Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: A case report and phenotypic comparison with a previously reported case


Akira Sano, MD, PhD, Department of Psychiatry, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Email:


Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype–phenotype correlation in MLD.

METACHROMATIC LEUKODYSTROPHY (MLD) is an autosomal recessive metabolic disorder. Deficiency in arylsulfatase A (ARSA), which breaks down cerebroside 3-sulfate, causes MLD, and a number of pathogenic mutations in the ARSA gene have been reported to be associated with ARSA activity.1 There is a strong genotype–phenotype correlation, and the particular ARSA mutation helps predict the clinical form of MLD.2,3 Here, we report a female patient with the adult form of MLD whose genotype is compound heterozygous for missense mutations, c.296G > A and c.1226C > T (p.G99D and p.T409I).


The patient was a 33-year-old Japanese woman who was born prematurely (birth weight 2300 g) with amblyopia from a non-consanguineous marriage. At the age of 25, she married and gave birth prematurely to a boy. At the age of 26, she became unable to take care of her child at home. Thereafter, she divorced her husband and changed jobs frequently. At the age of 31, it was noticed that her handwriting had deteriorated. Because emotional lability and memory loss were also noticed, she was assessed in a psychiatric hospital and was initially diagnosed with dissociative disorder at the age of 32. Brain magnetic resonance imaging (MRI) examination then revealed a diffuse T2 high-intensity lesion in the subcortical white matter and she was admitted to a hospital neurological ward for further examinations. She showed a high-arched palate, a foot deformity resembling pes cavus and had slurred speech. Neurological examination showed dysmetria, dysarthria, and resting tremor. In addition, she was unable to sense vibration and had diminished tendon reflexes. Babinski sign was present on the right and absent on the left. Her gait was wide-based and spastic. Tandem gait, walking on toes and on heels, and standing on one foot were performed with difficulty. On the Mini Mental State Examination (MMSE), she scored 15 (perfect score: 30). Her score on Hasegawa's Dementia Rating Scale Revised (HDS-R) was 11 (perfect score: 30). Alzheimer's Disease Assessment Scale–Japan cognitive subscale (ADAS-J cog.) was performed and she scored 27.7 (cut off: 10). Constructional apraxia and ideational apraxia were observed. No aphasia or agnosia were found. Limb kinetic apraxia was observed, although ideomotor apraxia was not found. The level of leukocyte ARSA activity toward 4-nitrocatechol sulfate was low at 14.1 nmol/mg protein/h (reference range is 109.0–217.2 nmol/mg protein/h). Cerebrospinal fluid was not remarkable except for a slightly elevated level of protein (59 mg/dL). Brain MRI showed a bilateral periventricular leukoencephalopathy with frontal predominance and cerebral atrophy. Single photon emission computed tomography (SPECT) images using 123I-IMP revealed marked hypoperfusion in frontal and temporal lobes (Fig. 1). An electroencephalogram showed a moderate amount of 8–9 Hz slow α waves of basic activity. In the neurology ward, she showed prominent disinhibited behaviors, such as frequently staying in the rooms of unacquainted male patients. As a result, she had to be moved to a psychiatric ward. Because she lacked seriousness or insight into her disease condition, we tried to evaluate higher brain dysfunction, including frontal lobe dysfunction. It was not possible to perform the Trail Making Test or the Modified Stroop Test because the patient was unable to understand or undertake these tasks. We performed repeated MMSE and HDS-R examinations during her hospitalization (MMSE scores: 18, 17, 19, 18, 13, 15, and 17; HDS-R scores: 11, 12, 14, 13, 16, 11, and 13). The frontal assessment battery at bedside (FAB)4 was performed every 2 weeks, and her scores varied between 5, 11 and 7 (perfect score: 18). However, she continuously scored 0 and 3 on the programming and environmental autonomy subsets of FAB, respectively. Digit span lengths were unchanged (forward 6, backward 3). On the Raven's Colored Progressive Matrices (RCPM) test, she scored 12 (cutoff: 31). The Tanaka–Binet Intelligence Scale (V) was performed and her IQ score was 27. At 6 months post-hospitalization, right–left disorientation and finger agnosia became marked, although no significant changes were observed on MRI or SPECT examinations. No aphasia was found even at this time. Written informed consent for genetic analysis and publication was obtained from the patient and from her guardian. A molecular genetic study revealed two mutations in the ARSA gene, c.296G > A and c.1226C > T (p.G99D and p.T409I) (Fig. 2).

Figure 1.

Fluid-attenuated inversion recovery imaging of brain magnetic resonance imaging shows a bilateral periventricular leukoencephalopathy with frontal predominance and cerebral atrophy.123I-IMP single photon emission computed tomography images using 3-D stereotactic surface projection with thalamic normalization (Z score), showing marked hypoperfusion of frontal and temporal lobes.

Figure 2.

These two mutations were found in compound heterozygosity in the patient. Nucleotide numbering for ARSA mutations is based on the ARSA cDNA sequence (GenBank accession number NM_000487.4).


In MLD, three different clinical forms (late infantile, juvenile and adult) are recognized, which are divided according to the age of onset.1 The patients with adult MLD are often misdiagnosed as having a psychiatric disorder, including schizophrenia or psychotic depression.1

MLD-causing mutations of the ARSA gene result in decreased enzyme activity.5,6 When considering the genotype–phenotype correlation, it has been suggested that MLD mutations are functionally divided into two different types: mutations encoding ARSA with extremely low enzymatic activity (0 alleles) and mutations with residual activity (R alleles).2,3,7 Homozygosity for 0 alleles is generally associated with the severe late infantile type of the disease. On the other hand, combinations of 0/R or R/R genotypes tend to be associated with juvenile or adult forms.2 It is considered that the clinical subtype of an MLD patient should be assessed not only by examining their medical history but also by investigating the genotype–phenotype correlation.8 In recent years, it has been revealed that patients initially showing motor symptoms are associated with the homozygous mutation p.P426L. In contrast, patients who have the p.I179S mutation tend to show psychiatric symptoms at the early stages of the disease.7,9

Here we report a female patient with adult-onset MLD with compound heterozygous mutations in ARSA, p.G99D and p.T409I. She shows frontal lobe dysfunction including euphoria, disinhibition, and difficulty in abstract thinking and problem-solving. Previously, Fukutani et al. reported a Japanese MLD case with the same mutations, showing frontal lobe symptoms quite similar to those in our case.8 The brain imaging studies also showed results similar to our case in predominantly frontal abnormalities. Frontal lobe dysfunction, including executive dysfunction and disinhibition, are associated with the dorsolateral prefrontal circuit and the orbitofrontal circuit, respectively.10 Leukoaraiosis was observed predominantly in the frontal white matter in the present case, which may result in dysfunction of the frontal-subcortical circuits leading to her frontal lobe symptoms. It is striking that both patients' conditions were initially noticed due to character changes with respect to negligence of child care. No aphasia was found in either case. There were some differences in symptoms between the previous and the current case. Our case exhibited agnosia and apraxia, whereas the previous case did not. MMSE, HDS-R and IQ scores for our case were lower than those of the previous case. One of the main reasons for the differences may be that, at examination, our patient was older than the previous case. The presence of numerous common symptoms between these patients suggests that these compound heterozygous mutations present strong genotype–phenotype correlation, although further MLD patients with this genotype will be required for confirmation.


We wish to thank Dr A. Uehara and Dr T. Nakamura for providing clinical data. We also thank Mr K. Matsumura and Ms M. Ishigami for their excellent technical assistance.