Low arylsulphatase A activity in the development of psychiatric disorders

Previous studies have suggested that arylsulphatase A (ASA) deficiency may be present in psychiatric patients. A number of patients with low ASA activity and various neuropsychiatric symptoms have been observed. Metachromatic leucodystrophy (MLD) is a disease caused by deficiency of the enzyme ASA. Clinically, adult MLD may present as a schizophrenia-like psychosis, deterioration of cognitive functions, personality changes, depression and dementia. However, there are individuals with low ASA activity without clinical symptoms of MLD. This state is described as ASA pseudodeficiency. It remains controversial whether low ASA activity predisposes to or influences the development of psychiatric symptoms. Relatively little attention has been paid to the role of neurodegenerative processes in the pathophysiology of psychiatric disorders. The hypothesis underlying this work is that there is a subclass of mentally ill patients whose psychiatric problems are at least partly caused by an abnormal ASA. The purpose of this particular study was to determine whether an abnormal ASA could be detected in schizophrenic, major depressed and demented patients and control subjects. There were 66 schizophrenic, 59 major depressed and 61 demented patients. The control group consisted of 102 healthy volunteers. Leucocyte ASA activity was determined from blood samples, using p-nitrocatechol sulphate as substrate. Our results show that low ASA activity is more frequently found in psychiatric patients than in control subjects. Our findings indicate that clinical types of major depression and schizophrenia could be connected with low ASA activity. The presence of a decreased ASA activity points to the conclusion that an enzyme deficit entails vulnerability to psychiatric disorders.     

Nonspecific and attenuated negative symptoms in patients at clinical high-risk for schizophrenia

BACKGROUND: Retrospective studies have shown that nonspecific psychopathology and negative symptoms, including social isolation and academic dysfunction, tend to precede onset of psychosis. The present report describes the baseline psychopathology of subjects in the Hillside Recognition and Prevention (RAP) Program, and presents an operationalized classification algorithm for the prospective study of both positive and negative symptoms of clinical high-risk (CHR) for schizophrenia. METHODS: Eighty-two adolescent and young adult patients were characterized using semi-structured interviews of both a parent informant and the patient. The Scale of Prodromal Symptoms (SOPS) was utilized to derive a three-part classification scheme: CHR- subjects (n=20) were defined as having at least one attenuated negative symptom with no positive symptoms; CHR+ subjects (n=42) were defined as having one or more attenuated positive symptoms without psychosis; schizophrenia-like psychosis (SLP) subjects (n=20) were defined as having a psychotic symptom, but without meeting criterion A, B, or C of DSM-IV schizophrenia. RESULTS: Social isolation was the most common presenting symptom. The three RAP subgroups did not significantly differ in levels of attenuated negative and disorganized symptoms, despite the fact that these were not required for inclusion in the CHR+ and SLP groups. Common co-morbid diagnoses included major depression, attention deficit hyperactivity disorder, avoidant personality disorder, and Cluster A personality disorders. CONCLUSIONS: Negative symptoms and other nonspecific behavioral abnormalities represent clinically important phenomena in prodromal patients, and may provide insight into pathophysiologic mechanisms in schizophrenia and possible preventive interventions.     

Isolated peripheral neuropathy in atypical metachromatic leukodystrophy: a recurrent mutation

BACKGROUND: Metachromatic leukodystrophy (MLD) is a genetic neurodegenerative disorder resulting from a deficiency of arylsulfatase A. Late onset forms are relatively rare. Central nervous system (CNS) involvement is characteristic at all ages. METHODS: A patient in her late 40s with peripheral neuropathy was assessed by EEG, evoked potentials, CT and nerve conduction studies. Nerve and muscle biopsy samples were investigated by electron microscopy. Arylsulfatase A activity in leukocytes and excreted cerebroside sulfate were determined. The arylsulfatase A gene was investigated for mutations using polymerase chain reaction (PCR) and DNA sequencing. The identified mutation was expressed transiently in African green monkey kidney (COS) cells to determine the effect of the mutation on arylsulfatase A activity. RESULTS: Central nervous system functions were normal. Nerve conduction velocities were decreased. Sural nerve biopsy showed inclusions typical of MLD. Arylsulfatase A was less than 5% of normal. A homozygous mutation thr286pro was identified in the arylsulfatase A gene and demonstrated to be deleterious through transient expression studies. CONCLUSIONS: Our patient has a progressive peripheral neuropathy but has apparently intact CNS function at her present age of 57 years. Biochemical, physiological and pathological findings are consistent with a diagnosis of MLD. A homozygous mutation, thr286pro, found in her arylsulfatase A gene, decreased enzyme activity to a level consistent with a late onset form of MLD.     

Molecular genetics of metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA). The ASA cDNA as well as the gene has been cloned. The gene is about 3 kb long and consists of 8 exons. The two most frequent alleles causing MLD have been characterized and the distribution of these alleles among patients with different clinical forms of MLD has revealed a simple genotype-phenotype correlation. Some individuals have low ASA activities but are healthy. This condition has been called ASA pseudodeficiency. These individuals are homozygous for the ASA pseudodeficiency allele which only encodes 5-10% of the ASA activity compared to the normal allele. The mutations in the PD allele have been characterized. Based on the knowledge of these mutations diagnostic assays have been developed to differentiate ASA deficiencies associated with PD or MLD.     

Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.

We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD.     

Affective reactivity of speech disturbances in schizotypy

Speech disturbances (SD) are a pernicious symptom of schizophrenia that increase when negative emotion is elicited. This increase is referred to as affective reactivity (AR). Although considerable research has examined SD in schizophrenia, few studies have investigated this symptom in individuals at risk for the disorder, who demonstrate schizophrenia-like, or schizotypic, traits. In the present study, we examined: (1) SD severity in schizotypy, (2) how SD varies as a function of stress reactivity in schizotypy, and (3) the relationship between SD/AR with Quality of Life (QOL). Individuals with psychometrically-defined schizotypy (n = 83) and controls (n = 22) completed a laboratory procedure in which they produced speech while viewing pleasant and stressful photographs. This speech was analyzed for subtle speech disorder using a well-validated measure. We found that the schizotypy group demonstrated significant increases in SD across both baseline and stressful conditions compared to the control group. AR was not significantly different between the groups. Within the schizotypy group, severity of disorganized schizotypy symptoms was associated with high levels of SD and AR while interpersonal schizotypy was associated with low levels of SD and AR. AR was also related to increased objective QOL in the schizotypy group. This study highlights the role of stress reactivity across the schizophrenia-spectrum. Moreover, the incongruous relationships between disorganized and interpersonal symptoms with SD underscore the marked heterogeneity in processes across schizotypy.     

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

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.     

A prospective longitudinal 10-year study of schizophrenia's three major factors and depression

This study investigated the nature, independence, and stability of schizophrenia's syndrome factors and depression at 2, 4.5, 7.5 and 10 years post-index hospitalization. At the four follow-ups, 71 patients (48 with schizophrenia and 23 with schizoaffective disorder) were assessed for symptoms hypothesized to constitute the reality distortion, disorganized, and negative factors of schizophrenia. At the last three follow-ups, the patients were also assessed for symptoms of depression. Factor analyses of schizophrenia symptoms revealed more than three syndrome factors at each follow-up. Longitudinally, reality distortion was a stable and relatively independent factor. The negative syndrome was independent but was bifurcated into two dimensions, interpreted as social/emotional withdrawal and diminished movement/expressiveness. Although signs of disorganization were not unified or independent early in schizophrenia's course, speech/thought disorder, disorganized affect, and poverty of speech content coalesced to form a disorganization factor by the 7.5-year follow-up. When depressive symptoms were added to the analyses, depression constituted an independent and stable dimension of schizophrenia over time. Each schizophrenia factor demonstrated a unique longitudinal course. Courses included stable symptom consistency (reality distortion), evolving symptom convergence (disorganization), and recurrent bifurcation and symptom instability (the negative syndrome).     

Obsessive-compulsive symptoms in pregnancy and the puerperium: a review of the literature

In this article, we review the available research on postpartum obsessive-compulsive disorder (OCD). Most studies are retrospective in nature, thus not answering questions as to overall prevalence of such symptoms. However, there are consistent findings with regard to symptom profile: obsessional thoughts in postpartum OCD tend to concern fears of harm to the infant. We discuss distinctions between postpartum OCD symptoms and postpartum depression and psychosis. Although preliminary, research on treatments for postpartum OCD indicates the effectiveness of medications and cognitive-behavioral therapy. We explore the relationship between OCD symptoms and postpartum depression and offer possible directions for future study. We also consider the proposed etiological models and offer a fresh conceptualization of this condition.     

Atypical clinical course in juvenile metachromatic leukodystrophy involving novel arylsulfatase A gene mutations

A male and female with juvenile metachromatic leukodystrophy (MLD) with unusual manifestations are presented, each involving a novel arylsulfatase A gene mutation. One patient demonstrated acute intermittent encephalopathic episodes for 1 year after having received the diagnosis of MLD at the age of 6 years. The other patient presented at the age of 5 years with acute hemiparesis, which was diagnosed as acute disseminated encephalomyelitis and resolved in 3 weeks. After 2 years of remission he started to show progressive neurological deterioration. The episodic manifestations in both patients were associated with acute, resolving cerebral lesions on magnetic resonance imaging accompanying or preceding the classical demyelinating lesions of MLD. The diagnosis of MLD was based on arylsulfatase A enzyme activity levels and genetic analysis, and after the exclusion of neurological conditions such as encephalitis, vasculopathy, or mitochondrial disorders. The pathogenesis of this previously undescribed finding in MLD is unknown but might be related to a susceptibility of myelin to acute damage.     

Molecular and structural analysis of metachromatic leukodystrophy patients in Indian population

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by mutations in arylsulfatase A (ARSA) gene. No work on molecular genetics of MLD has been reported from India and the mutational spectrum in Indian patients is not known. The present study was undertaken to identify mutations in arylsulfatase A gene in Indian MLD patients, to evaluate genotype-phenotype correlation, and to see the effect of the novel mutants on the protein. Twenty MLD patients (16 families) were screened by ARMS PCR for the most common mutation (c.459+1G>A). Pseudodeficiency alleles were tested by RFLP method whereas rare and novel mutations were scanned by Conformation Sensitive Gel Electrophoresis (CSGE), followed by sequencing. The genotype-phenotype correlation was also attempted. Protein homology modeling analysis was carried out for two novel missense mutations identified, to assess the effect of these mutations on the protein conformation. Nine pathogenic alleles were found in 13 patients (65%). Four previously reported mutations and five novel variants were identified. Five patients (35%) were found to have pseudodeficiency alleles, c.1049A>G (p.Asn350Ser) and c.1524+95A>G. Genotype-phenotype correlation was found to be difficult to establish. Protein modeling studies showed that the mutations cause loss of interactions leading to conformational change in ASA protein. The study identified the mutational spectrum of Indian MLD patients, which will be helpful in genetic counseling, carrier detection and establishing prenatal diagnosis. Homology modeling helped to study conformational change in protein and has implications in generating novel therapeutic molecules.     

Increased prevalence of pervasive developmental disorders in children with slight arylsulfatase A deficiency

Arylsulfatase A deficiency (less than 15% of controls) is responsible for a neurological disorder known as metachromatic leukodystrophy. Nonetheless, low levels of the enzyme (15-50% of controls, higher than in metachromatic leukodystrophy) in adult patients have been related to neuropsychiatric disorders. On the other hand, there are only few and controversial data on the significance of reduced arylsulfatase A activity in children. This led us to perform the present study. Various classes of arylsulfatase A activity in children have been related with different groups of neuropsychiatric disorders and compared with a similar number of healthy children. We found a high percentage of reduced arylsulfatase A (less than 50% of controls) in children with pervasive developmental disorders (10.25%). Unexpectedly, raising the threshold level for considering arylsulfatase A deficiency up to 70% of controls resulted in a marked increase in the incidence of pervasive developmental disorders. This new class, arylsulfatase A slight deficiency, contained the highest number of patients affected by psychiatric symptoms. This suggests that arylsulfatase A slight deficiency could be a marker of a subclass of pervasive developmental disorders.     

Anxiety symptoms and disorders at eight weeks postpartum

Although the prevalence, risk factors for, and consequences of postpartum depression have been studied extensively, little work has examined the nature of postpartum anxiety disorders in community samples. In the present study, 147 community women completed a diagnostic interview and a battery of self-report inventories approximately eight weeks after childbirth. The rate of generalized anxiety disorder was elevated as compared to the rate in women representative of the general population. Depending on the particular domain of anxiety being considered, 10-50% of women reporting anxiety symptoms endorsed comorbid depressive symptoms. In hierarchical multiple regression analyses, different combinations of demographic and vulnerability variables predicted symptoms of somatic anxiety, social anxiety, and depression, although there were no significant predictors of worry symptoms. In addition, number of children, depression, and social anxiety predicted postpartum relationship distress. These results suggest that postpartum anxiety disorders are more common than postpartum depression and worthy of systematic study.     

Gallbladder cancer with ascites in a child with metachromatic leukodystrophy

IntroductionMetachromatic leukodystrophy (MLD) refers to leukodystrophy caused by the accumulation of sulfatide from arylsulfatase A (ARSA) gene mutations. Sulfatide also accumulates in various organs, including the peripheral nerves, kidney, and gallbladder.Proliferative changes in the gallbladder have been reported in several patients, while gallbladder cancer is reported in only two adult MLD cases. We report what is likely the first pediatric case of MLD with gallbladder cancer.Case reportThe patient was a 5-year-old girl diagnosed with MLD using head magnetic resonance imaging and detecting a homozygous mutation of c.302G>A (p.Gly101Asp) in ARSA. Abdominal bloating was observed at the age of 4 years; CT revealed a giant tumor in the gallbladder and massive ascites. Cholecystectomy was performed and pathological examination revealed adenocarcinoma. Measurement of serum sulfatide revealed increased levels compared to the average healthy range.DiscussionRapidly increased ascites and large polyps which are reported as risk factors for cancer were characteristic in our MLD case. When such lesions are detected, they should be removed immediately because of the possibility of cancer, even in a pediatric patient.     

Olfactory identification deficits in first-episode psychosis may predict patients at risk for persistent negative and disorganized or cognitive symptoms

OBJECTIVE: One-third of patients with a schizophrenia spectrum disorder have a measurable olfactory identification deficit at first examination. The authors studied the relationship of this deficit to symptom remission after 1 year of treatment. METHOD: Fifty-eight patients naive to antipsychotic medication who entered the Nova Scotia Early Psychosis Program were symptomatically rated with the Positive and Negative Syndrome Scale (PANSS) (at baseline and 1 year). At baseline, the University of Pennsylvania Smell Identification Test (UPSIT) was also completed. Remission was determined for four symptom factors derived from the PANSS (positive, negative, cognitive/disorganized, and anxiety/depression). Patients with and without remission were compared on UPSIT scores. RESULTS: Patients with nonremission of negative and cognitive/disorganized symptoms had significantly lower baseline UPSIT scores compared with patients with remission. UPSIT scores were unrelated to remission of positive or anxiety/depression symptoms. CONCLUSIONS: UPSIT scores can be used to identify patients at risk for persistent negative and disorganized/cognitive symptoms.     

Adult forms of metachromatic leukodystrophy: clinical and biochemical approach.

The clinical and biochemical characteristics of metachromatic leukodystrophy (MLD), true adult forms and late juvenile forms which are still living at adulthood, are reviewed as they both are observed in adult Neurology and Psychiatry departments. Mental deterioration is often the first symptom, evolving progressively; and dementia finally occurs. The latency before the appearance of neurological objective symptoms may be long and extend for several years. In many cases, the behavioral abnormalities are the first symptoms. Some of these forms have been diagnosed as schizophrenia. Very seldom, neurological symptoms, especially ataxia, occur without cognitive or psychiatric disturbances. Most of these cases have pyramidal and cerebellar symptoms, at diverse degrees. Seizures can also occur which is some cases can be early symptoms associated to mental deterioration. The association of central and peripheral neurological symptoms is very characteristic of MLD. The peripheral neuropathy is not generally clinically evidenced, but is rarely missing electrophysiologically. Arylsulfatase A determination should be performed for diagnosis as a first step, and confirmed by the accumulation of sulfatide, either by quantitative determinations in urine or by the sulfatide loading test. It is as yet not clear why certain forms have a rather rapid evolution in 5 years, and others have a very protracted course during decades.     

Leukodystrophy Presenting as Acute-Onset Polyradiculoneuropathy

BackgroundSulfatides, the most abundant glycosphingolipids, are a major component of myelin. They are degraded by the combined action of sphingolipid activator protein and arylsulfatase A. Deficiency of either of these entities causes metachromatic leukodystrophy (MLD). On the basis of age of onset, this entity is divided into late infantile, juvenile, and adult subtypes. Late infantile form, the commonest subtype, can exhibit peripheral neuropathy as the initial manifestation. The other two forms usually manifest peripheral neuropathy later in the disease course.PatientA 1.5-year-old girl with preexisting isolated motor delay presented with acute-onset ascending flaccid quadriparesis, ptosis, and respiratory failure. Ptosis and respiratory failure responded completely to intravenous immunoglobulin, whereas quadriparesis showed minimal improvement. Nerve biopsy revealed metachromatic granules with demyelination, and serum arylsulfatase A levels were undetectable.ConclusionThe severity and nature of the disease coupled with the response to immunotherapy makes this case unusual. This child may represent either an atypical presentation of MLD with coincidental response to immunotherapy or an episode of immune mediated neuropathy in an individual with already diseased nerves due to MLD.     

Pitfalls in the diagnosis of multiple sulfatase deficiency

Multiple sulfatase deficiency (MSD, OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of several, in total seven, sulfatases. The disorder is clinically and biochemically variable. The clinical picture combines features of mucopolysaccharidosis and metachromatic leukodystrophy (MLD, OMIM 250100) in a variable spectrum. Here we report a 3-year old Iranian girl with an MLD-like presentation of MSD. Arylsulfatase A deficiency and sulfatide excretion were found. Differently from what was previously reported in Multiple sulfatase deficiency (MSD, OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of several, in total seven, sulfatases. The disorder is clinically and biochemically variable. The clinical picture combines features of mucopolysaccharidosis and metachromatic leukodystrophy (MLD, OMIM 250100) in a variable spectrum. Here we report a 3-year old Iranian girl with an MLD-like presentation of MSD. Arylsulfatase A deficiency and sulfatide excretion the literature, this girl never showed abnormal mucopolysaccharide excretion in the urine. There were no additional visceral or skeletal signs. She was originally diagnosed as having MLD. Only when she developed ichthyosis were seven additional sulfatases measured. In leukocytes, arylsulfatase A, steroid sulfatase and N-acetylglucosamine-6 sulfatase were profoundly deficient, while iduronate-2 sulfatase and arylsulfatase B were moderately reduced. In fibroblasts, N-acetylglucosamine-6 sulfatase was deficient, while arylsulfatase A was moderately reduced. This case illustrates the possible pitfalls in the clinical and laboratory diagnosis of MSD.     

The relationship between alexithymia and perinatal depressive symptomatology

OBJECTIVE: The purpose of this study was to examine the relationship between alexithymia and perinatal depressive symptoms and the stability of the alexithymia construct in a sample of low-income, predominantly Latina women during pregnancy and the early postpartum period. METHODS: Seventy-seven pregnant women completed self-report questionnaires and were classified as "high risk" or "low risk" for developing a major depressive episode based on a history of depression and/or current high depressive symptom scores. Measures included the Toronto Alexithymia Scale, the Center for Epidemiological Studies Depression Scale, and the Maternal Mood Screener, and were completed during pregnancy and at postpartum month 2. RESULTS: Alexithymia was positively associated with depressive symptoms during pregnancy and early postpartum. Women at high risk for depression had significantly higher alexithymia levels than low-risk women during pregnancy but not during postpartum. Alexithymia and depressive symptoms were independently and strongly correlated across the ante- and postpartum periods. Hierarchical regression analyses indicate that alexithymia scores at postpartum were predicted by alexithymia scores during pregnancy, above and beyond the variance explained by the depressive symptom scores during pregnancy and postpartum. CONCLUSION: Alexithymia is positively correlated with depressive symptoms during the perinatal period and is a stable phenomenon.