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<p class="ltrs-br-ltr-br-title"><span class="bold">Psychiatric Features in High-Functioning Adult Brothers With Fragile X Spectrum Disorders</span></p>
<p class="ltrs-br-ltr-br-body-text"><span class="semibold">To the Editor:</span> The awareness of psychiatric disability in the fragile X premutation (55–200 CGG repeats on Xq27.3) is low because these problems are not as obvious as in the full-mutation fragile X syndrome.<span class="htm-cite"><a href="#ref1">1–5</a></span> Symptoms of hyperactivity, social deficits, and autism spectrum disorders as well as anxiety disorders and mood disorders are present in premutation carriers of both genders.<span class="htm-cite"><a href="#ref1">1</a>,<a href="#ref2">2</a>,<a href="#ref6">6</a>,<a href="#ref7">7</a></span> Some individuals with the premutation have a mild-to-moderate deficit of fragile X–related mental retardation protein (FMRP).<span class="htm-cite"><a href="#ref8">8</a></span> The level of FMRP decreases with increased CGG repeat number more evident in the upper end of the premutation range, leading to physical and behavioral features similar to fragile X syndrome.<span class="htm-cite"><a href="#ref9">9</a>,<a href="#ref10">10</a></span> We present 2 cases of brothers with average and above intellectual abilities but emotional/neurocognitive deficits associated with the presence of expanded alleles from a larger fragile X family pedigree (see <span class="callout"><a target="_blank" onclick="createFigure('f1'); return false;" href="#">Figure 1</a></span>) with significant psychopathology.</p>
<div id="figure" class="right"> <a target="_blank" onclick="createFigure('f1'); return false;" href="#"><img border="0" id="f1" alt="Figure 1" src="12l01492f1.gif"/></a>
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<p class="ltrs-br-ltr-br-body-text">The brothers’ 62-year-old mother was identified as a premutation carrier with an unknown CGG repeat size. She is affected by hypertension and underwent menopause at age 49 years. One of the brothers’ sisters, who has 2 children with fragile X syndrome, was diagnosed with bipolar II disorder with intermittent hypomanic episodes and panic disorder without agoraphobia (predominantly, but not only, in social situations; diagnosis made using the <span class="italic">Structured Clinical Interview for</span> DSM-IV <span class="italic">Axis I Disorders</span> [SCID-I]<span class="htm-cite"><a href="#ref11">11</a></span>). The maternal grandfather died in his early 50s after a sudden stroke. The maternal grandmother is 86 years old and healthy. The brothers’ father suffered from alcoholism and died recently at age 67 years. A paternal uncle committed suicide in his 30s, while both paternal grandparents were “odd” and either depressed or irritable and had been hospitalized in psychiatric institutions. The paternal grandfather had received electroconvulsive treatment and had a history of alcoholism.</p>
<p class="ltrs-br-ltr-br-body-text"> </p>
<p class="ltrs-br-ltr-br-body-text"><span class="semibold-ital">Case 1.</span> Mr A is a 40-year-old man with full mutation and methylation mosaicism, including a methylated allele (190 CGG repeats) and unmethylated alleles in both the premutation and the full-mutation range (98 and 225–547 CGG repeats, respectively; full mutation detected in approximately 30% of the cells). His <span class="italic">FMR1</span> messenger RNA (mRNA) level was 5.8-fold above normal, and he showed decreased FMRP expression level of approximately 20% of normal (see <span class="callout"><a target="_blank" onclick="createFigure('f2'); return false;" href="#">Figure 2</a></span>).</p>
<div id="figure" class="right"> <a target="_blank" onclick="createFigure('f2'); return false;" href="#"><img border="0" id="f2" alt="Figure 2" src="12l01492f2.jpg"/></a>
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<p class="ltrs-br-ltr-br-body-text">His developmental history included a premature birth, delayed motor development, and delayed onset of language. He showed poor eye contact, signs of attention deficit and hyperactivity, and language and reading problems in childhood. His medical history included leg cramps, recurrent sinusitis, and varicose veins. He complained about poor balance and visual-motor coordination deficits since childhood. The medical examination demonstrated a prominent jaw, flat feet, increased deep tendon reflexes of 3+, macroorchidism, a mild hearing loss, and motor coordination problems including inability to tandem walk. His cognitive testing<span class="htm-cite"><a href="#ref12">12</a></span> at age 40 years demonstrated a full scale intelligence quotient (FSIQ) of 107 (68th percentile, in the average range), and his general memory score<span class="htm-cite"><a href="#ref13">13</a></span> was 98 (45th percentile). On psychiatric interview, Mr A reported several manic episodes with psychotic features during his teenage years, meeting SCID-I criteria for bipolar disorder type I, most recent episode manic with psychotic features in full remission at the time of the evaluation. He had had 3 psychiatric hospitalizations during his teenage years. As an inpatient, he was started on lithium treatment, which he did not tolerate and discontinued, followed by haloperidol and benztropine. After 3 years, he discontinued medications and psychiatric treatment and remained relatively symptom-free. Currently, he meets SCID-I criteria for alcoholism.</p>
<p class="ltrs-br-ltr-br-body-text">Although Mr A presented with an IQ considered to be average, which is remarkable for an adult man with <span class="italic">FMR1</span> mosaicism, he showed features of premutation and full-mutation involvement related to high mRNA levels and low FMRP levels. Overall, we hypothesize that Mr A demonstrates a “double hit” phenomenon—he is affected by both lowered FMRP and elevated mRNA levels.</p>
<p class="ltrs-br-ltr-br-body-text"><span class="semibold-ital">Case 2.</span><span class="italic"> </span>Mr B is a 41-year-old male premutation carrier with 118 CGG repeats and the brother of Mr A. Elevated <span class="italic">FMR1</span> mRNA levels (3.92-fold elevation) and a moderate decrease in FMRP expression were observed in blood (approximately 65% of normal levels; see <span class="callout"><a target="_blank" onclick="createFigure('f2'); return false;" href="#">Figure 2</a></span>). Mr B had normal development. His medical history included migraines, a blocked nasal passage secondary to a deviated septum, asthma, and eczema. On examination, he presented with a long, narrow face, long ears (><span class="thinspace"> </span>7 cm), and a prominent jaw. His neurologic examination showed slightly increased reflexes and a loss of vibratory sensation in the lower extremities. On psychiatric interview, he reported an untreated major depressive episode lasting 6 months at age 20 years; therefore, he met SCID-I criteria for major depressive disorder, single episode in full remission, at the time of the evaluation. His cognitive testing<span class="htm-cite"><a href="#ref11">11</a></span> at age 41 years demonstrated a superior FSIQ of 122 (93rd percentile), and his general memory score<span class="htm-cite"><a href="#ref13">13</a></span> was 103 (58th percentile).</p>
<p class="ltrs-br-ltr-br-body-text"> </p>
<p class="ltrs-br-ltr-br-body-text">We present 2 brothers with expanded <span class="italic">FMR1</span> alleles, elevated <span class="italic">FMR1</span> mRNA levels, and a distinct psychopathological profile, including mood disorders and substance abuse. The high prevalence of premutation alleles in the general population (approximately 1:250–810 in males and 1:130–250 in females) warrants increased awareness of the possible connection to medical and psychopathological features.<span class="htm-cite"><a href="#ref14">14</a>,<a href="#ref15">15</a></span></p>
<p class="ltrs-br-ltr-br-body-text">Individuals who have both lowered FMRP and elevated <span class="italic">FMR1</span> mRNA (ie, a “double hit”), carriers with a CGG repeat number in the upper premutation range and some mosaic full mutations, may be more common than previously thought, and they often present with psychiatric features.<span class="htm-cite"><a href="#ref16">16</a></span> The phenomenon of double involvement of toxic elevation of <span class="italic">FMR1</span> mRNA and reduced FMRP is worthy of further study, and it may represent a new phenotype in between the premutation and the full mutation with a more severe psychopathology that combines features of both types of mutations.</p>
<p class="ltrs-br-ltr-br-references-head"><span class="smallcaps">References</span></p>
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<p class="references-references-text-10-99"><a name="ref16"></a>16. Hessl D, Wang JM, Schneider A, et al. Decreased fragile X mental retardation protein expression underlies amygdala dysfunction in carriers of the fragile X premutation. <span class="italic">Biol Psychiatry</span>. 2011;70(9):859–865.<span class="pubmed-crossref"> <a href="
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<p class="ltrs-br-ltr-br-author"><span class="bold">Andrea Schneider, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><a href="
mailto:andrea.schneider@ucdmc.ucdavis.edu">
andrea.schneider@ucdmc.ucdavis.edu</a></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Andreea Seritan, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Flora Tassone, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Susan M. Rivera, PhD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">Randi Hagerman, MD</span></p>
<p class="ltrs-br-ltr-br-author"><span class="bold">David Hessl, PhD</span></p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Author affiliations:</span> MIND Medical Investigation of Neurodevelopmental Disorders Institute (Drs Schneider, Tassone, Hagerman, and Hessl) and Departments of Psychiatry and Behavioral Sciences (Drs Seritan and Hessl), Biochemistry (Dr Tassone), Psychology (Dr Rivera), and Pediatrics (Drs Schneider and Hagerman), University of California-Davis Medical Center, Sacramento.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Potential conflicts of interest:</span> <span class="semibold">Dr Hagerman</span> has been a consultant for Novartis and has received grant/research support from Seaside Therapeutics, Novartis, Roche, Forest, and Curemark. <span class="semibold">Dr Hessl</span> has been a consultant for Roche, Seaside Therapeutics, and Novartis; has received grant/research support from the National Institute of Mental Health; and has received honoraria from Adelphi. <span class="semibold">Drs Schneider</span>, <span class="semibold">Seritan</span>, <span class="semibold">Tassone</span>, and <span class="semibold">Rivera</span> report no potential conflicts of interest relevant to the subject of this letter.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Funding/support:</span> This work was supported by National Institutes of Health (NIH) grant MH078041 to Dr Hessl, grants HD036071 and AG032115 to Dr Hagerman, and grant HD02274 to Dr Tassone; NIH/National Institute on Aging grant RL1AG032115 (overall PI: Dr P. J. Hagerman; component PI: Dr R. J. Hagerman); NIH/National Institute of Mental Health grant R01MH078041 (PIs: Drs Hessl and Rivera); and Health and Human Services Administration of Developmental Disabilities grant 90DD0596.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Acknowledgments:</span> The authors thank the participants and the MIND Institute.</p>
<p class="ltrs-br-ltr-br-endmatter-fieldnotes"><span class="semibold-ital">Published online:</span> April 11, 2013.</p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">Prim Care Companion CNS Disord 2013;15(2):</span><span class="doi">doi:10.4088/PCC.12l01492</span></p>
<p class="ltrs-br-ltr-br-copyright-doi"><span class="italic">© Copyright 2013 Physicians Postgraduate Press, Inc.</span></p>
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