Hereditary diseases

Dr Iman Marzouk Prof of Pediatrics Head of Clinical Genetics Unit

Modes of Inheritance
Autosomal dominant (AD): Achondroplasia Autosomal recessive (AR): Phenyl ketonuria (PKU) X-linked recessive : Hunter syndrome (Mucoplysaridosis II MPS II)

Characters of AD diseases Male to male transmission is present.

Both males and females are affected. Affected offspring has chance

(50%)

for

both sexes to inherit the mutant gene. The affected individual may inherit the disorder from a parent or develop the condition as a new mutation.

Family tree (Pedigree) of an AD trait

I II III IV

Normal female Affected female

Normal male Affected male

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Examples of AD diseases
Achondroplasia. Adult polycystic kidney disease. Familial hypercholesterolemia.

Case (4) A three year old child.

C/O: Short limbed dwarfism although both of his parents have normal height. The child has normal intelligence. Examination revealed short limbs, saddle

shaped nose, trident hands and large head.

Achondroplasia
It is an AD inherited disease due to disturbance of the growth of bones formed from cartilage. This produce the characteristic disproportionate short dwarf with shortening of the limbs, hypoplasia of the cranial base, small foramen magnum. Bones of the trunk are almost normal. The intelligence is usually normal.

Achondroplasia is an AD disease

Large sized head with prominent frontal and parietal bossing. Saddle-shaped nose. The long bones are short especially at their proximal parts.

Incidence: 1: 28000 live births Sex: male (1): female (1) The gene is mapped on the short arm of chromosome number 4 (4p16)

Main clinical features:

Macrocephaly may represent mild hydrocephalus relating to a small foramen magnum in addition to the prominent forehead. Saddle shaped nose due to low nasal bridge with narrow nasal openings.

The long bones are short especially at their proximal parts with accentuation of the physiologic curves of the forearm and lower limbs.

The fingers are short, tapered, similar in length producing short trident hand. Infrequent respiratory problems due to narrow thoracic cage. radiology: small - elephant ear like- iliac wings.

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Characteristics of AR inheritance The parents are normal while sibs are affected.
Consanguinity in parents is more common than in the general population. When only one parent of an affected child is heterozygote; either: A new mutation occurred on the gamete inherited from the other parent or; Uniparental disomy when the child inherit 2 copies of the heterozygote mutant allele.

Family tree (pedigree) of an AR trait

Affected

Consanguineous mating

Examples of AR disorders:
Phenylketonuria. Galactosemia. Gaucher disease.

Case (5)

A ten month old infant with +ve consanguinity. The baby was normal till the age of five month, then there was gradual increase in the tone of the muscles, appearance of tremors and mental sub normality. The baby had blonde hair and blue eyes in spite of the black hair and eyes of his parents. Phenyl alanine and phenyl pyruvic acid and

Phenylketonuria (PKU)
Phenylalanine is an essential AA. It is either used for protein synthesis or degraded via tyrosine pathway and melanin formation.

Classic PKU
It is an AR disorder. Incidence: 1:10,000-20,000 live births. It is the result of Phenylalanine hydroxylase (PAH) deficiency. The gene is mapped on the long arm of chromosome 12 (12q).

The enzyme block leads to: Accumulation of PA (substrate) which is converted into phenylpyruvic acid and other metabolites which are excreted in the urine. Tyrosine reduction (products). deficiency of and consequent formation

melanin

Clinical manifestations
Age of detection: First week of life (biochemical data) First six months of life (clinical findings)

Main clinical features:

Small head, blonde hair and blue eyes. Nervous system involvement includes hypertonia and EEG changes. Progressive mental retardation (MR) if untreated.

It

is

better

to

offer

neonatal

screening of PKU during the first week of life (3rd day) to avoid the irreversible MR in patients.

Treatment of PKU
Newborn screening for PKU during the 1st week of life. Once it has been determined that the infants PA level is sufficiently elevated (8mg/dl), dietary therapy for PKU is initiated; it includes the use of PA free formula (Lofenalac) and special low protein medical foods. The diet provides small but adequate amounts of PA and sufficient energy to maintain normal growth and

development.

Maternal PKU
Mental retardation (MR) was almost always present in non PKU offspring of mothers with PKU it has been suggested that the reduced ability of the mother with PKU to deliver an appropriate amount of tyrosine to her fetus in utero could result in reduced fetal brain growth. Maternal PA level should be kept 2-6 mg/dl throughout pregnancy.

X-linked recessive inheritance

In severe X- linked conditions, affected males often dont survive long enough to have their own children. Consequently, these conditions are usually carriers. The carrier transmits the gene to of her transmitted only by healthy female

daughters (carriers) and of the sons (affected). If affected male have children, he will transmit his

The pedigree of X linked recessive disorder

I-

II-

III-

IV-

Examples of X linked recessive disorders:

Hunter syndrome (MPS II) Hemophilia A,B. Ocular albinism.

Case (6)

A five year old boy with normal normal birth facial weight, features

and normal intelligence

Hunter syndrome (MPS II)

It is an X-linked recessive disease. Incidence: 1:10000-1:15000 live births. No affected females. Etiology: It is one of the lysosomal storage diseases deficiency. due to induronate sulfatase

Clinical abnormalities:
Onset: 2-4 years. Growth deficiency; adult height: 120-150 cm. Performance: deterioration. Craniofacial: coarse facial features, full lips, Macrocephaly, macroglosia. Joints and bones: partial stiffness of the joints with broadening of the bones. Mental and neurologic

Hunter disease

Natural history of the disease:

The patient is apparently normal during infancy. Gradual decline in growth rate from 2 to 6 years with gradual coarsening of facial features. Deafness is frequently evident by 2 to 3 years. Severe neurologic complications develop in late stages. Death usually occurs by the age of 15 years by

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