Transcript Autosomal recessive inheritance

Many hundred disorders resulting from this type
of inheritance are known
An affected individual is homozygous for the
abnormal gene, having inherited an abnormal
allele from each parent, both of whom are
unaffected heterozygous carriers
For two carrier parents, the risk of each child, male
or female, being affected is 1 in 4 (25%)
All offspring of affected individuals will be carriers
Consanguinity
It is thought that we all carry at least one abnormal
recessive gene. Fortunately, our partners usually carry
a different one. Marrying a cousin or other relative
increases the chance of both partners carrying the
same abnormal autosomal recessive gene, inherited
from a common ancestor. A couple who are cousins
therefore have a small increase in the risk of having a
child with a recessive disorder
Racial factor
Recessive gene frequencies may vary between racial
groups
cystic fibrosis is common in north Europeans, sickle cell
disease in black Africans and Americans,
thalassaemias in Mediterranean or Asian ethnicity and
Tay-Sachs disease in Ashkenazi Jews.
Inborn errors of metabolism
Although individually rare, inborn errors of 
metabolism are an important cause of paediatric
morbidity and mortality. The specialised nature of the
diagnostic tests and subsequent management often
means that these patients are managed in specialist
centres. However, as the prognosis for most patients
depends upon the speed of diagnosis, all doctors need
to be familiar with their variable presentation and
diagnosis.
Presentation
An inborn error of metabolism may be suspected before
birth from a positive family history or previous
unexplained deaths in the family
After birth, inborn errors of metabolism usually, but not
invariably, present in one of five ways
1. as a result of newborn screening, e.g. phenylketonuria
(PKU), or family screening, e.g. familial
hypercholesterolaemia
2. after a short period of apparent normality, with a
severe neonatal illness with poor feeding, vomiting,
encephalopathy, acidosis, coma and death, e.g. organic
acid or urea cycle disorders
3. as an infant or older child with an illness similar to
that described above but with hypoglycaemia as a
prominent feature or as an ALTE (acute lifethreatening episode) or near-miss 'cot death', e.g. a fat
oxidation defect such as medium-chain acyl-CoA
dehydrogenase deficiency (MCADD)
4. in a subacute way, after a period of normal
development, with regression, organomegaly and
coarse facies, e.g. mucopolysaccharide disease or other
lysosomal storage disorder or with enlargement of the
liver and/or spleen alone, with or without
accompanying biochemical upset such as
hypoglycaemia, e.g. glycogen storage disease
5. as a dysmorphic syndrome.
Phenylketonuria
It is either due to a deficiency of the enzyme
phenylalanine hydroxylase (classical PKU) or in the
synthesis or recycling of the biopterin cofactor for this
enzyme. Untreated, it usually presents with
developmental delay at 6-12 months of age. There may
be a musty odour .
Many affected children are fair-haired and blue-eyed
and some develop eczema and seizures. Fortunately,
most affected children are detected through the
national biochemical screening programme (Guthrie
test).
Treatment of classical PKU is with restriction of dietary
phenylalanine, whilst ensuring there is sufficient for
optimal physical and neurological growth. The blood
plasma phenylalanine is monitored regularly. The
current recommendation is to maintain the diet
throughout life. This is particularly important during
pregnancy, when high maternal phenylalanine levels
may damage the fetus
Galactosaemia
This rare, recessively inherited disorder results from 
deficiency of the enzyme galactose-1-phosphate uridyl
transferase, which is essential for galactose
metabolism
presentation
When lactose-containing milk feeds such as breast or 
infant formula are introduced, affected infants feed
poorly, vomit and develop jaundice and hepatomegaly
and hepatic failure
Chronic liver disease, cataracts and developmental 
delay are inevitable if the condition is untreated.
treatment
Management is with a lactose- and galactose-free diet 
for life. Even if treated early, there are usually
moderate learning difficulties (adult IQ 60-80).
Glycogen storage disorders
These mostly recessively inherited disorders have
specific enzyme defects which prevent mobilisation of
glucose from glycogen, resulting in an abnormal
storage of glycogen in liver and/or muscle. There are
nine main enzyme defects
The disorder may predominantly affect muscle (e.g.
types II, V), leading to skeletal muscle weakness. In
type II (Pompe's disease) The heart is severely affected,
leading to death from cardiomyopathy. In other types
(e.g. I, III) the liver is the main organ of storage, and
hepatomegaly and hypoglycaemia are prominent
Management is to maintain blood glucose by frequent
feeds or by carbohydrate infusion via a gastrostomy or
nasogastric tube in infancy. In older children, glucose
levels can be maintained using slow-release
oligosaccharides (corn starch