Basics - Genetics

Notes & Notes

For MRCP part 1 & 11
By
Dr. Yousif Abdallah Hamad

Basic sciences
Genetics
Updated
2017

Contains:
1/ Passmedicine 2017
2/ On examination 2017
3/ Pastest 2017
4/ Red fonts --> previous exams
5/ Other updated UK sources

Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 1

 Basics - Genetics

Autosomal dominant conditions

The following conditions are autosomal dominant:

 Achondroplasia  Malignant hyperthermia
 Acute intermittent porphyria  Marfan's syndromes
 Adult polycystic disease  Myotonic dystrophy
 Antithrombin III deficiency  Neurofibromatosis
 Ehlers-Danlos syndrome  Noonan syndrome
 Familial adenomatous polyposis  Osteogenesis imperfecta
 Hereditary haemorrhagic telangiectasia  Peutz-Jeghers syndrome
 Hereditary spherocytosis  Retinoblastoma
 Hereditary non-polyposis colorectal  Romano-Ward syndrome
carcinoma  Tuberose sclerosis
 Huntington's disease  Von Hippel-Lindau syndrome
 Hyperlipidaemia type II  Von Willebrand's disease*
 Hypokalaemic periodic paralysis
As an autosomal dominant condition, two affected parents can expect:
 1 in 4 chance of an unaffected child
 1 in 2 chance of an affected heterozygous child
 1 in 4 chance of an affected homozygous child.
Which disease demonstrates autosomal co-dominant inheritance?
 Alpha-1-antitrypsin deficiency

*type 3 von Willebrand's disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients
have type 1 disease

Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 2

 Basics - Genetics

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Osteogenesis imperfecta
 Osteogenesis imperfecta (more commonly known as brittle bone disease) is a group of disorders
of collagen metabolism resulting in bone fragility and fractures.
 The most common, and milder, form of osteogenesis imperfecta is type 1.
Overview
 autosomal dominant
 abnormality in type 1 collagen due to decreased synthesis of pro-alpha 1 or pro-alpha 2
collagen polypeptides.

Features
 presents in childhood  deafness secondary to otosclerosis
 fractures following minor trauma  dental imperfections are common
 blue sclera due to visible choroidal
pigment.
Diagnosis
 bone biopsy can be used to diagnose osteogenesis imperfecta  type 1 collagen mutation

May 2009 exam: A pregnant woman is known to have polycystic kidney disease. What is the
chance her child will also have the disease? 50% (Polycystic kidney disease is usually inherited
in an autosomal dominant fashion and hence 50% of her children will be affected, regardless of
gender)
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Noonan’s syndrome
 Noonan’s syndrome is a mutation affecting the RAS-MAPK pathway.
 It is an autosomal dominant disorder
feature
 short stature,
 learning disabilities,
 pectus deformity and
 congenital cardiac defects (typically pulmonary stenosis, atrial septal defect (ASD) and
occasionally hypertrophic cardiomyopathy).
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Autosomal recessive conditions

Two copies of the defective gene (one

inherited from each parent) are required in order
to be born with the disorder.
Autosomal recessive conditions are often
thought to be 'metabolic' as opposed to
autosomal dominant conditions being 'structural',
notable exceptions:
 some 'metabolic' conditions such as
Hunter's and G6PD are X-linked
recessive whilst others such as
hyperlipidemia type II and hypokalemic
periodic paralysis are autosomal
dominant
 some 'structural' conditions such as
ataxia telangiectasia and Friedreich's
ataxia are autosomal recessive

Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 3

 Basics - Genetics

The following conditions are autosomal recessive:

 Albinism  Haemochromatosis
 Ataxia telangiectasia  Homocystinuria
 Congenital adrenal hyperplasia  Lipid storage disease: Tay-Sach's,
 Cystic fibrosis Gaucher, Niemann-Pick
 Cystinuria  Mucopolysaccharidoses: Hurler's
 Familial Mediterranean Fever  PKU
 Fanconi anaemia  Sickle cell anaemia
 Friedreich's ataxia  Thalassaemias
 Gilbert's syndrome*  Wilson's disease
 Glycogen storage disease

*this is still a matter of debate and many textbooks will list Gilbert's as autosomal dominant
May 2012 exam: A man diagnosed as having hereditary hemochromatosis. His wife is not a carrier.
What is the chance his child will develop haemochromatosis? 0% (Haemochromatosis is an autosomal
recessive condition. If one of the parents has haemochromatosis (i.e. is homozygous) and the other is not a
carrier/affected then all the children will inherit one copy of the gene from the affected parent and hence will be carriers)

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Pseudoxanthoma elasticum
 inherited condition (usually autosomal recessive*) characterised by an abnormality in elastic
fibres
 *there are reports of autosomal dominant inheritance in a minority of cases

Features
 retinal angioid streaks
 'plucked chicken skin' appearance - small yellow papules on the neck, antecubital fossa and
axillae
 cardiac: mitral valve prolapse, increased risk of ischaemic heart disease
 Due to loss of elastic tissue, patients have an increased incidence of mitral regurgitation,
aortic regurgitation and aortic dissection.
 gastrointestinal haemorrhage
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Phenylketonuria (PKU)
 Phenylalanine is an essential amino acid.
 Phenylketonuria (PKU) is an autosomal recessive condition
 Caused by a disorder of phenylalanine metabolism.
 usually due to defect in phenylalanine hydroxylase, an enzyme which converts
phenylalanine to tyrosine .
 In a small number of cases the underlying defect is a deficiency of the tetrahydrobiopterin-
deficient cofactor, e.g. secondary to defective dihydrobiopterin reductase.
 The gene for phenylalanine hydroxylase is located on chromosome 12.
 The incidence of PKU is around 1 in 10,000 live births.
 High levels of phenylalanine lead to problems such as learning difficulties and seizures.

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 Basics - Genetics

Features
 usually presents by 6 months e.g. with developmental delay, infantile spasms
 child classically has fair hair and blue eyes
 learning difficulties
 Even with dietary treatment some degree of cognitive impairment is seen
 Microcephaly, prominent maxilla, growth retardation and wide-spaced teeth are found in
untreated children.
 seizures, typically infantile spasms
 About 25% of infants have seizures, but over 50% have an abnormal EEG.
 Cerebral white matter changes are seen in older patients and may reflect a combination of late
diagnosis and dietary indiscretion.
 eczema
 'musty' odour to urine and sweat* (*secondary to phenylacetate, a phenylketone)
Diagnosis
 Diagnosis of classic PKU requires raised Phe levels, increased urinary Phe metabolites and
normal cofactor (tetrahydrobiopterin) concentrations.
 plasma levels of tyrosine are difficult to measure, and have diurnal variation. Whilst the
levels are often low in patients with PKU, the levels can be normal depending on what
time of the day the sample is taken and whether or not the patients are being treated.
 Guthrie test: the 'heel-prick' test done at 5-9 days of life - also looks for other biochemical
disorders such as hypothyroidism
 hyperphenylalaninaemia
 phenylpyruvic acid in urine
Management
 poor evidence base to suggest strict diet prevents learning disabilities
 dietary restrictions are however important during pregnancy as genetically normal fetuses may
be affected by high maternal phenylalanine levels
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Alkaptonuria
The black discoloration of sclera and urine becoming black on standing should alert you to the
likelihood of Alkaptonuria.

 autosomal recessive disorder of phenylalanine and tyrosine metabolism

 caused by a deficiency of homogentisic acid oxidase responsible for the degradation of
homogentisic acid produced from phenylalanine and tyrosine.
 Accumulation of homogentisic acid causes pigmentation of the urine, sclera and connective
tissues.
 Alkaptonuria is generally a benign and often asymptomatic condition.
Features
 pigmented sclera
 urine turns black if left exposed to the air
 Deposition in the joints causes cartilage pigmentation (ochronosis) and degeneration.
 Patients develop arthritis at 40 years of age.
 intervertebral disc calcification may result in back pain
 The knees and spine are commonly affected.
 The sacroiliac joint may be spared.
 renal stones
 Homogentisic acid is a reducing agent, therefore it gives a false positive Glucostix test but
normal Clinitest.
Treatment
 high-dose vitamin C
 dietary restriction of phenylalanine and tyrosine

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 Basics - Genetics

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X-linked recessive

 The abnormal gene is carried on the X chromosome, and in the carrier female, the normal allele
on her other X chromosome protects her from the disease. Since the male does not have this
protection, he manifests the disease.
 only males are affected. An exception to this seen in examinations are patients with Turner's
syndrome, who are affected due to only having one X chromosome.
 Females only occasionally show mild sign of disease
 X-linked recessive disorders are transmitted by heterozygote females (carriers) and male-to-
male transmission is not seen.
 Affected males can only have unaffected sons and carrier daughters.
 heterozygous female carrier 
 50% of male children are affected
 50% of female children are carrier
 The possibility of an affected father having children with a heterozygous female carrier is
generally speaking extremely rare. However, in certain Afro-Caribbean communities G6PD
deficiency is relatively common and homozygous females with clinical manifestations of the
enzyme defect are seen.
 Many of the inherited eye disorders such as retinitis pigmentosa and ocular albinism are
inherited in an x-linked recessive pattern.
 The following conditions are inherited in a X-linked recessive fashion:
 Androgen insensitivity syndrome  Hunter's disease
 Becker muscular dystrophy  Lesch-Nyhan syndrome
 Colour blindness  Nephrogenic diabetes insipidus
 Duchenne muscular dystrophy  Ocular albinism
 Fabry's disease  Retinitis pigmentosa
 G6PD deficiency  Wiskott-Aldrich syndrome
 Haemophilia A,B  Fragile X syndrome

 The following diseases have varying patterns of inheritance, with the majority being in an
X-linked recessive fashion:
- Chronic granulomatous disease (in > 70%)

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Fabry's disease
Definition
 Fabry's disease is an X-linked recessive lysosomal storage disorder characterised by myelin
deposits in tubular epithelium and vascular endothelium, resulting in ischaemic nephropathy
Aetiopathogenesis
 The molecular defect is a deficiency of α-galactosidase A
 The affected lysosomal enzyme, α-galactosidase A, converts trihexosyl ceramide to lactosyl
ceramide. Accumulation of trihexosyl ceramide in the endothelial and medial smooth muscle cells

Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 6

 Basics - Genetics

of blood vessels causes ischemia and infarction, particularly in the kidneys, which explains the
elevated BUN and proteinuria.
Features and Complications
The disorder has three distinct clinical entities:
1. Classical presentation in the male homozygote with early presentation in childhood -
angiokeratomas, heart failure, cataracts and renal disease
2. Male homozygotes with atypical presentation in adulthood with proteinuria,
acroparaesthesia, angiokeratomas and cardiomegaly
3. Female heterozygotes can present again in adulthood with similar mild symptoms.
 An X linked recessively inherited condition can exist in female carriers who may exhibit
mild to moderate symptoms. This is due to variable expression according to random X
inactivation of the affected gene in embryogenesis

 Opacity of the lens and cornea,

 skin lesions with telangiectasia and a warty, hyperkeratinized covering (angiokeratoma),
 paresthesias in the extremities, Peripheral neuropathy, which is usually burning in nature,
 vascular diseases of the brain, heart, and kidneys.
 Often, renal disease is progressive and can lead to death.
 cardiac conduction defects
Diagnosis
 The diagnosis is confirmed by demonstration of absent or deficient levels of alpha-
galactosidase A in leucocytes, plasma or cultured fibroblasts.
 The most efficient means of diagnosis is by slit-lamp examination of the cornea, which reveals
microscopic lipid deposits
 Microscopy of the spun urine sediment may demonstrate 'Maltese cross' lipid globules
 Further clues to the diagnosis include skin angiokeratomas, decreased sweating and leg
lymphedema

In Fabry disease, tissue accumulation of which is most likely to occur?

Trihexosyl ceramide

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X-linked dominant disorders

No carrier (the carrier of a defective gene associated with a disorder, will have the
disorder)
affected woman  Half of the daughters and sons are affected
affected father  all his daughters are affected but none of his sons.

 The gene responsible for a genetic disorder is located on the X chromosome, and only one copy
of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder.
 X linked dominant disorders are rare (for example, vitamin D-resistant rickets).
 They affect both sexes but females more than males.
 Males can only get an X chromosome from their mother whilst females get an X
chromosome from both parents. As a result, females tend to show higher prevalence of X-
linked dominant disorders because they have more of a chance to inherit a faulty X
chromosome.
 Homozygous mother  All children are affected.
 An affected mother with the trait  half the sons and half the daughters inherit the disorder
 when the mother alone is the carrier ; she herself will have the disorder.
 50% Of her daughters and sons will have the disorder,
 50% will be unaffected.
 Affected females will transmit the condition to 50% of their children, whether male or
female.
 When the father alone is the carrier of a defective gene associated with a disorder, he too will
have the disorder.
 100% Of his daughters will have the disorder, since all of his daughters will receive one
copy of his single X chromosome.
 none of his sons will have the disorder; sons do not receive an X chromosome from their
father.

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 Basics - Genetics

 affected father  all his daughters are affected but none of his sons.
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Vitamin D-resistant rickets
 Vitamin D-resistant rickets is a X-linked dominant condition
 affected female will transmit the disease to 50% of her sons and 50% of her daughters.
 affected male will transmit the condition to all of his daughters but none of his sons.
 usually presents in infancy with failure to thrive.
 It is caused by impaired phosphate reabsorption in the renal tubules
Features
 failure to thrive
 normal serum calcium, low phosphate, elevated alkaline phosphotase
 x-ray changes: cupped metaphyses with widening of the epiphyses
Diagnosis is made by demonstrating increased urinary phosphate

Management
 high-dose vitamin D supplements
 oral phosphate supplements
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Mitochondrial diseases

myoclonic epilepsy with ragged red fibres

(MERRF):
a young patient presenting with cognitive
impairment developing after a period of normal
development, seizures, myoclonic jerks, Wolff-
Parkinson White syndrome and worsening
vision (consistent with optic atrophy).
diagnosis  (MERRF), which is a
mitochondrial DNA disorder diagnosed by 
ragged red fibres on muscle biopsy.

 Whilst most DNA is found in the cell nucleus, a small amount of double-stranded DNA is present
in the mitochondria. It encodes protein components of the respiratory chain and some special
types of RNA
Mitochondrial inheritance has the following characteristics:
 inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote
 all children of affected males will not inherit the disease
 all children of affected females will inherit it
 generally encode rare neurological diseases
 poor genotype: phenotype correlation - within a tissue or cell there can be different
mitochondrial populations - this is known as heteroplasmy)
Histology
 muscle biopsy classically shows 'red, ragged fibres' due to increased number of mitochondria
Examples include:
 Leber's optic atrophy

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 Basics - Genetics

 Cyanocobalamin (a form of B12) should be avoided as it may lead to blindness in Leber's

disease patients.
 MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
 MERRF syndrome: myoclonus epilepsy with ragged-red fibres
 sensorineural hearing loss
 Kearns-Sayre syndrome:
 It is a slowly progressive neuromuscular disorder associated with progressive external
ophthalmoplegia and heart conduction defect.
 onset in patients < 20 years old
 external ophthalmoplegia
 retinitis pigmentosa
 Ptosis may be seen
 sensorineural hearing loss is almost universal in those who survive into the fourth decade
of life; this may not be fully corrected with hearing aids.
 Other associated features:cerebellar ataxia, cardiac conduction block, raised
cerebrospinal fluid (CSF) proteins, and proximal myopathy.
 short stature and multiple endocrinopathies including diabetes
mellitus, hypoparathyroidism, and Addison disease.
 Muscle biopsy may reveal ragged red fibers.
 Muscle histochemistry reveals deficiency of cytochrome c oxidase (mitochondrial
respiratory chain enzyme).

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Achondroplasia

 Achondroplasia is an autosomal dominant disorder associated with short stature.

 The incidence increases with paternal age.
 Epiphyseal growth cartilage fails, but there is normal bone formation and repair. There is
therefore no increased risk of fracture.
 The homozygous form is usually fatal.
 It is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR-3) gene.
 This results in abnormal cartilage giving rise to:
 short limbs (rhizomelia) with shortened fingers (brachydactyly)

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 Basics - Genetics

 The fingertips may only come down to the iliac crest, and the shortness of the limbs
is often most marked proximally.
 short stature due to shortening of the limbs, but spinal length is maintained.
 The limbs appear broad with deep creases.
 large head with frontal bossing
 midface hypoplasia with a flattened nasal bridge
 'trident' hands
 lumbar lordosis
 It may be diagnosed radiographically at birth, or becomes obvious within the first year with
disparity between a large skull, normal trunk length and short limbs.
 An x ray will show metaphyseal irregularity, flaring in the long bones, and late-appearing irregular
epiphyses.
 The pelvis is narrow in anteroposterior diameter with deep sacroiliac notches and short iliac
wings.
 The spine shows progressive narrowing of the interpedicular distance from top to bottom
(reverse of normal).
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Down's syndrome (trisomy 21)
Epidemiology and genetics
 the most common autosomal abnormality
Risk of Down's syndrome with increasing maternal age

Age (years) Risk

20 1 in 1,500

30 1 in 800

35 1 in 270

40 1 in 100

45 1 in 50 or greater

One way of remembering this is by starting at 1/1,000 at 30 years and then dividing the denominator by
3 (i.e. 3 times more common) for every extra 5 years of age

Cytogenetics
Mode % of cases Risk of recurrence

Non-disjunction 94% 1 in 100 if under mother < 35 years

Robertsonian translocation 5% 10-15% if mother is translocation carrier

(usually onto 14) 2.5% if father is translocation carrier

Mosaicism 1%

 The chance of a further child with Down's syndrome is approximately 1 in 100 if the mother is
less than 35 years old. If the trisomy 21 is a result of a translocation the risk is much higher.
 Down syndrome have one of the two karyotypes:
1. 47,XX,+21 (trisomy 21)
 more common
2. 46,XY,der(14;21).

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 Basics - Genetics

 characterized by the presence of two normal chromosomes 21, one normal

chromosome 14 and a product of Robertsonian translocation between
chromosomes 14 and 21 (der(14;21); der stands for derivative).

Features
Clinical features
 face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue,
small ears, round/flat face
 flat occiput
 single palmar crease, pronounced 'sandal gap' between big and first toe
 hypotonia
 congenital heart defects (40-50%, see below)
 duodenal atresia can be diagnosed by U/S at gestation  double bubble sign
 Hirschsprung's disease

associations
 Children with Down syndrome are at increased risk for developing acute myeloid
leukemia (AML) (approximately 1-2% of children with Down syndrome develop AML, the great
majority < 5 y) rather than acute lymphoblastic leukemia (ALL), which is a more common form of
leukemia in children.
 Other haematological disorders associated with Down's syndrome include:
 Fanconi's anaemia,
 Patients with learning disabilities may be prone to lead poisoning due to pica.

Cardiac complications
 multiple cardiac problems may be present
 endocardial cushion defect (c. 40%, also known as atrioventricular septal canal defects)
 ventricular septal defect (c. 30%)
 secundum atrial septal defect (c. 10%)
 tetralogy of Fallot (c. 5%)
 isolated patent ductus arteriosus (c. 5%)
Later complications
 subfertility: males are almost always infertile due to impaired spermatogenesis. Females are
usually subfertile, and have an increased incidence of problems with pregnancy and labour
 learning difficulties
 short stature
 repeated respiratory infections (+hearing impairment from glue ear)
 acute lymphoblastic leukaemia
 hypothyroidism
 Alzheimer's
 atlantoaxial instability
Diagnosis
Screening tests
 Increased nuchal translucency is a finding on ultrasound that may suggest trisomy 21 or
other chromosomal defects such as trisomy 18 or 45 XO, thus additional testing is required to
confirm the diagnosis.
 Alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), urine unconjugated estriol, and
inhibin are components of the quad screen for Down syndrome.
 ↓ AFP ↓ unconjugated estriol ↑ hCG ↑ inhibin is consistent with the diagnosis of
Down syndrome.
 quad screen done between the 15th and 22nd weeks of the pregnancy.
 In pregnancies where the fetus has Edwards syndrome (trisomy 18), unconjugated
estriol and hCG levels are low and AFP levels can be variable.
 Anencephaly will have a low hCG and a high AFP value.
 Beta hCG should double in value every 48-72 hours and a decreased hCG should raise
suspicion for an ectopic pregnancy or a missed abortion.
 Elevations of AFP are associated with neural tube defects, multiple gestations or
abnormal dating.
Diagnostic tests
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 Basics - Genetics

 amniocentesis

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Kallman's syndrome

 Kallman's syndrome is a recognised cause of delayed puberty secondary to hypogonadotrophic

hypogonadism.
 It is usually inherited as an X-linked recessive trait.
 Whilst the majority of cases are sporadic, perhaps up to 50% of cases are due to genetic
inheritance.
 caused by failure of GnRH-secreting neurons to migrate to the hypothalamus  gonadotrophin
releasing hormone (GnRH) deficiency
 may arise due to abnormalities of the KAL-1 or KAL-2 gene (encoding anosmin-1 and FGF-1).
 There is isolated gonadotrophic deficiency (may be evidenced by a normal prolactin).
 The clue given in many questions is lack of smell (anosmia) in a boy with delayed puberty
Incidence
 1 in 10,000 males,
 male to female ratio of 4:1.

Features
 delayed puberty
 hypogonadism,
 cryptorchidism (Cryptorchidism is more suggestive of Kallman's than Klinefelter's
syndrome)
 Cryptorchidism is the absence of one or both testes from the scrotum (undescended
testis).
 anosmia (Lack sense of smell) due to failure of the olfactory bulb to develop, leading to
loss of gonadotropin releasing hormones.
 Anosmia is present in 75%
 Cleft lip/palate and visual/hearing defects are also seen in some patients
 sex hormone levels are low
 patients are typically of normal or above average height
 LH, FSH levels are inappropriately low/normal
 Lack of development of secondary sexual characteristics
 Primary amenorrhoea.
 no mental retardation
Diagnosis
 Diagnostic test  Fluorescent in situ hybridisation (FISH) is currently the best means of a
genetic diagnosis
 Absent olfactory bulbs are present on 75% of MRI scans in these patients.
 The appearance on cerebral MRI  Absent olfactory bulbs

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 Basics - Genetics

Treatment
 For a male who begin a relationship with a woman
 Pulsed (NOT Continuous) GnRH treatment is needed to restore LH and FSH release.
 It needs to be continued for as long as fertility is required.
 As natural GnRH release is pulsatile, continuous therapy fails to lead to LH and
FSH release.
 Once his family is complete, switching to testosterone therapy may be more
convenient for him.
 Although Testosterone supplementation will restores secondary sexual
characteristics, it doesn’t restore fertility and is therefore not appropriate here.
 FSH can be used to induce fertility, but it is less effective than pulsed GnRH
therapy.
 LH can be used in conjunction with FSH to induce fertility in women with Kallmann syndrome.
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Klinefelter's syndrome

 Klinefelter's syndrome is associated with male phenotype and 47, XXY karyotype
 the commonest form of which is XXY, is the result of chromosomal non-dysjunction; as such, it
does not follow a mendelian pattern of inheritance.
 Population studies suggest that the rate of occurrence in live male births is between 1 in 500 and
1 in 1000.
 The rate of chromosomal non-dysjunction increases with increasing maternal age and increasing
paternal age, each parent contributing 50% of the risk. Around 60% of Klinefelter cases do not
survive the fetal period.
 has no specific genetic pattern of inheritance
 chances of inheriting the disorder  < 1%

Features
 often taller than average
 lack of secondary sexual characteristics
 small, firm testes
 infertile
 gynaecomastia - increased incidence of breast cancer
 elevated gonadotrophin levels ( ↑↑LH/FSH) due to testicular failure
 Low testosterone levels
 Low HDL cholesterol, elevated triglyceride ,normal or increased (LDL)
 increased cardiovascular risk due to lipid abnormality.
 decrease libido
 decrease bone mineral density  increased risk of osteoporotic fractures.

Investigation
 Diagnosis is by chromosomal analysis
 the most appropriate investigation in suspected cases  FSH, LH
 Both FSH and LH are raised in Klinefelter syndrome, and elevation would be a strong
pointer to confirming the underlying diagnosis.
 more useful than Testosterone (wouldn’t indicate whether the defect was at the level of
the pituitary or the testes)
Treatment with testosterone
 Testosterone is known to improve bone mineralization and is the treatment of
choice
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Turner's syndrome
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 Basics - Genetics

 Turner's syndrome is a chromosomal disorder affecting around 1 in 2,500 females.

 It is caused by either the presence of only one sex chromosome (X) or a deletion of the short arm
of one of the X chromosomes.
 Turner's syndrome is denoted as 45,XO or 45,X
Features
 short stature
 shield chest, widely spaced nipples
 webbed neck
 cardiac defects: bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
 primary amenorrhoea
 associated absent uterus and streak ovaries
 cystic hygroma (often diagnosed prenatally)
 high-arched palate
 short fourth metacarpal
 multiple pigmented naevi
 keloid scars
 lymphoedema in neonates (especially feet)
 Horseshoe kidney is strongly associated with Turner’s syndrome
 often initially presents with stone disease, pelviureteric junction (PUJ) obstruction, trauma,
infections and tumors.
 In a pediatric patient with multiple urinary tract infections or renal stones, imaging must be
performed to rule out this congenital anomaly.
 Which anatomical structures is responsible for horseshoe kidney anomaly during
normal embryological development?
Inferior mesenteric artery
occurs when the isthmus of the kidney becomes trapped behind the inferior
mesenteric artery as the kidneys ascend during embryonic life.
Associated conditions
 autoimmune diseases:
 autoimmune thyroiditis (hypothyroidism (much more common in Turner’s) )
Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 14
 Basics - Genetics

 and Crohn's disease

 Hypertension is quite common in Turner syndrome (10%) and is typically idiopathic -
essential. In a small proportion causes can include:
 coarctation of the aorta
 and renal dysfunction due to horsehoe kidney.
 metabolic abnormalities (dyslipidaemia and glucose intolerance)
 recurrent otitis media.
Diagnosis
  made by  karyotype  identification of 45X0 .

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Marfan's syndrome
 autosomal dominant connective tissue disorder.
 caused by a defect in the fibrillin-1 gene on chromosome 15
 affects around 1 in 3,000 people.
 may occur as a spontaneous mutation, (1/3rd of cases), and this occurs more commonly to
offspring of older males.
Features
 tall stature with arm span to height ratio > 1.05
 high-arched palate
 arachnodactyly
 pectus excavatum
 pes planus
 scoliosis of > 20 degrees
 Heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic aneurysm, aortic
dissection, aortic regurgitation, mitral valve prolapse (75%),
 lungs: repeated pneumothoraces
 eyes: upwards lens dislocation (superotemporal ectopia lentis) seen in 50% of patients, blue
sclera, myopia
 dural ectasia (ballooning of the dural sac at the lumbosacral level)
 Dural ectasia affects around 60% of patients with Marfan's syndrome.
 It may cause lower back pain associated with neurological problems such as
bladder and bowel dysfunction.

Diagnosis
 Unfortunately DNA testing for fibrillin gene mutations, whilst helpful, cannot exclude a
diagnosis of Marfan because a number of mutations exist (at least 130).
 Hence diagnosis is made on the major and minor features associated with the syndrome.
Prognosis & treatment :
 The life expectancy of patients used to be around 40-50 years.
 With the advent of regular echocardiography monitoring and beta-blocker/ACE-inhibitor therapy
this has improved significantly over recent years.
 Treatment with β-blockers reduces the rate of aortic dilatation and the risk of rupture
 Aortic dissection and other cardiovascular problems remain the leading cause of death however.
 Pregnancy is associated with increased risk of aortic rupture

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Homocystinuria
 Homocystinuria is a rare autosomal recessive disease
 caused by deficiency of cystathionine beta synthase which is responsible for converting
homocysteine to cystathionine. Cystathionine is later converted to cysteine, so patients who have
this enzyme deficiency need to supplement their diets with exogenous cysteine.
 Results in an accumulation of homocysteine which is then oxidized to homocystine.
Types
 homocystinuria type 1  a defect in cystathionine synthetase is responsible.
 homocystinuria type 2  defects in methylene tetrahydrofolate reductase

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 Basics - Genetics

 However, individuals with this condition rarely survive the neonatal period or, if they
survive longer than this, they often have more severe mental retardation.
Features
 fine, fair hair
 musculoskeletal: may be similar to Marfan's - arachnodactyly etc
 neurological: learning difficulties, mild to moderate mental handicap ,seizures
 ocular: downwards (inferonasal) dislocation of lens
 The sudden visual deterioration could either be due to a thrombotic episode or to the lens
dislocation associated with this condition.
 increased risk of arterial and venous thromboembolism (atherosclerosis, thrombosis, MI)
 also malar flush, livedo reticularis
Diagnosis is made by the cyanide-nitroprusside test, which is also positive in cystinuria

Treatment is vitamin B6 (pyridoxine) supplements

Homocystinuria VS Marfan's

homocystinuria Marfan's syndrome

inheritance autosomal recessive autosomal dominant
lens downward lens dislocation upward lens dislocation
dislocation
aortic heart rarely affected aortic incompetence may
incompetence occur
intellectual mental retardation (nearly 50%) normal
development
livedo seen due to the venous thrombosis in the small NO
reticularis vessels of the skin
other osteoporosis, recurrent thromboembolism; flat feet, herniae, scoliosis;
principle characteristic laboratory features: there is a 50% reduction in
features plasma methionine and homocystine levels are life expectancy
elevated, homocystine is excreted in the urine,
plasma cystine levels are reduced, positive urine
cyanide-nitroprusside test; response to treatment
with pyridoxine
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Fragile X syndrome
Characteristics of individuals with Fragile X syndrome may include:
 moderate to severe mental retardation large ears
 macroorchidism
 prognathism
 speech delays
 prominent forehead
 double-jointedness
 autistic symptoms, and
 occasional self-mutilation.
 The face is typically long and narrow, with a high arched palate and large ears.
 Otitis media, strabismus, and dental problems may be present
 hyperextensible joints
 hypotonia, and
 heart problems, including mitral valve prolapse.
 In post pubertal males, abnormally large testes are a distinctive feature.
The following can occur In young children:
 delayed motor development
 hyperactivity
 behavioural problems
 toe walking, and
 occasional seizures.
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Porphyrias
Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 16
 Basics - Genetics

Overview

 Porphyria is a group of diseases characterised by excess production and excretion of porphyrins

and their precursors.
 They are caused by enzyme defects within the haem metabolic pathway.
 Stress, infection, pregnancy, menstruation, starvation, and certain drugs may precipitate
acute attacks.
 Definite precipitants include sulphonamides, barbiturates, and phenytoin.
 may be acute or non-acute
 The most common presenting sign of PCT is fragility of sun exposed skin after mechanical trauma,
leading to erosions and bullae, worst on dorsal hands, forearms, and face.

Acute intermittent porphyria (AIP)

 autosomal dominant
 defect in porphobilinogen deaminase
 caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of
haem.
 20-40 year olds more likely to be affected (only rarely presents before puberty)
 AIP is more common in females (5:1)
 90% of affected individuals remain asymptomatic throughout their lives.
 typically present with abdominal symptoms, neuropsychiatric symptoms
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 Basics - Genetics

 Seizures occur in 10-20% of patients with acute intermittent porphyria (AIP).

 A range of psychiatric symptoms, including hypomania and delirium may be seen.
 hypertension and tachycardia common
 urine turns deep red on standing
 Patients excrete urinary porphobilinogen (PBG) between and during acute attacks.
 Faecal porphyrin excretion is usually normal or slightly increased.
 Photosensitivity is unusual in AIP
 All attacks of porphyria increase the activity of hepatic 5-aminolevulinate (ALA) synthase.
 Lab features
 hyponatraemia,
 mild leukocytosis.
Factors precipitate an acute attack:
treatment of seizures in AIP  Gabapentin

 Stress,
 Infection
 Pregnancy
 Menstruation
 starvation
 Drugs
 sulphonamides,
 barbiturates
 phenytoin.
 Most anti-epileptics should not be given, but gabapentin is safe and the most
appropriate choice for seizures occur in (AIP).
 ACE inhibitors and calcium channel blockers
 Ibuprofen is safe for use in acute intermittent porphyria, but diclofenac should be
avoided.
Acute intermittent porphyria: drugs

Drugs which may precipitate attack Safe Drugs

 Alcohol  Sulphonylureas  Paracetamol
 Barbiturates  Theophylline  Aspirin
 Benzodiazepines  Antihistamines  Ibuprofen
 Tricyclic antidepressants  MAOIs  Codeine
 Halothane  Amiodarone  Morphine
 Oral contraceptive pill  Simvastatin.  Chlorpromazine
 Sulphonamides  Diuretics  β-blockers
 Cephalosporins  calcium channel  Gabapentin
 Erythromycin blockers  Penicillin
 Isoniazid  ACE inhibitors  Metformin
 flucloxacillin  amoxicillin
 Anabolic steroids

Diagnosis
 Urinary porphobilinogen assay is the optimal way to establish the diagnosis.
Treatment:
 glucose and heme, which inhibit delta-aminolevulinic acid synthase, thereby decreasing heme
precursor synthesis.
 Two procedures have been shown to decrease the activity of ALA synthase in animals:
1. carbohydrate loading and
2. parenteral infusion of haem arginate.
Consequently, these two procedures are the mainstay of the treatment along with opiate
analgesia.

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 Basics - Genetics

 The treatment of choice in acute porphyria is intravenous haem arginate

 high-glucose diets or infusions have been used for mild attacks of pain without neurological
symptoms

Distinguishing between lead poisoning and acute intermittent porphyria

Which one of the following features in an adult patient presenting with porphyrinuria would
most suggest lead poisoning rather than acute intermittent porphyria as a cause?
 Anaemia
 Anaemia occurs only in lead poisoning and is due to:
 inhibition of ferrochelatase (the activity of this enzyme is normal in acute intermittent
porphyria)
 a decrease in red cell lifespan
 enzyme inhibition (pyrimidine 5'-nucleotidase) leading to the accumulation of pyrimidine
nucleotides in red cells, which in turn reduces the stability of the cell membrane (and is
seen on a blood film as basophilic stippling)

Porphyria cutanea tarda (PCT)

 most common hepatic porphyria
 defect in uro-porphyrinogen decarboxylase
 can be both acquired and inherited
 may be caused by hepatocyte damage e.g. alcohol, oestrogens (oral contraceptive pill)
 classically photosensitive rash with bullae,
 Bullae develop on sun-exposed areas
 When exposed to light, uroporphyrinogen generates free radicals that cause blistering of
the skin.
 lesions heal slowly, leaving scars.
 skin fragility on face and dorsal aspect of hands
 Factors contributing to PCT are:
 alcohol (the commonest cause),
 excess iron and
 excess oestrogens.
 Urine: elevated uroporphyrinogen (Urinary porphyrins)and pink fluorescence of urine under
Wood's lamp
 Porphyrins are increased in liver, plasma, urine and stool.
 Porphobilinigen (PBG) is normal.
 Assay of red blood cells for uroporphyrinogen decarboxylase (UROD) activity is now available
 Antinuclear antibodies are frequently seen
 manage with Chloroquine
 PCT can be treated with phlebotomy to deplete the excess iron stores that exacerbate the
porphyria.
Variegate porphyria
 autosomal dominant
 defect in protoporphyrinogen oxidase
 photosensitive blistering rash
 abdominal and neurological symptoms
 more common in South Africans

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Trinucleotide repeat disorders

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 Basics - Genetics

 Trinucleotide repeat disorders are genetic conditions caused by an abnormal number of repeats
(expansions) of a repetitive sequence of three nucleotides.
 These expansions are unstable and may enlarge which may lead to an earlier age of onset in
successive generations - a phenomenon known as anticipation. In most cases, an increase in the
severity of symptoms is also noted
Examples - note dominance of neurological disorders
 Fragile X (CGG)
 Huntington's (CAG)
 myotonic dystrophy (CTG)
 Friedreich's ataxia* (GAA) (*Friedreich's ataxia is unusual in not demonstrating anticipation)
 spinocerebellar ataxia
 spinobulbar muscular atrophy
 Kennedy disease, also known as 'X-linked bulbospinal neuronopathy'
 dentatorubral pallidoluysian atrophy
__________________________________________________________________
Human genome
Human genome - 25,000 protein-coding genes
 The human genome is stored on 23 chromosome pairs.
 The haploid human genome has a total of 3 billion DNA base pairs, making up an estimated
20,000-25,000 protein-coding genes
__________________________________________________________________
Pseudoxanthoma elasticum
 Pseudoxanthoma elasticum is an inherited condition (usually autosomal recessive*)
characterised by an abnormality in elastic fibres.
 *there are reports of autosomal dominant inheritance in a minority of cases

Features
 retinal angioid streaks
 'plucked chicken skin' appearance - small yellow papules on the neck, antecubital fossa and
axillae
 cardiac: mitral valve prolapse, increased risk of ischaemic heart disease
 gastrointestinal haemorrhage
__________________________________________________________________
Causes of early developmental delay and learning difficulties
Chromosomal abnormalities and fragile X syndrome are among the commonest causes of early
developmental delay and learning difficulties.
Other potential causes of intellectual impairment include:
 birth asphyxia  trisomy 21
 intraventricular haemorrhage  Tay-Sachs
 rhesus disease  Cornelia De Lange
 congenital infections (toxoplasmosis,  homocystinuria
CMV, rubella, herpes)  phenylketonuria
 hypoglycaemia  tryptophanuria, and
 meningitis  galactosaemia.
 congenital hypothyroidism  Maple syrup urine disease
 tuberous sclerosis

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 Basics - Genetics

__________________________________________________________________
Autosomal recessive conditions

Abetalipoproteinaemia
Abetalipoproteinaemia is autosomal recessive and is associated with:
 Hypocholesterolaemia syndrome resembling Friedreich's ataxia
 Abnormally shaped red blood cells (RBC) (acanthocytes)
 Steatorrhoea and
 Fatty liver.
 fundoscopy reveals retinitis pigmentosa.
__________________________________________________________________
Hurler's syndrome (MPS-1) & Hunter's syndrome (MPS-2)
Which feature suggests a diagnosis of Hurler's syndrome rather than
Hunter's syndrome?  Cloudy cornea.
 Hunter's syndrome (MPS-2) is of X linked inheritance. The corneas are clear. The skeletal
involvement tends to be mild with no gibbous present, though scoliosis is often [Link]
retardation and heart involvement are less severe than in Hurler's syndrome.
 Hurler's syndrome (MPS-1) is autosomal recessive in inheritance and is associated with cloudy
cornea. There is severe mental retardation, and gibbous deformation of the spine is
characteristic. There is the characteristic coarse facies with hepatosplenomegaly.
__________________________________________________________________
Gaucher's disease
 autosomal recessive mutation in a gene located on chromosome 1
 Both parents must be carriers for a child to be affected.
 If both parents are carriers, the chance of the disease is one in four, or 25%, with each
pregnancy for an affected child
 Caused by deficiency of the enzyme glucocerebrosidase (also known as
glucosylceramidase),(also known as beta-glucosidase) which acts on glucocerebroside.
 When the enzyme is defective, glucocerebroside accumulates in white blood cells spleen, liver,
kidneys, lungs, brain, and bone marrow.
 Gaucher's disease is the most common of the lysosomal storage [Link] is a form of
sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional
metabolism of sphingolipids.
 About one in 100 people in the United States are carriers of the most common type of Gaucher
disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is one in
450.
 Parkinson's disease is more common in Gaucher's disease patients (the most common
known genetic risk factor for Parkinson's)
 Cancer risk may be increased, particularly myeloma.
 Patients with all types of disease have hepatosplenomegaly and large glucocerebroside-rich
cells (Gaucher cells) infiltrating the bone marrow.
Types
 GD type I (Chronic non-neuropathic; adult Gaucher disease)
 most common form of the disease, occurring in about one in 40,000 live births.
 It occurs most often among persons of Ashkenazi Jewish heritage.
 patients may live well into adulthood.
 Symptoms:
 massive hepatosplenomegaly; the spleen may rupture
 bone weakness (Osteoporosis , aseptic necrosis of the femur joint).
 pancytopaenia .Spleen enlargement and bone marrow replacement cause anemia,
thrombocytopenia, and leukopenia. bruise easily (due to low levels of platelets).
 Yellowish-brown skin pigmentation
 Characteristic yellow or yellow-brown papules (pingueculae) develop at the
sclerocorneal junctions.
 The brain is not affected pathologically.
 GD type II (Acute neuropathic; infantile Gaucher disease)

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 Basics - Genetics

 typically begins within 6 months of birth

 incidence : 1 in 100,000 live births.
 Symptoms include, hepatosplenomegaly, progressive brain damage, eye movement
disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow.
 carries the worst prognosis, Affected children usually die by age two.
 GD type III (Subacute neuropathic; juvenile Gaucher disease)
 can begin at any time in childhood or even in adulthood,
 occurs in about one in 100,000 live births.
 characterized by slowly progressive, but milder neurologic symptoms compared to the
acute or type II version.
 Patients often live into their early teen years and adulthood
Investigations
 Diagnosis  enzyme analysis (Enzyme studies of blood leucocytes)
 Some lysosomal enzymes are elevated, including:
 tartrate-resistant acid phosphatase,
 hexosaminidase,
 chitinase
 chitotriosidase  very useful for monitoring Gaucher's disease activity in
response to treatment, and may reflect the severity of the disease
 biochemical abnormalities : high alkaline phosphatase, angiotensin-converting enzyme, and
immunoglobulin levels
 cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.
Treatment
 recombinant glucocerebrosidase.

The slide shows yellow papules (pingueculae) in the cornea; these are characteristic of Gaucher
disease.

The exertional thigh cramps, the presence of myoglobin and change in colour of
urine after exercise suggests glycogen storage disease type V - McArdle's
syndrome. the next most appropriate investigation Muscle biopsy which reveals
subsarcolemmal deposits of glycogen appearing at the periphery of fibres.

Pompe's disease or acid maltase deficiency (glycogen storage disorder type 2): is a
deficiency in alpha-glucosidase. It produces a myopathy , restrictive cardiomyopathy and
hepatomegaly.

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 Basics - Genetics

Glycogen
 Glycogen is the storage form of carbohydrate, found predominantly in muscle and liver.
 Chains of glucose residues are linked by alpha-1,4 glycosidic bonds, i.e. between the first
carbon of one glucose and the fourth carbon of the next. Branches occur about every ten
residues, and are formed by alpha-1,6 glycosidic linkages.
 Glycogen synthesis and degradation occur at the tips of branches, with the branching structure
increasing the number of sites at which glucose residues can be added or removed.
__________________________________________________________________
Prader-Willi syndrome

Prader-Willi syndrome is an example of genetic imprinting where the phenotype depends on whether
the deletion occurs on a gene inherited from the mother or father:
 Prader-Willi syndrome if gene deleted from father
 Angelman syndrome if gene deleted from mother
Prader-Willi syndrome is associated with the absence of the active Prader-Willi gene on the long arm of
chromosome 15. This may be due to:
 microdeletion of paternal 15q11-13 (70% of cases)
 maternal uniparental disomy of chromosome 15
Features
 hypotonia during infancy
 dysmorphic features
 short stature
 hypogonadism and infertility
 learning difficulties
 childhood obesity
 behavioural problems in adolescence
September 2007 exam: Which one of the following is the most common genetic cause of
Prader-Willi syndrome? Microdeletion of the paternal 15q11-13
Other notes

__________________________________________________________________
linkage disequilibrium
 linkage disequilibrium is the non-random association of alleles at different loci in a given
population.
 Loci are said to be in linkage disequilibrium when the frequency of association of their different
alleles is higher or lower than what would be expected if the loci were independent and
associated randomly.
 Consider the scenario of two separate genetic loci A and B, where each locus carries two
possible alleles. If these two loci A and B are in linkage disequilibrium  An individual with
locus A is likely to have locus B
 Linkage disequilibrium almost always, but not invariably, occurs between alleles at genetic loci
that are closely linked in the genome.
__________________________________________________________________
Imprinting
 imprinting is a phenomenon by which certain genes are expressed in a parent-of-origin-specific
manner.
 If the allele inherited from the father is imprinted, it is thereby silenced, and only the allele from
the mother is expressed.
 If the allele from the mother is imprinted, then only the allele from the father is expressed.
 diseases involving genomic imprinting include Angelman syndrome and Prader–Willi syndrome.

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 Basics - Genetics

 the term 'imprinting' refers to  Differential expression of alleles contingent on their

parental origin
 The mechanism is poorly understood, but does involve DNA methylation.
 Some genes may be maternally imprinted, others paternally.
 Disease may occur as a result of a defect in one allele if the other allele is imprinted and hence
not expressed.
__________________________________________________________________
Mutations
 Missense mutation
 substitution in one amino acid in a protein
 e.g: glutamic acid is substituted by valine in sickle-cell disease
 nonsense mutation
 the altered DNA sequence prematurely signals the cell to stop building a protein. This
type of mutation results in a shortened protein that may function improperly or not at all.
 insertion mutation
 changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the
protein made by the gene may not function properly.
__________________________________________________________________
McCune–Albright syndrome
 McCune–Albright syndrome is due to a mutation in a G-protein.
Clinical presentations:
 Precocious puberty (typically gonadotropin-independent). This includes breast development,
genital maturation (with or without pubic hair growth), increased height velocity and macro-
orchidism in males.
 Café-au-lait pigmentation. This consists of spots ranging from light brown to dark brown in colour.
These often display a segmental distribution and frequently are predominant on one side of the
body without crossing the midline; these spots must be differentiated from those characteristic of
neurofibromatosis.
 Polyostotic fibrous dysplasia. Multiple pathological fractures may be prominent early in the
history; in many cases, bony involvement is found to predominate clinically on one side; clinical
manifestations include gait anomalies, visible bony deformities (including abnormal bone growths
of the skull), bone pain and joint stiffness with pain.
 Hyperthyroidism, which in infants can result in failure to thrive.
 There is an increased risk of osteosarcoma and other connective tissue tumours, especially if the
patient has had multiple radiographs of affected areas. In relation to precocious puberty, the
patient is at increased risk of developing breast carcinoma. The increased risk of osteosarcoma
is in the setting of polyostotic fibrous dysplasia, although it still has an overall incidence of only
around 1%.

Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad 24