Alport syndrome

Baby Detect > Nephrology > Alport syndrome

COL4A5, COL4A3 and COL4A4 genes

Also known as: Familial Nephritis, Hereditary Nephritis, Thin Basement Membrane Disease, Thin Basement Membrane Nephropathy; Nephropathy and deafness, X-Linked

Includes:

Alport syndrome 1, X-Linked – OMIM#301050 https://omim.org/entry/301050

Alport syndrome 2, autosomal recessive – OMIM#203780 https://omim.org/entry/203780

Alport syndrome 3, autosomal dominant – OMIM#104200 https://omim.org/entry/104200

1. The Disease:

In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS).

2. The Symptoms:

AS can present anywhere from childhood to elderly age, although it generally manifests earlier (during childhood or adolescence) in XL and AR forms. Infants are usually initially asymptomatic at birth and in the neonatal period. Lack of early signs or symptoms does not exclude the diagnosis.

  • Males are severely affected in XLAS and present with microhematuria very early in life, followed by micro-albuminuria, macroproteinuria and progression to end-stage renal disease (ESRD) before the age of 40 years old. XLAS is highly variable in females, ranging from an asymptomatic disease to lifelong microscopic hematuria (with preserved renal function), or renal failure at a young age. Sensorineural hearing loss is common. Occasional ocular anomalies (e.g. anterior lenticonus, retinal flecks, corneal lesions) may develop in late childhood or early adulthood, males being more commonly affected than females. Rarely, leiomyomatosis (esophagus, tracheobronchial tree or female genitalia) can be associated, forming the X-linked diffuse leiomyomatosis-AS (XL-DLAS).
  • ARAS is similar to XLAS in males, but presents without any gender differentiation in the disease course and the family history.
  • ADAS varies from an asymptomatic disease (mostly presenting as a familial benign hematuria) to AD forms of proteinuria and focal segmental glomerulosclerosis (in cases without hematuria or not as a first line presentation). The progression to ESRD is usually slower than in XLAS, and extra-renal manifestations are less common.

3. Actions to take in case of early diagnosis

  • Infants with a positive genetic test (males with 1 mutation in X-linked COL4A5 gene or 1 or 2 mutations in COL4A3 gene or 2 mutations in the COL4A4 gene) should continue breastfeeding
  • The diagnosis is based on genetic results, familial history, and clinical signs.
  • AS is a lifelong condition that requires lifetime management and regular follow-up with a nephrology specialist and a multidisciplinary approach to care, including paediatrics and genetics.
  • The management of AS is only symptomatic, mainly aiming at slowing the progression to ESRD. It includes angiotensin blockade (e.g. angiotensin converting enzyme inhibitors, angiotensin receptor blockers), diuretics, and a salt-restricted diet. The most severe cases require dialysis and renal transplant.
  • Audiologic evaluation of children every one to two years beginning at age of six to seven years. Minimize exposure to loud noise. Hearing aids should be prescribed when needed.
  • Monitoring for ocular abnormalities. Protection of corneas from minor trauma, in those with recurrent corneal erosions. Surgical intervention for ocular anomalies can be considered.
  • Evaluation for aortic dilation (for males with XLAS).
  • Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings, especially in X-linked cases.

4. For more information: