Homozygous hydroxymethylbilane synthase knock-in mice provide pathogenic insights into the severe neurological impairments present in human homozygous dominant acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an inborn error of heme biosynthesis due to the deficiency of hydroxymethylbilane synthase (HMBS) activity. Human AIP heterozygotes have episodic acute neurovisceral attacks that typically start after puberty, whereas patients with homozygous dominant AIP (HD-AIP) have early-onset chronic neurological impairment, including ataxia and psychomotor retardation. To investigate the dramatically different manifestations, knock-in mice with human HD-AIP missense mutations c.500G>A (p.Arg167Glu) or c.518_519GC>AG (p.Arg173Glu), designated R167Q or R173Q mice, respectively, were generated and compared with the previously established T1/T2 mice with ~30% residual HMBS activity and the heterozygous AIP phenotype. Homozygous R173Q mice were embryonic lethal, while R167Q homozygous mice (R167Q+/+) had ~5% of normal HMBS activity, constitutively elevated plasma and urinary 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), profound early-onset ataxia, delayed motor development and markedly impaired rotarod performance. Central nervous system (CNS) histology was grossly intact, but CNS myelination was delayed and overall myelin volume was decreased. Heme concentrations in liver and brain were similar to those of T1/T2 mice. Notably, ALA and PBG concentrations in the cerebral spinal fluid and CNS regions were markedly elevated in R167Q+/+ mice compared with T1/T2 mice. When the T1/T2 mice were administered phenobarbital, ALA and PBG markedly accumulated in their liver and plasma, but not in the CNS, indicating that ALA and PBG do not readily cross the blood-brain barrier. Taken together, these studies suggest that the severe HD-AIP neurological phenotype results from decreased myelination and the accumulation of locally produced neurotoxic porphyrin precursors within the CNS.

Clinical Guide and Update on Porphyrias.

Physicians should be aware of porphyrias, which could be responsible for unexplained gastrointestinal, neurologic, or skin disorders. Despite their relative rarity and complexity, most porphyrias can be easily defined and diagnosed. They are caused by well-characterized enzyme defects in the complex heme biosynthetic pathway and are divided into categories of acute vs non-acute or hepatic vs erythropoietic porphyrias. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficient porphyria) manifest in attacks and are characterized by overproduction of porphyrin precursors, producing often serious abdominal, psychiatric, neurologic, or cardiovascular symptoms. Patients with variegate porphyria and hereditary coproporphyria can present with skin photosensitivity. Diagnosis relies on measurement of increased urinary 5-aminolevulinic acid (in patients with aminolevulinic acid dehydratase deficient porphyria) or increased 5-aminolevulinic acid and porphobilinogen (in patients with other acute porphyrias). Management of attacks requires intensive care, strict avoidance of porphyrinogenic drugs and other precipitating factors, caloric support, and often heme therapy. The non-acute porphyrias are porphyria cutanea tarda, erythropoietic protoporphyria, X-linked protoporphyria, and the rare congenital erythropoietic porphyria. They lead to the accumulation of porphyrins that cause skin photosensitivity and occasionally severe liver damage. Secondary elevated urinary or blood porphyrins can occur in patients without porphyria, for example, in liver diseases, or iron deficiency. Increases in porphyrin precursors and porphyrins are also found in patients with lead intoxication. Patients with porphyria cutanea tarda benefit from iron depletion, hydroxychloroquine therapy, and, if applicable, elimination of the hepatitis C virus. An α-melanocyte-stimulating hormone analogue can reduce sunlight sensitivity in patients with erythropoietic protoporphyria or X-linked protoporphyria. Strategies to address dysregulated or dysfunctional steps within the heme biosynthetic pathway are in development.

Trends in renal calculus composition and 24-hour urine analyses in patients with neurologically derived musculoskeletal deficiencies.

PURPOSE: To better characterize metabolic stone risk in patients with neurologically derived musculoskeletal deficiencies (NDMD) by determining how patient characteristics relate to renal calculus composition and 24-hour urine parameters. MATERIALS AND METHODS: We performed a retrospective cohort study of adult patients with neurologically derived musculoskeletal deficiencies presenting to our multidisciplinary Kidney Stone Clinic. Patients with a diagnosis of NDMD, at least one 24-hour urine collection, and one chemical stone analysis were included in the analysis. Calculi were classified as primarily metabolic or elevated pH. We assessed in clinical factors, demographics, and urine metabolites for differences between patients who formed primarily metabolic or elevated pH stones. RESULTS: Over a 16-year period, 100 patients with NDMD and nephrolithiasis were identified and 41 met inclusion criteria. Thirty percent (12 / 41) of patients had purely metabolic calculi. Patients with metabolic calculi were significantly more likely to be obese (median body mass index 30.3kg / m2 versus 25.9kg / m2), void spontaneously (75% vs. 6.9%), and have low urine volumes (100% vs. 69%). Patients who formed elevated pH stones were more likely to have positive preoperative urine cultures with urease splitting organisms (58.6% vs. 16.7%) and be hyperoxaluric and hypocitraturic on 24-hour urine analysis (37mg / day and 265mg / day versus 29mg / day and 523mg / day). CONCLUSIONS: Among patients with NDMD, metabolic factors may play a more significant role in renal calculus formation than previously believed. There is still a high incidence of carbonate apatite calculi, which could be attributed to bacteriuria. However, obesity, low urine volumes, hypocitraturia, and hyperoxaluria suggest an underrecognized metabolic contribution to stone formation in this population.

Measurements of C-reactive protein (CRP) and nerve-growth-factor (NGF) concentrations in serum and urine samples of dogs with neurologic disorders.

BACKGROUND: The purpose of this study was to prove the hypothesis that C-reactive protein (CRP) and nerve growth factor (NGF) may be potential biomarkers for lower urinary tract disorders and may be able to distinguish between micturition dysfunctions of different origin in dogs with spinal cord diseases. NGF- and CRP- concentrations were measured in serum and urine samples using specific ELISA-Kits. Results in urine were standardized by urine-creatinine levels. RESULTS: CRP in serum was detectable in 32/76 and in urine samples in 40/76 patients. NGF could be measured in all serum and in 70/76 urine samples. Urinary CRP concentrations were significantly higher in dogs with micturition dysfunction (p = 0.0009) and in dogs with different neurological diseases (p = 0.0020) compared to the control group. However, comparing dogs with spinal cord disorders with and without associated micturition dysfunction no significant difference could be detected for NGF and CRP values in urine or serum samples. Additionally, levels did not decrease significantly, when measured at the time when the dogs regained the ability to urinate properly (urinary NGF p = 0.7962; urinary CRP p = 0.078). Urine samples with bacteria and/or leukocytes had no significant increase in urinary NGF (p = 0.1112) or CRP (p = 0.0534) concentrations, but higher CRP-levels in urine from dogs with cystitis were found compared to dogs without signs of cystitis. CONCLUSIONS: From these data we conclude that neither CRP nor NGF in urine or serum can be considered as reliable biomarkers for micturition disorders in dogs with spinal cord disorders in a clinical setting, but their production might be part of the pathogenesis of such disorders. Significantly higher levels of CRP could be found in the urine of dogs with micturition dysfunctions compared to control dogs. This phenomenon could potentially be explained by unspecific extrahepatic CRP production by smooth muscle cells in the dilated bladder.

A quantitative evaluation of brain dysfunction and body-burden of toxic metals.

BACKGROUND: Toxic metal exposure (e.g. Hg, Pb, As) exposure is known to induce significant adverse effects on human brain function. The aim this study was to assess toxic metal body-burden in relation to potential brain dysfunction in patients diagnosed with neurological disorders (NDs). MATERIAL/METHODS: The Liberty Institutional Review Board (Deland, FL) approved the present study. Quantitative, fractionated, random urinary porphyrin testing (µg/L) from the Clinical Laboratory Improvement Act/Amendment (CLIA)-approved Laboratory Corporation of America (LabCorp) and cortical perfusion index (CPi) values from single-photon-emission-computed-tomography (SPECT) brain scans were employed to evaluate a prospective cohort of qualifying patients with diagnosed NDs (n=52) presenting for medical care at an endocrinology practice in the Cincinnati, OH area. RESULTS: Patients with more severe in comparison to mild brain dysfunction had significant increases in the mean urinary concentration of uroporphyrins (uP), coproporphyrins I (cP I), and total cP (cP I + III), as well as a trend towards significantly increased mean urinary concentration of pentacarboxyporphyins (5cxP) and cP III. A significant positive correlation between Hg body-burden associated porphyrins (5cxP + cP I + cP III) and increased brain dysfunction was observed. CONCLUSIONS: The present study associated brain dysfunction with Hg body-burden in a cohort of patients diagnosed with NDs, but the contributions of other heavy metals or genetic factors cannot be ruled-out. Additional studies should be conducted to evaluate the consistency of the present findings with examinations of other populations.

Urinary concentrations of neonicotinoid insecticides were related to renal tubular dysfunction and neuropsychological complaints in Dry-zone of Sri Lanka.

Neonicotinoids are systemic insecticides used since the 1990's , that possess renal tubular toxicity. We conducted a field-based descriptive study in the North Central Dry-zone of Sri Lanka, where chronic kidney disease (CKD) of unknown etiology has been increasing since the 1990's. To elucidate the relationship between renal tubular dysfunctions and urinary neonicotinoids concentrations, we collected spot urine samples from15 CKD patients, 15 family members, and 62 neighbors in 2015, analyzed two renal tubular biomarkers, Cystatin-C and L-FABP, quantified seven neonicotinoids and a metabolite N-desmethyl-acetamiprid by LC-MS/MS; and we investigated their symptoms using a questionnaire. Cystatin-C and L-FABP had a positive correlation (p < 0.001). N-Desmethyl-acetamiprid was detected in 92.4% of the urine samples, followed by dinotefuran (17.4%), thiamethoxam (17.4%), clothianidin (9.8%), thiacloprid and imidacloprid. Dinotefuran and thiacloprid have never been registered in Sri Lanka. In High Cystatin-C group (> 70 µg/gCre, n = 7), higher urinary concentration of dinotefuran (p = 0.009), and in Zero Cystatin-C group (< LOQ, n = 7), higher N-desmethyl-acetamiprid (p = 0.013), dinotefuran (p = 0.049), and thiacloprid (p = 0.035), and more complaints of chest pains, stomachache, skin eruption and diarrhea (p < 0.05) were found than in Normal Cystatin-C group (n = 78). Urinary neonicotinoids may be one of the potential risk factors for renal tubular dysfunction in this area.

Urinary nerve growth factor level is correlated with the severity of neurological impairment in patients with cerebrovascular accident.

OBJECTIVE: To measure urinary nerve growth factor (uNGF, essential in nerve growth and regeneration) levels in patients with a cerebrovascular accident (CVA), to determine whether uNGF could be a biomarker for predicting the neurological deficits in CVA, as the level of uNGF increases in patients with idiopathic detrusor overactivity (DO) and incontinence. PATIENTS, SUBJECTS AND METHODS: uNGF levels were measured using an enzyme-linked immunosorbent assay in normal subjects and patients with CVA and different severities of neurological impairment. Total uNGF levels were normalized to the concentration of urinary creatinine (uNGF/Cr). RESULTS: The median (interquartile range) uNGF/Cr levels were significantly higher in patients, at 0.13 (0-1.04), than in normal subjects (undetectable). The uNGF/Cr levels correlated well with the severity of neurological impairment. Patients with none/minimal neurological impairment had no detectable uNGF/Cr level, like the controls. Patients with mild/moderate impairment had levels of 0.27 (0.09-0.8) and with severe impairment level of 1.53 (0.5-3.0) (both P < 0.001), significantly greater than that of none/minimal impairment or controls. However, uNGF/Cr levels were not correlated with age, location of CVA, multiplicity of CVA, duration of CVA, urodynamic findings or the presence of urge urinary incontinence. CONCLUSIONS: The uNGF level is correlated with the severity of neurological impairment in patients with CVA but not with urge symptoms or urodynamic findings, suggesting elevated uNGF might be a result of the neurological lesion rather than lower urinary tract dysfunction in CVA.

Psychiatric patients in the pediatric emergency department undergoing routine urine toxicology screens for medical clearance: results and use.

OBJECTIVE: We sought to determine the use and results of urine toxicology screens (UTS) in psychiatric patients undergoing a UTS test for medical clearance in a pediatric emergency department. METHODS: A structured retrospective study was conducted over a 6-month period. All emergency department (ED) charts were reviewed of patients 8 to 17 years who had a UTS. Urine toxicology screens were identified as medically indicated or routine-driven. Medically indicated UTS were patients who presented with seizures, syncope, headache, altered mental status, ingestion, chest pain/palpitation, shortness of breath, sexual assault, or those who were brought in for motor vehicle accident (MVA). Routine-driven UTS were uncomplicated psychiatric patients who presented with aggressive or out of control behavior, intentional self-inflicted wounds, or symptoms of depression, all of whom presented without any evidence of drug or alcohol ingestion or altered mental status. Routine-driven UTS were quantified for positive tests. In addition, we determined the change in management and disposition of those patients. We also determined the concordance of provided drug use history with UTS result. RESULTS: Of the 652 charts reviewed, 267 UTS were medically indicated; 385 were routine-driven. Of the routine-driven UTS group, 254/267 (95%) patients with negative screens and 115/118 (97%) with positive screens were referred for psychiatric treatment after psychiatric evaluation. Fisher exact test of the comparison of the disposition after psychiatric assessment with the UTS result was nonsignificant. The UTS result also had no effect on the type of psychiatric disposition (ie, outpatient therapy, partial hospitalization, inpatient hospitalization). Concordance with provided history of illicit drug use was significant. CONCLUSIONS: Routine-driven UTS in uncomplicated pediatric psychiatric patients being evaluated in the ED offered little additional information, did not influence management, and potentially increased both ED cost and time. Patients with straightforward psychiatric complaints may be medically cleared without a UTS.

Discerning the Mauve Factor, Part 1.

"Mauve Factor" was once mistaken for kryptopyrrole but is the hydroxylactam of hemopyrrole, hydroxyhemopyrrolin-2-one (HPL). Treatment with nutrients--particularly vitamin B6 and zinc--reduces urinary excretion of HPL and improves diverse neurobehavioral symptoms in subjects with elevated urinary HPL. Heightened HPL excretion classically associates with emotional stress, which in turn is known to associate with oxidative stress. For this review, markers for nutritional status and for oxidative stress were examined in relationship to urinary HPL. In cohorts with mixed diagnoses, 24-hour urinary HPL correlated negatively with vitamin B6 activity and zinc concentration in red cells (P < .0001). Above-normal HPL excretion corresponded to subnormal vitamin B6 activity and subnormal zinc with remarkable consistency. HPL correlated inversely with plasma glutathione and red-cell catalase, and correlated directly with plasma nitric oxide (P < .0001). Thus, besides implying proportionate needs for vitamin B6 and zinc, HPL is a promising biomarker for oxidative stress. HPL is known to cause non-erythroid heme depression, which lowers zinc, increases nitric oxide, and increases oxidative stress. Administration of prednisone reportedly provoked HPL excretion in animals. Since adrenocorticoid (and catecholamine) stress hormones mediate intestinal permeability, urinary HPL examined in relationship to urinary indicans, presumptive marker for intestinal permeability. Urinary HPL associated with higher levels of indicans (P < .0001). Antibiotics reportedly reduce HPL in urine, suggesting an enterobic role in production. Potentially, gut is a reservoir for HPL or its precursor, and stress-related changes in intestinal permeability mediate systemic and urinary concentrations.

Discerning the Mauve factor, Part 2.

"Mauve Factor" was once mistaken for kryptopyrrole but is the hydroxylactam of hemopyrrole, hydroxyhemopyrrolin-2-one (HPL). Treatment with nutrients--particularly vitamin B6 and zinc--reduces urinary excretion of HPL and improves diverse neurobehavioral symptoms in subjects with elevated urinary HPL. Heightened HPL excretion classically associates with emotional stress, which in turn is known to associate with oxidative stress. For this review, markers for nutritional status and for oxidative stress were examined in relationship to urinary HPL. In cohorts with mixed diagnoses, 24-hour urinary HPL correlated negatively with vitamin B6 activity and zinc concentration in red cells (P < .0001). Above-normal HPL excretion corresponded to subnormal vitamin B6 activity and subnormal zinc with remarkable consistency. HPL correlated inversely with plasma GSH and red-cell catalase, and correlated directly with plasma nitric oxide (P < .0001). Thus, besides implying proportionate needs for vitamin B6 and zinc, HPL is a promising biomarker for oxidative stress. HPL is known to cause non-erythroid heme depression, which lowers zinc, increases nitric oxide, and increases oxidative stress. Administration of prednisone reportedly provoked HPL excretion in animals. Since adrenocorticoid (and catecholamine) stress hormones mediate intestinal permeability, urinary HPL was examined in relationship to urinary indicans, presumptive marker for intestinal permeability. Urinary HPL associated with higher levels ofindicans (P < .0001). Antibiotics reportedly reduce HPL in urine, suggesting an enterobic role in production. Potentially, gut is reservoir for HPL or its precursor, and stress-related changes in intestinal permeability mediate systemic and urinary concentrations.

Urinary 6-hydroxymelatonin excretion in patients with orthostatic hypotension.

The rates of melatonin formation and its diurnal fluctuations have been examined in patients with three types of orthostatic hypotension by measuring the urinary excretion rates of 6-hydroxymelatonin, the major metabolite of the pineal gland hormone. Deficiencies in the peripheral autonomic nervous system resulted in markedly diminished daily excretion (2.5 +/- 1.3 micrograms) relative to control (12.2 +/- 1.2). Patients with impaired central nervous system function exhibited low and/or abnormal excretion patterns. Two patients with sympathotonic orthostatic hypotension excreted greater amounts of 6-hydroxymelatonin than any of the control subjects. Melatonin secretion by the pineal gland can be used as an index of sympathetic nerve function. The study of patients with altered function may reveal the role of the pineal gland in human physiology.

Increased oxidative damage to DNA in ALS patients.

Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, substantial evidence indicates that oxidative toxicity is associated with neuronal death in this disease. We examined levels of a well-established marker of oxidative damage to DNA, 8-hydroxy-2'-deoxyguanosine (8OH2'dG) in plasma, urine, and cerebrospinal fluid (CSF) at a single time point from subjects with ALS, other neurological diseases, or no known disorders. We also measured the rate of change of 8OH2'dG levels in plasma and urine from ALS and in urine from control subjects over 9 months and examined the relationship to disease severity. In each fluid, 8OH2'dG levels were significantly elevated in the ALS group as compared to control subjects. In all subjects, the plasma and CSF 8OH2'dG levels increased with age, providing further evidence for a role of oxidative damage in normal aging. Plasma and urine 8OH2'dG levels increased significantly with time in the ALS group only. The rate of increase in urine 8OH2'dG levels with time was significantly correlated with disease severity. These findings are consistent with the hypothesis that oxidative pathology accompanies the neurodegenerative process in ALS and suggest that 8OH2'dG may provide a useful tool for monitoring therapeutic interventions in this disease.

Increased free light chains in the urine from patients with multiple sclerosis.

We quantitated free kappa (kappa) and lambda light (L) chains in coded urine specimens from subjects with clinically definite multiple sclerosis (MS) (N = 56), other neurologic diseases (OND) (N = 30), and age-matched normal controls (N = 28). Urine from MS patients showed statistically significant increases in free L chains compared with the other groups, although there was overlap between MS patients and OND patients. The ratio of kappa/creatinine was significantly greater in the relapsing-remitting MS group than in patients with clinically stable MS, OND, and normal controls. Elevated free L chains were usually independent of urinary albumin and beta 2-microglobulin levels. Serial studies showed that urinary free kappa/creatinine ratios were elevated during periods of clinical worsening in seven of eight MS patients and subsequently decreased during clinical recovery. The measurement of free L chains in urine obtained at intervals from MS patients may be useful as a marker to monitor disease activity.

Adult onset glutaric aciduria type I presenting with a leukoencephalopathy.

Glutaric aciduria type I usually presents with an acute metabolic crisis during infancy. The authors report a previously healthy 19-year-old woman who presented with recurrent headaches, oculomotor symptoms, and a severe leukoencephalopathy on MRI. The diagnosis was made by urinary organic acid analysis and confirmed by enzyme studies. Genetic analysis revealed compound heterozygosity with a deletion c.219delC in exon 3 and a novel missense mutation R132G in exon 5 of the glutaryl CoA dehydrogenase (GCDH) gene.

CSF levels of carnitine in children with meningitis, neurologic disorders, acute gastroenteritis, and seizure.

Carnitine concentrations in CSF, serum, and urine in normal febrile children and children with meningitis, neurologic disorders, and dehydration were studied. Carnitine levels in CSF were 1/10 compared with serum in normal febrile children. These levels increased two- to three-fold in the pathologic conditions studied. Since damage to the blood-brain barrier occurs in these conditions, higher blood-brain barrier permeability might explain CNS carnitine accumulation.

Neurological correlates of fetal cocaine exposure: transient hypertonia of infancy and early childhood.

OBJECTIVE: To assess whether prenatal cocaine exposure has any long-term effects on neurodevelopment. DESIGN: A prospective cohort study with examiners blind to drug exposure and human immunodeficiency virus (HIV) status. SUBJECTS: Of 144 high-risk infants enrolled in a perinatal HIV neurodevelopmental study, 119 (83%) infants with both neurological and urine toxicology measures were followed up to age 24 months. METHODS: Neurological and developmental assessments were analyzed at 6-month intervals grouped according to the presence of cocaine in urine toxicology: 51 infants were cocaine-positive. Adjusted odds ratios (ORs) and 95% confidence interval (CI) were obtained by logistic regression equations that adjusted for perinatal variables, including measures of fetal growth, gestation, HIV status, and infant toxicology results. SETTING: Harlem Hospital Center from 1988 to 1992. RESULTS: At age 6 months, 21 of 51 (41%) cocaine-positive children exhibited hypertonia of any type (hypertonic tetraparesis, hypertonic diparesis, and hypertonic hemiparesis) compared with 17 of 68 (25%) cocaine-negative infants (OR = 2.1, CI = 1.0-4.6). Cocaine-positive infants were four times more likely to show hypertonic tetraparesis (HTP) than cocaine-negative infants (OR = 4.0; CI = 1.5-10.8). The association remained significant in multivariate analyses. Hypertonia, consistent with cerebral palsy, diminished over time in both groups. In 97% of affected infants hypertonia resolved by 24 months. Arm hypertonia abated first; leg hypertonia remained in some children up to age 18 months. No differences in development scores between cocaine-positive and cocaine-negative were noted at any age interval. However, among cocaine-positive infants those with early HTP showed significantly lower mean developmental scores at 6 and 12 month compared to infants without HTP. CONCLUSION: Cocaine positivity urine toxicology at birth is associated with hypertonia during infancy. Such cocaine-induced effects are usually symmetrical, transient, and the majority of exposed children outgrow hypertonia by 24 months of life. Among cocaine-positive infants, HTP may be a marker for later developmental impairments.

Biomarker research in neurotoxicology: the role of mechanistic studies to bridge the gap between the laboratory and epidemiological investigations.

There is an increasing interest in the development and validation of biomarkers for use in biochemical/molecular epidemiological studies. Though the area of neurotoxicology has received much attention in the past several years, it still lags behind with regard to the development of biomarkers, particularly those of health effects and susceptibility. This review discusses several aspects of biomarker research as it relates to neurotoxic compounds and focuses on selected agents (organophosphorus insecticides, styrene, n-hexane, carbon disulfide, acrylamide), which have been the subject of a number of investigations in animals and humans. While traditional biomonitoring approaches and novel techniques (e.g., hemoglobin adducts) provide several measurements for monitoring exposure to neurotoxic chemicals, potential markers of genetic susceptibility have been seldom investigated in a neurotoxicology context. Furthermore, the complexity of the nervous system, together with the multiplicity of end points and the limited knowledge of the exact mechanism(s) of action of neurotoxicants, has led to only limited advancements in the development of biomarkers for neurotoxic effects. Significant progress in this area will depend upon an increased understanding of the cellular, biochemical, and molecular targets directly involved in neurotoxicity.

Behr's syndrome and 3-methylglutaconic aciduria.

We examined three patients from two families of Jewish-Iraqi origin who had progressive reduction of visual acuity and childhood onset of bilateral optic nerve atrophy without additional retinal abnormalities. They had neurologic symptoms compatible with Behr's syndrome. Neurologic signs included increased tendon reflexes, a positive Babinski sign, progressive spastic paraplegia, dysarthria, head nodding, and horizontal nystagmus. Neurologic involvement varied between affected siblings. The patients excreted excessive amounts of 3-methylglutaconic acid and 3-methylglutaric acid in their urine. We compared the characteristic ophthalmic features and the spectrum of neurologic signs encountered in this recently delineated autosomal recessive clinical entity with those of previously described entities associated with 3-methylglutaconic aciduria. Patients with early-onset optic atrophy should be examined for neurologic signs and screened for organic aciduria. A detailed ophthalmic examination is important in patients with neurologic abnormalities compatible with Behr's syndrome.

Urinary dopamine sulfate: regulations and significance in neurological disorders.

Dopamine-3-O-sulfate (DA-3-O-S) and dopamine-4-O-sulfate (DA-4-O-S) are important end products of L-dopa metabolism. Therefore they may give indications of disturbances in the peripheral metabolism of catecholamines, when measured in urine samples of patients with Parkinson's disease (PD). In addition, information about the reliability of DA sulfatation after L-dopa therapy may be of significance for its role in the elimination of DA from the peripheral nervous system. Although DA-3-O-S appears to be the predominant sulfo-conjugate in urine, there are no changes in PD nor in depression syndrome compared to controls with or without other neurological disorders. By contrast, DA-4-O-S is significantly decreased in de novo PD subjects. However, a similar reduction is notable in patients with other neurological disorders. In depressed persons the loss of this compound was less pronounced as compared to de novo PD. Treatment with combined L-dopa therapy caused increased excretion of DA-3-O-S, while changes in DA-4-O-S were only marginal. It is concluded that urinary DA-3-O-S cannot be used as marker for PD, while DA-4-O-S is significantly reduced in a variety of neurological disorders and in particular in de novo PD. Further studies are necessary to elucidate its role as possible peripheral marker to distinguish preclinical PD and depression syndrome.

The nervous system effects of occupational exposure on workers in a South African manganese smelter.

Five hundred and nine production workers at a manganese (Mn) smelting works comprising eight production facilities and 67 external controls were studied cross-sectionally for Mn related neuroehavioural effects. Exposure measures from personal sampling included Mn in inhalable dust as cumulative exposure indices (CEI) and average intensity (INT). Biological exposure and biological effect measures included blood (MnB), urine (MnU) manganese and serum prolactin. Endpoints included items from the Swedish nervous system questionnaire (Q16), World Health Organisation neurobehavioural core test battery (WHO NCTB), Swedish performance evaluation system (SPES), Luria-Nebraska (LN), and Danish product development (DPD) test batteries, and a brief clinical examination. Potential confounders and effect modifiers included age, educational level, alcohol and tobacco consumption, neurotoxic exposures in previous work, past medical history, previous head injury and home language. Associations were evaluated by multiple linear and logistic regression modelling. Modelling assumptions were tested. Average exposure intensity across all jobs ranged from near 0 (0.06 microg/m3) for external controls to 5.08 mg/m3 for inhalable Mn, and was greater than the ACGIH TLV for 69% of subjects. Results from the large number of tests performed resolved into three groups. Group 1 shows differences between external unexposed referents and all the exposed and/or differences between internal low exposed referents and the rest of the exposed but no further exposure-response relationships. It includes the Santa Ana, Benton and digit-span tests from the WHO NCTB; the hand tapping and endurance tapping tests from the SPES; Luria-Nebraska item 2L; questionnaire items tired, depressed, irritated, having to take notes in order to remember things, and subjects' perception that they had sex less often than normal; a test of clinical abnormality; and increased sway under two conditions (eyes open without foot insulation, eyes open with foot insulation). Group 2 shows the presence of a more substantive exposure-response relationship. It consists of only two tests: and includes the WHO digit-symbol test (although the major impact is at low exposure and therefore counterintuitive, arguably placing this test in group 3) and the LN item 1R which has a step to a poorer score at high exposure. Group 3 contains the overwhelming majority of test results (almost all the questionnaire items, almost all the DPD tests including tremor, sway and diadochokinesia, and serum prolactin) which were either null or counterintuitive (did not make sense). The CEI was the strongest predictor of test abnormalities, except for the clinical test which was more strongly associated with blood manganese. Despite a comprehensive range of endpoints, and levels of exposure ranging from environmental to industrial, this large study of Mn workers found little convincing evidence for a continuum of effects, contributing further questions to current debates about the adequacy of the current ACGIH TLV.