Fatigue is a non-specific symptom that is common in chronic diseases and represents one of the most disabling symptoms in Parkinson's disease. PD patients often experience cognitive deficits related above all to executive functions. The relationship between cognitive changes and fatigue in PD patients has not been explored in depth. The Attention Network Test (ANT) is a rapid, widely used test to measure the efficiency of three attentional networks, i.e., alerting, orienting, and executive, by evaluating reaction times (RTs) in response to visual stimuli. To assess the association between fatigue and the efficiency of the attentional networks, according to the Posnerian view, ANT was administered to 15 parkinsonian patients with fatigue (PFS-16 > 2.95), 17 parkinsonian patients without fatigue, and 37 age- and sex-matched healthy controls. Anxiety, depression, quality of sleep, and quality of life were also assessed. Parkinsonian patients displayed significantly longer RTs and lower executive network efficiency than controls. Patients with fatigue displayed significantly lower executive network efficiency than patients without fatigue. Moreover, patients with fatigue exhibited a lower accuracy than either patients without fatigue or controls. Finally, patients without fatigue displayed a more efficient alerting network than either patients with fatigue or controls. Although the pathogenesis of fatigue is multifactorial, our results indicate that fatigue may be closely related to an alteration of the striato-thalamo-cortical loop connecting the neostriatum to the prefrontal cortex, which is also responsible for the executive dysfunction that is typical of Parkinson's disease.

The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11;

KCND3 encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K+ current. KCND3 defect causes both cardiological and neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA type 19/22, a complex neurological disorder encompassing a wide spectrum of clinical features beside ataxia. To better define the phenotypic spectrum and course of KCND3-related neurological disorder, we review the clinical presentation and evolution in 68 reported cases. We delineated two main clinical phenotypes according to the age of onset. Neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms. Furthermore, we described a 37-year-old patient with a de novo KCND3 variant [c.901T>C (p.Ser301Pro)], previously reported in dbSNP as rs79821338, and a clinical phenotype paradigmatic of the early onset forms with neurodevelopmental disorder, epilepsy, parkinsonism-dystonia, and ataxia in adulthood, further expanding the clinical spectrum of this condition.

Methyl CpG-binding protein 2 (MeCP2) deficiency is associated to Rett syndrome (RTT), an X-linked neurodevelopmental disorder affecting females, accounting for 95% to 97% of typical RTT. 1 The first male patient with MECP2 mutation was described in 1999, overcoming the concept of lethality of MeCP2 deficiency in males, and, later on, a number of patients with early-onset severe encephalopathy were described. 2 MECP2 is now recognized to be causative of a wide spectrum of clinical manifestations in males, including cognitive impairment, movement disorders, and epilepsy. 3 Here we report on a new phenotypic presentation of MeCP2 deficiency characterized by intellectual disability, early-onset parkinsonism, and vertical supranuclear gaze palsy (VSGP).This 17-year-old male was born at term without complications from nonconsanguineous healthy parents. He was able to walk at 16 months and spoke his first words at 24 months of age. At the age of 4 years, upper limb tremor was noticed, and at the age of 8, a neuropsychological evaluation revealed a borderline intellectual functioning. At that time, karyotype, FMR1 sequencing, and single-nucleotide polymorphism array revealed no abnormalities.At the age of 16 years, he suffered from an acute-onset psychomotor agitation, confabulation, and visual hallucinations. On examination, a few weeks later, he presented a catatonic state, with stupor, akinesia, waxy flexibility, mutism, staring, and catalepsy (Video 1, segment 1). He also had hypostaturism. A lorazepam trial (2 mg) rapidly resolved the catatonic state. Once catatonia resolved VSGP, intermediate-frequency low-amplitude postural and kinetic tremor with superimposed distal jerks and only minimal rest component, upper limb slight dystonic posturing, bradykinesia, rigidity, and anterior neck flection became evident (Video 1, segments 2-4). Finger tapping showed decrement in both rate and amplitude (Video 1, segment 3). Lower limb reflexes were brisk. A reevaluation of his cognitive function revealed moderate cognitive impairment (IQ = 40).An extensive metabolic workup, including plasma aminoacids, urinary organic acid, acylcarnitine, plasma oxysterols, lactate, pterins, and cerebrospinal fluid neurotransmitter metabolites failed to detect any specific alterations. Brain MRI and DaT-scan were both normal.

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Over the last years, a constantly increasing number of genetic diseases associated with epilepsy and movement disorders have been recognized. An emerging group of conditions in this field is represented by genetic disorders affecting G-protein-coupled receptors (GPCRs)–cAMP signaling. This group of postsynaptic disorders includes genes encoding for proteins highly expressed in the central nervous system and involved in GPCR signal transduction and cAMP production (e.g., GNAO1, GNB1, ADCY5, GNAL, PDE2A, PDE10A, and HPCA genes). While the clinical phenotype associated with ADCY5 and GNAL is characterized by movement disorder in the absence of epilepsy, GNAO1, GNB1, PDE2A, PDE10A, and HPCA have a broader clinical phenotype, encompassing movement disorder, epilepsy, and neurodevelopmental disorders. We aimed to provide a comprehensive phenotypical characterization of genetic disorders affecting the cAMP signaling pathway, presenting with both movement disorders and epilepsy. Thus, we reviewed clinical features and genetic data of 203 patients from the literature with GNAO1, GNB1, PDE2A, PDE10A, and HPCA deficiencies. Furthermore, we delineated genotype–phenotype correlation in GNAO1 and GNB1 deficiency. This group of disorders presents with a highly recognizable clinical phenotype combining distinctive motor, epileptic, and neurodevelopmental features. A severe hyperkinetic movement disorder with potential life-threatening exacerbations and high susceptibility to a wide range of triggers is the clinical signature of the whole group of disorders. The existence of a distinctive clinical phenotype prompting diagnostic suspicion and early detection has relevant implications for clinical and therapeutic management. Studies are ongoing to clarify the pathophysiology of these rare postsynaptic disorders and start to design disease-specific treatments.

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