By: Sean G. Lennox

Alport syndrome (AS) is a combination of genetically inherited alleles that primarily affects renal function, hearing, and vision. Audiologists should have a firm grasp of this syndrome so they can better assess and manage these patients. This syndrome was discovered by Cecil Alport in 1927. He investigated a family with 3 generations of renal failure, and progressive hearing and vision loss, and he noted that males were more adversely affected than females (Kashtan and Michael, 1996).

The etiology of AS is primarily through an X-linked allele transmission from parents to offspring. Missing, spliced, or flawed DNA code for collagen genes known as the COL4A… family leads to inappropriate production of basement membrane proteins important for renal function. The lack of properly formed collagen leads to scarring of kidney cells known as glomeruli in the glomerular basement membrane (GBM) of the kidney (see Figure 1). This scarring can cause end stage renal disease (EDRD) over time. For hearing, normally coded genes for COL4A3, COLA4, and COL4A5 are required for normal stria vascularis and organ of Corti functioning. Faulty production for collagen proteins leads to gradual loss of cochlear integrity (see Kashtan and Michael, 1996 for in depth reading; Musiek et al, 2012; Northern and Downs, 2002).

Figure 1. Kidney GBM splitting and thinning 49 year old male (from Haas, 2009 p. 230).

The incidence of AS has been reported to be 1 in every 50, 000 live births (Musiek, Baran, Shinn, and Jones, 2012). Overall incidence of AS is 1 per every 200, 000 people in the general population (Northern and  Downs, 2002), and the prevalence has been pegged at 0.2% of people with ESRD (Haas, 2009; Saxena, 2011).

The symptoms of AS include:

1. Hematuria-Blood in urine.
2. Proteinuria- excess protein  concentrations in urine indicative of poor protein reuptake at kidneys.
3. Hypertension.
4. Hearing loss: More common for x-linked inherited males and autosomal dominant inherited females and males.
5. Ocular degeneration / ocular changes.

(Haas, 2009; Musiek et al, 2012; Nortern and Downs, 2002; Tryggvason et al, 1997).

The genetic inheritance pattern of this syndrome dictates how a patient is affected with the disease. X-linked recessive patients make up 80-85% of the AS population.  The COL4A5 gene is negatively affected for this population (Haas, 2009). Males are much more affected because they do not have a normal allele on a paired X chromosome to stabilize the disorder (Musiek et al, 2012). In this inheritance pattern an affected father cannot pass AS to his son (Musiek et al, 2012). Autosomal recessive inheritance occurs around 15% of the time and this subtype of AS targets the COL4A3 and COL4A4 genes (Tryggvason, Heikkila, Perttersson, Tibell, and Thorner, 1997). According to Haas, (2009) symptoms and associated disorders are more variable for autosomal recessive AS; however males are still more affected than females. Autosomal dominant AS is the least common type with a 5% occurrence. Interestingly, both females and males are equally affected for the rarest subtype of AS.

Hearing loss is more common for x-linked inherited males and autosomal dominant inherited females and males. Hearing loss is never present at birth and tends to have a childhood onset (Kashtan and Michael, 1996). Hearing loss affects around 55% for males and 45% for females, and the age of onset is around 30 years of age (Haas, 2009; Kashtan and Michael, 1996; Northern and Downs, 2002; Tryggvason et al, 1997) Configuration of HL can be bilateral high frequency sensory neural hearing loss between 2–8 KHz (Kashtan and Michael, 1996; Northern and Downs, 2002; Tryggvason et al, 1997). A flat conductive loss can be common according to Musiek et al, (2012).

Differential diagnosis of AS is difficult given renal failure and hearing loss are commonly associated symptoms for many syndromes (See Table 1). Muckle-Wells Syndrome includes renal failure and hearing loss; however, patients with this disorder also experience amyloidosis leading to a starchy substance in the blood and urticarial that is a vascular reaction of skin leading to an elevated rash.  Thin Glomerular Basement Membrane Nephropathy is a less serious disease state than AS, and requires electron microscopy and renal biopsy to differentiate from AS. This disorder shares similar renal symptoms of blood in urine and proteinuria. In addition, there are other associated diseases with AS and these are listed in table 2.

Table 1- Differential Diagnosis for AS

Renal Disease with Progressive Hearing Loss:

• Muckle-Wells Syndrome (Nortern and Downs, 2002).
• Thin Glomerular Basement Membrane Nephropathy. Less serious disease state requires electron microscopy and renal biopsy to differentiate.Shares similar renal symptoms of blood in urine and proteinuria (Haas, 2009).

Other Kidney Disorders

• Acute Poststreptococcal Glomerulonephritis
• Medullary Cystic Disease
• Multicystic Renal Dysplasia
• Nail-Patella Syndrome
• Polycystic Kidney Disease

(Devarajan, 2011; Haas, 2009).

Table 2- Associated Disorders

• Hearing loss.
• Ocular degeneration including changing lens shape known as lenticonus.
• Bilateral Proptosis.
• Ankylosis- joint stiffness .
• Craniofacial dysostosis- abnormal bone growth of cranium.
• Spina bifida.
• Saddle nose.
• Branchiocephaly.
• Vestibular hypofunction  (Musiek et al, 2012; Tryggvason et al, 1997)

AS is a slowly progressing disease for most patients, so there must be planned serial audiology and medical management. Medications such as ACE inhibitors can be used to manage proteinuria and to slow sclerosis of glomeruli (Saxena, 2011) Dialysis is required once the patient enters ESRD and eventual kidney transplant will become a necessity for many AS patients (Kashtan and Michael, 1996). At this time, gene therapy for AS is not available (Tryggvason et al, 1997).

The prognosis for patients with AS differs by gender. For men, ESRD is expected for all males with X-linked AS. Dialysis then kidney transplantation will become necessary, and unfortunately a shorter lifespan is expected for many Men with AS. Women with AS are at a much lower risk of ESRD and need for kidney transplant. A long life expected for a majority of women who are closely followed medically and audiologically (Kashtan and Michael, 1996).

[CASE STUDY]

References

Davarajan. (2011). Pediatric Alport Syndrome. Retrieved September 3^rd, 2012 from

http://emedicine.medscape.com/article/981126-overview

Haas. (2009). Alport Syndrome and Thin Glomerular Basement Membrane Nephropathy. Arch Pathol Lab Med. Vol 133, 224-232.

Kashtan and Michael. (1996). Alport Syndrome. Kidney International (1996) 50, 1445–1463; doi:10.1038/ki.1996.459

Musiek, Baran, Shinn, and Jones. (2012) Hereditary and Congenital Hearing Loss. In Musiek, Baran, Shinn and Jones eds. Disorders of the Auditory System. (2^nd Ed., ; pp. 385-386). San Diego: Plural Publishing.

Northern and Downs. (2002). Appendix of Hearing Disorders. In Julet ed. Hearing in Children. (5^th Ed.; p. 379). Baltimore: Lipponcott Williams and Wilkins.

Niaudet. (2010). Living donor kidney transplantation in patients with hereditary nephropathies. Nature Review Nephrology. Volume 6, 736-743.

Saxena. R. (2011). Alport Syndrome Medication. Retrieved September 3^rd, 2012 from http://emedicine.medscape.com/article/238260-medication#2

Tryggvason, Heikkila, Perttersson, Tibell, and Thorner. (1997). Can Alport syndrome be treated by gene therapy? Kidney International, Vol. 51, pp. 1493—1499.

For more information on Alport Syndrome visit:

1. The Kidney Foundation of Canada. http://www.kidney.ca/page.aspx?pid=324
2. Alport Syndrome Support Program in Canada.  http://www.alportsyndrome.ca/

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