Dr.athal
Autosomal Recessive Inheritance
PEDIATRIC
 Disorders that are inherited in an AR manner manifest
only when both copies of a gene pair located on an
autosome chromosome have a mutation.
 Affected children usually are born to unaffected parents,
each of whom carries one copy of the mutation. If both
members of a couple are carriers (or heterozygotes) for
this mutation, each of their offspring has a 25% chance of
being affected
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 an increase in the risk of having a child with a recessive disorder.
pedigree of autosomal recessive inheritance consanguineous marriage
Racial Factor:
 Recessive gene frequencies may vary between racial groups. Certain recessive mutations are far
more common in some genetic isolates (small populations separated by geography, religion,
culture, or language) than in the general population.
 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.
 Screening programs have been developed among some such groups to detect persons who
carry common disease-causing mutations and therefore are at increased risk for having affected
children.
Rules of AR inheritance:
1. Affected individual are homozygous for the abnormal gene, each parent is a heterozygous
carrier.
2. 1 in 4 risk of having an affected child for 2 carrier parents.
3. All offspring of affected individuals will be carriers.
4. Males and females are likely to be affected equally.
5. Risk of AR disorder increased by consanguinity and withen specific racial groups.
6. Often affect metabolic pathways (enzymopathy) and associated with serious illness and
shorten life span.
E.g. of some AR inheritance
Inborn Errors of Metabolism (IEM)
 Optimal outcomes for children with IEM depend upon recognition of the signs and symptoms of
metabolic disease, and prompt evaluation and referral to a center familial with their
management. Delay in diagnosis may result in end organ damage including progressive
neurologic injury or death, therefore, , all doctors need to be familiar with their variable
presentation and diagnosis.
 Most metabolic disorders are individually rare, but they significantly contribute to the paediatric
morbidity and mortality.
Presentation:
 An IEM 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.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(mimicking late onset
sepsis) 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 life-threatening 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, e.g. maternal phenylketonuria syndrome.
Phenylketonuria (PKU)
 PKU is AR aa metabolic disorder, primarily affects the brain. It is either due to:
 Deficiency of the enzyme phenylalanine hydroxylase (classical PKU).
 Defect in the synthesis or metabolism of tetrahydrobiopterin, the cofactor for this
enzyme.

Affected infants are normal at birth, if untreated severe mental retardation (IQ 30)
develops in the first year of life, seizure, blond hair, blue eyes, eczema, and mousy odor
of the urine.
 Fortunately, most affected children are detected through the national biochemical screening
programme (Guthrie test). A positive screening test must be followed up by performing
quantitative plasma amino acid analysis.
Treatment:
 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.
 Maternal hyperphenylalaninemia requires rigorous management before conception and
throughout pregnancy to prevent fetal brain damage, congenital heart disease, and
microcephaly.
Galactosaemia
 This rare, recessively inherited carbohydrate metabolic disorder results from deficiency of the
enzyme galactose-1-phosphate uridyl transferase, which is essential for galactose metabolism.
 The neonatal screening test must have a rapid because affected infants may die in the first week
of life.
Presentation:
Manifestations are most striking in a neonate who, when fed milk, generally exhibits evidence of:
 liver failure: (hyperbilirubinemia, coagulation defect, and hypoglycemia)
 Disordered renal tubular function (acidosis, glycosuria, and aminoaciduria)
 Cataracts.
 Affected infants are at increased risk for severe neonatal Escherichia coli sepsis.
 older children have learning disorders.
Lab. Manifestation:
Depend on dietary galactose intake. When galactose is ingested (as lactose):
 levels of plasma galactose increase.
 Erythrocyte galactose-1-phosphate are elevated.
 Hypoglycemia is frequent.
 Albuminuria is present.
 Galactose frequently is present in the urine (Clinitest +ve).
 DNA testing for the mutations in galactose-1-phosphate uridyltransferase confirms the
diagnosis.
 Renal tubular dysfunction may be evidenced by a normal anion gap hyperchloremic metabolic
acidosis.
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
 AR inherited carbohydrate 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.
 Glycogen storage diseases fall into the following four categories:
1. Diseases that predominantly affect the liver and have a direct influence on blood glucose
(types I, VI, and VIII)
2. Diseases that predominantly involve muscles and affect the ability to do anaerobic work
(types V and VII)
3. Diseases that can affect the liver and muscles and directly influence blood glucose and
muscle metabolism (type III)
4. Diseases that affect various tissues but have no direct effect on blood glucose or on the
ability to do anaerobic work (types II and IV). type II (Pompe's disease) The heart is
severely affected, leading to death from cardiomyopathy.
Treatment:
 Aim is to maintain satisfactory blood glucose level 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).