Approach

Where the diagnosis of Alport syndrome is suspected, a full clinical and family evaluation, together with molecular or pathological examination, (depending on local availability), are typically used to establish a diagnosis.[22] Direct gene testing is recommended if patients have two or more diagnostic criteria for Alport syndrome.[21][23][24]​​ Targeted molecular examination (e.g., detection of a COL4A5/6 contiguous gene deletion) may be used where symptoms and signs suggest a diagnosis of Alport syndrome with diffuse leiomyomatosis.

Clinical evaluation

Diagnosis should be considered in any child or adult (male or female) who presents with features compatible with a diagnosis of Alport syndrome. These include haematuria, proteinuria, deafness, hypertension, and renal failure. Symptoms may be vague and only relate to the development of renal failure such as fatigue, breathlessness, peripheral oedema, growth restriction, hypertension, and signs and symptoms of acidosis. If renal disease is associated with deafness then there is a high suspicion of the diagnosis, especially in males. A family history of these features should always be sought and screening for haematuria offered to first-degree relatives, especially parents, as this may identify familial disease. Patients should be screened for high-frequency sensorineural hearing loss and lenticonus (bulging of the lens capsule and the underlying cortex)/retinopathy even in the absence of symptoms.[2][3]​​ The presence of the characteristic central retinopathy, present in 40% to 70% of males, is said to be pathognomonic of the disease.[4][25]

The following historical and symptomatic criteria suggest strong clinical evidence for the diagnosis of classic Alport syndrome.[24][26]

  • Haematuria with or without progression to chronic kidney disease, together with a family history of haematuria or renal failure

  • Proteinuria

  • Progressive sensorineural hearing loss

  • Characteristic ocular changes (anterior lenticonus [bulging of the lens capsule and the underlying cortex]/maculopathy).[2][3]​ Cataracts may be a presenting symptom.[15]

  • Typical ultra-structural changes in the glomerular basement membrane

Large family-based studies of X-linked Alport syndrome, the most common form, show that in male patients the most common clinical presentation (about 80%) is microscopic or macroscopic (gross) haematuria with or without proteinuria.[4]

  • Other presentations include proteinuria, deafness, chronic kidney disease, and hypertension.

  • Gross haematuria occurs in about 60% of patients.

  • Proteinuria is eventually found in most patients (>95%).

  • Hearing loss is present in about 80% of patients and eye signs in about 35%.

  • Aortic abnormalities have also been rarely described in affected males and may be found with echocardiogram.[27]

In women with X-linked Alport syndrome, more than 95% will have microscopic haematuria and 75% will develop proteinuria.[7]

  • Approximately 30% will have some hearing impairment and 15% will have eye signs.

  • Chronic kidney disease will develop in 12% before aged 40 years, which is correlated with the presence of proteinuria and deafness. Between 15% and 30% of women may develop renal failure by the aged 60 years, but further studies are required to verify this due to likely ascertainment bias in early studies.[28]

Steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis, familial IgA glomerulonephritis, and end-stage kidney failure of unknown cause have also been associated with variants in COL4A3, COL4A4, and COL4A5 and are therefore considered an extension of the classical Alport phenotype.[26]

Further rare signs and symptoms associated with Alport syndrome are learning disability, dysphagia (caused by oesophageal leiomyomas), altered bowel habit (diffuse leiomyomatosis of the bowel wall) and cough or recurrent bronchitis (caused by bronchial leiomyomas).[13][14]

Audiometry and ophthalmoscopy are recommended in all patients with suspected Alport syndrome to support diagnosis and guide management of the specific complications such as hearing loss and visual acuity.

See Assessment of hearing loss.

Molecular genetic testing

If, after a full clinical and family evaluation, there is a strong clinical suspicion of Alport syndrome, molecular diagnosis can be initially offered by targeted next generation sequencing, which can also confirm the mode of inheritance (see Aetiology).[16][21]​​​[22]​​​​​[29]​​ It can be used to predict phenotype, and to help in offering prenatal and pre-implantation genetic diagnosis. Genetic counselling should be sought before testing. In Europe, genetic testing to confirm diagnosis is indicated over renal biopsy; however, in countries with a higher cost or lower availability, renal biopsy may be preferred.[26][29]​​ The current mutation detection rate in COL4A5 is high when direct sequencing and deletion screening strategies are used in patients who fulfil two or more diagnostic criteria (see Diagnostic criteria).[23][30][31]​​​ Many genetic testing laboratories deposit COL4A3, COL4A4, and COL4A5 variants in a fully curated and standardised database, with the aim of improving the accuracy of genetic testing and prediction of phenotype.[32]

cDNA may also be tested and can be obtained from hair root and skin biopsy samples.[33] Testing can confirm linkage to COL4A5 in X-linked Alport syndrome or COL4A3/4 in autosomal Alport syndrome.

Genetic testing can also aid in establishing a diagnosis when patients present with non-classical findings, as presentation can vary greatly depending on age of presentation, sex, and mode of inheritance.[26]​ Diagnosis is established by the identification of a pathogenic or likely pathogenic variant in COL4A3, COL4A4, or COL4A5.[16][26]​​ Finding a relevant COL4A3-COL4A5 variant also indicates that other family members should be investigated.[26]

Renal investigations and complication monitoring

Renal biopsy with electron microscopy and immunohistochemical analysis for type IV collagens allows for diagnosis of Alport syndrome to be confirmed in most cases. Occasionally renal biopsy is contraindicated, which would prevent a pathological diagnosis being made. It is the characteristic electron microscopic changes of thinning, thickening, splitting, and lamellation of the glomerular basement membrane that should be sought in renal biopsies where Alport syndrome is a possible diagnosis. Renal ultrasound also excludes any structural abnormality of the renal tract that may suggest an alternative diagnosis.

Routine investigations for renal disease are also done. They can also be used to monitor decline in renal function:

  • FBC

  • Urinalysis

  • Fasting lipid panel

  • Metabolic panel

  • Serum intact PTH

  • ECG

  • Echocardiogram

Skin biopsy

Skin biopsy is less invasive than renal biopsy, and where immunohistochemistry for type IV collagens is available it can be considered as part of the diagnostic approach although is rarely used. It is also faster than molecular testing. Total absence of alpha-5(IV) staining in the epidermal basement membrane is seen in males, and focal absence (or mosaic distribution) in females is seen in 50% to 60% of families.[34] Skin biopsy is of little value in autosomal forms of Alport syndrome.

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