Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis.

Metachromatic leukodystrophy is a rare inherited disorder of the nervous system. Symptoms initially can present during childhood, adolescence, or adulthood. Psychiatric symptoms, including complex auditory hallucinations and bizarre delusions, are a prominent feature of metachromatic leukodystrophy presenting when the patient is between 12 and 30 years. One hundred twenty-nine published case reports were reviewed, focusing on the presence of psychosis. Psychosis was present in 53% of the published case reports of adolescent and early adult-onset metachromatic leukodystrophy, a much higher prevalence than that seen with other primary neurological disorders. The pathological lesion of metachromatic leukodystrophy is demyelination of the central and peripheral nervous systems, particularly the subfrontal white matter, suggesting that psychosis may result from the disruption of corticocortical and corticosubcortical connections, especially involving the frontal lobes. While similar lesions appear in the infantile, juvenile, and late adult forms of metachromatic leukodystrophy, psychotic symptoms were reported only in those cases presenting in adolescence and young adulthood, suggesting that age is another important neurobiological factor in the development of psychosis.     

Juvenile metachromatic leukodystrophy. Clinical, biochemical, and neuropathologic studies in nine new cases

We describe nine patients with metachromatic leukodystrophy. Seven patients had the juvenile form; in two others, the age at onset was 1 year, but the clinical course was different from the late infantile form. The age at onset ranged from 1 to 18 years; the duration ranged from three to 17 years. Mental retardation associated with motor impairment and pathological EEG and electromyographic findings were the main clinical findings. In patients with early onset, mental retardation was almost the only symptom for the first ten years. Segmental demyelination, remyelination, onion bulb formation, and occasional perivascular macrophages containing metachromatic lipid were the main findings in sural nerves studied after biopsy. The mean arylsulfatase-A (ASA) activity was 1.3 nmoles of nitrocatechol sulfate per milligram of protein per 30 minutes in peripheral leukocytes of the patients, 62.0 in the heterozygotes, and 139.0 in the controls. The ASA band could not be detected in enzyme electrophoresis.     

Metachromatic leukodystrophy and age: A comparative study of clinical, enzymological and ultrastructural findings

The clinical findings of three cases of metachromatic leukodystrophy, one of the late infantile, one of the juvenile and one of the adult variant are described and compared with those mentioned in relevant publications. Comparison of our findings lead us to conclude that a difference exists between the late infantile case on the one hand and the juvenile and the adult case on the other hand.

This conclusion concurs with the results obtained by the enzymological study of the enzyme arylsulfatase A derived from the three cases.

As to the characteristics of the enzyme arylsulfatase A, a difference was found to exist between the enzyme of the late infantile case on the one hand and that of the juvenile and the adult case on the other hand.

The results of the electronmicroscopic investigation of peripheral nerve biopsy specimens of the three cases are briefly summarized.

It is postulated that the ultrastructural findings do not justify any such distinction.     

Partial seizures in two cases of metachromatic leukodystrophy: electrophysiologic and neuroradiologic findings.

This report concerns two cases of metachromatic leukodystrophy presenting partial seizures. One was a 2-year-old boy with a late infantile type and the other a 17-year-old girl with a juvenile type. The former had tonic-clonic seizures on the left with concomitant twitching of the left side of the face and adversive conjugate deviation of the eyes. After a while, his interictal sleep electroencephalogram (EEG) showed spikes in the right central area. The second case had hemiconvulsions on the right side, consisting mainly of tonic flexion of the upper limb followed by clonic flexions, and accompanied by adversive conjugate deviation of the head and eyes. Her ictal EEG showed rhythmic 6- to 7-Hz wave bursts in the left frontal area. To this date, no report has given a detailed discussion of the type of seizures and ictal EEG in metachromatic leukodystrophy. In addition, there have been few detailed reports of magnetic resonance imaging (MRI) in the juvenile type. It is interesting that typical partial seizures were observed in a hereditary metabolic disorder characterized by diffuse demyelination of the white matter, and the pathophysiology is discussed here mainly in relation to MRI findings of the case with the juvenile type.     

Electron microscopic investigation of inclusion material in a case of adult metachromatic leukodystrophy; Observations on kidney biopsy,peripheral nerve and cerebral white matter

Summary The fine structural characteristics of storage products in peripheral nerve, kidney and cerebral white matter, from a case of adult metachromatic leukodystrophy are described. There were pronounced differences from the fine structural aspects in late infantile cases. A large proportion of the inclusions did not exhibit a unit membrane. An hypothesis is proposed to clarify the delayed manifestation of this type of metachromatic leukodystrophy until adulthood.     

Intraepidermal morphologic manifestations in lysosomal diseases

This paper reports the ultrastructural findings for the epidermis of biopsied skin specimens in numerous lysosomal diseases, which can be grouped as follows: a) presence of vacuolar lysosomal residual bodies in mucopolysaccharidoses I, II and III, Salla disease, GM1-gangliosidoses and infantile type II glycogenosis; b) avacuolar lysosomal residual bodies in Niemann-Pick disease type C, mucolipidosis IV, Farber disease, Fabry disease, and late infantile and juvenile neuronal ceroid-lipofuscinoses; c) absence of lysosomal residual bodies in GM2-gangliosidoses, metachromatic leukodystrophy, Gaucher disease and sialidosis type III. Whenever possible, a biopsy of the skin for morphological diagnosis of lysosomal disorders ought not to be confined to the epidermis.     

无脑白质影像学改变的晚发婴儿型异染性脑白质营养不良

目的 分析3例脑白质影像学无改变的晚发婴儿型异染性脑白质营养不良患儿的临床、电生理、影像学和病理学改变特点，总结其特征表现和诊断规律。方法 3例均为男性婴儿，月龄分别为20个月、27个月和28个月。均于出生后15～21个月出现运动发育停滞和倒退，以下肢运动障碍为主，表现有锥体束征。收入院后予以体格检查、电生理检查、头部MRI检查及腓肠神经活检。结果 （1）体格检查：例1双下肢肌力4级，肌张力降低；双膝腱反射亢进，双侧Babinski征阳性。例2四肢肌力5级，肌张力明显增高；腱反射亢进，双侧Babinski征阳性。例3眼球向左、右注视时可发现细小水平眼震，四肢肌力4级，肌张力低；四肢腱反射对称引出，双下肢病理征阴性。（2）辅助检查：3例患儿电生理检查均提示为周围神经病变，MRI检查无异常发现。（3）实验室检查：仅例1行外周血白细胞芳基硫酯酶A检查，显示活性显著下降。（4）腓肠神经活检：3例患儿均显示髓神经纤维显著减少，残存的有髓神经纤维的髓鞘变薄，甲苯胺蓝染色见部分雪旺细胞及吞噬细胞内出现紫红色异染颗粒，超微结构呈指纹样、髓样和平行排列的棒状结构。结论 病理检查证实细胞内沉积物具有异染性，而周围神经病变具有髓鞘发育不良特点。由于脑白质MRI无改变，这组以周围神经损害为主的息儿可能是异染性脑白质营养不良的一种特殊类型，诊断为伴有中枢神经系统损害的异染性周围神经病更符合临床表现规律。     

Sweat gland pathology in neurodegenerative disorders]

Ultrastructural pathology on sweat gland epithelium was studied in various neurodegenerative disorders; neuronal ceroid-lipofuscinosis (NCL), Lafora disease, mucopolysaccharidosis, GM1 gangliosidosis, Nieman-Pick disease, Fabry disease, Krabbe disease and metachromatic leukodystrophy (MLD). Every disease had its own characteristic inclusions in sweat gland epithelium. Curvilinear profiles and fingerprint patterns were seen in NCL, but there were no morphological differences among late infantile, early juvenile and juvenile types. On the other hand, the granular matrix was characteristic of the infantile type. The presence of specific inclusions in a 23-year-old female carrier with Fabry disease indicated that a skin biopsy was one of the useful methods to detect a female carrier. In MLD and Krabbe disease, there were disease specific inclusions in sweat gland epithelium. These results indicate that the sweat glands should be investigated when a skin biopsy is performed for the diagnosis of neurodegenerative diseases.     

Multiple molecular forms of arylsulfatase A in different forms of metachromatic leukodystrophy (MLD).

Arylsulfatase A (ARA) can be separated into six to eight individual enzymatic bands of activity by isoelectric focusing on cellulose acetate membranes. The residual ARA activity in juvenile metachromatic leukodystrophy (MLD) has a single band of activity with apI of 5.5, whereas the residual ARA in the late infantile form of MLD has three bands of activity with pI range of from 5.4 to 5.8. The technique of isoelectric focusing on cellulose acetate membranes demonstrates enzymatic differences which can be correlated with the clinical form of the disease.     

Epileptic seizures and electroencephalographic evolution in genetic leukodystrophies.

The purpose of this study is to explore and compare epileptic seizures and EEG evolution in the various types of genetic leukodystrophy (GL). The authors reviewed the medical records and analyzed 69 serial EEGs in 27 patients with GLs: 13 with late infantile metachromatic leukodystrophy, one with juvenile metachromatic leukodystrophy, one with globoid cell leukodystrophy, six with X-linked childhood adrenoleukodystrophy, one with neonatal adrenoleukodystrophy, four with classic Pelizaeus-Merzbacher disease (PMD), and 1 with connatal Pelizaeus-Merzbacher disease. The diagnoses were made by biochemical and molecular studies. Two or more EEG studies with both awake and sleep traces were recorded during the varying clinical stages for each patient. At the beginning of the GLs, the EEGs were normal or showed mild slowing of background activity. Clinical seizures, mainly of focal origin, with progressive slowing and paroxysmal discharges on EEGs, usually appeared during the later stages of metachromatic leukodystrophy, X-linked childhood adrenoleukodystrophy, and classic Pelizaeus-Merzbacher disease. However, intractable seizures, mainly generalized in nature, and more severe slowing and abundant paroxysmal discharges on EEGs, with commensurate neurologic deterioration, were observed during the earlier course of globoid cell leukodystrophy, neonatal adrenoleukodystrophy, and connatal Pelizaeus-Merzbacher disease. These results indicate that GLs involve not only white matter, but gray matter as well. In all types of GL, there is good correlation between the severity of EEG changes, the severity of the diseases, and the clinical state of the patient.     

Intestinal involvement in metachromatic leukodystrophy

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of the enzyme arylsulfatase A. If arylsulfatase A is deficient, sulfatide accumulates. Functionally, this accumulation results in progressive neurological deterioration. The reports about the extra nervous system manifestations of metachromatic leukodystrophy are related to the gallbladder involvement such as polyposis. Unexplained vomiting began in a 5½-year-old girl with late infantile metachromatic leukodystrophy. Endoscopy showed multiple polypoid masses in the pylor of the stomach and duodenum. Severe gastrointestinal bleedings occurred during nasogastric feeding. Intestinal intussusception developed later. To the authors' knowledge, intestinal polypoid masses and obstruction with metachromatic leukodystrophy have not previously been reported. The persistent vomiting may be a symptom of intestinal obstruction due to intestinal polypoid masses with metachromatic leukodystrophy. There may be a trend for the development of polypoid masses in intestine as well as in the gallbladder in metachromatic leukodystrophy.     

Changes of brainstem auditory and somatosensory evoked

Objective: to investigate the characteristics and clinical value of evoked potentials in late infantile form of metachromatic leukodystrophy. Methods: Brainstem auditory, and somatosensory evoked potentials were recorded in 6 patients, and compared with the results of CT scan. Results: All of the 6 patients had abnormal results of BAEP and MNSEP. The main abnormal parameters in BAEP were latency prolongation in wave I, inter-peak latency prolongation in Ⅰ-Ⅲ and Ⅰ-Ⅴ. The abnormal features of MNSEP were low amplitude and absence of wave N9, inter-Peak latency prolongation in Ng-N13 and N13-N20, but no significant change of N20 amplitude. The results also revealed that abnormal changes in BAEP and MNSEP were earlier than that in CT. Conclusion: The detection of BAEP and MNSEP in late infantile form of metachromatic leukodystrophy might early reveal the abnormality of conductive function in nervous system and might be a useful method in diagnosis.     

The natural course of gross motor deterioration in metachromatic leukodystrophy

Aim Motor deterioration is a key feature in metachromatic leukodystrophy (MLD). The lack of data about its natural course impedes evaluation of therapeutic interventions. This study aimed to provide data about motor decline in MLD. Method Fifty‐nine patients (27 males, 32 females) with MLD (21 with late‐infantile MLD and 38 with juvenile MLD) were recruited within a nationwide survey (the German LEUKONET). Median (range) age at onset was 17 months (9–27) for the group with late‐infantile MLD and 6 years 2 months (2y 11mo–14y) for the group with juvenile MLD. Gross motor function was assessed using the Gross Motor Function Classification for MLD. Results In late‐infantile MLD, all patients showed loss of all gross motor function until 3 years 4 months of age. Patients with juvenile MLD showed a more variable and significantly longer motor decline (p<0.001). For a patient with the juvenile form showing first gait disturbances, the probability of remaining stable for more than 1 year was 84%, and 51% for more than 2 years. Having lost independent walking, subsequent motor decline was as steep as in the late‐infantile form (median 5mo, interquartile range 3–22). Interpretation The course of motor disease was more variable in juvenile MLD with respect to onset and dynamics. However, the motor decline after the loss of independent walking was similarly steep in both forms. These data can serve as a reference for clinical studies that are topics of current research and allow definition of inclusion/exclusion criteria.     

An Italian Cohort Study Identifies Four New Pathologic Mutations in the ARSA Gene

Metachromatic leukodystrophy is an autosomal recessive neurodegenerative disorder of the myelin metabolism due to the impaired function of the lysosomal enzyme arylsulfatase A. Three major clinical variants of metachromatic leukodystrophy (MLD) have been described: late infantile, juvenile, and late onset. The infantile form, whose clinical onset is usually before the age of 2 years, is the most frequent. The juvenile form manifests itself between 3 and 16 years and the late-onset form manifests at any time after puberty. As of today, more than 150 mutations causing MLD have been identified in the ARSA gene that encodes arylsulfatase A. In this paper, we report our experience with the diagnosis of MLD in seven Italian patients from unrelated families. We found 11 different mutations, four of which have not been previously described: c.1215_1223del9 (p.406_408del), c.601 T>C (p.Tyr201His), c.655 T>A (p.Phe219Ile), and c.87C>A (p.Asp29Glu). Our data show once more that there are still several mutations to be discovered in the ARSA gene and there are rarely repeating ones found in the population. The predictive value of the enzyme activity tests in regard to clinical manifestations is extremely limited.     

Comparative ultrastructural observations on peripheral nerve abnormalities in the late infantile,juvenile and late onset forms of metachromatic leukodystrophy

Summary The ultrastructural findings in nerve biopsies from two cases of late onset metachromatic leukodystrophy were compared with those in cases of late infantile and juvenile onset. Hypertrophic changes and regenerating clusters were more evident in the late onset cases, in which macrophages were less frequent, presumably reflecting the chronicity of the disorder in this form. Inclusions within Schwann cells and endoneurial macrophages were similar in all four cases. Myelin figures, in which the periodicity of major dense lines was 8 nm, were present in Schwann cells associated with myelinated axons. The electron lucent zones between the major dense lines were bisected by lines of lesser electron density. These inclusions were probably related to myelin breakdown. All other inclusions displayed a periodicity of 5.8 nm and consisted of zebra bodies, vacuoles containing irregularly orientated lamellar material and stacks of flattened discs. These inclusions represented the metachromatic sulphatide deposits. Occasional inclusion bodies were observed within axons.     

Longitudinal neurophysiologic studies in a patient with metachromatic leukodystrophy following bone marrow transplantation.

We describe a girl with late infantile metachromatic leukodystrophy. The patient has been followed up with serial neurologic and neurophysiologic examinations for 8 years following bone marrow transplantation, which she underwent when she was 4 3/4 years old. Her older sister died from metachromatic leukodystrophy at the age of 8 years, whereas our patient has retained significant cognitive and motor skills. Serial neurophysiologic studies initially demonstrated continued deterioration after the bone marrow transplantation, but since then, most results have remained stable or improved. Although, to our knowledge, there have been no previous serial studies of metachromatic leukodystrophy, individual case studies suggest that these findings in our patient are very unusual. With the advent of possible treatment for this condition, there is a need for further serial neurophysiologic studies to characterize the natural progression and the possible detection of progression or reversal with treatment.     

Cerebral glycolipidoses: clinical characteristics of 41 pediatric patients

A retrospective clinical and biochemical analysis of 41 pediatric patients with cerebral lipidoses seen between 1995 to 2003 was performed at a tertiary referral center for neurologic disorders in southern India. Enzyme assays in serum and leukocytes, including histopathology, neuroimaging, and neurophysiology studies, were performed. There were 20 cases of metachromatic leukodystrophy (infantile,14; juvenile, 6), 12 cases of Tay-Sachs disease (infantile, 9; late G(M2-M3) gangliosidoses, 3), 8 cases of Sandhoff's disease, and 1 male case with multiple sulfatase deficiency. Consanguinity was present in 51.2% of cases. The male-to-female ratio was 23:17. Similar illness in the families was noted in 24.4%. The prominent clinical features in sulfatide lipidoses were regression of motor and mental milestones, seizures, and speech impairment, and in G(M2) gangliosidoses, the features were delayed milestones, startle myoclonus, seizures, and the presence of cherry-red spots. The case with multiple sulfatase deficiency had low levels of arylsulfatase A and B. This study indicates that these autosomal recessive inherited disorders are indeed prevalent in India.     

Slow progression of juvenile metachromatic leukodystrophy 6 years after bone marrow transplantation.

Metachromatic leukodystrophy refers to a group of genetic neurologic diseases caused by deficiencies of the enzyme arylsulfatase A and the resulting accumulation of sulfatides in white matter. Bone marrow transplantation has been advocated as a treatment in an attempt to correct the enzyme deficiency. Such a transplant was performed in 1991 in a 16-year-old girl with a form of late juvenile metachromatic leukodystrophy caused by a homozygous P426L mutation in the arylsulfatase A gene. Engraftment was prompt and resulted in constant enzymatic normalization of circulating lymphocytes. The elevated urinary excretion of sulfatides remained unaffected. Clinical findings up until transplantation consisted of gait disturbances, impairment of cognitive functioning, and deterioration in school performance over several years. During a 6-year follow-up period, the patient's condition was subject to major fluctuations but, on the whole, findings showed slow neurologic and neurophysiologic deterioration. The clinical course observed after bone marrow transplantation probably more or less reflects the natural course expected in this form of late-onset metachromatic leukodystrophy.     

Stabilization of juvenile metachromatic leukodystrophy after bone marrow transplantation: a 13-year follow-up

A 29-year-old female patient with juvenile metachromatic leukodystrophy diagnosed at age 14 years received a bone marrow transplant at age 16 years. A report was published 6 years after bone marrow transplantation concluding that the disease had slowly progressed in the 2 years following bone marrow transplantation. We now report on a further 7-year follow-up, typified by a steady state of spastic paraplegia and mild dementia. Neurophysiological, neuroradiological, and psychological status also remained stable. In the patient's leukocytes, the activity of arylsulfatase A, the enzyme deficient in untreated metachromatic leukodystrophy, was within the normal range whereas urinary sulfatides remained elevated. Data on the natural course of juvenile metachromatic leukodystrophy are rare, so in the present case it is difficult to establish whether the rather favorable course can be attributed with certainty to bone marrow transplantation. The long-term stabilization in this patient, however, suggested that bone marrow transplantation may halt the progression of juvenile metachromatic leukodystrophy.     

Metachromatic leukodystrophy: report of 2 cases with histochemistry of nerves and muscles

Two cases of metachromatic leukodystrophy, of the late infantile form are reported. The patients were a girl and a boy of 2 years 10 months old, with initial normal development, but by the age of 18 months began with gait disturbances, difficulty to speak and developed progressive mental deterioration, with signs of long tract involvement, absence of deep tendon reflexes, spasticity, blindness, muscle atrophy and finished in a vegetative state. The diagnosis was made electromyography (signs of denervation), motor nerve conduction velocity (very decreased), assay of arylsulfatase A in the urine (absence of activity), sural nerve biopsy (demyelination and presence of metachromatic granules by the cresyl-violet and toluidine blue) and muscle biopsy (atrophy of type I fibers and presence of metachromatic material in the intramuscular nerve fibers). A quick revision about diagnostic methods, transmission, pathogenesis and variant forms is made.