Automatic imitation in youngsters with Gilles de la Tourette syndrome: A behavioral study.

It is widely known that humans have a tendency to imitate each other and that appropriate modulation of automatic imitative behaviors has a crucial function in social interactions. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric disorder characterized by motor and phonic tics. Apart from tics, patients with GTS are often reported to show an abnormal tendency to automatically imitate others' behaviors (i.e., echophenomena), which may be related to a failure in top-down inhibition of imitative response tendencies. The aim of the current study is to explore the top-down inhibitory mechanisms on automatic imitative behaviors in youngsters with GTS. Error rates and reaction times from 32 participants with GTS and 32 controls were collected in response to an automatic imitation task assessing the influence of observed movements displayed in the first-person perspective on congruent and incongruent motor responses. Results showed that participants with GTS had higher error rates than controls, and their responses were faster than those of controls in incompatible stimuli. Our findings provide novel evidence of a key difference between youngsters with GTS and typically developing participants in the ability to effectively control the production of own motor responses to sensory inputs deriving from observed actions.

Globus pallidus internus activity during simultaneous bilateral microelectrode recordings in status dystonicus.

Limited data are available regarding the electrophysiology of status dystonicus (SD). We report simultaneous microelectrode recordings (MERs) from the globus pallidus internus (GPi) of a patient with SD who was treated with bilateral deep brain stimulation (DBS). Mean neuronal discharge rate was of 30.1 ± 10.9 Hz and 38.5 Hz ± 11.1 Hz for the right and left GPi, respectively. On the right side, neuronal electrical activity was completely abolished at the target point, whereas the mean burst index values showed a predominance of bursting and irregular activity along trajectories on both sides. Our data are in line with previous findings of pallidal irregular hypoactivity as a potential electrophysiological marker of dystonia and thus SD, but further electrophysiological studies are needed to confirm our results.

R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome.

TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.

Pallidal stimulation for acquired dystonia due to cerebral palsy: beyond 5 years.

BACKGROUND AND PURPOSE: There is increasing evidence that deep brain stimulation (DBS) of the globus pallidus internus (GPi) is effective in patients with idiopathic or inherited generalized dystonia. There is comparatively less experience about the effects of GPi DBS on acquired dystonia, particularly dystonia due to cerebral palsy (DCP). Clinical and demographic outcome predictors for DBS in dystonia syndromes are also poorly defined. Our aim was to examine the efficacy and safety of GPi DBS for the treatment of generalized DCP. METHODS: Fifteen patients with DCP up to 6.2 years after DBS surgery were studied. Only mild limb spasticity or mild static brain magnetic resonance imaging abnormalities were acceptable for inclusion. Dystonia severity and disability were assessed by the Burke-Fahn-Marsden dystonia rating scale (BFMDRS), and health-related quality of life was assessed by the Short Form General Health Survey (SF-36) scale. The amount of energy delivered was calculated, and adverse events and side effects were collected. RESULTS: At last follow-up, BFMDRS motor score improved on average by 49.5%, and the disability score improved by 30%. Health-related quality of life improved in most patients. Age at implant, age at onset and disease duration did not correlate to outcome, whilst higher pre-operative dystonia severity and occurrence of spasticity were associated with poorer outcome. The patients received a stable amount of energy after the first 2 years post-implant and throughout all the observation period. There were few serious adverse events or side effects. CONCLUSIONS: The outcome was encouraging in the majority of DCP patients, with a stable outlook and a good safety profile.

Extragenetic factors and clinical penetrance of DYT1 dystonia: an exploratory study.

Factors modifying the clinical penetrance of DYT1 dystonia are incompletely defined. Particularly, the contribution of extragenetic factors has been subject to only limited investigation and remains largely unexplored. A possible effect of childhood infections has been proposed, and the effect of other factors, such as perinatal adversity and trauma, has not been systematically investigated. We performed an exploratory analysis of the exposure to perinatal adversity, childhood infections, general anaesthesia and trauma comparing 39 manifesting carriers of the ∆GAG mutation, 23 non-manifesting carriers and 48 non-carriers from a multi-centre European series of 28 families with DYT1 dystonia, by means of a self-completed questionnaire and clinical interview. Detailed information on perinatal adversities (pre-term birth, complications at natural delivery, urgent caesarean section), previous childhood infections, and prior general anaesthesia or physical trauma was recorded. A positive association between a history of complications of vaginal delivery and manifestation of dystonia was detected, which was not confounded by age, gender, or education level (odds ratio 8.47, 95 % confidence interval 1.45-49.4, p = 0.02). We could not observe any significant association between presence of dystonia and the other investigated variables. Comparing non-manifesting carriers to non-carriers, the presence of the ∆GAG mutation per se was not associated with any of the environmental exposures explored. Perinatal adversities might modulate the clinical penetrance of DYT1 dystonia; their interaction with known genetic factors modifying penetrance of this condition should be investigated in new, larger collaborative studies.

The "eye-of-the-tiger" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disorder associated with brain iron accumulation. The brain MRI abnormality consists of T2 hypointensity in the globus pallidus with a small hyperintensity in its medial part, called the "eye-of-the-tiger" sign. We report on 2 patients affected by PKAN, in whom MRI examination did not demonstrate the "eye-of-the-tiger" sign in the early stages; the typical abnormalities were detected only in the following examinations. Case 1 is a 4-year-old boy first studied at age 2 years for psychomotor delay. The brain MRI was normal. In the following 2 years, the motor impairment progressed. The second brain MRI at age 4 years demonstrated the "eye-of-the-tiger" sign. Molecular analysis of the PANK2 gene revealed a missense mutation F228S in exon 2 in homozygosis. Case 2 is a 6-year-old boy first studied at age 2 years because of psychomotor delay. His brain MRI did not demonstrate abnormalities in the globus pallidus. In the following years spastic-dystonic tetraparesis became evident. A brain MRI at age 4 years demonstrated the "eye-of-the-tiger" sign. Molecular analysis of the PANK2 gene revealed a missense mutation in exon 5 (N501I). Our 2 cases demonstrate that the observation of a normal globus pallidus in the early stage of the disease does not exclude the diagnosis of classic PKAN.

Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with rarer neurological presentation. When this occurs, diagnosis may be delayed. This report aims to call attention to clinical, laboratory, and radiological features that should prompt the correct diagnosis. A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia. MRI showed a diffuse tumor-like swelling of the cerebellum with tonsillar herniation and patchy white matter post-contrast enhancement. Regression of swelling with steroids ruled out glioma and medulloblastoma, and brain lymphoma was considered. Diagnosis of HLH was reached 2 months after onset when uncontrolled fever and severe elevation of liver enzymes occurred. Two bone marrow biopsies were needed to demonstrate hemophagocytosis. Familial HLH was confirmed by perforin gene mutations. Bone marrow transplantation was performed. The early diagnosis of HLH may be life saving. Awareness of the disease is necessary to investigate its characteristic findings, thus avoiding a delay in diagnosis.

EFNS guidelines on diagnosis and treatment of primary dystonias.

OBJECTIVES: to provide a revised version of earlier guidelines published in 2006. BACKGROUND: primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people. DIAGNOSIS: primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder. TREATMENT: botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.

Neurodegeneration associated with genetic defects in phospholipase A(2).

OBJECTIVE: Mutations in the gene encoding phospholipase A(2) group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A(2). METHODS: We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations. RESULTS: Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations. CONCLUSION: Defects in phospholipase A(2) lead to a range of phenotypes. PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy but a minority of cases of idiopathic neurodegeneration with brain iron accumulation, and genotype correlates with phenotype. Cerebellar atrophy predicts which patients are likely to be mutation-positive. The neuropathologic changes that are caused by defective phospholipase A(2) suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.

Impaired body movement representation in DYT1 mutation carriers.

OBJECTIVE: The only known genetic cause of early-onset primary torsion dystonia is the GAG deletion in the DYT1 gene. Due to the reduced penetrance, many mutation carriers remain clinically asymptomatic, despite the presence of subclinical abnormalities, mainly in the motor control circuitry. Our aim was to investigate whether the DYT1 mutation impairs the inner simulation of movements, a fundamental function for motor planning and execution, which relies upon cortical and subcortical systems, dysfunctional in dystonia. METHODS: DYT1 manifesting patients, DYT1 non-manifesting carriers and control subjects were asked to fixate body (hand, foot, face) or non-body (car) stimuli on a computer screen. Stimuli were presented at different degrees of orientations and subjects had to mentally rotate them, in order to give a laterality judgement. Reaction times and accuracy were collected. RESULTS: DYT1 carriers, manifesting and non-manifesting dystonic symptoms, were slower in mentally rotating body parts (but not cars) than control subjects. CONCLUSIONS: The DYT1 gene mutation is associated with a slowness in mental simulation of movements, independently from the presence of motor symptoms. SIGNIFICANCE: These findings suggest that the cognitive representation of body movements may be altered subclinically in dystonia, thus contributing to the endophenotypic trait of disease.

Polymyography in the diagnosis of childhood onset movement disorders.

UNLABELLED: We report on the results of a clinical and polymyographic retrospective study of 61 paediatric patients with tremor, dystonia and/or myoclonus. Aim of the study was to verify the contribution of polymyography in the classification of these movement disorders and in their aetiological definition. METHODS: The movement disorders were clinically classified by two experts, based on clinical and videotape recordings evaluation; all patients underwent standardized polymyographic evaluation; aetiological diagnosis was performed according to diagnostic protocols for dystonia, myoclonus, tremor and psychogenic movement disorders. The polymyographic features were summarized in five different patterns (dystonia, subcortical myoclonus, myoclonic dystonia, tremor, normal) and compared with the clinical classification and with aetiological diagnosis. RESULTS: In more than 70% of the patients the polymyographic features were in accordance with the clinical classification; in 31% the polymyographic features allowed to identify a clinically unclassified movement disorder and in 19.6% disclosed a not clinically evident associated movement disorder. The polymyographic study did not contribute to the aetiological diagnosis, but was useful in supporting the clinical diagnosis of psychogenic movement disorder.

Revelation of a novel CLN5 mutation in early juvenile neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (NCLs) are relatively common storage diseases of childhood and early adolescence. Ultrastructural shape of storage cytosomes, type of disease gene, and age of onset serve to classify the different NCLs, some of which appear to cluster in Scandinavian countries. The CLN5 form usually presents as a classical epileptiform encephalopathy of late infancy but a more aggressive cognitive impairment has been described in a single family. We report two sibs harbouring a novel mutation (p.Tyr258Asp) in the CLN5 gene and displaying behaviour disturbances and mental deterioration, rather than epilepsy, as the dominant disease manifestation at onset.

Persistent fixed torticollis due to Atlanto-axial rotatory fixation: report of 4 pediatric cases.

Atlanto-axial rotatory fixation (AARF) is a rare cause of childhood torticollis that may occur spontaneously or in association with trauma and upper respiratory infections. We describe the clinical findings, as well as the effectiveness of imaging in the diagnosis and the treatment of 4 children with AARF, in whom acute fixed non-dystonic torticollis was the presenting symptom. Onset of torticollis was spontaneous in Case 1, after general anesthesia for cholesteatoma surgery in Case 2, after a trauma in Case 3, and during hypersomnia in Case 4. Duration of torticollis prior to diagnosis was 3 months in the first two patients and 20 days in the other two. All the patients underwent cervical X-rays examinations, which were not contributory to the diagnosis, followed by CT, which demonstrated C1-C2 rotatory fixation. One patient had a spontaneous resolution; treatment with Gardner's tongs and soft collar permitted restoration of the normal alignment in the other 3 patients. AARF must be considered in all the patients with persistent painful torticollis.

Infantile neuroaxonal dystrophy and pantothenate-kinase-associated neurodegeneration: locus heterogeneity.

Common clinical, radiologic, and pathologic features in infantile neuroaxonal dystrophy (INAD) and pantothenate kinase-associated neurodegeneration (PKAN) have led to the hypothesis of an allelic relationship. With the discovery of the gene defect in PKAN, this can now be tested directly. The authors excluded linkage in one consanguineous INAD family by haplotype analysis. Moreover, sequencing in seven INAD families revealed no mutations in PANK2 or in other genes of CoA biogenesis. Thus, INAD and PKAN are genetically heterogeneous disorders.

GTP-cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP-CH1 deficiency: identification and functional characterization of four novel mutations.

GTP-cyclohydrolase I (GTP-CH1, EC 3.5.4.16) is encoded by the GCH1 gene. Mutations in the GCH1 gene cause both dopa-responsive dystonia (McKusick 128230) and recessive GTP-CH1 deficiency (McKusick 600225). The exact molecular mechanism resulting in decreased GTP-CH1 activity in the patients is still obscure. We report the clinical features and molecular and functional study of the GCH1 gene in eight Italian patients affected by dominant and recessive GTP-CH1 deficiency. All the studied patients had mutations in the GCH1 gene. Three missense mutations (V205G, K224R, P199A), a frameshift mutation (Delta G693), and a splice-site mutation (ivs5 + 1g > c) were found. Except for K224R these are all novel mutations. To analyse the defect caused by the novel mutations, an in vivo functional assay in a Saccharomyces cerevisiae strain lacking the endogenous gene encoding GTP-CH1 ( FOL2 ) was performed. Complementation analysis showed that the Delta G693 and V205G mutations abolish the enzymatic function, while the P199A mutation causes a conditional defect. In conclusion, the clinical phenotypes displayed by our patients confirm the wide clinical spectrum of the disease and further support the lack of correlation between a given mutation and a clinical phenotype. Complementation analysis in yeast is a useful tool for confirming the pathogenetic effect of GCH1 mutations.

Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a genetic disorder featuring diffuse MRI white matter abnormalities and a discrepantly mild clinical picture. It is related to different mutations in MLC1 gene encoding a putative membrane protein of still unknown function. We report on a genetically proven MLC patient who presented with a peculiar clinical course characterized by a prolonged comatose state following a minor head trauma at 12 years of age. The disturbance of consciousness lasted for over four months and then gradually improved. Proton MR spectroscopic imaging studies showed a moderately severe depletion of N-acetylaspartate restricted to the white matter with sparing of the cortical grey matter. The full recovery from coma suggests a transitory functional impairment of the structures implicated in the maintenance of consciousness.