X-Linked Dominant Disease Flashcards
Alport’s Syndrome
= RENAL F + DEAF
Alport’s syndrome is usually inherited in an X-linked dominant pattern*. It is due to a defect in the gene which codes for type IV collagen resulting in an abnormal glomerular-basement membrane (GBM). The disease is more severe in males with females rarely developing renal failure
A favourite question is an Alport’s patient with a failing renal transplant. This may be caused by the presence of anti-GBM antibodies leading to a Goodpasture’s syndrome like picture
*in around 85% of cases - 10-15% of cases are inherited in an autosomal recessive fashion with rare autosomal dominant variants existing
Alport’s syndrome usually presents in childhood. The following features may be seen:
microscopic haematuria
progressive renal failure
bilateral sensorineural deafness
lenticonus: protrusion of the lens surface into the anterior chamber
retinitis pigmentosa
renal biopsy: splitting of lamina densa seen on electron microscopy
Example Question:
A 19 year-old man presents with frank haematuria. He had just recovered from a severe cold and states that the symptoms of the cold have now resolved. He took paracetamol for the cold and was not prescribed any antibiotics. His past medical history includes hearing problems from a young age, for which he wears hearing aids and a recent corneal ulcer. His observations are stable and urine dipstick reveals protein ++ and blood +++ in his urine.
It is decided that he will undergo a renal biopsy. What is the most likely finding under light microscopy?
> Nothing Rapidly progressive glomerulonephritis Membranous nephritis Mesangiocapillary glomerulonephritis Acute tubular necrosis
This patient has Alport’s syndrome - a combination of nephritis causing microscopic haematuria with episodic frank haematuria, high frequency sensorineural deafness and ocular problems which include corneal ulcers and bilateral lenticonus. Light microscopy is usually unremarkable and electron microscopy is usually required.
Alport’s Syndrome - Example Question
A 46-year-old male was admitted to the Emergency Department with a five-day history of feeling generally unwell. He was unable to identify the exact cause of the illness, except that he had a sore throat a couple of weeks ago which spontaneously resolved. Over the last few hours, he has had three episodes of frank haematuria. Since then he has rapidly deteriorated, with a reducing urine output. His past medical history included hypertension for which he was treated with ramipril 5mg OD. He recalled being under the care of the paediatric nephrology as a child for isolated proteinuria for which no cause was found. He also had cochlear implants fitted as a child for hearing impairment but was otherwise fit and well. Upon specific questioning, he admitted that his mother was also under the care of the nephrology team for sporadic haematuria for which no cause was found, and as far as he was aware of her renal function was normal. He smoked 20 cigarettes per day and consumed 15 units of alcohol per week.
On examination, he was unwell with a heart rate of 125/min, respiratory rate of 28/min and blood pressure 96/74 mmHg. Examination of the cardiovascular system revealed a reduced JVP and skin turgor, and the presence of bilateral pedal oedema. Examination of his respiratory rate revealed tachypnoea but was otherwise unremarkable, with an oxygen saturation of 97% on air. Examination of his gastrointestinal system was unremarkable, as was the examination of his neurological system.
Initial investigations revealed the following:
Na+ 129 mmol/l
K+ 6.8 mmol/l
Urea 22.1 mmol/l
Creatinine 465 µmol/l
Bilirubin 11 µmol/l
ALP 101 u/l
ALT 22 u/l
Albumin 30 g/l
Urinalysis: blood ++++, protein ++++, leuc/nit negative gluc negative
ECG: HR 126bpm normal sinus tachycardia, tented T waves, QRS interval 132ms
Chest x-ray: unremarkable
The urea and electrolytes 6 months ago were as follows:
Na+ 132 mmol/l
K+ 5.3 mmol/l
Urea 11.2 mmol/l
Creatinine 138 µmol/l
What is the most likely diagnosis?
Post streptococcal glomerulonephritis Autosomal dominant polycystic kidneys Goodpasture's syndrome > Alport's syndrome Granulomatosis with polyangiitis
This gentleman developed a rapid deterioration of renal function with associated haematuria. Crucially he had proteinuria in childhood, and similarly, his mother was investigated for haematuria with normal renal function. He also suffered from hearing impairment. The most likely diagnosis that would unify all aspects of the history is, therefore, Alport’s syndrome. Note that females do not develop progressive renal failure with this condition. There is no evidence of pulmonary involvement which would make options 3 and 5 unlikely, and whilst option 1 is a possibility, it would not account for the history of proteinuria, deafness and maternal haematuria.
Vitamin D Resistant Rickets
= X-linked dominant condition
Usually presents in infancy with FAILURE TO THRIVE
Caused by impaired phosphate reabsorption in renal tubules
Features:
- N serum calcium
- Low phosphate
- Elevated ALP
- X-ray changes: cupped metaphyses with widening of epiphyses
Diagnosis:
- Demonstrated by increasing urinary phosphate
Mx:
- High dose Vit D supplements
- Oral phosphate supplements
Fragile X
= a trinucleotide repeat disorder
X-linked dominant
Features in Males:
- learning difficulties
- large low set ears, long thin faces, high arched palate
- macroorchidism
- hypotonia
- autism is more common
- mitral valve prolapse
Features in Females who have 1 fragile chromosome and one Normal X
- Range from normal to mild
Diagnosis:
-can be made antenatally by chorionic villus sampling or amniocentesis
Analysis of the number of CCG repeats using restriction endonuclease digestion and Southern blot analysis
X-Linked Dominant Conditions
- Alport’s syndrome (85% X-linked dominant, 10-15% autosomal recessive)
- Rett Syndrome
- Vitamin D Resistant Rickets
