HOMOCYSTINURIA
Clinical features
● Neurological
○ Mild learning disability, Psychiatric disease
○ Seizures
● Eye anomalies:
○ Ectopia lentis – Downward dislocation
○ Myopia (nearsightedness)
○ Glaucoma, Cataracts
○ Optic atrophy
○ Retinal detachment
● Malar flush
● Livedo reticularis
● Musculoskeletal
○ Tall, thin build resembling Marfanoid habitus
○ Long limbs (dolichostenomelia)
○ High-arched feet (pes cavus)
○ Knock knees (genu valgum)
○ Pectus excavatum & Pectus carinatum
● Vascular disease
○ Extensive atheroma formation at a young age which affects many arteries but not
coronary arteries
○ Intravascular thrombosis
Investigations
● increased homocysteine levels in serum and urine
● cyanide-nitroprusside test: also positive in cystinuria
Treatment : Vitamin B6 (pyridoxine) supplements.
ALKAPTONURIA(OCHRONOSIS)
● Disorder of phenylalanine and tyrosine metabolism
● Caused by a lack of enzyme homogentisic dioxygenase (HGD) which results in a build-up
of toxic homogentisic acid
● Features
○ Generally a benign and often asymptomatic condition
○ Pigmented sclera
○ Urine turns black if left exposed to the air
○ Intervertebral disc calcification may result in back pain
○ Renal stones
Treatment
● High-dose vitamin C
● DIetary restriction of phenylalanine and tyrosine
PHENYLKETONURIA
● Usually due to a defect in phenylalanine hydroxylase, an enzyme which converts
phenylalanine to tyrosine.
● In a small number of cases underlying defect is a deficiency of tetrahydrobiopterin-deficient
cofactor, e.g. secondary to defective dihydrobiopterin reductase.
● Features
○ usually presents by 6 months e.g. with developmental delay
○ learning difficulties, seizures typically infantile spasms
○ child classically has fair hair and blue eyes
○ eczema
○ 'musty' odour to urine and sweat*
FABRY DISEASE
Overview
● X-linked recessive
● deficiency of alpha-galactosidase A
Features (FABRY)
● Febrile episodes
● Angiokeratomas most prominently periumbilically
● Burning pain / paraesthesia (intermittent) in childhood evoked by vigorous exercise, hot
weather & febrile illness
● Renal failure / Proteinuria
● Early cardiovascular disease
● Lens opacities
Dystrophinopathies
Overview
● X-linked recessive
● due to mutation in the gene encoding dystrophin, dystrophin gene on Xp21
● dystrophin is part of a large membrane associated protein in muscle which connects the
muscle membrane to actin, part of the muscle cytoskeleton
● Duchenne muscular dystrophy : frameshift mutation resulting in one or both of the binding
sites are lost leading to a severe form
● Becker muscular dystrophy : non-frameshift insertion in the dystrophin gene resulting in
both binding sites being preserved leading to a milder form
Duchenne muscular dystrophy
● Progressive proximal muscle weakness from 5 years
● Calf pseudohypertrophy
● Gower's sign: child uses arms to stand up from a squatted position
● 30% of patients have intellectual impairment
Becker muscular dystrophy
● Develops after the age of 10 year
● May present with heart failure due to dilated cardiomyopathy
● intellectual impairment much less common
Allele : One for of gene
Penetrance
Describes 'how likely' it is that a condition will develop
Incomplete penetrance : retinoblastoma and Huntington's disease
in contrast, achondroplasia shows 100%, or complete, penetrance
Expressivity
describes the 'severity' of the phenotype
High level of expressivity : neurofibromatosis
🔴 Chromosome
Alpha thalassemia : Chromosome 16
Beta thalassemia : Chromosome 11
ADPKD 1 : Chromosome 16
ADPKD 2 : Chromosome 4
ARPKD : Chromosome 6
Neurofibromatosis 1 : Chromosome 17
Neurofibromatosis 2 : Chromosome 22
Chromosome 3 : Von hippel lindau
Chromosome 4
ADPKD 2
Huntington disease
Chromosome 5 : Familial adenomatous polyposis
Chromosome 6 :
Sickle cell disease (Substitution of glutamic acid by valine)
HLA
Chromosome 7 : Cystic fibrosis
Chromosome 11 : Wilm’s tumor
Chromosome 16
ADPKD 1
Alpha thalassemia
Tuberous sclerosis
Chromosome 17
p53
Neurofibromatosis 1
Chromosome 22 : Mesothelioma
Gitelman syndrome : SLC12A3 gene mutation
Hereditary non polyposis colon cancer : MSH 2 mutation
CADASIL : NOTCH 3 Mutation
CHROMOSOMAL DISORDERS
🔴 AUTOSOMAL DOMINANT
Achondroplasia
Ehlers-Danlos syndrome
Marfan's syndromes
Myotonic dystrophy
Osteogenesis imperfecta
Facioscapulohumeral muscular dystrophy
Neurofibromatosis
tuberous sclerosis
Von Hippel-Lindau syndrome
Adult polycystic disease
Acute intermittent porphyria
Antithrombin III deficiency
Factor V leiden
Protein C deficiency
Von Willebrand's disease*
type 3 von Willebrand's disease (most severe form) : autosomal recessive trait
Hereditary haemorrhagic telangiectasia
Hereditary spherocytosis
Familial adenomatous polyposis
Hereditary non-polyposis colorectal carcinoma
Peutz-Jeghers syndrome
Huntington's disease
Hyperlipidaemia type II
Hypokalaemic periodic paralysis
Liddle syndrome
Li Fraumeni syndrome
Malignant hyperthermia
Noonan syndrome
Retinoblastoma
Romano-Ward syndrome
🔴 AUTOSOMAL RECESSIVE
Bartter syndrome
Gitelmans syndrome
Ataxia telangiectasia
Friedreich's ataxia
Albinism
Congenital adrenal hyperplasia
Cystic fibrosis,Haemochromatosis,Wilson's disease
Cystinuria,Homocystinuria, Phenylketonuria
Familial Mediterranean Fever
Gilbert's syndrome*
Glycogen storage disease
Lipid storage disease: Tay-Sach's, Gaucher, Niemann-Pick
Mucopolysaccharidoses: Hurler's
pseudoxanthoma elasticum
Pendards syndrome
Fanconi anaemia
Sickle cell anaemia
Thalassaemias
AUTOSOMAL DOMINANT
AUTOSOMAL RECESSIVE
Liddle syndrome
Acute intermittent porphyria
Antithrombin III deficiency
Factor V leiden
Protein C deficiency
Von Willebrand's disease*
type 3 (most severe) : autosomal recessive
Hereditary haemorrhagic telangiectasia
Bartter syndrome
Gitelmans syndrome
Fanconi anaemia
Sickle cell anaemia
Thalassaemias
Ataxia telangiectasia
Friedreich's ataxia
AUTOSOMAL RECESSIVE
X LINKED RECESSIVE
Albinism
Congenital adrenal hyperplasia
5-α reductase deficiency
Glycogen storage disease
Ocular albinism
RETINITIS pigmentosa
Androgen insensitivity syndrome
Fabry's disease,Hunter's disease
X LINKED DOMINANT
Alports syndrome
Rett syndrome
Vitamin D resistant rickets
🔴 X LINKED RECESSIVE DISORDERS (VVVVI)
Androgen insensitivity syndrome
Becker muscular dystrophy
Duchenne muscular dystrophy
Colour blindness,Ocular albinism,Retinitis pigmentosa
Fabry's disease,Hunter's disease
G6PD deficiency
Haemophilia A,B
Lesch-Nyhan syndrome
Kallmann syndrome
Nephrogenic diabetes insipidus
Wiskott-Aldrich syndrome
AUTOSOMAL DOMINANT CONDITION
Noonan syndrome
Often thought of as male Turner's
Autosomal dominant condition associated with a normal karyotype
Defect in a gene on chromosome 12
Features
triangular-shaped face, ptosis, low-set ears
short stature, webbed neck, widely-spaced nipples, pectus carinatum and excavatum
cardiac: pulmonary valve stenosis
Factor XI deficiency
MARFAN'S SYNDROME
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)
blue sclera
myopia
dural ectasia (ballooning of the dural sac at the lumbosacral level)
Achondroplasia
Achondroplasia is an autosomal dominant disorder associated with short stature. 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)
large head with frontal bossing and narrow foramen magnum
midface hypoplasia with a flattened nasal bridge
'trident' hands
lumbar lordosis
In most cases (approximately 70%) it occurs as a sporadic mutation. The main risk factor is
advancing parental age at the time of conception. Once present it is typically inherited in an
autosomal dominant fashion.
Treatment
There is no specific therapy. However, some individuals benefit from limb lengthening procedures.
These usually involve application of Ilizarov frames and targeted bone fractures. A clearly defined
need and end point is the cornerstone of achieving success with such procedures.
AUTOSOMAL RECESSIVE
VITAMIN D RESISTANT RICKET
caused by impaired phosphate reabsorption in renal tubules
Features
failure to thrive
normal serum calcium, low phosphate, elevated alkaline phosphotase
x-ray changes: cupped metaphyses with widening of epiphyses
Diagnosis is made by demonstrating increased urinary phosphate
Management
high-dose vitamin D supplements
oral phosphate supplements
X LINKED RECESSIVE
DYSTROPHINOPATHIES
● X-linked recessive
● Due to mutation in the gene encoding dystrophin, dystrophin gene on Xp21
● dystrophin is part of a large membrane associated protein in muscle which connects the
muscle membrane to actin, part of the muscle cytoskeleton
Duchenne muscular dystrophy
● Frameshift mutation resulting in loss of one or both of binding sites leading to a severe form
● Progressive proximal muscle weakness from 5 years
● Calf pseudohypertrophy
● Gower's sign: child uses arms to stand up from a squatted position
● 30% of patients have intellectual impairment
Becker muscular dystrophy
● Non-frameshift insertion in dystrophin gene resulting in both binding sites being preserved
leading to a milder form
● Develops after the age of 10 years
● Intellectual impairment much less common
FABRY DISEASE
Overview
X-linked recessive
deficiency of alpha-galactosidase A
Features (FABRY)
Febrile episodes
angiokeratomas
burning pain/paraesthesia in childhood
Renal failure / Proteinuria
lens opacities
early cardiovascular disease
Tay-Sachs disease
developmental delay, cherry red spot on the macula, liver and spleen normal size
Niemann-Pick disease
cherry red spot on the macula, Hepatosplenomegaly
MITOCHONDRIAL DISEASES
● Mitochondrial DNA : Encodes protein components of respiratory chain & some special
types of RNA
Characteristics :
● inheritance is only via maternal line as the sperm contributes no cytoplasm to the zygote
● none of the children of an affected male will inherit the disease
● all of the children of an affected female will inherit the disease
● generally, encode rare neurological diseases
● poor genotype : phenotype correlation
● within a tissue or cell there can be different mitochondrial populations - known as
heteroplasmy
Examples include:
● Leber's optic atrophy
● MELAS syndrome : Mitochondrial encephalomyopathy lactic acidosis and stroke-like
episodes
● MERRF syndrome : Myoclonus epilepsy with ragged-red fibres
● Kearns-Sayre syndrome
○ < 20 years old
○ Ptosis, External ophthalmoplegia, Retinitis pigmentosa
○ Sensorineural hearing loss
Investigation
● Muscle biopsy : Red, ragged fibres due to increased number of mitochondria
CHILDHOOD SYNDROMES
Turner's syndrome
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
bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
an increased risk of aortic dilatation and dissection are the most serious long-term health problems
for women with Turner's syndrome
regular monitoring in adult life for these complications is an important component of care
primary amenorrhoea
cystic hygroma (often diagnosed prenatally)
high-arched palate
short fourth metacarpal
multiple pigmented naevi
lymphoedema in neonates (especially feet)
gonadotrophin levels will be elevated
hypothyroidism is much more common in Turner's
horseshoe kidney: the most common renal abnormality in Turner's syndrome
There is also an increased incidence of autoimmune disease (especially autoimmune thyroiditis)
and Crohn's disease
Patau syndrome (MCPS)
Microcephalic, Micro eyes
Cleft lip/palate
Polydactyly
Scalp lesions
Edward syndrome
Micrognathia, Low-set ears
Rocker bottom feet,Overlapping of fingers
McCune-Albright syndrome
● It's not inherited, it is due to a random, somatic mutation in GNAS gene.
Features
● Short stature
● Precocious puberty
● Cafe-au-lait spots
● Polyostotic fibrous dysplasia
Trinucleotide repeat disorders
● CAG : Huntington disease
● CGG : Fragile X syndrome
● CTG : MyoTonic dysTrophy
● GAA : Friedrich ataxia
● spinocerebellar ataxia
● spinobulbar muscular atrophy
● dentatorubral pallidoluysian atrophy
● Friedreich's ataxia is unusual in not demonstrating anticipation
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