Alport syndrome is a genetic disease characterized by symptoms of chronic nephritis, hearing loss, and eye complications. The most common type of Alport syndrome is X-linked Alport syndrome due to COL4A5 mutations, which can evidently become more severe in men than in women.
The disease is characterized by the following three symptoms:
1) Chronic nephritis
Typically, patients present with blood in the urine from a young age. Blood is usually not
visible in the urine and is identified only after urinary analysis is performed. However,
patients may have red or cola-colored urine called gross hematuria when they have a cold.
Patients may develop proteinuria as they get older and progress to end-stage kidney disease very
slowly. In cases of the most common X-linked Alport syndrome due to COL4A5 mutations, about 90%
of male patients progress to end-stage kidney disease by 40 years of age. On the other hand,
about 10% of female patients progress to end-stage kidney disease by 40 years of age. Once these
patients have progressed to end-stage kidney disease, they need to have renal replacement
treatment such as dialysis or renal transplantation.
2) Loss of hearing
Hearing loss is not evident at birth or in childhood. However, in cases of the most common
X-linked Alport syndrome due to COL4A5 mutations, the majority of male patients develop hearing
loss after 10 years of age and 80% develop hearing loss eventually. On the other hand, about 20%
of female patients develop hearing loss.
3) Eye complications
Cataract or lenticonus may occur. In cases of the most common X-linked Alport syndrome due to
COL4A5 mutations, approximately one third of male patients have eye complications, while it is
very rare in female patients.
4) Diffuse leiomyomatosis
Diffuse leiomyomatosis is a very rare co-mplication and the neoplasms are benign. Most commonly,
it occurs in the esophagus but it may also occur in the trachea and female genital organ.
There is no curative treatment at present. The treatment policy is focused on what can be done to
slow progression to end-stage kidney disease. Specifically, angiotensin converting enzyme inhibitors
or angiotensin receptor blockers are given orally to protect the kidneys. The treatment is usually
started when proteinuria in addition to hematuria are detected; however, we have reports from
overseas recommending that treatment should be initiated as soon as the disease is diagnosed in male
patients.
The disease progresses to end-stage kidney disease in male patients at a higher rate. The average
age at onset of end-stage kidney disease is reported to be about 25 years of age in male patients,
who then require renal replacement treatment such as hemodialysis or renal transplantation.
Sometimes, they may need hearing aids due to loss of hearing.
Alport syndrome is a hereditary chronic nephritis and often progresses to end-stage renal
failure. Patients with chronic nephritis do not experience any symptoms, but hematuria (blood in
urine) and proteinuria (protein in urine) are common and kidney function gradually becomes
impaired. End-stage renal failure refers to the state where kidney function is impaired and does
not go get back to normal and dialysis or kidney transplantation becomes necessary.
Patients with Alport syndrome characteristically have hearing loss and eye disease as
complications. However, patients without these may also be diagnosed with Alport syndrome.
This disease was named after Dr. Cecil Alport, a South African doctor, who reported a case of a
large family affected by familial chronic nephritis, addressing for the first time that the
condition is more severe in male patients than in female patients and that patients with chronic
nephritis often have concurrent hearing loss.
In many cases, Alport syndrome is found when hematuria is detected by urinalysis during screening physical examination. If a family member has the same disease, the disease may be found by performing urinalysis in advance. Among patients with X-linked Alport syndrome, the most common form caused by mutations in the COL4A5 gene, hematuria is often found in boys from birth and, if severe, reddish stains on diapers may be the first sign of Alport syndrome.
In most cases, the diagnosis can be confirmed by a test called kidney biopsy, a procedure that involves taking tissue directly from the kidney for analysis. In Japan, this procedure is performed under the coverage of regular health insurance. In some cases, a diagnosis can be made by a test called skin biopsy, a procedure which involves taking skin tissue for analysis. Being less invasive compared to kidney biopsy, skin biopsy can sometimes help with diagnosis when kidney biopsy cannot be performed, etc. Furthermore, since Alport syndrome is a genetic disease, the diagnosis and inheritance pattern can be investigated by studying the gene. There is a known association between the type of genetic mutation and severity, and genetic diagnosis can be helpful in determining the severity of the disease. However, in some cases diagnosis cannot be made even with these examinations. Currently, diagnosis by skin biopsy or gene analyses is not covered by the regular health insurance system.
In general, there are three types of inheritance (common in genetic diseases), all of which can occur in Alport syndrome. The most common form is X-linked Alport syndrome, which is caused by mutations in the COL4A5 gene. Male patients with this form develop severe symptoms, more clinically apparent than female patients. Although relatively uncommon, both autosomal recessive and autosomal dominant hereditary mutations in the COL4A3 or the COL4A4 gene have been reported. Characteristics of each genetic form are shown in the table below. However, it is important to note that there are patients with atypically severe or mild symptoms with all disease forms.
Patients with family members with nephritis account for 85 to 90% of patients. The remaining 10 to 15% of patients do not have a family history but develop the disease from de novo gene mutations. Even in the case of patients who developed the disease from de novo gene mutations, the disease will be inherited by the next generation.
The following symptoms are observed:
In typical cases, hematuria is seen from childhood. Usually you cannot tell if the urine is tinged with blood just by looking at it until hematuria is detected by urinalysis. However, brown or cola-colored urine, called gross hematuria, may occur during a cold. Proteinuria begins to occur with age, and the disease takes a very slow course advancing to end-stage renal failure. Among patients with X-linked Alport syndrome, the most common form caused by mutations in the COL4A5 gene, approximately 90% of male patients advance to end-stage renal failure by the age of 40. On the other hand, approximately 10% of female patients advance to end-stage renal failure by the age of 40. When the disease has advanced to end-stage renal failure, treatment called renal replacement therapy such as dialysis or kidney transplantation is necessary.
Hearing loss is not seen at birth or during young childhood. However, among patients with X-linked Alport syndrome, the most common form caused by mutations in the COL4A5 gene, male patients develop hearing loss after the age of 10 in most cases, and 80% of these patients end up having hearing loss, while hearing loss occurs in only 20% of female patients.
Cataract and lenticonus, etc. may be seen. Among patients with X-linked Alport syndrome, the most common type caused by mutations in the COL4A5 gene, approximately one third of male patients are reported to have eye complications, which are believed to be very rare among female patients.
Diffuse leiomyomatosis is a very rare complication and benign tumors occur. Diffuse leiomyomatosis is often seen in the esophagus but can also be seen in female genitalia and the trachea.
There is no curative treatment to date. The treatment approach focuses on how to prevent patients from progressing to end-stage renal failure. Specifically, patients are treated with oral drugs called angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, expecting an inhibitory effect on the progression of renal failure (renoprotective effect). Most of the time, treatment is started when proteinuria, in addition to hematuria, begins to be evident, but there have been reports from outside Japan that initiation of treatment with oral medication is recommended for male patients as soon as the diagnosis is made.
Male patients with X-linked Alport syndrome progress to end-stage renal failure at a high frequency. It has been reported that the mean age of end-stage renal failure is approximately 25 years and replacement therapy such as dialysis or, kidney transplantation, etc. becomes necessary after that. A hearing aid may be needed due to hearing loss.
During the period without renal dysfunction, patients can basically lead a normal life without any limitations on daily activities. No physical or dietary restrictions are needed. There is no need to restrict protein or to take excessive protein though protein leaks into urine. However, treatment with oral angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is recommended in patients with urinary protein in addition to occult blood. Patients are prone to dehydration as an adverse reaction of these drugs and therefore special caution against dehydration is necessary while on treatment. Even during the period when renal function is normal, edema may be seen if a large amount of protein leaks into urine, and adjustment for physical activity is necessary in such a case. If hypertension is detected during the course of disease, restriction of salt intake may be considered. When kidney function begins to decline, physical and dietary restrictions may become necessary depending on the severity, but excessive restrictions are not desirable. Especially for children in the growing stage, there are development issues, and dietary restrictions such as protein restriction are not typically required.
Many of the female patients with X-linked Alport syndrome do not develop renal failure during childbearing years. Having a normal pregnancy and childbirth is possible. However, for patients with severe cases of the X-linked form and those with the autosomal recessive form, appropriate treatments need to be taken according to the degree of renal function, and it may not be easy to get pregnant. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, mentioned above, cause teratogenicity. If fertility is desired by the female patient, it is necessary to discontinue these drugs.
