Alport syndrome (ORPHA:63)
A rare renal disease characterized by glomerular nephropathy with hematuria progressing to end-stage renal disease (ESRD), frequently associated with sensorineural deafness, and occasionally with ocular anomalies.
Epidemiology
The global prevalence of Alport syndrome (AS) is unknown. The prevalence at birth in Finland is estimated at 1/53,000. In the USA, Alport syndrome reportedly accounts for up to 2% of new cases of pediatric ESRD.
Clinical description
The clinical subtypes of AS include X-linked (XL), autosomal recessive (AR) and autosomal dominant (AD) AS and count for about 80%, 15% and 5% of all AS cases, respectively. AS can present anywhere from childhood to elderly age, although it generally manifests earlier (during childhood or adolescence) in XL and AR forms. Males are severely affected in XLAS and present with microhematuria very early in life, followed by micro-albuminuria, macroproteinuria and progression to 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.
Etiology
AS involves a structural defect of type IV collagen, an essential component of the glomerular basal membrane. XLAS is due to mutations in COL4A5 (Xq22.3) gene coding for the alpha 5 chain of type IV collagen. ARAS and ADAS are due to mutations in both COL4A3 (2q36.3) and COL4A4 (2q36.3) genes coding for the alpha 3 and 4 chains of type IV collagen, respectively. XL-DLAS is due to COL4A5 (Xq22.3) and COL4A6 (Xq22.3).
Diagnostic methods
The diagnosis is based on familial history, clinical signs, electron microscopy examination of renal biopsy (showing abnormalities of the glomerular basal membrane), and immunohistochemical findings on renal and cutaneous biopsy (even if it cannot establish the diagnosis in all the patients). Molecular genetic testing can confirm the diagnosis.
Differential diagnosis
The differential diagnoses include hematuria related to urologic diseases and cancer, IgA nephropathy, nephropathy related to MYH9 mutation, and familial benign hematuria.
Antenatal diagnosis
A prenatal and pre-implantation diagnosis is possible for at-risk pregnancies, if a causative mutation has been found in a member of the affected family.
Genetic counseling
Most AS cases follow an X-linked dominant mode of inheritance, but AR and AD cases have also been reported. A genetic counseling should be proposed to affected families.
Management and treatment
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 replacement therapy. Regular hearing and ocular follow-up are recommended. Hearing aids should be prescribed when needed, and surgical intervention for ocular anomalies can be considered.
Prognosis
The prognosis of AS is poor due to the progression to ESRD (often affecting young adults). However, renal transplantation is usually successful, since the development of anti-type IV collagen antibodies is a rare event. The extra-renal features can affect the quality of life.

                            Last update: 
                            March 2020


                            - Expert reviewer(s): 
                            Dr Laurence HEIDET | ERKNet* - Pr Rachel LENNON | ERKNet*


                                * European Reference Network