition
 MAD deficiency
Myoadenylate deaminase de®ciency is a rare metabolic disorder that is characterised
by a de®ciency of the muscle enzyme adenosine monophosphate (AMP) deaminase
enzyme. AMP deaminase and the purine nucleotide cycle have an important role in
providing energy for skeletal muscles during exercise. There are two forms of
myoadenylate deaminase de®ciency, namely an acquired form and an inherited
form. This summary will focus on the inherited form.
This disorder is genetically inherited from the parents in an autosomal recessive
fashion.
Symptoms of this disorder can present at any time after the age of 2 years, and
mainly occur after moderate to vigorous exercise. They include tiring easily, muscle
cramps and muscle pain. There may also be an increase in blood serum levels of the
muscle enzyme creatine kinase, due to muscle damage. In this disorder the skeletal
muscle fails to produce ammonia during exercise. This mild disorder only a€ects
skeletal muscle.
The disorder can be diagnosed by testing whether the skeletal muscle fails to
produce ammonia during exercise. A muscle biopsy and blood tests may also be
necessary. Treatment of the disorder aims to relieve any symptoms and to provide
support in the care of the individual. Administration of ribose may be of bene®t, but is
only e€ective for short periods of time. It increases stamina and may eliminate
symptoms in some individuals, but may be ine€ective in others.
Reviewed by Dr L Fairbanks

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Purine, pyrimidine and porphyria disorders 91
Purine nucleoside phosphorylase de®ciency
Other names for this condition
 PNP deficiency
Purine nucleoside phosphorylase de®ciency is a rare disorder of purine metabolism in
which the normal breakdown (catabolism) of the nucleosides inosine and guanosine
to their constituent purine bases ± hypoxanthine and guanine ± does not occur.
Purine nucleosides are derived from nucleotides such as ATP and the nucleic acids
that make up our DNA, and they contain a sugar (ribose) and a purine base. When
this breakdown is interrupted, there is a build-up of the corresponding nucleosides
coupled with the excretion of reduced amounts of the constituent purine bases and
uric acid.
This disorder is inherited from the parents in an autosomal recessive manner.
Symptoms of the disorder generally become apparent around the age of 2 to 3
years, but sometimes appear up to the age of 7 years. The main symptom is recurrent
infections. A€ected individuals are particularly prone to viral infections, including
chickenpox and mumps. Other symptoms include a low red blood cell count
(anaemia), shaky movements and unsteady gait (ataxia), tremor and severe
immune de®ciency.
This disorder can be diagnosed by urine tests that demonstrate decreased levels of
uric acid, and by enzyme tests on red blood cells, providing that there have been no
prior blood transfusions. Treatment includes bone-marrow transplantation and
irradiated blood transfusions. All other treatments aim to prevent infections, relieve
any symptoms and provide support in the care of the individual.
Reviewed by Dr A Simmonds

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92 Inherited metabolic diseases
Pyrimidine 5H-nucleotidase de®ciency
Other names for this condition
 UMP hydrolase deficiency
This is a rare disorder caused by a de®ciency of the enzyme pyrimidine 5H-nucleotidase
(also known as UMP hydrolase). This enzyme removes phosphate groups from
organic compounds known as pyrimidine-5H-ribomonophosphates, converting the
latter to the corresponding compounds that consist of a nitrogen-containing pyr-
imidine base and a sugar (nucleoside).
This disorder is inherited from the parents in an autosomal recessive manner.
The symptoms of pyrimidine 5H-nucleotidase de®ciency may present at any age.
The main symptom is non-spherocytic haemolytic anaemia, characterised by
basophilic stippling. Other ®ndings may include an enlarged spleen (splenomegaly),
enlarged kidneys, gallstones, and the excretion of iron in the urine. There may be an
increase in the number of immature red blood cells (reticulocytosis), and red blood
cells may be unequal in size (anisocytosis). Additional ®ndings include an increase in
the yellowish pigment found in bile (bilirubin), and increased levels of glutathione in
the red blood cells.
This disorder should be suspected in any individual who has mild chronic non-
spherocytic haemolytic anaemia with basophilic stippling. It can be diagnosed by
enzyme analysis and by demonstrating the accumulation of pyrimidine nucleotides
in red blood cells. Pyrimidine 5H-nucleotidase de®ciency is a relatively harmless
disorder. If the anaemia becomes severe, a transfusion may be necessary. However,
this is rarely needed.
Reviewed by Dr L Fairbanks

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