Localising movement disorders in childhood.

The diagnosis and management of movement disorders in children can be improved by understanding the pathways, neurons, ion channels, and receptors involved in motor learning and control. In this Review, we use a localisation approach to examine the anatomy, physiology, and circuitry of the basal ganglia and highlight the mechanisms that underlie some of the major movement disorders in children. We review the connections between the basal ganglia and the thalamus and cortex, address the basic clinical definitions of movement disorders, and then place diseases within an anatomical or physiological framework that highlights basal ganglia function. We discuss how new pharmacological, behavioural, and electrophysiological approaches might benefit children with movement disorders by modifying synaptic function. A better understanding of the mechanisms underlying movement disorders allows improved diagnostic and treatment decisions.

Amyloid-Mediated Cholinergic Dysfunction in Motor Impairment Related to Alzheimer's Disease.

BACKGROUND: Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear. OBJECTIVE: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer's disease (AD)-related early motor disturbances. METHODS: The motor phenotype, as defined with Unified Parkinson's Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-ß 42 (Aß42), total-tau, and phosphorylated-tau were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations. RESULTS: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aß42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aß42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers. CONCLUSIONS: The association of motor disturbances with low Aß42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies.

Gamma-aminobutyric acid levels in cerebrospinal fluid in neuropaediatric disorders.

AIM: Gamma-aminobutyric acid (GABA) is a major modulator in brain maturation and its role in many different neurodevelopmental disorders has been widely reported. Although the involvement of GABA in different disorders has been related to its regulatory function as an inhibitory neurotransmitter in the mature brain, co-transmitter, and signalling molecule, little is known about its role as a clinical biomarker in neuropaediatric disorders. The aim of this study is to report the cerebrospinal fluid (CSF) free-GABA concentrations in a large cohort of patients (n=85) with different neurological disorders. METHOD: GABA was measured in the CSF of neuropaediatric patients using capillary electrophoresis with laser-induced fluorescence detection. Other neurotransmitters (amino acids and monoamines) were also analysed. RESULTS: GABA concentrations in CSF were abnormal, with a greater frequency (44%) than monoamines (20%) in neuropaediatric patients compared with our reference values. Although we included a few patients with inborn errors of metabolism, GABA levels in CSF were more frequently abnormal in metabolic disorders than in other nosological groups. INTERPRETATION: Our work suggests further research into brain GABAergic status in neuropaediatric disorders, which could also lead to new therapeutic strategies. WHAT THIS PAPER ADDS: Homeostasis of GABA seems more vulnerable than that of monoamines in the developing brain. The highest GABA levels are found in the primary GABA neurotransmitter disorder SSADH deficiency. GABA alterations are not specific for any clinical or neuroimaging presentation.

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, clinical laboratory geneticists should apply their professional judgment to the specific circumstances presented by the patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these Standards and Guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cerebral creatine deficiency syndromes are neurometabolic conditions characterized by intellectual disability, seizures, speech delay, and behavioral abnormalities. Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis. These guidelines are intended to standardize these procedures to help optimize the diagnosis of creatine deficiency syndromes. While biochemical methods are emphasized, considerations for confirmatory molecular testing are also discussed, along with variables that influence test results and interpretation.Genet Med 19 2, 256-263.

Baseline CSF/Serum-Ratio of Apolipoprotein E and Rate of Differential Decline in Alzheimer's Disease.

BACKGROUND/OBJECTIVE: Apolipoprotein E (ApoE) has an active part in the pathogenesis of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and plasma level alterations have been reported in AD patients. In search of a biomarker potentially predictive of cognitive, functional, or motor decline, we analyzed the CSF to serum ratios of ApoE levels (CSF/serum ApoE) in AD patients in this regard. METHODS: Subjects with newly diagnosed AD were followed within a longitudinal observational study (rpAD study). Annual neuropsychological testing and physical examination were performed. Multiple regression analyses were used to determine possible associations of the ApoE CSF/serum concentration ratios and velocity of decline on a variety of cognitive, functional and motor scales (MMSE, iADL, bADL, GDS, UPDRSIII) adjusted for relevant co-variables. RESULTS: CSF/serum ratios of ApoE levels were associated with progression on the UPDRSIII (change of UPDRSIII slope [pt/yr] per unit of ApoE CSF/serum = -0.06, p <  0.01) and instrumental ADL scale (change of iADL slope [pt/yr] per unit of ApoE CSF/serum = 0.01, p = 0.01) ("the lower the ratio, the faster the deterioration" and vice versa). Secondarily, higher age at onset was associated with faster UPDRSIII progression, antidepressant use with faster iADL decline, and better baseline function with more rapid decline on either MMSE, iADL, or GDS scale. CONCLUSION: Here, CSF/serum ApoE at time of AD diagnosis was shown to be inversely associated with medium-term functional and motor progression. Whether this ratio qualifies for the use as a predictive biomarker must be validated in larger cohort studies over the long term.

Cerebrospinal Fluid Monoamine Metabolite Analysis in Pediatric Movement Disorders.

Abnormal concentrations of dopamine and serotonin metabolites in the cerebrospinal fluid is the diagnostic hallmark of a group of treatable conditions known as the monoamine neurotransmitter disorders. We assessed cerebrospinal fluid dopamine and serotonin metabolite concentrations in a series of 69 patients affected by movement disorders of unknown etiology. Abnormal results were disclosed in 13/69 subjects (19%). Both primary and secondary monoamine neurotransmitter disorders were observed. The clinical presentation of both forms was hypokinetic-rigid syndrome or dystonia. L-Dopa treatment resulted in significant improvement of the clinical picture in the majority of primary neurotransmitter disorders. Eight patients presented a secondary neurotransmitter disorder. One suffered from a GM2 gangliosidosis and one from infantile bilateral striatal necrosis. Etiologic diagnoses were not established in the others. L-Dopa was started in four patients, leading to a significant improvement of hypokinesia in the patient suffering from GM2 gangliosidosis and a slight improvement in 3 unclassified patients.

Is pineal melatonin released in the third ventricle in humans? A study in movement disorders.

In order to determine sources and metabolism of melatonin in human cerebrospinal fluid (CSF), melatonin and 6-sulfatoxymelatonin (aMT6S) concentrations were measured in CSF sampled during neurosurgery in both lateral and third ventricles in patients displaying movement disorder (Parkinson's disease, essential tremor, dystonia or dyskinesia) and compared with their plasma levels. Previous determinations in nocturnal urine had showed that the patients displayed melatonin excretion in the normal range, compared with healthy controls matched according to age. A significant difference in melatonin concentration was observed between lateral and third ventricles, with the highest levels in the third ventricle (8.75±2.75pg/mL vs. 3.20±0.33pg/mL, P=0.01). CSF aMT6s levels were similar in both ventricles and of low magnitude, less than 5pg/mL. They were not correlated with melatonin levels or influenced by the area of sampling. Melatonin levels were significantly higher in third ventricle than in the plasma, whereas there was no difference between plasma and lateral ventricle levels. These findings show that melatonin may enter directly the CSF through the pineal recess in humans. The physiological meaning of these data remains to be elucidated.

CSF biomarkers and clinical progression of Parkinson disease.

OBJECTIVE: To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD). METHODS: Patients and controls were recruited from hospitals in southern Sweden as part of the prospective and longitudinal Swedish BioFinder Study. In the present study, we included 42 patients with PD and 69 controls who had clinical assessment and lumbar puncture at baseline. Baseline CSF samples were analyzed for α-synuclein (αSyn), ß-amyloid 1-42 (Aß42), tau, phosphorylated tau, and neurofilament light. Associations between CSF markers at baseline and change in clinical characteristics after 2 years of follow-up were investigated using multivariate models adjusting for age, sex, disease duration, and levodopa-equivalent daily dose. RESULTS: Higher levels of αSyn within the PD group were associated with progression of motor symptoms and cognitive decline over 2 years, indicated by significant relationships between αSyn and change in Hoehn and Yahr (ß = 0.394, p = 0.043), Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III) (ß = 0.449, p = 0.013), Timed Up and Go (ß = 0.406, p = 0.023), and A Quick Test of Cognitive Speed (ß = 0.423, p = 0.018). Lower levels of Aß42 were associated with worsening of performance on delayed memory recall (F = 5.834, p = 0.022). Finally, high levels of phosphorylated tau were associated with worsening in motor symptoms (UPDRS-III, ß = 0.350, p = 0.045; Hoehn and Yahr, ß = 0.366, p = 0.038). CONCLUSION: We found evidence of a link between higher levels of αSyn at baseline and worsening of motor symptoms and cognitive speed over 2 years in PD. Increased αSyn might be a marker of more intense synaptic degeneration in PD. The results indicate that cortical amyloid pathology (low CSF Aß42) is associated with memory decline.

Case study for the evaluation of current treatment recommendations of guanidinoacetate methyltransferase deficiency: ineffectiveness of sodium benzoate.

BACKGROUND: Guanidinoacetate methyltransferase deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. We report a new patient with guanidinoacetate methyltransferase deficiency and her >3-year treatment outcome. PATIENT: This is a 6-year-old girl who was diagnosed with guanidinoacetate methyltransferase deficiency at the age of 28 months. She presented with moderate global developmental delay, one afebrile seizure, and hypotonia between 6 and 18 months of life. She was treated with creatine and ornithine supplementation and a strict arginine-restricted diet for 42 months. RESULTS: Mutation analysis (compound heterozygous mutations, a known c.327G>A and a novel c.58dupT [p.Trp20LeufsX65]) and enzyme studies in primary fibroblasts confirmed the diagnosis. After 33 months of therapy, her cerebrospinal fluid guanidinoacetate level decreased from 47 to 5.3 times the normal level. Brain creatine by proton magnetic resonance spectroscopy increased by >75% but did not normalize in the basal ganglia and white matter after 3 years of therapy. Additional treatment with sodium benzoate for 17 months did not further improve plasma guanidinoacetate levels, which questions the relevance of this therapy. CONCLUSION: Treatment did not improve moderate intellectual disability or normalize guanidinoacetate accumulation in the central nervous system.

Melatonin is released in the third ventricle in humans. A study in movement disorders.

In order to determine sources and metabolism of melatonin in human cerebrospinal fluid (CSF), melatonin and 6-sulfatoxymelatonin (aMT6S) concentrations were measured in CSF sampled during neurosurgery in both lateral and third ventricles in patients displaying movement disorder (Parkinson's disease, essential tremor, dystonia or dyskinesia) and compared with their plasma levels. Previous determinations in nocturnal urine had showed that the patients displayed melatonin excretion in the normal range, compared with healthy controls matched according to age. A significant difference in melatonin concentration was observed between lateral and third ventricles, with the highest levels in the third ventricle (8.75+/-2.75 pg/ml vs. 3.20+/-0.33 pg/ml, p=0.01). CSF aMT6s levels were similar in both ventricles and of low magnitude, less than 5 pg/ml. They were not correlated with melatonin levels or influenced by the area of sampling. Melatonin levels were significantly higher in third ventricle than in the plasma, whereas there was no difference between plasma and lateral ventricle levels. These findings show that melatonin may enter directly the CSF through the pineal recess in humans. The physiological meaning of these data remains to be elucidated.

Neurochemical biomarkers in the differential diagnosis of movement disorders.

In recent years, the neurochemical analysis of neuronal proteins in cerebrospinal fluid (CSF) has become increasingly accepted for the diagnosis of neurodegenerative dementia diseases such as Alzheimer's disease and Creutzfeldt-Jakob disease. CSF surrounds the central nervous system, and in the composition of CSF proteins one finds brain-specific proteins that are prioritized from blood-derived proteins. Levels of specific CSF proteins could be very promising biomarkers for central nervous system diseases. We need the development of more easily accessible biomarkers, in the blood. In neurodegenerative diseases with and without dementia, studies on CSF and blood proteins have investigated the usefulness of biomarkers in differential diagnosis. The clinical diagnoses of Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration still rely mainly on clinical symptoms as defined by international classification criteria. In this article, we review CSF biomarkers in these movement disorders and discuss recent published reports on the neurochemical intra vitam diagnosis of neurodegenerative disorders (including recent CSF alpha-synuclein findings).

The expanding phenotype of GLUT1-deficiency syndrome.

Transport of glucose from the bloodstream across the blood-brain barrier to the central nervous system is facilitated by glucose transport protein type 1 (GLUT1), the first member of the solute carrier family 2 (SLC2). Heterozygous mutations in the GLUT1/SLC2A1 gene, occurring de novo or inherited as an autosomal dominant trait, result in cerebral energy failure and a clinical condition termed GLUT1-deficiency syndrome (GLUT1-DS). Clinical features usually comprise motor and mental developmental delay, seizures with infantile onset, deceleration of head growth often resulting in acquired microcephaly, and a movement disorder with ataxia, dystonia, and spasticity. Subsequent to the delineation of this classic phenotype the variability of signs and symptoms in GLUT1-DS is being recognized. Patients with (i) carbohydrate-responsive symptoms, with (ii) predominant ataxia or dystonia, but without seizures, and with (iii) paroxysmal exertion-induced dyskinesia and seizures have been reported. Common laboratory hallmark in all phenotypes is the reduced glucose level in cerebrospinal fluid with lowered CSF-to-blood glucose ratio. Treatment with a ketogenic diet results in marked improvement of seizures and movement disorders.

CSF neurofilament protein analysis in the differential diagnosis of ALS.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have been studied to differentiate between patients with ALS and neurological controls, but not in comparison to clinically more relevant disorders mimicking ALS. METHODS: In this retrospective study, CSF concentrations of various brain-specific proteins were analyzed in patients with ALS (n = 32) and ALS-mimic disorders (n = 26). RESULTS: CSF concentrations of neurofilament light (NFL) and heavy chain (NFHp35), but not other brain-specific proteins, were significantly higher in patients with ALS than in patients with an ALS-mimic disorder, however with maximum sensitivity or specificity of 80%. The mean CSF level of NFHp35 was 781 ng/L in the ALS group vs. 338 ng/L in the ALS-mimic disorders group and for NFL the mean CSF levels were 62 ng/L vs. 24 ng/L. CONCLUSION: Although CSF concentrations of NFL and NFHp35 are higher in patients with ALS, the diagnostic accuracy for differentiating ALS from ALS-mimic disorders seems insufficient. Our results suggest that, in the clinical work-up of patients suspected of ALS, application of CSF analysis alone is limited but may have potential in combination with other clinical and electrophysiological markers.

Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of paediatric patients: reference values for a paediatric population.

BACKGROUND: Cerebral folate deficiency (CFD) has been described as a neurological syndrome associated with low 5-methyltetrahydrofolate (5-MTHF) values in cerebrospinal fluid (CSF) with normal folate concentrations in plasma. Our aim was to analyse CSF 5-MTHF concentrations in a paediatric control population and in patients with various neurological disorders. METHODS: We studied plasma and CSF samples from 63 paediatric controls (age range: 2 days to 18 years, average: 3.8 years) and from 165 patients (age range: 1 day to 22 years, average: 5.0 years) with severe epileptic encephalopathies of unknown origin, movement disorders, Rett syndrome and mitochondrial diseases. CSF 5-methyltetrahydrofolate was analysed by reverse phase HPLC with fluorescence detection (excitation: 295 nm and emission: 355 nm). RESULT: A negative correlation between 5-MTHF values and age of controls was observed (r=-0.468; p<0.0001) and reference values were therefore stratified into 3 age groups. Regarding patients, 122 out of 165 showed normal CSF 5-MTHF values while 43 showed decreased values ranging from profound to mild deficiencies. Increased CSF total protein values were associated with the presence of low 5-MTHF concentrations (chi(2)=7.796; p=0.005). CONCLUSIONS: The application of this method has been useful for the establishment of reference values and for diagnosis of CFD in paediatric patients. Furthermore, increased CSF total protein concentrations should be considered as a marker of a possible CFD.

Cerebrospinal fluid catecholamine levels in Japanese encephalitis patients with movement disorders.

Norepinephrine and dopamine have important role in movement disorders but their role in movement disorders associated with Japanese encephalitis (JE) has not been evaluated. Therefore, in the present study, cerebrospinal fluid (CSF) catecholamine levels and its metabolites in JE patients with movement disorders were compared with those without JE. CSF was collected by lumbar puncture and analyzed by HPLC-ED. Norepinephrine, dopamine and homovanillic acid concentrations were significantly (P<0.005) lower in JE patients compared to control groups. Low levels of catecholamines in JE associated movement disorders compared to idiopathic Parkinson's disease and other extrapyramidal symptoms may be due to severe structural damage to thalamus, basal ganglia and brainstem in JE patients as revealed by MRI findings.

The increase of neuron-specific enolase in cerebrospinal fluid and plasma as a marker of neuronal damage in patients with acute brain infarction.

Our goal was to determine the neuron-specific enolase (NSE) concentration in cerebrospinal fluid (CSF) and plasma in patients with the acute brain infarction (BI) and analyze the correlation between the measured NSE concentration and infarct volume and the degree of neurological and functional deficit. The study included 55 patients aged 56-68 with BI in the acute phase. The control group consisted of 16 patients subjected to diagnostic radiculography. The results showed a significant increase of NSE concentration within the first seven days in patients compared to the controls (2.838 +/- 0.504 ng/ml CSF and 4.479 +/- 0.893 ng/ml plasma). A significant correlation was found between NSE concentration and infarction volume and the degree of neurological and functional deficit both in the CSF (r = 0.828, r = 0.735, r = 0.796; p < 0.001) and in plasma (r = 0.810, r = 0.681, r = 0.783; p < 0.001). The results suggest that an early determination of this marker in CSF and plasma in patients with BI could be a valuable diagnostic factor.