eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Alport Syndrome

Author: Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Contributor Information and Disclosures

Updated: Oct 1, 2008

Introduction

Background

Alport syndrome encompasses a group of heterogeneous inherited disorders involving the basement membranes of the kidney and frequently involving the cochlea and the eye. These disorders are the result of mutations in type IV collagen genes. The mode of inheritance is X-linked in 80%, autosomal recessive in 15%, and autosomal dominant in about 5% of individuals with Alport syndrome.

In 1927, Alport first described the combination of progressive hereditary nephritis with sensorineural deafness. The presence of 3 of the following 4 proposed diagnostic criteria establishes the diagnosis of Alport syndrome:

  1. Family history of hematuria, progressing mostly in males to end-stage renal disease (ESRD)
  2. Thickening and splitting of the glomerular basement membrane detected by electron microscopy
  3. Progressive, high-frequency, sensorineural deafness
  4. Anterior lenticonus and perimacular flecks

Children with Alport syndrome may initially present with only persistent hematuria and a family history of hematuria. Auditory or ocular manifestations may appear later in life. The typical changes of the glomerular basement membrane are also age dependent and may be absent from initial biopsy samples obtained from young children with Alport syndrome.

Pathophysiology

Recent advances in study of the cellular and molecular biology of proteins of the basement membrane have been instrumental in elucidating the pathophysiology of Alport syndrome.1,2,3 Basement membranes are sheetlike structures that support endothelial and epithelial cells. They are composed of various proteins that these cell secrete, including a network of type IV collagen. The family of type IV collagens consists of 6 chains designated a1 through a6(IV) that share a collagenous domain and a carboxy-terminal noncollagenous (NC1) domain.

The genes for type IV collagen are distributed in pairs on 3 chromosomes. The genes COL4A1 and COL4A2 on chromosome 13 encode for the a1 and a2 changes, COL4A3 and COL4A4 on chromosome 2 encode for the a3 and a4 chains, and COL4A5 and COL4A6 on the X chromosome encode for a5 and a6. The a1 and a2 chains are present in all basement membranes. The a3 and a4 chains are restricted to the basement membranes of the glomerulus, cochlea, and eye. The a5 chain is expressed in the glomerulus, cochlea, eye, and epidermis.

Patients with Alport syndrome have mutations in COL4A3, COL4A4, or COL4A5, with consequent abnormalities in the basement membranes of the glomerulus (leading to hematuria, glomerulosclerosis, and ESRD), cochlea (causing deafness), and eye (resulting in lenticonus and perimacular flecks).

Children with Alport syndrome usually have normal development and intelligence. However, a rare contiguous gene-deletion syndrome involving chromosome Xq22.3 has been described; this has been named Alport syndrome and mental retardation (ATS-MR).4

Frequency

United States

The genetic frequency for Alport syndrome is estimated to be 1 case in 5000 population. According to the 2007 annual data report of the United States Renal Data System, Alport syndrome accounts for approximately 2.1% of pediatric patients with ESRD.5  More than 85% of these patients are males.

International

In Europe, Alport syndrome may be responsible for as many as 2.3% of cases of ESRD.

Mortality/Morbidity

Male individuals with X-linked Alport syndrome and people of both sexes with autosomal recessive disease have increasing proteinuria, hypertension, progression to ESRD, and hearing loss during the second to fourth decades of life. Male patients with the typical X-linked disease have a renal half-life of about 25 years, and about 90% develop ESRD before 40 years of age.

In female patients, progression to ESRD was previously thought to be rare. However, observations have shown that as many as 12% of female patients also develop ESRD by age 40 years; this rate increases to 30% by age 60 years and 40% by age 80 years. Among female patients, risk factors for progression to ESRD include the degree of proteinuria and hearing loss.

Race

No racial predilection is reported.

Sex

The common X-linked form of Alport syndrome leading to ESRD predominantly affects male individuals. Many female patients with X-linked Alport syndrome have mild disease, but studies have shown significant renal morbidity in female patients who develop proteinuria and hearing loss.6 The uncommon autosomal recessive form of Alport syndrome equally affects both sexes (see Mortality/Morbidity).

Age

Most patients with Alport syndrome present with persistent microscopic hematuria and episodic gross hematuria during the first 2 decades of life. Two clinical subtypes of Alport syndrome have been distinguished on the basis of their rates of progression. The first is a juvenile type in which ESRD occurs when an individual is aged approximately 20 years; its course is fairly constant within a given family. The second is an adult variety in which ESRD occurs when the individual is older than 40 years. This form has notable intrakindred variability. Also see Mortality/Morbidity.

Clinical

History

  • Hematuria
    • Hematuria is the most common presenting symptom.
    • Persistent microscopic hematuria is usually present from early childhood.
    • Episodic gross hematuria, at times precipitated by upper respiratory infections, is common during the first 2 decades of life.
    • Other renal manifestations are described in Physical.
  • Hearing defect
    • Bilateral high-frequency sensorineural hearing loss usually begins by late childhood or early adolescence.
    • In the early stages of the disease, hearing loss is detectable only by means of audiometry.
    • As hearing loss progresses, it extends to the low frequencies, including those of human conversation, and patients require hearing aids.
    • About 50% of male patients with X-linked Alport syndrome show sensorineural deafness by age 25 years, and about 90% are deaf by age 40 years.
  • Ocular defect: Various ocular defects, including anterior lenticonus, perimacular flecks, and corneal ulceration, lead to increasing myopia and visual disturbances.
  • Family history
    • In any child or adolescent with persistent microscopic hematuria, carefully seek a family history of hematuria, early onset deafness, and renal insufficiency (especially in male patients).
    • In patients with typical clinical findings of Alport syndrome but a negative family history for the disease, suspect the autosomal recessive form.

Physical

  • Renal findings
    • Hypertension is usually detectable by the second decade of life.
    • Edema and the nephrotic syndrome are not common in early childhood; however, the incidence progressively increases with age and is present in 30-40% of young adults.
    • With onset of renal insufficiency, symptoms of chronic anemia and osteodystrophy may become evident.
  • Ocular findings
    • The anterior lenticonus is a regular conical protrusion of the central portion of the lens into the anterior chamber. With the exception of traumatic lenticonus, this lesion is pathognomonic for Alport syndrome. Anterior lenticonus predominantly affects males, is frequently bilateral, and develops during the second decade of life. Anterior lenticonus may appear as an oil droplet during the red reflex, but formal ophthalmologic examination is usually required for early detection. Anterior lenticonus may be complicated by progressive distortion of the lens and subcapsular cataracts from rupture of the anterior lens capsule, leading to visual impairment. Anterior lenticonus is reported in about 25% of children with Alport syndrome. Patients with Alport syndrome and this finding usually progress to end-stage renal disease (ESRD) and deafness before age 30 years.
    • The retinal changes of perimacular flecks affect 35% of individuals with Alport syndrome but are usually asymptomatic. The changes consist of a bilateral dot-and-fleck retinopathy resulting from superficial, densely packed, yellow-white granulations surrounding the foveal area. These lesions are specific for Alport syndrome.
    • Other uncommon lesions in persons with Alport syndrome include recurrent corneal ulceration and corneal endothelial vesicles.
  • Cochlear findings
    • Bilateral high-frequency sensorineural hearing loss usually occurs by late childhood or early adolescence in individuals with Alport syndrome. This hearing loss is most prevalent and progressive in male patients with the disease.
    • In its early stages, hearing loss is detectable only on audiometry and only in the high-frequency range (ie, 2000-8000 Hz). In one series, audiometry documented initial hearing loss in 85% of boys and male adolescents were younger than 15 years with Alport syndrome.
    • As hearing loss progresses, it extends to low frequencies, including those of human conversation, and its course roughly parallels the loss of renal function.
  • Variants
    • An association of Alport syndrome with diffuse leiomyomatosis of the esophagus and tracheobronchial tree is reported in at least 26 families. These patients have typical X-linked Alport syndrome, usually the juvenile type, with a high incidence of cataracts. Female patients have vulvar and clitoral leiomyomatosis and other findings like those of male patients. Symptoms appear in late childhood and include dysphagia, postprandial vomiting, recurrent bronchitis, dyspnea, cough, and stridor.
    • An association between hereditary nephritis, deafness, and megathrombocytopenia is reported as part of 2 distinct syndromes. Fechtner syndrome consists of nephritis, sensorineural hearing loss, cataracts, macrothrombocytopenia, and characteristic polymorphonuclear inclusion bodies. Epstein syndrome is similar to Fechtner syndrome but without neutrophilic inclusions. Transmission appears to be autosomal dominant in both syndromes. Platelet abnormalities may be asymptomatic or cause hemorrhagic complications. Patients have normal expression of type IV collagen and no mutations in COL4A5. The specific genetic defects underlying these associations are now known. Mutations affecting nonmuscle myosin heavy-chain type II-A results in MYH9-related hereditary macrothrombocytopenia syndromes, including 4 autosomal dominant platelet disorders (ie, Fechtner syndrome, Epstein syndrome, May-Hegglin syndrome, and Sebastian syndromes).

Causes

  • Approximately 50-80% of patients with X-linked Alport syndrome have mutations in the COL4A5 gene. Several hundred mutations, including missense mutations, splice-site mutations, and small deletions account for most cases of X-linked Alport syndrome. Few mutations have been found in more than 1 family.
  • The most common mutation involves substitution for glycine in the collagenous domain of the a5(IV) chain by a bulky amino acid, resulting in protein-folding abnormalities.
  • Other common mutations lead to premature termination of protein translation and loss of the carboxy-terminal NC1 domain, resulting in defective interchain association and formation of the collagen network.
  • The X-linked Alport syndrome and the diffuse leiomyomatosis complex results from large deletion mutations in both COL4A5 and COL4A6. In contrast, patients with autosomal recessive Alport syndrome have mutations in COL4A3 and COL4A4.
  • An incidental observation is that heterozygous mutations in COL4A3 and COL4A4 account for most cases of the relatively benign thin basement membrane disease. In some cases, mutations found in families with this disease are identical to those that cause autosomal recessive Alport syndrome in the homozygous or compound heterozygous forms.
  • Patients with autosomal dominant Alport syndrome also have heterozygous mutations in the COL4A3 and COL4A4 genes

More on Alport Syndrome

Overview: Alport Syndrome
Differential Diagnoses & Workup: Alport Syndrome
Treatment & Medication: Alport Syndrome
Follow-up: Alport Syndrome
Multimedia: Alport Syndrome
References
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Further Reading

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Keywords

Alport syndrome, Alport's syndrome, hereditary nephritis, familial nephritis, hereditary nephritis with neurosensory deafness, Alport syndrome and mental retardation, ATS-MR, end-stage renal disease, ESRD, hematuria, glomerulosclerosis, proteinuria, hypertension, hearing loss, upper respiratory infection, renal insufficiency, nephrotic syndrome, chronic anemia, osteodystrophy, leiomyomatosis, bronchitis, megathrombocytopenia, Epstein syndrome, Fechtner syndrome, May-Hegglin syndrome, Sebastian syndrome, hypoalbuminemia, hypercholesterolemia, stone disease, cystic dysplasia

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Contributor Information and Disclosures

Author

Prasad Devarajan, MD, Louise M Williams Endowed Chair in Pediatrics, Professor of Pediatrics and Developmental Biology, Director of Nephrology and Hypertension, Director of Clinical Nephrology Laboratories, Chief Executive Officer of Dialysis Unit, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine
Prasad Devarajan, MD is a member of the following medical societies: American Heart Association, American Society of Nephrology, American Society of Pediatric Nephrology, National Kidney Foundation, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Uri S Alon, MD, Director of Research and Education, Department of Pediatrics, Division of Pediatric Nephrology, Children's Mercy Hospital of Kansas City; Professor, University of Missouri at Kansas City
Uri S Alon, MD is a member of the following medical societies: American Federation for Medical Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital
Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, and Texas Pediatric Society
Disclosure: Nothing to disclose.

CME Editor

Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine
Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD, The Isaac A Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University; Division Head of Kidney Diseases, Children's Memorial Hospital, Chicago
Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology
Disclosure: Amgen Grant/research funds None; Abbott Honoraria Speaking and teaching; Altus Pharmaceuticals Grant/research funds None; Genzyme Grant/research funds None; Merck Grant/research funds None; NIH Grant/research funds None

 
 
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