Schizophrenia
Research,
3 (1990)
235
235-239
Elsevier
SCHIZO
00106
A family with Alport syndrome and psychosis Gail W. Shields, Carolee Department
q/Psychiatry,
(Received
T-IO, Health
14 September
Sciences
Center,
Pataki SUNY
1989, revised received
and Lynn E. DeLisi
Stony Brook,
16 January
Stony Brook,
1990, accepted
Neua York, NY 11794.
18 January
U.S.A.
1990)
A family is described with a history of both hereditary nephritis (Alport syndrome) and chronic psychosis in multiple family members. Although the disorders do not segregate together in all cases, the finding of this family may provide a clue for the location of a psychosis gene. Alport syndrome has been mapped to the long arm of the X chromosome. Some studies also support a genomic locus on the X chromosome in at least some cases of manic-depressive disorder and schizophrenia. Key words: Alport
syndrome;
Psychosis
syndrome;
X chromosome;
INTRODUCTION
A 9-year-old male was referred to the Child Psychiatry Department at Stony Brook University Hospital after disclosing suicidal ideation secondary to persistent frightening auditory and visual hallucinations. His past history included poor socialization, defiant behavior and a chronic preoccupation with a complicated delusional system into which his hallucinations were incorporated. The hallucinations and delusions dated back approximately 5 years. His mother shared parts of the delusional belief system including the ability to communicate with ‘spirits’, and the presence of ‘ghosts’. Due to the severity of the schizophrenic-like symptoms as well as the depressive ideation and mood, he was hospitalized on the Child Psychiatry Inpatient unit and a full evaluation was done. During the course of routine laboratory testing, hematuria and proteinuria were noted on repeated urinalyses. A 24 h urine collection revealed significant proteinuria, and a renal biopsy was consistent with a diagnosis of early hereditary nephritis (Alport syndrome), revealing ‘lipoid nephrosis with Correspondence to: L.E. DeLisi, Department T-10, Health Sciences Center, SUNY Stony Brook, New York, NY 11794, U.S.A.
0920-9964/90/$03.50
c
of Psychiatry, Brook, Stony
1990 Elsevier Science Publishers
(Schizophrenia)
mild splitting of the basement membrane’. A 24 h urine collection showed a creatinine clearance at 82 ml/min per 1.73 m2 and a protein excretion of 782 mg/24 h. The glomerular filtration rate was considered borderline low. Since Alport syndrome can be associated with ocular and auditory defects, further evaluation of these systems was also performed. While the ophthalmology examination was normal, an audiology evaluation revealed abnormal auditory processing and mild hearing loss for pure tones. A brain magnetic resonance imaging scan (MRI) was performed and showed moderate enlargement of the lateral ventricles. An EEG was read as generalized abnormal slowing and epileptiform activity in the right temporal parietal area. There was no clinical history, however, of seizure-like episodes. A family history of chronic nephritis (diagnosed as medullary cystic kidney disease on occasion) in multiple family members from at least two generations was present. An X-linked pattern of inheritance for this disorder is suggested in previous reports (Gubler et al., 1981) and is also consistent with inheritance of both kidney disease and psychosis in the referred family, although it is recognized that population data are also consistent with autosomal dominant and recessive forms of illness transmission (Feingold et al., 1985). Thus, a detailed genetic evaluation as well as psychiatric
B.V. (Biomedical
Division)
236
history and direct interviews members were obtained.
of all available
family
METHODS
Psychiatric diagnoses of all family members diagrammed in Fig. 1 were made using DSM-III-R criteria (American Psychiatric Association), based on information obtained from SADS interviews (Schedule for Affective Disorders and Schizophrenia (Spitzer and Endicott, 1978)), medical records, and information from clinicians and other family members. In-person interviews were performed on 15 of the related individuals informative for linkage analyses. The remainder, which included the three maternal great-aunts, were diagnosed based on information from multiple other family members. Two of these were reclusive and refused contact. The other was in a nursing home with severe Parkinson’s disease. If the kidney disease is assumed to be X-linked, this latter individual (the maternal great-grandmother of the proband) would be an obligate carrier of the abnormal gene. Although she does not have documented kidney pathology, she
Key *
Alport
= Kidney
was noted to have had several abnormal urinalyses that presently are positive for blood and protein. It should be further noted that none of the obligate female carriers are noted to have definite kidney disease, and only males are noted to have the disease. This may indicate that the disease is inherited as an X-linked recessive, rather than dominant disorder at least in this family. Although there is only a small amount of linkage information that can be obtained from a single small family, the odds ratio for the likelihood of linkage of the two diseases (lod score) was estimated. 2-point lod scores were calculated assuming an X-linked dominant model for transmission of psychosis and both X-linked dominant and recessive models for Alport syndrome. Calculations were performed for both high and low levels of disease penetrance (from 10 to 70%) and from 0 to 40% recombination.
RESULTS
As illustrated in the family pedigree (Fig. 1), six males have a history of definite kidney disease
Syndrome
Pedigree
Disease
= Proband
cl=
Normal Chronic Schaaphrenla
9,
Schuoaffectwe Disorder
q= Poly
and
-vy ,
w
\
Drq
w
Abuse
Psychosis
NOS
Generation Age Range
w
75-88 years
( 39-56 years
-
14-31 years
3 months14 years Fig. I.
231
confirmed by the family physician (two diagnosed as medullary cystic disease, one recognized as Alport syndrome, and three males aged 14-18 years diagnosed as having chronic hematuria and proteinuria); three of these, in addition, have a chronic psychosis (schizoaffective disorder, bipolar disorder, psychosis not-otherwise-specified (NOS)). A total of six family members have a diagnosis of schizophrenia or other psychosis (two chronic schizophrenia, one chronic schizoaffective disorder, one bipolar psychosis, two psychosis NOS); these include three males with kidney disease. The following are case descriptions of each of the six psychotic individuals. Case no. I: (proband, detailed above): a lo-yearold male with chronic nephritis, suicidal ideation, depression, loss of interest in school work, auditory and visual hallucinations of ‘ghosts and imaginary playmates’ with multiple related delusionary system-onset approximately 2-3 years prior to evaluation, presently hospitalized on psychiatric unit for above symptoms. He was diagnosed as having DSM-III-R schizoaffective disorder, chronic, depressed, and Alport syndrome. Case no. 2: a 14-year-old half-brother of case no. 1, has attention problems in school, easily distractible, unorganized, sets fires, steals, damages public property, and has had auditory and olfactory hallucinations intermittently since age 7. He was diagnosed as DSM-III-R (1) attention deficit disorder; (2) oppositional/defiant disorder; and (3) psychotic disorder, not otherwise specified. He also has Alport syndrome. Case no. 3: a 31-year-old female, married three times, mother of four children (nos. 1 and 2). Has been arrested three times for selling drugs, believes in psychic powers, frequently angry and irritable, TABLE
has had multiple paranoid delusions and olfactory hallucinations (smells roses) and has seen ‘saints’. Some, but not all, of these symptoms occur at times other than during drug intake. She was diagnosed as DSM-III-R (1) borderline personality disorder; (2) alcohol abuse; (3) polydrug abuse; (4) chronic psychotic disorder, not otherwise specified. Case no. 4: an 18-year-old male nephew of no. 3, who has had psychiatric treatment since age 7 and one psychiatric hospitalization at age 17, auditory hallucinations occurring during LSD intake, paranoid delusions during episodes of mania, and has had multiple major depressive episodes. He was diagnosed as DSM-III-R (1) antisocial personality disorder; (2) polysubstance abuse with organic delusional syndrome; (3) organic hallucinosis; (4) bipolar disorder, mixed. He also has Alport syndrome. Case no. 5: An 84-year-old female paternal greataunt of no. 3, who has lived with sister all her life, never employed, with over 40 years of psychotic symptoms that include multiple paranoid and bizarre delusions, formal thought disorder, and severe obsessive compulsive behavior. Her diagnoses were DSM-III-R (1) obsessive compulsive disorder; (2) schizophrenia, chronic undifferentiated type. Case no. 6: An 87-year-old sister of no. 5 and paternal great-aunt of no. 3, lives alone with sister, never employed or married, no friends, rarely leaves home, multiple paranoid delusions, and formal thought disorder. At least 40+ years of illness. Her symptoms are somewhat similar to her sister’s (case no. 5). She was diagnosed as DSMIII-R schizophrenia, chronic undifferentiated type. The maximum LOD score obtained for linkage of psychosis with Alport syndrome was 0.74 at a penetrance of 30% for psychosis and 99% for Xlinked recessive kidney disease (see Table 1).
1
2-point LOD scores for varying degrees of disease penetrance and percent recombination (Psychosis was considered in all cases to be X-linked dominant. Alport syndrome was considered X-linked recessive inheritance and is indicated by D or R, respectively.) Penetrance
Recombination fraction
Psychosis
Alport
0.30 0.60 0.30 0.60
0.99R 0.99R 0.70D 0.70D
Synd.
0
0.05
0.10
0.20
0.30
0.40
0.74 0.75 0.41 -0.14
0.70 0.70 0.42 0.05
0.65 0.65 0.41 0.18
0.54 0.54 0.37 0.27
0.39 0.39 0.28 0.21
0.31 0.31 0.16 0.16
for cases of X-linked
dominant
or
238
DISCUSSION
The above family evaluation reveals the co-occurrence of hereditary nephritis and psychotic illness in some, although not all, family members with either of these disorders. Since renal failure, or advanced kidney pathology was not yet present when psychosis was diagnosed in these individuals, the occurrence of psychotic symptoms does not appear to be a consequence of uremic toxicity to the central nervous system. There is no evidence that psychosis occurs at an increased frequency in patients with Alport syndrome, or that hereditary kidney disease is increased in families with psychosis. One previously published report (Wise, 1977) describes psychotic symptoms in two patients with Alport syndrome, although in these subjects the psychosis was attributed to direct toxic effects of renal failure. No mention was made of psychosis in family members, nor do other reports of such a co-existence appear in the literature. It is therefore assumed unlikely that these disorders are etiologically related, but rather that they could be genetically linked to the same chromosomal region. Linkage studies thus far in Alport syndrome have mapped the gene for this disorder in some families to the long arm of the X chromosome X q21_24 (Atkin et al., 1988; Brunner et al., 1988; Flinter et al., 1988; Szpiro-Tapia et al., 1988); however, the previous studies suggesting only partial X linkage and the presence of male-to-male transmission suggest that other genomic regions may also be worth examining. Though speculative, some clinical similarities between the presentation of this disorder and schizophrenia may be clues to a similar genomic location or genetic mechanism for transmission of both diseases: the clinical onset of both disorders commonly occurs in adolescence or early adulthood, in Alport syndrome, reaching an end-point of renal death by age 40, in schizophrenia reaching a peak age of onset before age 40. In both disorders males have an earlier onset and more severe course to illness than females. Similarly, both illnesses do not follow a classical Mendelian pattern of inheritance. Thus the conclusion suggested by some investigators is that these illnesses are likely to be genetically heterogenous (Evans et al., 1980; Gold-
stein and Tsuang, 1988; Kendler, 1988). With respect to schizophrenia, it has also been proposed that a gene for illness may be pseudoautosomal (Crow, 1987, 1988)-located within the region of the short arms of the sex chromosomes where recombination between X and Y chromosomes occurs in meiosis, thus allowing for transmission from fathers to sons, or partial sex linkage. The above finding of schizophrenia and Alport syndrome (or the carrier state) segregating together in some members of the same pedigree, suggests that the pseudoautosomal region should be examined for linkage in both disorders, and likewise, the X qZ1_24 region further examined in families with schizophrenia.
ACKNOWLEDGEMENTS
We thank Joseph Mannino and Angela Boccio for technical assistance, Dr. Patricia Grayson for performing diagnostic assessments of the children and Joseph D. Terwilliger for calculating the lod scores.
REFERENCES
Atkin, C.L., Hasstedt, S.J., Menlove, L., Casnnon, L., Kirschner, N., Schwartz, C., Nguyen, K. and Skolnick, M. (1988)Mapping of Alport syndrome to the long arm of the X chromosome. Am. J. Hum. Genet. 42, 249-255. Brunner, H., Schroder, C., Bennehom, C.V., Lambermon, E., Tuerlings, J., Menzel, D., Olbing, H., Monnens, L., Wieringa, B. and Ropers, H.-H. (1988) Location of the gene for X-linked Alport’s syndrome. Kidney Int. 34, 507-510. Crow, T.J. (1987) Pseudoautosomal locus for psychoses? Lancet ii, 1532. Crow, T.J. (1988) Sex chromosomes and psychosis: The case for a pseudoautosomal locus. Br. J. Psychiatry 153, 6755683. Evans, H., Erickson, R.P., Kelsch, R. and Pierce, J.C. (1980) Apparently changing patterns of inheritance in Alport’s hereditary nephritis: Genetic heterogeneity versus altered diagnostic criteria. Clin. Genet. 17, 285-292. Feingold, J., Bois, E., Chompret, S.A., Broyer. M., Gubler, M.C. and Grunfeld, J.-P. (1985) Genetic heterogeneity of Alport syndrome. Kidney Int. 27, 672-677. Flinter, F.A., Cameron, J.S., Chantler, C., Houston, I. and Bobrow, M. (1988) Genetics of classic Alport’s syndrome. Lancet ii, 1005-1007. Goldstein, J.M. and Tsuang, M.T. (1988) The process of subtyping schizophrenia: strategies in the search for homogeneity. In: M.T. Tsuang and J.C. Simpson (Eds.), Nosology, Epidemiology and Genetics of Schizophrenia. Elsevier, Amsterdam, pp. 63-84.
239
Gubler, M., Levy, M., Broyer, M., Naizot, C., Gonzales, G., Perrin, D. and Habib, R. (1981) Alport’s syndrome: A report of 58 cases and a review of the literature. Am. J. Med. 70, 493-505. Kendler, KS. (1988) The genetics of schizophrenia: an overview. In: M.T. Tsuang and J.C. Simpson (Eds.), Nosology, Epidemiology, and Genetics of Schizophrenia. Elsevier, Amsterdam, pp. 437-462. Shaw, R.F. and Kallen, R.J. (1976) Population genetics of Alport’s syndrome.Nephron 16,427-432.
Spitzer, R.L. and Endicott, J. (1978) Schedule for Affective Disorders and Schizophrenia (SADS-L). New York State Psychiatric Institute, Biometrics Research Division, New York. Szpiro-Tapia, S., Bobrie, G., Guilloud-Bataille, M., Heuertz, S., Julier, C., Frezal, J., Grunfeld, J.P. and Hors-Cayla, M.C. (1988) Linkage studies in X-linked Alport’s syndrome. Hum. Genet. 81, 85-87. Wise, T.N. (1977) Psychotic reactions in hereditary chronic nephritis. MD State Med. J., July, 53-54.
Research,
3 (1990)
235
235-239
Elsevier
SCHIZO
00106
A family with Alport syndrome and psychosis Gail W. Shields, Carolee Department
q/Psychiatry,
(Received
T-IO, Health
14 September
Sciences
Center,
Pataki SUNY
1989, revised received
and Lynn E. DeLisi
Stony Brook,
16 January
Stony Brook,
1990, accepted
Neua York, NY 11794.
18 January
U.S.A.
1990)
A family is described with a history of both hereditary nephritis (Alport syndrome) and chronic psychosis in multiple family members. Although the disorders do not segregate together in all cases, the finding of this family may provide a clue for the location of a psychosis gene. Alport syndrome has been mapped to the long arm of the X chromosome. Some studies also support a genomic locus on the X chromosome in at least some cases of manic-depressive disorder and schizophrenia. Key words: Alport
syndrome;
Psychosis
syndrome;
X chromosome;
INTRODUCTION
A 9-year-old male was referred to the Child Psychiatry Department at Stony Brook University Hospital after disclosing suicidal ideation secondary to persistent frightening auditory and visual hallucinations. His past history included poor socialization, defiant behavior and a chronic preoccupation with a complicated delusional system into which his hallucinations were incorporated. The hallucinations and delusions dated back approximately 5 years. His mother shared parts of the delusional belief system including the ability to communicate with ‘spirits’, and the presence of ‘ghosts’. Due to the severity of the schizophrenic-like symptoms as well as the depressive ideation and mood, he was hospitalized on the Child Psychiatry Inpatient unit and a full evaluation was done. During the course of routine laboratory testing, hematuria and proteinuria were noted on repeated urinalyses. A 24 h urine collection revealed significant proteinuria, and a renal biopsy was consistent with a diagnosis of early hereditary nephritis (Alport syndrome), revealing ‘lipoid nephrosis with Correspondence to: L.E. DeLisi, Department T-10, Health Sciences Center, SUNY Stony Brook, New York, NY 11794, U.S.A.
0920-9964/90/$03.50
c
of Psychiatry, Brook, Stony
1990 Elsevier Science Publishers
(Schizophrenia)
mild splitting of the basement membrane’. A 24 h urine collection showed a creatinine clearance at 82 ml/min per 1.73 m2 and a protein excretion of 782 mg/24 h. The glomerular filtration rate was considered borderline low. Since Alport syndrome can be associated with ocular and auditory defects, further evaluation of these systems was also performed. While the ophthalmology examination was normal, an audiology evaluation revealed abnormal auditory processing and mild hearing loss for pure tones. A brain magnetic resonance imaging scan (MRI) was performed and showed moderate enlargement of the lateral ventricles. An EEG was read as generalized abnormal slowing and epileptiform activity in the right temporal parietal area. There was no clinical history, however, of seizure-like episodes. A family history of chronic nephritis (diagnosed as medullary cystic kidney disease on occasion) in multiple family members from at least two generations was present. An X-linked pattern of inheritance for this disorder is suggested in previous reports (Gubler et al., 1981) and is also consistent with inheritance of both kidney disease and psychosis in the referred family, although it is recognized that population data are also consistent with autosomal dominant and recessive forms of illness transmission (Feingold et al., 1985). Thus, a detailed genetic evaluation as well as psychiatric
B.V. (Biomedical
Division)
236
history and direct interviews members were obtained.
of all available
family
METHODS
Psychiatric diagnoses of all family members diagrammed in Fig. 1 were made using DSM-III-R criteria (American Psychiatric Association), based on information obtained from SADS interviews (Schedule for Affective Disorders and Schizophrenia (Spitzer and Endicott, 1978)), medical records, and information from clinicians and other family members. In-person interviews were performed on 15 of the related individuals informative for linkage analyses. The remainder, which included the three maternal great-aunts, were diagnosed based on information from multiple other family members. Two of these were reclusive and refused contact. The other was in a nursing home with severe Parkinson’s disease. If the kidney disease is assumed to be X-linked, this latter individual (the maternal great-grandmother of the proband) would be an obligate carrier of the abnormal gene. Although she does not have documented kidney pathology, she
Key *
Alport
= Kidney
was noted to have had several abnormal urinalyses that presently are positive for blood and protein. It should be further noted that none of the obligate female carriers are noted to have definite kidney disease, and only males are noted to have the disease. This may indicate that the disease is inherited as an X-linked recessive, rather than dominant disorder at least in this family. Although there is only a small amount of linkage information that can be obtained from a single small family, the odds ratio for the likelihood of linkage of the two diseases (lod score) was estimated. 2-point lod scores were calculated assuming an X-linked dominant model for transmission of psychosis and both X-linked dominant and recessive models for Alport syndrome. Calculations were performed for both high and low levels of disease penetrance (from 10 to 70%) and from 0 to 40% recombination.
RESULTS
As illustrated in the family pedigree (Fig. 1), six males have a history of definite kidney disease
Syndrome
Pedigree
Disease
= Proband
cl=
Normal Chronic Schaaphrenla
9,
Schuoaffectwe Disorder
q= Poly
and
-vy ,
w
\
Drq
w
Abuse
Psychosis
NOS
Generation Age Range
w
75-88 years
( 39-56 years
-
14-31 years
3 months14 years Fig. I.
231
confirmed by the family physician (two diagnosed as medullary cystic disease, one recognized as Alport syndrome, and three males aged 14-18 years diagnosed as having chronic hematuria and proteinuria); three of these, in addition, have a chronic psychosis (schizoaffective disorder, bipolar disorder, psychosis not-otherwise-specified (NOS)). A total of six family members have a diagnosis of schizophrenia or other psychosis (two chronic schizophrenia, one chronic schizoaffective disorder, one bipolar psychosis, two psychosis NOS); these include three males with kidney disease. The following are case descriptions of each of the six psychotic individuals. Case no. I: (proband, detailed above): a lo-yearold male with chronic nephritis, suicidal ideation, depression, loss of interest in school work, auditory and visual hallucinations of ‘ghosts and imaginary playmates’ with multiple related delusionary system-onset approximately 2-3 years prior to evaluation, presently hospitalized on psychiatric unit for above symptoms. He was diagnosed as having DSM-III-R schizoaffective disorder, chronic, depressed, and Alport syndrome. Case no. 2: a 14-year-old half-brother of case no. 1, has attention problems in school, easily distractible, unorganized, sets fires, steals, damages public property, and has had auditory and olfactory hallucinations intermittently since age 7. He was diagnosed as DSM-III-R (1) attention deficit disorder; (2) oppositional/defiant disorder; and (3) psychotic disorder, not otherwise specified. He also has Alport syndrome. Case no. 3: a 31-year-old female, married three times, mother of four children (nos. 1 and 2). Has been arrested three times for selling drugs, believes in psychic powers, frequently angry and irritable, TABLE
has had multiple paranoid delusions and olfactory hallucinations (smells roses) and has seen ‘saints’. Some, but not all, of these symptoms occur at times other than during drug intake. She was diagnosed as DSM-III-R (1) borderline personality disorder; (2) alcohol abuse; (3) polydrug abuse; (4) chronic psychotic disorder, not otherwise specified. Case no. 4: an 18-year-old male nephew of no. 3, who has had psychiatric treatment since age 7 and one psychiatric hospitalization at age 17, auditory hallucinations occurring during LSD intake, paranoid delusions during episodes of mania, and has had multiple major depressive episodes. He was diagnosed as DSM-III-R (1) antisocial personality disorder; (2) polysubstance abuse with organic delusional syndrome; (3) organic hallucinosis; (4) bipolar disorder, mixed. He also has Alport syndrome. Case no. 5: An 84-year-old female paternal greataunt of no. 3, who has lived with sister all her life, never employed, with over 40 years of psychotic symptoms that include multiple paranoid and bizarre delusions, formal thought disorder, and severe obsessive compulsive behavior. Her diagnoses were DSM-III-R (1) obsessive compulsive disorder; (2) schizophrenia, chronic undifferentiated type. Case no. 6: An 87-year-old sister of no. 5 and paternal great-aunt of no. 3, lives alone with sister, never employed or married, no friends, rarely leaves home, multiple paranoid delusions, and formal thought disorder. At least 40+ years of illness. Her symptoms are somewhat similar to her sister’s (case no. 5). She was diagnosed as DSMIII-R schizophrenia, chronic undifferentiated type. The maximum LOD score obtained for linkage of psychosis with Alport syndrome was 0.74 at a penetrance of 30% for psychosis and 99% for Xlinked recessive kidney disease (see Table 1).
1
2-point LOD scores for varying degrees of disease penetrance and percent recombination (Psychosis was considered in all cases to be X-linked dominant. Alport syndrome was considered X-linked recessive inheritance and is indicated by D or R, respectively.) Penetrance
Recombination fraction
Psychosis
Alport
0.30 0.60 0.30 0.60
0.99R 0.99R 0.70D 0.70D
Synd.
0
0.05
0.10
0.20
0.30
0.40
0.74 0.75 0.41 -0.14
0.70 0.70 0.42 0.05
0.65 0.65 0.41 0.18
0.54 0.54 0.37 0.27
0.39 0.39 0.28 0.21
0.31 0.31 0.16 0.16
for cases of X-linked
dominant
or
238
DISCUSSION
The above family evaluation reveals the co-occurrence of hereditary nephritis and psychotic illness in some, although not all, family members with either of these disorders. Since renal failure, or advanced kidney pathology was not yet present when psychosis was diagnosed in these individuals, the occurrence of psychotic symptoms does not appear to be a consequence of uremic toxicity to the central nervous system. There is no evidence that psychosis occurs at an increased frequency in patients with Alport syndrome, or that hereditary kidney disease is increased in families with psychosis. One previously published report (Wise, 1977) describes psychotic symptoms in two patients with Alport syndrome, although in these subjects the psychosis was attributed to direct toxic effects of renal failure. No mention was made of psychosis in family members, nor do other reports of such a co-existence appear in the literature. It is therefore assumed unlikely that these disorders are etiologically related, but rather that they could be genetically linked to the same chromosomal region. Linkage studies thus far in Alport syndrome have mapped the gene for this disorder in some families to the long arm of the X chromosome X q21_24 (Atkin et al., 1988; Brunner et al., 1988; Flinter et al., 1988; Szpiro-Tapia et al., 1988); however, the previous studies suggesting only partial X linkage and the presence of male-to-male transmission suggest that other genomic regions may also be worth examining. Though speculative, some clinical similarities between the presentation of this disorder and schizophrenia may be clues to a similar genomic location or genetic mechanism for transmission of both diseases: the clinical onset of both disorders commonly occurs in adolescence or early adulthood, in Alport syndrome, reaching an end-point of renal death by age 40, in schizophrenia reaching a peak age of onset before age 40. In both disorders males have an earlier onset and more severe course to illness than females. Similarly, both illnesses do not follow a classical Mendelian pattern of inheritance. Thus the conclusion suggested by some investigators is that these illnesses are likely to be genetically heterogenous (Evans et al., 1980; Gold-
stein and Tsuang, 1988; Kendler, 1988). With respect to schizophrenia, it has also been proposed that a gene for illness may be pseudoautosomal (Crow, 1987, 1988)-located within the region of the short arms of the sex chromosomes where recombination between X and Y chromosomes occurs in meiosis, thus allowing for transmission from fathers to sons, or partial sex linkage. The above finding of schizophrenia and Alport syndrome (or the carrier state) segregating together in some members of the same pedigree, suggests that the pseudoautosomal region should be examined for linkage in both disorders, and likewise, the X qZ1_24 region further examined in families with schizophrenia.
ACKNOWLEDGEMENTS
We thank Joseph Mannino and Angela Boccio for technical assistance, Dr. Patricia Grayson for performing diagnostic assessments of the children and Joseph D. Terwilliger for calculating the lod scores.
REFERENCES
Atkin, C.L., Hasstedt, S.J., Menlove, L., Casnnon, L., Kirschner, N., Schwartz, C., Nguyen, K. and Skolnick, M. (1988)Mapping of Alport syndrome to the long arm of the X chromosome. Am. J. Hum. Genet. 42, 249-255. Brunner, H., Schroder, C., Bennehom, C.V., Lambermon, E., Tuerlings, J., Menzel, D., Olbing, H., Monnens, L., Wieringa, B. and Ropers, H.-H. (1988) Location of the gene for X-linked Alport’s syndrome. Kidney Int. 34, 507-510. Crow, T.J. (1987) Pseudoautosomal locus for psychoses? Lancet ii, 1532. Crow, T.J. (1988) Sex chromosomes and psychosis: The case for a pseudoautosomal locus. Br. J. Psychiatry 153, 6755683. Evans, H., Erickson, R.P., Kelsch, R. and Pierce, J.C. (1980) Apparently changing patterns of inheritance in Alport’s hereditary nephritis: Genetic heterogeneity versus altered diagnostic criteria. Clin. Genet. 17, 285-292. Feingold, J., Bois, E., Chompret, S.A., Broyer. M., Gubler, M.C. and Grunfeld, J.-P. (1985) Genetic heterogeneity of Alport syndrome. Kidney Int. 27, 672-677. Flinter, F.A., Cameron, J.S., Chantler, C., Houston, I. and Bobrow, M. (1988) Genetics of classic Alport’s syndrome. Lancet ii, 1005-1007. Goldstein, J.M. and Tsuang, M.T. (1988) The process of subtyping schizophrenia: strategies in the search for homogeneity. In: M.T. Tsuang and J.C. Simpson (Eds.), Nosology, Epidemiology and Genetics of Schizophrenia. Elsevier, Amsterdam, pp. 63-84.
239
Gubler, M., Levy, M., Broyer, M., Naizot, C., Gonzales, G., Perrin, D. and Habib, R. (1981) Alport’s syndrome: A report of 58 cases and a review of the literature. Am. J. Med. 70, 493-505. Kendler, KS. (1988) The genetics of schizophrenia: an overview. In: M.T. Tsuang and J.C. Simpson (Eds.), Nosology, Epidemiology, and Genetics of Schizophrenia. Elsevier, Amsterdam, pp. 437-462. Shaw, R.F. and Kallen, R.J. (1976) Population genetics of Alport’s syndrome.Nephron 16,427-432.
Spitzer, R.L. and Endicott, J. (1978) Schedule for Affective Disorders and Schizophrenia (SADS-L). New York State Psychiatric Institute, Biometrics Research Division, New York. Szpiro-Tapia, S., Bobrie, G., Guilloud-Bataille, M., Heuertz, S., Julier, C., Frezal, J., Grunfeld, J.P. and Hors-Cayla, M.C. (1988) Linkage studies in X-linked Alport’s syndrome. Hum. Genet. 81, 85-87. Wise, T.N. (1977) Psychotic reactions in hereditary chronic nephritis. MD State Med. J., July, 53-54.
