An 18-year-old girl was admitted to the Child and Adolescent Psychiatry Unit in the Department of Paediatrics, Maribor Teaching Hospital, Maribor, Slovenia, for suspected disorganized (formerly called hebephrenic) schizophrenia. A year before that, at the age of 17, she had begun to laugh without reason, and her behaviour had become silly and disorganized. Her emotional responses were inappropriate. She started grimacing and became paramimic and parathymic. She withdrew socially and began to shut herself in her room. She had auditory hallucinations, consisting of a running commentary on her behaviour. At that time, there were no changes in her school performance, which was already consistently below average; however, her school performance deteriorated 3 months before admission to hospital, when she became unable to do any schoolwork. She also became disoriented as to her whereabouts and got lost several times.
There had been no aberrations in her developmental milestones. Until recently, she had not had any diseases or needed any medical attention.
Her family history was interesting. She had a 24-year-old brother with moderate mental retardation according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders
, fourth edition (DSM-IV).8
He had delayed developmental milestones and difficulties with walking and speaking. She also had a 25-year-old sister who, 4 years before, had had an episode of postpartum depression (according to DSM-IV criteria) that started a few days after she had delivered a baby. She had depressed mood and no interest in her baby or in any other activities. She showed decreased motor activity, complained about loss of energy and diminished ability to think and concentrate, and she reported feelings of worthlessness and guilt about being ill and not being able to take care of her baby. She cried constantly, had no appetite and suffered from insomnia. She recovered in a month without any antidepressants. The sister's school performance had been below average throughout all 10 years of her education, and she had been unable to find a job either before or after the episode of postpartum depression. She attended night school to become a cook and had achieved average success at the time of writing. There was no history of psychiatric disturbance before or after the episode of postpartum depression. The patient's mother had 7 half-siblings. Two had died, probably of pneumonia, at the age of 6 months. The third sibling was mentally retarded and probably had poliomyelitis at the age of 2 years. Otherwise there was no family history of psychiatric disorders.
At admission, our patient was disoriented regarding time, place, and person or identity. Her thought process was disorganized, and her behaviour was disorganized and uninhibited. She was paramimic and parathymic with blunted affect. Her rapport with others was poor and her speech monotonous, and her understanding of questions was poor. She had a poor attention span and reported auditory hallucinations, consisting of a running commentary on her behaviour, which she found pleasant. She described the hallucinations as a single young male voice, which was talking to her using short sentences, mostly encouraging her to do everyday tasks and commenting on her behaviour. She revealed a lack of initiative, had poor contact with reality and had no insight into her illness. She was incontinent of urine and had dyspraxia. Psychologic tests (Rorschach projective test and Bender Visual–Motor Gestalt test) revealed psychotic disturbance. The results of routine laboratory tests, including thyroid- stimulating hormone, vitamin B12 and folic acid, were normal. The findings of syphilis and HIV-1 serology were negative, as was serology for Borrelia burgdorferi. Levels of proteins in the cerebrospinal fluid were elevated (0.77 g/L). Electroencephalography showed abnormal bilateral synchronous, mainly theta activity, which was most prominent temporally.
According to DSM-IV diagnostic criteria, the patient's disease presented like disorganized schizophrenia (disorganized thought process and behaviour, flattening of the affect, auditory hallucinations and social dysfunction). These symptoms persisted for about 9 months without any marked signs of cognitive impairment, apart from poor attention and slowing in thought process. Therefore, treatment with small doses of an atypical antipsychotic, risperidone (1 mL twice a day), was initiated.
After 1 week of treatment, the patient stopped reporting auditory hallucinations. Although her behaviour was still disorganized, she was more willing to cooperate during the required medical examinations. Neurologic examination revealed positive pyramidal signs in the upper extremities. Tendon-stretch reflexes in the lower extremities were absent distally. Computed tomography revealed signs of advanced cortical atrophy, as well as symmetrical ventricular enlargement and periventricular white-matter hypodensity. Magnetic resonance imaging of the brain showed diffuse signal hyperintensity of the white matter, especially in the periventricular area, as well as in the corpus callosum, cerebral atrophic changes and symmetrical ventricular enlargement. Electromyography showed slowing of nerve conduction velocities (NCV) (NCV of the peroneal nerve was 23 m/s [reference range 44–57 m/s]) and marked prolongation of F-wave latency. Visual evoked potentials showed a normal retinogram, but cortical responses had prolonged latencies with a normal response distribution. Somatosensory and acoustic evoked potentials were within normal limits. Abdominal ultrasonography revealed polyposis of the gallbladder.
Four weeks later, the disorganized and psychotic clinical picture diminished and the patient's cognitive impairment became increasingly obvious. Apart from poor attention and slowing of the thought process, memory (recollection and recent past) was disturbed the most. Therefore, neuropsychologic tests (Wechsler Intelligence Scale, Wechsler Memory Scale, Trail-making Test, Stroop Test, Hooper Visual Organization Test, Rivermead Behavioural Memory Test and the Controlled Oral Word Association Test) were carried out. The patients' full-scale IQ fell to within the range of severe mental retardation (according to DSM-IV criteria). There was a minor difference between the patient's verbal and performance IQ, favouring the former. The impairments were severe over the whole range of mental functioning. Attention processes, perception, executive functions, communication and motor skills were impaired. The patient's processing speed was very slow. Memory for verbally presented information and visual memory were found to be severely impaired. She could not independently perform any simple or routine operations. Therefore, an acetylcholinesterase (AChE) inhibitor was added to the therapy (galantamine, 4 mg, twice a day for 1 month, then galantamine, 8 mg, twice a day).
Taking into account the diagnostic findings of neurologic examinations, neuropsychologic tests, urinary incontinence and imaging, it was clear that there was most probably an organic disorder underlying the disorganized schizophrenia–like symptoms, which also caused later symptoms of dementia. Therefore, further tests were performed, focusing especially on inherited metabolic disorders.
The results of urine screening tests and screening for very long chain fatty acids in the serum were normal, excluding adrenoleukodystrophy and several disorders of peroxisomal function. Arylsulfatase A activity in leukocytes was markedly reduced (0.05 nmol/min per milligram [reference range 1.1–8.7 nmol/min per milligram]). Measurement of urinary sulfatides by electrospray ionization–tandem mass spectrometry9
showed a 10-fold elevation of 609 nmol/L (reference range 5–148 nmol/L), thus confirming the diagnosis of MLD.
In the patient's sister, who remained clinically asymptomatic apart from the single episode described earlier, biochemical tests also showed clear arylsulfatase A deficiency in leukocytes (0.16 nmol/min per milligram) and markedly elevated sulfatides in urine (436 nmol/L), thus proving the presence of MLD. In accordance with their obligate heterozygosity, intermediate arylsulfatase A activity was found in both of our patient's parents. Our patient's mentally retarded older brother had normal arylsulfatase A activity and normal values of sulfatides in the urine. A preliminary search for mutations excluded the presence of the most common alleles associated with adult MLD, Ile-179-Ser and Pro-426-Leu on exons 3 and 8, respectively. A detailed genotype analysis of the entire family is currently underway.