Genetics Flashcards
What are the features of MELAS syndrome?
Myopathy, encephalopathy, lactic acidosis, and stroke like episodes
What type of inheritance is MELAS syndrome and Kearns-Sayre syndrome?
Mitochondrial
What are the features of Kearns-Sayer syndrome?
Ptosis and external ophthalmoplegia
Retinitis pigmentosa
Proximal myopathy
AV nodal block
How is MELAS syndrome diagnosed?
Multifocal hyperintense cortical lesions
Increased lactate in serum and CSF
Biopsy - ragged red fibres
When should you suspect MELAS syndrome?
Young people with atypical stroke like episodes that cross vascular territories
How is Kearns-Sayer syndrome diagnosed
Ragged red fibres
Elevated serum lactate and pyruvate
What is the cause of homocystinuria?
Autosomal recessive
Deficiency of cystathione beta synthase
What are the features of homocystinuria?
Marfinoid body habitus LD Kyphosis Downwards dislocation of lens and myopia Increased risk of VTE Malar flush and livedo reticularis
How is homocystinuria diagnosed?
Increased homocysteine in serum and urine
Cyanide nitroprusside test
What is the treatment of homocystinuria?
Vitamin B6 pyridoxine
What is the cause of cystinuria?
Autosomal recessive
Chromosome 2: SLC3A1 gene or chromosome 19: SLC7A9 gene
Defect in membrane transport of cystine, ornithine, lysine, arginine –> inadequate reabsorption in PCT
What is the main feature of cystinuria?
Yellow and crystalline nephrocalcinosis
What is the treatment of cystinuria?
Hydration
D-penicillamine
Urinary alkalinisation
How is cystinuria diagnosed?
Cyanide nitroprusside test
What is the cause of phenylketonuria?
Autosomal recessive
Chromosome 12 - phenylalanine hydroxylase defect
What are the features of phenylketonuria and when does it present?
LD Infantile spasms Eczema Fair hair and blue eyes Musty odour to urine and sweat
Presents by 6 months
How is PKU diagnosed?
Guthrie test
Hyperphenylalaninaemia
Phenylpyruvic acid in urine
What is the inheritance of Fabry disease?
X-linked recessive
What is the pathophysiology of Fabry disease
Deficiency of galactosidase A –> accumulation of glycosphingolipids (ceramide trihexoside) in lysosomes
What are the features of Fabry disease?
Acute neuropathic/limb pain episodes with stress, hot, cold Angiokeratomas Corneal whirls Hypohidrosis CV complications
What is the most common lysosomal storage disorder?
Gaucher disease
What is the treatment of Fabry disease?
Agalsidase alpha replacement
In which 2 lysosomal storage disorders is a cherry red spot seen on the macula?
Tay-Sachs disease
Niemann-Pick disease
What is the difference between Tay-Sachs disease and Niemann Pick disease?
TS: defect in hexosaminidase A, normal liver and spleen size
NP: defect in sphingomyelinase, hepatosplenomegaly
What are the other symptoms of Tay-Sachs disease?
After 3 months - hypotonia, myoclonic jerks, LD and regression, seizures, dementia
What is the cause of Gaucher disease?
Autosomal recessive
b-glucocerebrosidase accumulates in brain, liver, spleen
What are the features of Gaucher disease?
Hepatosplenomegaly Anaemia Osteopenia Type 1: less severe, no neuro symptoms, may be incidental Types 2 and 3 present in infancy
Which glycogen storage disorder is caused by deficiency of glycogen phosphorylase?
McArdle’s disease type V
Hypotonia from skeletal muscle glycogen accumulation
What type of immunodeficiency is present in Di-George syndrome?
T cell
What is the inheritance of Di-George syndrome?
Autosomal dominant
22q11.2 deletion
What are the features of Di-George syndrome?
CATCH-22
Cardiac abnormalities Abnormal facies Thymic aplasia Cleft palate Hypocalcaemia/hypoparathyroid
What type of infections are patients with Di-George syndrome at risk of?
Viral and fungal infections
Mutation in the WASP gene causes what syndrome?
Wiskott-Aldrich
X-linked recessive
What are the features of Wiskott-Aldrich syndrome?
Recurrent bacterial infection - combined B and T cell dysfunction
Eczema
Thrombocytopenia
Which antibody is low in Wiskott-Aldrich syndrome?
IgM
What is the name of the condition which results in juvenile gout, learning difficulties, and aggression?
Lesch-Nyhan syndrome
What is the inheritance of Lesch-Nyhan syndrome?
X-linked recessive
Why does uric acid accumulate in Lesch-Nyhan syndrome?
Defect in purine synthesis salvage pathway and absence of HGPRT enzyme
What is the karyotype of Turner’s syndrome?
45XO
Only 1 sex chromosome, or deletion of short arms of 1 X chromosome
What are the features of Turner’s syndrome?
Short stature Shield chest Webbed neck Primary amenorrhoea Hypothyroidism High arched palate Horseshoe kidney
What are the cardiac abnormalities in Turner’s syndrome and the prevalence?
Bicuspid aortic valve - 15%
Coarctation of the aorta - 10%
Are gonadotrophin levels low or high in Turner’s syndrome?
High
Which autosomal dominant condition with a defect on chromosome 12, results in factor XI deficiency?
Noonan syndrome
What are the other features of Noonan syndrome?
Short stature Webbed neck Pectus carinatum/excavatum Pulmonary stenosis Ptosis Triangle face Low set ears
What is the genetics of Prader-Willi syndrome?
Genetic imprinting
Paternal 15q11-12 in 70%
What are the features of Prader-Willi syndrome?
Hypotonia Dysmorphic face Short stature Hypogonadism LD Obesity
A mutation in the fibroblast growth factor receptor (FGFR3) gene causes what condition?
Achondroplasia
Autosomal dominant
What is a risk factor for achondroplasia?
Advancing parental age
What is the trinucleotide repeat in Fragile X syndrome?
CGG
What are the features of Fragile X syndrome?
LD Large low set ears Long thin face High arched palate Macro-orchidism Hypotonia MV prolapse
What is the cause of Alport syndrome?
X-linked dominant
Defective T4 collagen = defective glomerular basement membrane
What are the features of Alport syndrome?
Microscopic haematuria –> end stage renal failure
Bilateral sensorineural deafness
Lenticonus and retinitis pigmentosa
What is seen electron microscopy of renal biopsy in Alport syndrome?
Splitting of lamina densa of GBM - basket weave
In which gender is Alport syndrome more severe?
Males
What is the inheritance and cause of Kallmann’s syndrome?
X-linked recessive
Failure of GnRH secreting neurons to migrate to the hypothalamus
What are the features of Kallmann’s syndrome?
Anosmia Delayed puberty and hypogonadism Tall stature cryptorchidism Visual/hearing defects
How is Kallmann’s syndrome diagnosed?
Low sex hormones
LH and FSH low/normal
What is the karyotype of Klinefelter’s syndrome?
47XXY
What are the features of Klinefelter’s syndrome?
Tall stature Small firm testes Gynaecomastia Lack of secondary sexual characteristics Infertile
How is Klinefelter’s syndrome diagnosed?
Elevated gonadotrophins
Low testosterone
Which AR syndrome results from defect of sodium-chloride cotransporter in the distal convuluted tubule?
Gitelman’s syndrome
What are the features of Gitelman’s syndrome?
Low K Low Mg Low Ca in urine Alkaline urine Normotension
Which AR syndrome results from defect in Na-K-Cl co-transporter of LoH?
Bartter’s syndrome
What are the features of Bartter’s syndrome?
Low K
Normotension
Weakness
Polyuria
What is the cause and features of Liddle’s syndrome?
Defect in epithelial sodium channels in DCT
Low K
Hypertension
What tumours are seen in von-hippel-lindau syndrome?
Cerebellar haemangiomas
Retinal haemangiomas —> vitreous haemorrhage
Phaeochromocytoma
Renal/liver/pancreatic cysts
Where is the VHL gene located?
Chromosome 3
What is the condition characterised by pigmented freckles on lips, face, palms, and soles, and GI bleeds?
Peutz-Jegher’s syndrome
What is the cause of Peutz-Jegher’s syndrome?
Autosomal dominant
Serine threonine kinase LKB-1 or STK-11
50% of people with Peutz-Jegher’s syndrome die from what?
GI tract cancer
What is the cause of Friedreich’s ataxia?
Autosomal recessive
Chromosome 9 GAA triplet repeat which codes for frataxin
What are the features of FA?
Mixed UMN/LMN/cerebellar signs Pes cavus Optic atrophy Diabetes HCOM
What are the features of the AR condition ataxia telangiectasia?
Cerebellar ataxia
Telangiectasia
IgA deficiency
Increased risk of leukaemia/lymphoma
When do FA and AT present?
FA: 10-15 years
AT: 1-5 years
What is the cause of Gilbert’s syndrome?
Deficiency of UDP-glucuronosyltransferase –> defective conjugation of bilirubin
What type of bilirubin is seen in Gilbert’s syndrome?
Unconjugated
No bilirubin in urine
What is Dubin-Johnson syndrome?
Defective hepatic bilirubin excretion due to defect in canallicular multispecific organic anion transporter
What are the features of Dubin-Johnson syndrome?
Presents in teenage years with jaundice
Conjugated hyperbilirubinaemia
Bilirubin in urine
Black liver
Which protein holds DNA together to form chromosomes?
Histone
What is the structure of DNA?
Nitrogenous base - adenine, cytosine, guanine, thymine
Sugar-phosphate backbone
DNA replication is achieved by splitting DNA into what, and how?
Leading and lagging strands
By DNA helicase
In which conditions is anticipation seen?
Huntington’s
Fragile X syndrome
Myotonic dystrophy
What are the features of Leber’s optic atrophy?
Subacute loss of binocular vision
Improper colour vision
Lesion of central vision
Optic nerve atrophy
How is myotonic dystrophy diagnosed?
Genetic testing - expanded CTG repeat in DMPK gene
>50 repeats = confirmatory
What is a rare cause of adrenal insufficiency that can be mistaken for multiple sclerosis?
X-linked adrenoleukodystrophy
Mutation in ABCD1 gene - codes for ALD which is a peroxisomal membrane transporter protein
Peripheral neuropathy/myelopathy with adrenal failure
