American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:222–224 (1998)
Clinical Description of an Adult Male With
Psychosis Who Showed FMR1 Gene
Methylation Mosaicism
Ni A. Khin,1* Jack Tarleton,2 Bellamkonda Raghu,1 and S.K. Park1
1
Department of Psychiatry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo,
Buffalo, New York
2
Laboratory for Molecular Diagnostics, Mission Genetics Center, Memorial Mission Hospital,
Asheville, North Carolina
Unstable trinucleotide repeat DNA con-
tained in numerous genes has been pro-
posed as the underlying mechanism in the
clinical phenomenon of genetic anticipation
in fragile X syndrome and other neurode-
generative diseases. No clear evidence has
been found for the role of these abnormal
trinucleotide repeat expansion-containing
genes in schizophrenia or other psychiatric
disorders. This report describes an adult
male with psychosis who was later found to
have methylation mosaicism of the FMR1
gene. We discuss history, examination, and
investigation which led to the diagnosis and
treatment response of this patient. Am. J.
Med. Genet. (Neuropsychiatr. Genet.) 81:
222–224, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: fragile X syndrome; unstable
DNA; psychosis
INTRODUCTION
Many investigations in the last decade have ex-
tended our knowledge of the clinical manifestations
suggestive of fragile X syndrome (fra X), including
mental retardation, abnormal craniofacies (long face
and prominent ears), and macroorchidism. Behavioral
dysfunctions include hyperactivity, and autistic-like
behaviors such as poor eye contact, repetitive hand
flapping, self-mutilation (hand biting), learning dis-
abilities, and speech cluttering. Psychiatric manifesta-
tions, including schizoaffective disorder, have been
noted sporadically in various case studies associated
with the fra X chromosome [Chudley and Hagerman,
1987; Cronister and Hagerman, 1989]. The cause-effect
*Correspondence to: Dr. Ni A. Khin, Department of Psychiatry,
SUNY at Buffalo, Erie County Medical Center, 462 Grider Street,
Buffalo, NY 14215.
Received 29 April 1997; Revised 14 January 1998
© 1998 Wiley-Liss, Inc.
significance of the association between these psychiat-
ric manifestations and the finding of fra X has not been
well-established.
Numerous research efforts have explored the mo-
lecular etiology of fragile X syndrome [Warren and Nel-
son, 1994]. It has been shown to be caused by an un-
stable CGG repeat within the fragile X mental retar-
dation (FMR1) gene. The repeat is normally
polymorphic, with 6–52 repeats. Affected individual ex-
hibit an expansion to more than 230 repeats, called
‘‘full mutation.’’ Full mutation is usually accompanied
by abnormal DNA methylation of the FMR1 gene,
which inhibits transcription of FMR1, leading to the
absence of the encoded protein, FMRP. Nonpenetrant
male carriers and many female carriers exhibit ‘‘pre-
mutation’’ alleles of intermediate length, ranging from
50–230 repeats, from which transcription is not im-
paired.
A recent study by Hagerman et al. [1994] demon-
strated that a greater percentage of high-functioning
(HF) males with an IQ of 70 or higher had a mosaic
pattern or an incompletely methylated full mutation of
FMR1 than the FMR1 gene pattern of retarded males.
Incomplete methylation from cell to cell appears to
result in production of some FMRP in those cells where
the abnormal methylation has not occurred. Therefore,
cellular mosaicism may ‘‘rescue’’ those cells with no
FMR1 methylation, even in the presence of expanded
CGG repeats. The psychiatric status of these HF males
was not included in the report of Hagerman et al.
[1994].
This report describes the case of a high-functioning
adult male who, when presented for initial examina-
tion of psychosis, was later found to have methylation
mosaicism of the FMR1 gene. We discuss the history,
examination, and investigation which led to the diag-
nosis and treatment response of this patient.
CASE HISTORY
A.B. is a 44-year-old single white male who works as
a dishwasher in the dietetic department at a hospital.
His chief complaint was a concern about ‘‘a girl from

work followed me with a knife.’’ A.B. stated that he was
at work when he sensed a female co-worker standing
behind him with a knife pointing at him. When he
looked back, she was in the same room, at a distance,
doing her job. He then explained without clear reason
that he was fearful that she might harm him. The fol-
lowing week, he came out of the shower several times
undressed claiming that he felt someone was breaking
into the house, even after his sister reassured him re-
peatedly that no stranger was there. The sister brought
the patient to the hospital because of this abnormal,
suspicious behavior. He denied experiencing hallucina-
tions or neurovegetative symptoms. There was no his-
tory of substance abuse.
Fifteen years ago, A.B. was diagnosed with paranoid
schizophrenia in another state. He stated then that he
had searched the town looking for his boss with whom
he fantasized a romantic life. He was also fearful that
people were going to kill him and he attempted to jump
out of the car as his mother brought him to the hospi-
tal. For 2 weeks prior to that admission, he was treated
with haloperidol 10 mg and benztropine 2 mg at bed-
time. He continued on medication for 3 years, and then
returned to work as a horticulturist. He later moved to
his present location.
On examination at the time of this admission, A.B.
was described as a thin, tall, pleasant young male ex-
hibiting some facial grimaces. He was able to engage in
conversation with articulate, coherent speech but with
vague content, including sarcastic remarks and inap-
propriate laughter. He was preoccupied with the para-
noid thoughts he had previously experienced and re-
peatedly verbalized his concerns about going into ‘‘a
psychotic depression like in the past.’’ He denied sui-
cidal or homicidal ideation. He was easily distracted
during the interview, turning to the door if he heard
someone pass in the hall. He had limited insight and
judgment. The staff noted that there was minimal so-
cial interaction with others. Routine blood biochemis-
try tests were within normal limits. CT scan of the
head showed mild cortical atrophy and enlarged ven-
tricles with no space-occupying lesions.
A.B. was given supportive care and milieu therapy.
He was started on thiothixene 5 mg with benztropine
1 mg twice a day, and he indicated significant relief of
his paranoia within a week.
During the family interview, his parents stated that
at times they found the patient rocking his body. His
sister mentioned a family history of mental retardation
in 4 of their maternal cousins, who were diagnosed
with fra X. All 4 are currently living in supervised
group homes. They have significantly subaverage in-
tellectual functioning, and concurrent deficits in adap-
tive functioning in self-care, home living, and academic
skills. They also have poor quality in social interaction
and communication with others. One of them manifests
loud speech and repetitive use of language, and is pre-
occupied with stereotyped and restricted patterns of
interests and behaviors such as hand twisting. As per
family, they claimed to have no psychiatric manifesta-
tions.
In neuropsychological testing, A.B. demonstrated a
low-average level of global intellectual performance
FMR1 Gene Methylation Mosaicism 223
with a relatively consistent performance across intel-
lectual domains. His verbal IQ was 85, with a perfor-
mance IQ of 84 and a full-scale IQ of 84. A.B.’s capa-
bility for new learning and memory was found to be
moderately reduced, especially in immediate and de-
layed verbal memory recall. In retrospect, his physical
features of fra X, i.e., long face, prominent and long (8.2
cm) ears, high-arched palate, and hyperextensible
metacarpal phalangeal joints, were appreciated. Direct
DNA analysis of peripheral blood lymphocytes showed
a methylation mosaic pattern in FMR1 which was later
confirmed by skin biopsy fibroblasts. His mother was
found to be a premutation carrier.
Since A.B. reported significant improvement of para-
noia with a 10 mg per day dose of thiothixene, he was
continued on the same medication for almost a year.
His medication was then decreased to thiothixene 5 mg
at bedtime, which he has continued for the past 9
months without symptom recurrence.
Review of his old discharge summary from 1980
noted that, ‘‘Within 5 days, his psychosis had cleared.
He remained a somewhat schizoid young man who pre-
sented absolutely no management problems but rather
inert and did not initiate socialization. He was encour-
aged to do this throughout the remainder of his hospi-
talization and became somewhat more comfortable in
social interactions.’’ This observation seemed to be con-
sistent with his responses at this time. There was no
significant deterioration in his daily life functioning
following these two hospitalizations. These findings ar-
gue against the diagnosis of schizophrenia and are
rather suggestive of an individual with schizoid per-
sonality and a superimposed acute psychosis.
DISCUSSION
Several studies have reported an association be-
tween autism in prepubertal boys with fra X. Screening
for fra X is recommended, since approximately 15%
would be positive [Cronister and Hagerman, 1989]. As
can be seen in this case, a workup for fra X should be
considered when individuals with a family history of
mental retardation present psychiatric symptoms, re-
gardless of their age. In addition, the physical findings
suggestive of genetic diseases like fra X should also be
looked for on examination.
In patients with fra X, there is very little information
available on acute or long-term treatment with neuro-
leptics. While previous case studies in the treatment of
behavioral and psychiatric manifestations of fra X with
stimulants, folic acids, and neuroleptics [Chudley and
Hagerman, 1987; Reiss et al., 1986] have been de-
scribed, no agent has been found to be effective in all
cases. One case of a fra X male with chronic psychosis
which met Research Diagnostic Criteria (RDC) for
schizoaffective disorder and 3 cases with autistic be-
havior were reported by Reiss et al. [1986]. They also
reported that 2 carrier mothers of these autistic males
had severe affective and psychotic symptoms which
were refractory to treatment with psychotropic agents.
Unstable trinucleotide repeat DNA contained in nu-
merous genes may result in the clinical phenomenon of
genetic anticipation, i.e., more severe or earlier onset of
224 Khin et al.
symptoms in subsequent generations due to a larger
expansion of DNA repeats in offspring [reviewed by
Petronis and Kennedy, 1995]. A.B.’s mental impair-
ment is not as severe as that of his mentally retarded
cousins with fra X. A.B. could represent an ‘‘interme-
diate’’ phenotype arising from cellular mosaicism,
where incomplete methylation of FMR1 in some of his
cells appears to result in production of some FMRP in
those cells where the abnormal methylation has not
occurred. Therefore, cellular mosaicism may rescue
those cells with no FMR1 methylation, even in the
presence of expanded trinucleotide repeats. His psy-
chosis may also be explained by the mosaicism in his
brain. One may argue the fact that this intermediate
phenotype can also be a result of cellular mosaicism,
which can occur in the absence of unstable DNA, e.g.,
in Down syndrome, or may be explainable by a lack of
correlation between CAG length and cognitive and psy-
chiatric symptoms, such as in Huntington disease
[Baumgardner et al., 1994; Hernandez and Fisher,
1996; Zappacosta et al., 1996].
However, further investigations are needed for a bet-
ter understanding of the underlying mechanism of the
trinucleotide repeat expansion and of what role it plays
in the causation of neuropsychiatric manifestations in
these genetic diseases.
ACKNOWLEDGMENTS
Thanks go to Dr. Michael Luce and Dr. Michele T.
Pato for their valuable comments on this case.
REFERENCES
Baumgardner TL, Green KE, Reiss AL (1994): A behavioral neurogenetics
approach to developmental disabilities: Gene-brain-behavior associa-
tions. Curr Opin Neurol 7:172–178.
Chudley AE, Hagerman RJ (1987): Fragile X syndrome. J Pediatr 110:821–
831.
Cronister AE, Hagerman RJ (1989): Fragile X syndrome. J Pediatr Health
Care 3:9–19.
Hagerman RJ, Hull CE, Safanda JF, Carpenter I, Staley LW, O’Connor
RA, Seydel C, Mazzocco M, Snow K, Thibodeau SN, Kuhl D, Thomas
Caskey NC, Taylor AK (1994): High functioning fragile X males: Dem-
onstration of an unmethylated fully expanded FMR1 mutation associ-
ated with protein expression. Am J Med Genet 51:298–308.
Hernandez D, Fisher EM (1996): Down syndrome genetics: Unravelling a
multifactorial disorder. Hum Mol Genet 5:1411–1416.
Petronis A, Kennedy JL (1995): Unstable genes—Unstable mind? Am J
Psychiatry 152:164–172.
Reiss AL, Feinstein C, Toomey KE, Goldsmith B, Rosenbaum K, Caruso
MA (1986): Psychiatric disability associated with the fragile X syn-
drome. Am J Med Genet 23:393–401.
Warren ST, Nelson DL (1994): Advances in molecular analysis of fragile X
syndrome. JAMA 271:536–542.
Zappacosta B, Monza D, Meoni C, Austoni L, Siliveri P, Gellera C, Alberti
R, Mantero M, Penati G, Caraceni T, Girotti F (1996): Psychiatric
symptoms do not correlate with cognitive decline, motor symptoms, or
CAG repeat length in Huntington’s disease. Arch Neurol 53:493–497.