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Published Online: 1 July 2014

“Undifferentiated Schizophrenia” Revisited

Publication: The Journal of Neuropsychiatry and Clinical Neurosciences
To the Editor: The C9orf72 hexanucleotide repeat expansion found in some cases of motor neuron disease and behavioral variant frontotemporal dementia may be associated with psychiatric symptomatology, in particular with florid delusions. However, this mutation has not been found in patients with schizophrenia. The authors report on a patient with a provisional diagnosis of undifferentiated schizophrenia (DSM-IV-TR criteria) who, 4 years after diagnosis, developed neurological symptoms and signs, leading to definitive genetic diagnosis.
DSM-IV included a diagnostic category of undifferentiated schizophrenia as a catch-all for patients who failed to meet criteria for other schizophrenia subtypes (paranoid, disorganized, catatonic). As such, its differential diagnosis was likely to be broad. DSM-V has abandoned schizophrenia subtypes because of their perceived limited diagnostic stability, low reliability, and poor validity. The authors report on a patient with a provisional diagnosis of undifferentiated schizophrenia (DSM-IV-TR criteria) who eventually developed neurological symptoms and signs, leading to definitive genetic diagnosis.

Case Report

A 48-year-old man was noted by the care staff in his nursing home to have reduced use of his left hand and arm, progressing over 1 month and prompting neurological referral.
He had been a resident in the nursing facility for around 3 years, with a provisional diagnosis of undifferentiated schizophrenia. This diagnosis had been based on a progressive decline in professional occupational function and change of personality from outgoing to apathy and social withdrawal. There was no prior psychiatric history. The attending psychiatrists judged that there were no first-rank symptoms, but the patient did transiently express the view that he was a hermaphrodite because he had a female brain capable of multitasking. There were also some strange behaviors, particularly impulsivity when eating and shopping. He became both bowel and bladder incontinent.
At the time of neurological referral, he required assistance with all activities of daily living. His only medical treatments were sertraline 50 mg/day and clozapine 300 mg/day. The patient himself could contribute little historical information, giving only yes/no answers.
Salient findings on neurological examination were left wrist drop, wasted musculature in the left arm, fasciculations in the biceps muscles, and hyperreflexia throughout, with extensor plantar responses. There was hypomimia and some mild dysarthria, but cranial nerves were otherwise intact, and there were no parkinsonian signs.
Investigations showed a normal blood creatine kinase level, but neurophysiological studies were abnormal, with widespread active denervation and fasciculations on electromyography, consistent with an anterior horn cell disorder.
On the basis of the history and clinical and investigational findings, a diagnosis of frontotemporal dementia with motor neuron disease was suspected. Consent for neurogenetic testing was obtained, and the abnormal C9orf72 GGGGCC hexanucleotide repeat expansion was detected, confirming the clinical diagnosis of frontotemporal dementia with motor neuron disease. No family history of dementia or motor neuron disease was forthcoming.

Discussion

Hexanucleotide repeat expansions in the C9orf72 gene on chromosome 9p were first described in association with frontotemporal dementia, motor neuron disease, and frontotemporal dementia with motor neuron disease overlap syndrome in 2011.1,2 This expansion is the most common genetic cause of frontotemporal dementia, accounting for more than 20% of familial cases and 5% of sporadic cases.
The clinical phenotype of C9orf72 expansions has been associated with a number of neuropsychiatric features.3 For example, in a patient cohort from the United Kingdom, it was noted that 38% of mutation carriers presented with florid psychotic symptoms, for which initial psychiatric diagnoses of delusional psychosis, somatoform psychosis, and paranoid schizophrenia had been made. An additional 28% had paranoid, delusional, and irrational thinking. Delusions were much more common than hallucinations4; these may sometimes be bizarre in form.5 The mutation has on occasion been associated with obsessive compulsive disorder6 and bipolar disorder.7,8 Although a schizophrenia-like phenotype has been reported in frontotemporal dementia,4,9 a study of schizophrenia patients identified no examples of C9orf72 expansion.10
This case illustrates the potential for the C9orf72 mutation to present to psychiatric services without overt neurological features. No neuropsychological assessment was undertaken at initial presentation, which might potentially have shown impairments of frontal lobe function. This diagnosis may need to be considered in young patients with psychiatric symptoms whom might previously have been diagnosed with undifferentiated schizophrenia. The observations in this case are consistent with the policy of DSM-V to abandon the category of undifferentiated schizophrenia.

References

1.
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al.: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72:245–256
2.
Renton AE, Majounie E, Waite A, et al.: ITALSGEN Consortium: A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72:257–268
3.
Takada LT, Sha SJ: Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease. Alzheimers Res Ther 2012; 4:38
4.
Snowden JS, Rollinson S, Thompson JC, et al.: Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012; 135:693–708
5.
Larner AJ: Delusion of pregnancy: a case revisited. Behav Neurol 2013; 27:293–294
6.
Calvo A, Moglia C, Canosa A, et al.: Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive-compulsive disorder associated to GGGGCC expansion of the c9orf72 gene. J Neurol 2012; 259:2723–2725
7.
Floris G, Borghero G, Cannas A, et al.: Bipolar affective disorder preceding frontotemporal dementia in a patient with C9ORF72 mutation: is there a genetic link between these two disorders? J Neurol 2013; 260:1155–1157
8.
Meisler MH, Grant AE, Jones JM, et al.: C9ORF72 expansion in a family with bipolar disorder. Bipolar Disord 2013; 15:326–332
9.
Velakoulis D, Walterfang M, Mocellin R, et al.: Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: clinicopathological series and review of cases. Br J Psychiatry 2009; 194:298–305
10.
Huey ED, Nagy PL, Rodriguez-Murillo L, et al.: C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol Aging 2013; 34:1309.e9–1309.e10

Information & Authors

Information

Published In

Go to The Journal of Neuropsychiatry and Clinical Neurosciences
Go to The Journal of Neuropsychiatry and Clinical Neurosciences
The Journal of Neuropsychiatry and Clinical Neurosciences
Pages: E62 - E63
PubMed: 25093798

History

Published online: 1 July 2014
Published in print: Summer 2014

Authors

Details

Besa Ziso, M.R.C.P.(UK)
Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
Debbie Marsden, M.R.C.Psych.
Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
Sundus Alusi, F.R.C.P.
Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
Andrew J. Larner, M.D.
Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom

Notes

Correspondence: Andrew J. Larner; e-mail: [email protected]

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