Download Alport Syndrome: Clinical Update

J Am Acad Audiol 6 : 73-79 (1995)
Alport Syndrome : Clinical Update
Derin C. Wester*
Curtis L. Atkint
Martin C. Gregory$
Abstract
This review of the literature on Alport syndrome (AS) places emphasis on genetic and clinical issues related to the sensorineural hearing loss in type III and type IV X-linked AS . The
review covers prevalence, medical issues, genetic issues, audiologic findings, vestibular findings, the pathophysiology of hearing loss in type III AS, age- and phenotype-specific normative
data and concludes with a discussion regarding future auditory-genetic research with AS .
Key Words: Alport syndrome, genetic heterogeneity, linkage-analysis, phenotypic
heterogeneity, X-linked
n 1927, Alport described a kindred with
dominantly inherited kidney disease that
was characterized in both sexes by red
blood cells in the urine (hematuria), red bloodcell casts in the urine, variable amounts of protein in the urine (proteinuria), and a predilection in males for progressive "perceptive deafness ." The hematuria was a chronic sign, present
at birth and showing exacerbation with upper
respiratory and other infections . Affected males
died during adolescence from renal failure (endstage renal disease, ESRD), and, due to their
poor health, they produced no offspring.
Today, Alport syndrome (AS) is conceptualized as a group of hereditary diseases characterized by progressive defects of capillaries in the
glomerular basement membranes of the kidneys (glomerulonephritis), with various nonrenal features including progressive sensorineural
hearing loss (SNHL), ocular problems, and blood
platelet defects (Savage et al, 1986 ; Rumpelt,
1987 ; Atkin et al, 1988b) . According to Atkin et
al (1988b), AS may have seven subtypes (Table
1), which exhibit juvenile and adult forms and
two modes of inheritance.
`Department of Otolaryngology, Naval Medical Center San Diego, San Diego, California ; tDepartment of Biochemistry, University of Utah, Salt Lake City, Utah ; and
tDepartment of Clinical Nephrology, University of Utah,
Salt Lake City, Utah
Reprint requests : Derin C . Wester, Department of
Otolaryngology, Naval Medical Center San Diego, 34800
Bob Wilson Drive, San Diego, CA 92134-5000
PREVALENCE OF AS
A
S has been reported throughout the
world, it is not associated with any race
or geography, and the worldwide prevalence
of AS has not been determined (Atkin et al,
1988b) . The incidence ofAS has been reported
at 1 in 200,000 (Brown et al, 1986) . According to Fraser (1976) and Konigsmark and
Gorlin (1976), AS accounts for approximately
1 percent of genetic hearing loss . Table 2 displays a breakdown in percentages of AS individuals receiving dialysis and kidney transplant versus those developing ESRD for
Europe, the United States, and Utah (Brunner et al, 1978 ; Gottschalk et al, 1978 ; Atkin
et al, 1988b) .
MEDICAL ISSUES
Differential Diagnosis
AS has traditionally been difficult to define
clinically. Currently, there is no universally
standardized method for differential diagnosis.
Atkin et al (1988b) point out that over 40 conditions have been reported as hereditary nephritides . In addition, Gubler et al (1981) caution
that : "Renal disease with hearing loss, even if
familial, should not be equated with Alport
syndrome .. . . Truly congenital hearing loss is
unlikely to be due to Alport syndrome" (p . 493) .
Consequently, proper differential diagnosis for
AS should rule out all other causes of hematuria. A diagnostic work-up to provide refined
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
Table 1
Classification of Alport Syndrome
Type
Description
Autosomal-dominant mode of inheritance, juvenile
onset for ESRD and SNHL
X-linked dominant mode of inheritance juvenile
onset for ESRD and SNHL
X-linked dominant mode of inheritance, adult
onset for ESRD and SNHL
X-linked dominant mode of inheritance, adult
onset for ESRD and normal hearing
Autosomal-dominant nephritis, SNHL, and
thrombocytopathia (blood platelet defect)
Autosomal-dominant juvenile nephritis and SNHL
I
II
III
IV
V
VI
Adapted from Atkin et al, 1988a.
phenotype characterization for genetic linkage analysis should include a combination of
medical examination, accurate and complete
family history, careful urinalysis, and audiologic
assessment (Gregory et al, 1990, 1991) .
Early identification ofAS is important to prevent and counter the effects of associated high
blood pressure and kidney dysfunction. Equally
important, a correct diagnosis is essential to
avoid using an unidentified, gene-carrying family member as a kidney donor.
Medical Management
Optimal medical care for AS includes controlling blood pressure, avoiding ototoxic
drugs, a low-protein diet, monitoring visual
acuity, and an eventual kidney transplant or
dialysis treatment (Atkin et al, 1988b) . Genetic
counseling and audiologic management are
also helpful.
Medical Prognosis
Once diagnosed, the prognosis for a person
with AS is variable . Prognosis depends upon
the disease subtype and the age of diagnosis
(Atkin et al, 1988b) .
Table 2 Prevalence of Alport Syndrome for
Persons Needing Dialysis/Kidney Transplant
or Having End Stage Renal Disease
Europe (o)
Dialysis/K . Transplant
ESRD
-= no data .
74
3 .0
1 .0
USA (91-)
2 .2
-
Utah (%)
1 .0 (Females)
5 .0 (Males)
GENETIC ISSUES
S is phenotypically, and perhaps genetA ically, heterogeneous X-linked dominant
nephritis that results from different mutations of the COL4A5 collagen gene (Barker et
al, 1990). More than one gene or gene mutation produces the disease (genetic heterogeneity), and AS can show tremendous clinical variability between kindreds (phenotypic
heterogeneity) (Gregory et al, 1990).
In adult X-linked AS, the hearing loss for
the standard test frequencies (STFs) is different in progression, degree, and audiometric contour from descriptions of hearing loss
reported with juvenile AS . The adult audiologic data confirm phenotypic heterogeneity
and support a theory of auditory genetic heterogeneity in AS (Barker et al, 1990 ; Gregory et al, 1990 ; Zhou et al, 1991) .
Recent genetic linkage studies using
restriction fragment length polymorphisms
(RFLPs) technology and clinical tests of renal
function to define the phenotype have mapped
type III AS to near Xg22, with little evidence
for genetic heterogeneity (Atkin et al, 1988a;
Gregory et al, 1990). It is noteworthy that
the two adult-type AS kindreds from the Utah
studies had single base mutations ; however,
to date, there appear to be no clear connections between the severity of SNHL or severity of renal disease and the site or position of
mutants in COL4A5 (Gregory, 1991). Thus,
both renal and auditory genetic heterogeneity in AS are hypothesized but need molecular level confirmation .
Recently, new DNA probe markers became
available, which effectively reduce the number of affected family members required for
a successful linkage analysis with adult Xlinked AS (Barker, personal communication,
1992). Linkage analysis studies of AS using
an auditory classification of phenotype should
be initiated. Finally, Kimberling (1991) mentioned that AS represents the first hereditary hearing loss condition in which the gene
has been identified and cloned to study its biochemical nature at a molecular level.
AUDIOLOGIC FINDINGS IN AS
A
pproximately 45 percent of AS females
and 55 percent of males are reported to
experience a slowly progressive, symmetrical, mild to moderately severe, mid- and highfrequency SNHL (Sohar, 1956 ; Cassidy et al,
Auditory Phenotypes in AS/Wester
1965 ; Chiricosta et al, 1970 ; Bergstrom et al,
1973 ; Bergstrom and Thompson, 1983 ; Gleeson, 1984 ; Flinter et al, 1988 ; ZientalskaRuminska et al, 1989) . Routine and special
audiometric studies by Sohar (1956), Miller et
al, (1970), Rintelmann (1976), Eichwald
(1978), Gleeson (1984), and Zientalska-Ruminska et al (1989) have demonstrated a cochlear
site of lesion .
Rintelmann (1976) reported wide variability in the degree of hearing loss and audiometric contour. Males generally show more
severe hearing loss . Females typically show
only a mild degree of hearing loss (Wester,
1990) . Only Zollinger and Mihatsch (1978)
mentioned an asymmetric SNHL following the
renal disorder in AS . Bergstrom et al (1979)
reported a mixed hearing loss as typical in AS ;
however, that observation has not been confirmed in subsequent studies.
Hearing loss has recently been reported
as one of the first symptoms of AS (Gleeson,
1984 ; Flinter et al, 1988 ; Wester, 1990) ; it can
occur as early as 10 years and has been
described as socially nonsignificant until the
second decade of life (Gubler et al, 1981 ; Gleeson, 1984) . Wester (1990) documented the
simultaneous deterioration of STF and ultra
high-frequency (UHF) hearing in adult type
III AS and conjectured involvement of the entire
stria vascularis rather than progressive involvement from the basal to the apical end of the
cochlear partition. Arnold (1983) indicated that
the SNHL generally followed progressive renal
dysfunction. Eichwald (1978) obtained statistically significant and moderate correlations
between the degree of hearing loss and renal
dysfunction on adult type III AS persons. He
used the pure-tone average, blood urea nitrogen, and blood creatinine, respectively, as
covariates .
VESTIBULAR FINDINGS IN AS
V
ery few systematic oculovestibular function assessments have been reported with
AS . Histologic sections have shown cyst-like
vesicle formations under each utricular macule,
which could support a cellular level basis for disequilibrium in AS (Celes-Blaubach et al, 1974 ;
Oda et al, 1974). Nystagmus was not consistently confirmed as an ocular symptom in AS
by Perrin (1964) . Caloric testing has been equivocal with reports of normal and bilaterally
decreased caloric response (Suzuki and Kan-
zake, 1964 ; Goetz et al, 1965 ; Miller et al, 1970 ;
Celes-Blaubach et al, 1974).
PATHOPHYSIOLOGY OF
HEARING LOSS IN AS
Temporal Bone Findings
A clear understanding of the cellular-level
cochlear changes in AS have been clouded by
the inherent difficulty of histopathologic analy-.
sis (Arnold, 1983). Early reports included loss
of basal spiral ganglion cells, degeneration of
the stria vascularis and hair cells of the organ
of Corti, as well as reports of no clear association of damaged cochlear tissues, (Gregg and
Becker, 1963 ; Babai and Bettez, 1968 ; Fujita
and Hayden, 1969 ; Westergaard et al, 1972 ;
Bergstrom et al, 1972) .
Arnold (1983) reported electron microscope
studies of two temporal bones that were appropriately processed . He found that the most
severely involved cochlear structure was the
stria vascularis, which showed thickening and
lamination similar to that of the capillary
basement membrane in the classic glomerular
lesion . In contrast to the typical renal lesion,
there was no evidence of intramembranous
granules (Arnold, 1983) . Near the origin of
Reissner's membrane, Arnold found extensive
marginal cell loss and perivascular intercellular edema. The remaining strial epithelial
cells were characterized by vacuolation and
apical cytoplasmic protrusions.
Johnsson and Arenberg (1981) studied four
AS cases and found severe atrophy of the stria
vascularis in the middle and apical turns .
Abnormalities and degeneration of the stria
vascularis have been correlated with the SNHL
in AS (Pauler et al, 1988).
Etiologic Issues
Controversy exists regarding the etiology
of SNHL in AS . This is focused upon a direct
genetic effect versus a secondary environmental/metabolic or iatrogenic effect . Johnsson
and Arenberg (1981) and Arnold (1983) have
proposed that the SNHL in AS may represent
a secondary metabolic effect of the progressive
kidney dysfunction. They further suggested
that ototoxic medications used in the medical
management of kidney patients undergoing
transplants were an additional explanation
for the associated SNHL . The findings of
McDonald et al (1978) also support the indirect
Journal of the American Academy of Audiology/ Volume 6, Number 1, January 1995
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1
Within-group comparisons of mean hearing thresholds for type III AS females.
iatrogenic hypothesis ; they reported the reversal of deafness after renal transplantation in
AS persons.
From a genetic perspective, Wester (1990)
found that the progressive SNHL of adult types
III and IV AS was consistent with the X-linked
mode of inheritance established by mutation
analysis in two kindreds studied by Barker et
al (1990) . Thus, the SNHL in adult X-linked AS
may represent allelic variation, rather than a
76
separate genetic or indirect uremia-related
condition. Additionally, confirmation of hearing
loss years to decades before the findings of
elevated serum creatinine levels (the first
indication of kidney dysfunction) supported
a direct genetic effect (Wester, 1990). Finally,
the documentation of hearing loss in subjects
with otherwise unremarkable auditory
histories suggested a direct genetic effect
(Wester, 1990).
Auditory Phenotypes in AS/Wester
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Within-group comparisons of mean hearing thresholds of type IV AS females .
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Within-group comparisons of mean hearing thresholds of type IV AS males .
COMPOSITE AUDIOGRAMS OF
ADULT X-LINKED AS
igures 1, 2, 3, and 4 are mean composite STF
F and UHF audiograms that illustrate the
deterioration of hearing sensitivity as a function
of age and gender for types III and IV AS (Wester,
1990). The individual audiologic characteristics
typically included a flat to gently sloping, mild
to moderately severe sensorineural hearing loss,
with preserved word identification (90% to 100%)
and a manageable dynamic range of 30 to 60 dB
HL . AS patients typically did very well with
amplification .
DISCUSSION
W
ester (1990) described the progressive
hearing loss by age and gender for type
III AS but only partially completed age and gen-
Journal of the American Academy of Audiology/ Volume 6, Number 1, January 1995
der norms for type IV AS . No clear pattern of
UHF hearing loss developing prior to involvement of the STFs emerged from that data as
hypothesized in young adult type III AS males
(ages 21 to 30 years), hearing loss first appeared
at all STFs and UHFs . This finding differed
from the earlier reports that described severe
high-frequency hearing loss in the STFs (Sohar,
1956 ; Rintelmann, 1978 ; Gleeson, 1984 ; Flinter
et al, 1988). This difference may have reflected
previous studies ofjuvenile forms of AS. Although
they provided no description of their kindreds in
terms of adult versus juvenile nephritis, it is the
documentation of hearing loss in children alone
that suggests that those kindreds had juvenile
types I, II, or VI AS .
Thus, one priority for future research is the
continued collection of hearing sensitivity data
for type IV AS . Continued documentation of
SNHL in men and women with type IV AS and
otherwise unremarkable auditory histories will
have implications to include late-onset mild
SNHL as a characteristic of type IV AS in Atkin's
classification scheme . To that end, UHF audiometry is recommended along with STF testing,
family history, and other clinical tests.
Konigsmark and Gorlin (1976) point out
that contrary to popular thought, many hereditary hearing losses are asymmetrical in audiometric contour. In adult X-linked AS, however,
the progressive SNHL is remarkably symmetrical for audiometric contour across age and
gender (Wester, 1990). Audiologic confirmation
of either unilateral or asymmetrical hearing
loss in adult X-linked AS subjects would most
likely signify an additional systemic or environmental etiology. Thus, for either clinical or
linkage analysis of AS, an in-depth auditory
history is critical for the rigorous exclusion of
extraneous causes of SNHL .
The use of audiologic procedures for genetic
linkage research should be evaluated from three
perspectives . The first is the efficacy for early
(even subclinical) identification . Second, all
audiologic procedures, whether behavioral or
electrophysiologic, are at best an indirect reflection of a biochemical gene action . Thus, any
audiologic procedure used to clinically define the
phenotype for linkage analysis should be as
"close" to gene action as possible . Auditory functions measured by behavioral audiometry represent complex levels of phenotype description
"distant" from gene action . As such, behavioral
testing is subject to greater modification by
multiple genetic and environmental factors
(Fain et al, 1986), which may lead to marked
78
variability in the phenotype classification. Consequently, the use of behavioral tests should
be minimized in the context of genetic linkage
studies. Finally, the audiologic procedure(s)
should provide information to improve the overall understanding of auditory physiology for
any particular condition.
In Wester's (1990) study, behavioral audiometry enhanced the clinical description of phenotypes between type III and IV AS ; however,
behavioral audiometry did not help with early
identification to rule out suspected gene carriers . Behavioral audiometry should be limited to
normative age and gender-referenced hearing
sensitivity studies with other AS subtypes .
In summary, electrophysiologic procedures
should provide more germane specification of
auditory phenotype(s) for correlation with molecular genetics . Future linkage analysis with
AS should include the use of otoacoustic emissions and electrocochleography to provide more
direct cellular-level data for phenotype classification (Fain et al, 1986) . Such objective
data will also provide improved information on
the neurophysiologic nature of SNHL in AS .
Whether objective procedures will contribute
to early identification of individuals at risk
for AS needs to be systematically determined .
Linkage analysis correlated to objective audiologic procedures may provide confirmation
of hypothesized auditory genetic heterogeneity in AS .
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