Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia


Correspondence address: Y.FukutaniMD Department of Neuropsychiatry, Fukui Medical University, 23 Shimoaizuki, Matsuoka-cho, Fukui, 910-1193, Japan


A 26-year-old Japanese woman slowly developed a change of character such as hypospontaneity and blunted affect, followed by obvious mental deterioration. She was diagnosed as having a disorganized type of schizophrenia at the first examination. Brain magnetic resonance imaging demonstrated diffuse high intensity in the cerebral white matter, particularly in the frontal lobes. The single photon emission computed tomography images using 123I-IMP disclosed diffuse cerebral hypofusion, especially in the frontal lobes. Electroencephalogram showed a moderate amount of 5–6 Hz θ waves on the background of α activity. Nerve conduction velocities in the extremities were delayed. The level of leucocyte arylsulphatase was low. In the arylsulphatase A gene analysis, a compound heterozygote having the 99Gly→Asp and 409Thr→Ile mutations was confirmed. The patient was diagnosed as having metachromatic leukodystrophy. She gradually showed obvious dementing symptoms such as memory disturbance and disorientation. The characteristics of the psychiatric symptoms in the leukodystrophy are discussed.


Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulphatase A (ASA). 1 It is characterized by accumulation of sulphatide in the white matter in the central nervous system and peripheral nerves. 1

Patients with MLD often have psychiatric symptoms. 2,3 Before examination by magnetic resonance imaging or ASA, the patients are often misdiagnosed as having schizophrenia, affective disorder, or personality disorder. 2 We report on a patient who is genetically verified as having MLD, and who was initially diagnosed with a disorganized type of schizophrenia in the presence of character change and developed dementia.


A 26-year-old Japanese woman presented with no remarkable history of illness until 23 years of age. She graduated from a senior high school with a high grade and enrolled in a nursing school. She worked as a nurse until she married in 1995. A cousin of the patient’s mother was admitted to a mental hospital for a period of time, but the medial history details were unclear. Her family members and other relatives had no remarkable medical history. After the age of 23 years, she gradually developed a lack of interest, social withdrawal and blunted affect. From October 1996, she could not take care of her home or her child. She showed signs of inappropriate giggling. In August 1997, when she first visited our department at the age of 25 years, she was diagnosed with a disorganized type of schizophrenia. Neither hallu-cination nor paranoid delusion was found. From September 1997, she became untidy and disinhibited. Brain MRI examination revealed a diffuse cerebral white matter involvement, particularly in the frontal lobes ( Fig. 1). In October, she was admitted to our department for further examinations. She lost depth of feeling and had no insight into her illness. She was less worried and had the feeling of euphoria. She had difficulty with abstract thinking and problem solving. In November, Wechsler Adult Intelligence Scale was performed and showed a full scale IQ of 41 (verbal IQ of 53, performance IQ of under 45). On the Mini Mental State Examination (MMSE), a simple screening test for mental status including test for language function, she scored 19 (perfect score: 30). Her score on Hasegawa’s Dementia Rating Scale Revised (HDS-R), a simple test for mental status, particularly for memory function commonly used in Japan to screen for dementia, was 17 (perfect score: 30). Memory disturbance, disorientation, difficulty maintaining attention, calculating disturbance and disturbed word fluency were obvious. No aphasia, apraxia or agnosia were found. Ordinary ichthyosis was detected in the skin. Neurological examinations revealed no significant findings except for absent deep tendon reflex. Repeated MRI examinations demonstrated spreading involvement throughout the forebrain. In June 1998, coronal sections through the hippocampus demonstrated diffuse demyelination in the deep white matter of the temporal lobes ( Fig. 2). The white matters under the perhinal cortex, entorhinal cortex and parahippocampal gyrus, all of which were located in the medial temporal lobe, were also affected. The SPECT images using 123I-IMP disclosed diffuse cerebral hypofusion, especially in the frontal lobes. Electroencephalogram showed a moderate amount of 5–6 Hz θ waves on the background of α activity. Motor nerve conduction velocities were delayed to 20.0 m/s in median nerve (normal range 55.9 ± 2.6 m/s) and 7.0 m/s in tibial nerve (43.6 ± 5.1 m/s). Sensory nerve conduction velocity was also delayed to 28.0 m/s in median nerve (65.8 ± 3.1 m/s). Blood chemistry was not remarkable. Cerebro-spinal fluid was not remarkable except for a slightly elevated protein (46 mg/dL). The level of leucocyte arylsulphatase was low at 10.4 nmol/h/mg protein. Informed consent for the genetic analysis was obtained from the patient and her family. In the ASA gene analysis, 4,5 a compound heterozygote having the 99Gly→Asp and 409Thr→Ile mutations was detected. In June 1998, her mental deterioration such as memory disturbance and disorientation, and hypospontaneity became more obvious, whereas her disihibition became unclear. On MMSE and HDS-R, she scored 17 and 12, respectively. No aphasia, apraxia or agnosia was found even at this time.

Figure 1.

. Fluid-attenuated inversion recovery images of brain magnetic resonance imaging in the horizontal plane of the patient, showing diffuse hyperintensity in the cerebral white matter, particularly in the frontal lobes.

Figure 2.

. Fluid-attenuated inversion recovery images of brain magnetic resonance imaging in the coronal plane through the hippocampus of the patient, showing hyperintensity in the white matter in the medial temporal lobes (arrows).


This young adult patient was first diagnosed as having a disorganized type of schizophrenia, in the presence of hypospontaneity and blunted affect. In the absence of hard neurological signs, it is not surprising that many of these patients with MLD are considered to suffer from schizophrenia or other primary psychotic disorders. 2 In 1965, Yokoi et al.6 reported the first Japanese case with MLD clinically diagnosed as having a hebephenic type (disorganized type) of schizophrenia. In our case, the character changes such as hypospontaneity, blunted affect, euphoria and disinhibition, and difficulty with abstract thinking and problem solving are explained to be frontal lobe syndrome. 7 Cummings 7 regards such frontal lobe symptoms as the features of frontal-subcortical circuit dysfunction, and he demonstrated three frontal lobe symptoms: (1) an orbitofrontal syndrome with disinhibition and irritability; (2) a medial frontal–anterior cingulate syndrome with apathy and diminished initiative and; (3) a dorsolateral pre-frontal syndrome with excutive function deficits such as problem solving. The severe, diffuse demyelination in the bilateral frontal white matter in the present case may result in a disconnection between frontal–subcortical circuits. The present case showed gradual obvious dementing symptoms such as memory disturbance and disorientation. This clinical manifestation with its disease progress may be due to demyelination spread throughout the forebrain. It is likely that the character change became unclear, replaced by dementia. In the absence of aphasia, agnosia or apraxia, the character of dementia in our case is different from that of Alzheimer’s disease which affects the cortical gray matter. This intellectual decline, such as memory disturbance, may result from disconnection of cortical regions from the hippocampus. As shown in Fig. 2, the white matter in the bilateral temporal lobes, including the medial temporal lobes, were also severely involved in a later stage. Both the medial temporal lobe and hippocampus play important roles in memory function. The medial temporal lobe is an intermediate centre between hippocampus and cerebral association cortex such as prefrontal area. 8 Conversely, these clinical features together with character change and intellectual decline are thought to be a manifestation of a white matter dementia (Mark-Demenz). 9 White matter dementia is also seen in various diseases involving the cerebral white matter such as the other types of leukodystrophy, Binswanger type of cerebral vascular dementia, multiple sclerosis and carbon monoxide poisoning. 9

A large number of MLD patients with psychosis and dementia have been reported; 2,3 however, as far as we know, there have been few case reports, confirmed by gene analysis, with detailed descriptions of the psychiatric features. Recently, several point mutations in ASA gene in MLD have been identified. 4,5 Neuropsychiatric diseases with point mutations in the responsible genes show various clinical manifestations. Familial Alzheimer’s diseases with presenilin 1 gene mutations develop different neurological symptoms such as myoclonus and convulsions depending on the sites of mutation. 10 Human prion diseases also show different neuropsychiatric symptoms and clinical courses due to the sites of mutations in the prion protein gene. 11 Conversely, dentatorubropallidoluisian atrophy, a neurodegenerative disorder associated with an unstable trinucleotide (CAG) repeat in a gene on chromosome 12, shows various psychiatric manifestations related to unstable expansions of trinucleotide repeat. 12 A depressed mood is observed in patients with smaller expansions, whereas euphoria and hypererorexia are noted in patients with larger expansions. 12 In previous reviews on MLD, approximately 50% of cases showed psychiatric symptoms. 2 Therefore, it is important to clarify the relationships between clinical manifestations and gene abnormalities in MLD. More verified genetically MLD cases are needed to elucidate the pathogenesis of psychiatric symptoms in this condition.


We are deeply indebted for the kind support of Professor Yoshikatsu Eto, Department of Gene Therapy, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan.