Psychosis as the initial manifestation of adult-onset Niemann-Pick disease type C

Inborn errors of metabolism are well recognized in children, but neurometabolic genetic disorders presenting later in life are less appreciated and more difficult to diagnose. Both the delayed onset of symptoms and the variability of phenotypic presentation may lead to misdiagnosis.

Niemann-Pick disease type C (NPC) is a neuronopathic form of Niemann-Pick disease characterized by later onset, a more indolent course, variable visceromegaly, and abnormalities of intracellular cholesterol metabolism. ^[1] Whereas the infantile forms, types A (neurovisceral) and B (purely visceral), reflect a primary and severe sphingomyelinase deficiency, types C and D are characterized by secondary and variable sphingomyelinase alterations. We present a patient with adult-onset NPC who was misdiagnosed as having schizophrenia for 8 years and review clinical features of the adult-onset cases previously reported.

Case report.

A 38-year-old Peruvian man was initially evaluated at the Movement Disorders Center at the University of Miami School of Medicine in June 1993. He presented with an 8-year history of psychosis, diagnosed as chronic schizophrenia and treated with neuroleptic medications throughout this period. His chief complaint was progressive gait impairment associated with a movement disorder.

Following a normal infancy, childhood, and adolescence, the patient graduated from college with a degree in business management. He was successfully employed as a comptroller and cashier at a stock brokerage firm until the age of 30, when he developed anxiety and hypochondriacal thoughts that progressed to paranoid delusions. After a visit to the police department, where he reported that he was a spy requiring police protection, he was given thioridazine for the treatment of chronic schizophrenia, paranoid type. Despite chronic neuroleptic therapy, including depot preparations of fluphenazine, the years that followed were characterized by a persistent psychosis and a diminishing functional level with an inability to remain employed. There was an unsuccessful suicide attempt in early 1993. Shortly thereafter, the onset of involuntary movements was noted, characterized by lip puckering and pursing, repetitive tongue protrusions, head nodding, and lower extremity stereotypies. When gait impairment developed, the patient was evaluated by a neurologist. Tardive dyskinesia was diagnosed and neuroleptic administration was discontinued. Ambulation continued to deteriorate and the patient was referred to us.

The family history reveals both Spanish and Irish ancestry. There is a history of consanguinity three generations prior. Two male cousins have had progressive neurologic disorders in their fourth decade. One cousin died undiagnosed and the other has been diagnosed with amyotrophic lateral sclerosis.

On neurologic examination the patient was pleasant and cooperative, although inattentive. Immediate memory was intact, but both recent and remote memory were impaired. Speech was mildly dysarthric. There was no spontaneous speech, and although he would answer questions appropriately, responses reflected limited insight. Cranial nerve examination revealed a mild impairment of upgaze and intermittent lid retraction. There were no Kayser-Fleischer rings.

Motor strength and tone were normal. Oral-buccal choreiform movements and repetitive head nodding and foot tapping were noted. There was no tremor. Tests of finger dexterity were performed well and there were no cerebellar signs. He had difficulty rising from a chair and he required a widened base to stand and to walk. Gait was abnormal, with dystonic truncal arching. Sensory examination was unremarkable. Deep tendon reflexes were symmetric and plantar responses were flexor. Glabellar and snout reflexes were elicited.

Over the next 4 months, his gait and balance deteriorated rapidly and he progressed from the use of a cane to a wheelchair. Cognitive function declined and he developed dysphagia and both bladder and bowel incontinence. Neurologic reexamination demonstrated a moderate vertical supranuclear ophthalmoplegia (VSO), more pronounced in upgaze than downgaze. Horizontal ocular movements were full, with apparent reduction of saccadic velocity. Limb ataxia of both the upper and lower extremities was now evident.

There was no hepatomegaly or splenomegaly noted on consultation with hepatology. Formal neuropsychological testing indicated the presence of a moderate dementia with impairment of mental tracking, word retrieval, verbal fluency, conceptual reasoning, attention, and memory.

Laboratory evaluation included normal CBC, thyroid function tests, FTA-ABS, ESR, serum copper, and ceruloplasmin. Chemistry panel was normal other than mildly elevated gamma-glutamyl transpeptidase and alkaline phosphatase. Human immunodeficiency virus testing was seronegative. CSF examination was normal and slitlamp examination was unremarkable. Generalized slowing was observed on EEG. MRI of the brain with gadolinium demonstrated diffuse cerebral atrophy, and diffuse decreased activity was seen on single-photon emission computed tomography. Bone marrow biopsy revealed the presence of sea-blue histiocytes. Skin biopsy samples were obtained for cholesterol esterification testing; however, the fibroblast cultures were contaminated and the test could not be completed.

One year after the initial neurologic examination there has been significant deterioration in cognitive status and intelligibility of speech as well as the appearance of more advanced parkinsonian and cerebellar signs. A partial complex seizure disorder developed.

Discussion.

More than half of the total number of patients diagnosed with Niemann-Pick disease have NPC. ^[1] Three phenotypes of NPC are described: (1) an early-onset, rapidly progressive form appearing in infancy; (2) a delayed-onset, slowly progressive form appearing in childhood; and (3) a late-onset, slowly progressive form appearing in adolescence or adulthood. ^[2] Adult-onset NPC represented 5% of the patients in a series of 125 NPC cases. ^[3]

The three phenotypes of NPC demonstrate the clinical variability of this disorder. The major clinical features are dementia, dysarthria, ataxia, VSO, and hepatosplenomegaly. Extrapyramidal signs including dystonia and choreoathetosis are frequently present. Seizures, pyramidal signs, and dysphagia may appear with disease progression. ^[2,4,5]

There are a number of clinical descriptions of NPC with adult onset. ^[2,6-14] Although it is recognized that the psychotic manifestations of NPC may be especially prominent in the adult form, this case report is the first description of an initial presentation with psychosis resulting in an 8-year misdiagnosis of chronic schizophrenia. In retrospect, the longstanding psychiatric diagnosis and the administration of neuroleptic agents obscured the picture of the emerging neurologic symptoms and the progressive neurologic deterioration.

The initial presentation of bizarre paranoid delusions that progressively interfered with occupational and social function lends credence to the original diagnosis of schizophrenia. Review of the psychiatric records revealed no hint of organicity. However, the relatively late age of onset, the chronic progressive course, and the poor response to neuroleptics were atypical. The developing dementia was the most significant sign of an underlying organic disorder.

The administration of chronic neuroleptics further obscured the emerging neurologic dysfunction. A number of clinical features of NPC overlap with the adverse effects of neuroleptics, including mental dulling, dysarthria, incoordination, gait impairment, movement disorders, and parkinsonism. The appearance of choreoathetotic movements or dystonia secondary to neuroleptic administration cannot be differentiated from an emerging primary movement disorder. The exacerbation of the movement disorder following cessation of neuroleptic therapy is not a differentiating characteristic.

Besides our patient, review of the medical literature reveals 15 previous case reports of NPC with adult onset Table 1. ^{[2,6-10,12-14]} The male-to-female ratio is 7:7, with the gender of two patients unreported. Seven of the 16 patients came from three families. The mean age of onset of either neurologic or psychiatric symptoms was 32. The most common signs at the time of initial clinical presentation were dysarthria (44%), dementia (31%), psychosis (25%), limb ataxia (25%), and gait ataxia (25%). VSO, extrapyramidal or pyramidal signs, dysphagia, and seizures were never observed at the onset of the disorder.

The most common clinical signs in NPC with adult onset are dementia (81%), gait ataxia (75%), limb ataxia (69%), dysarthria (56%), VSO (56%), and splenomegaly (50%). A minority of patients developed psychosis (38%), extrapyramidal signs (38%), pyramidal signs (31%), dysphagia (25%), hepatomegaly (13%), or seizure disorder (6%). Thirty-one percent of patients were reported to have a choreic, dystonic, or athetoid movement disorder while only 13% had parkinsonian features. Duration of the illness for the five patients who died was from 1 to 32 years, with a mean of 19 years.

Previous analyses of NPC patients examined groups of juvenile-onset patients as well as mixed groups. ^[2,10,15] Dementia, ataxia, and dysarthria are prominent neurologic manifestations in juvenile-and adult-onset patients. The frequency and time course of both extrapyramidal and pyramidal symptoms were also quite similar. However, organomegaly and seizures are much less common in adult-onset patients. Splenomegaly occurred in 90% to 96% of younger patients, in contrast to the frequency of 50% with adult onset. Seizures occurred in 32% to 39% of previous case reports but had not been reported in adult-onset NPC prior to this patient. Psychosis was considerably more common in the adult-onset group and was virtually confined to the adolescent and adult age groups. While 56% of adult-onset patients that we reviewed had VSO, Turpin et al ^[11] report that its appearance is nearly invariable with disease progression.

We made the diagnosis of NPC in our patient because of the presence of progressive dementia, psychosis, dysarthria, ataxia, and VSO and the identification of lipid storage cells in the bone marrow. It is regrettable that the cholesterol esterification test is not available. Because neither the presence of foam cells in the bone marrow nor VSO are pathognomonic for NPC, we must consider the patient to have ``probable'' NPC. Adult-onset NPC may be challenging to diagnose because of the absence of organomegaly and the insidious progression. ^[13,16] We add the presentation of an isolated psychosis and the confounding effects of neuroleptic administration to the possible diagnostic problems. NPC, progressive supranuclear palsy, and olivopontocerebellar atrophy account for most adult with advanced VSO, although the differential diagnosis of VSO includes spinocerebellar degeneration, Parkinson's disease, Huntington's disease, Whipple's disease, and Parinaud's syndrome. A subgroup of adult patients with neurodegenerative disorders or atypical psychoses may be patients with undiagnosed lateonset neurometabolic genetic diseases.

The importance of identifying patients with NPC is highlighted by recent advances in the genetic and biochemical substrates of this disorder. The linkage of the NPC gene ^[17] to chromosome 18 and the utility of the cholesterol esterification test, for both prenatal screening and the identification of asymptomatic carriers, facilitate genetic counseling. Recent trials of cholesterol-lowering agents ^[18] suggest the possibility of therapeutic interventions. The successful application of these new tools will depend upon our ability to identify these patients in our neurologic and psychiatric clinics.