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Background and Aims: The parent‐proxy reports can offer complementary informations or be the only source of Quality of Life measurement in young children. The aim of this study was to provide and validate the Italian version of the recently published parent‐proxy pCMT‐QOL for patients aged 8–18 years old, making it available for possible trials in Italian speaking children. Methods: The English‐language instrument was translated and adapted into the Italian language using standard procedures: translation, transcultural adaptation, and back‐translation. Parent‐proxy pCMT‐QOL was administered to parents of patients with a genetic diagnosis of CMT, aged 8–18 years old. All parents were retested 2 weeks later to assess reliability. Results: A total of 21 parents of CMT patients (18 CMT1A, 2 CMT2A, 1 CMT2K) were assessed during their children clinical appointments. The Italian‐pCMT‐QOL showed a high test–retest reliability; none of the parents had any difficulties with the completion of the questionnaire and no further revisions were necessary after completion. Interpretation: The Italian parent‐proxy pCMT‐QOL is a reliable, culturally adapted, and comparable version of the original English instrument. This questionnaire will improve the quality of the follow‐up and will make it possible to monitor more accurately the severity of the disease in Italian‐speaking families. [ABSTRACT FROM AUTHOR]

Paroxysmal dyskinesia (PD) refers to a group of heterogeneous syndromes characterized by recurrent attacks of dystonia and/or chorea, without loss of consciousness.[1] PD are classified by triggers as paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exertion-induced dyskinesia (PED). In our series, 2 of 29 patients with genetically undefined PD carried pathogenetic mutations in I TMEM151A i gene attesting a frequency of 6.9%. PED, also observed in a few PRRT2-related patients, was already reported in one I TMEM151A i patient.[5] Our data supports the hypothesis that I TMEM151A i variants may have decreased penetrance, as already observed in previous reports.[[2], [6]] In addition, a clinical variability could be suggested with migraine as part of I TMEM151A i -related phenotypic spectrum. [Extracted from the article]

The pediatric Charcot‐Marie‐Tooth (CMT) specific quality of life (QOL) outcome measure (pCMT‐QOL) is a recently developed and validated patient‐reported measure of health QOL for children with CMT. The aim of this study was to provide and validate an Italian version of the pCMT‐QOL. The original English version was translated and adapted into Italian using standard procedures. pCMT‐QOL was administered to patients genetically diagnosed with CMT, aged 8 to 18 years. A retest was given 2 weeks later to assess reliability in all patients. A total of 22 patients (median age 14 years, DS 2.5; M:F 1:1) affected with CMT (19 CMT1A, 2 CMT2A, 1 CMT2K) were assessed as part of their clinical visit. The Italian‐pCMT‐QOL demonstrate a high test‐retest reliability. None of the patients experienced difficulty in completing the questionnaire, no further corrections were needed after administration in patients. The Italian‐pCMT‐QOL is a reliable, culturally adapted and comparable version of the original English pCMT‐QOL. This questionnaire is expected to be valuable in monitoring disease progression and useful for future clinical trials in Italian‐speaking children with CMT. [ABSTRACT FROM AUTHOR]

Charcot‐Marie‐Tooth disease (CMT) is a clinically and genetically heterogeneous group of distal symmetric polyneuropathies due to progressive and length‐dependent degeneration of peripheral nerves. Cranial nerve involvement has been described in association with various CMT‐genes mutations, such as GDAP1, TRPV4, MFN2, MTMR2 and EGR2. Compound heterozygous mutations in the TRIM2 gene, encoding an E3 ubiquitin ligase, were previously identified in two patients with early‐onset axonal CMT (CMT2). One of them also had bilateral vocal cord paralysis. The aim of this study is to further delineate the phenotypic and molecular genetic features of TRIM2‐related CMT. We studied clinical, genetic and neurophysiological aspects of two unrelated CMT2 patients. Genetic analysis was performed by next generation sequencing of a multigene CMT panel. Patients presented with congenital hypotonia and bilateral clubfoot, delayed motor milestones, and severely progressive axonal neuropathy. Interestingly, along with vocal cord paralysis, they exhibited clinical features secondary to the involvement of several other cranial nerves, such as facial weakness, dysphagia, dyspnoea and acoustic impairment. Genetic analysis revealed two novel TRIM2 mutations in each patient. Our results expand the genotypic and phenotypic spectrum of TRIM2 deficiency showing that cranial nerves involvement is a core feature in this CMT2‐subtype. Its finding should prompt physicians to suspect TRIM2 neuropathy. Conversely, patients carrying TRIM2 variants should be carefully evaluated for the presence of cranial nerve dysfunction in order to prevent and manage its impact on auditory and respiratory function and nutrition. [ABSTRACT FROM AUTHOR]

An ever-increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the 'genetic epilepsy-dyskinesia' spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease-specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. WHAT THIS PAPER ADDS: Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required. [ABSTRACT FROM AUTHOR]

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified amarked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context. [ABSTRACT FROM AUTHOR]

The article discusses a case report of a 12-year-old girl with paroxysmal non-kinesigenic dyskinesias (PNKD) associated with biallelic POLG variants. The patient experienced hyperkinetic complex movements involving limbs and face, with episodes lasting 3 to 20 minutes, occurring mainly in the morning. Extensive testing ruled out other genetic causes, and treatment with riboflavin and coenzyme Q reduced the intensity and frequency of episodes. The study broadens the understanding of movement disorders associated with mitochondrial DNA polymerase γ (POLG) variants. [Extracted from the article]

Objective: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1 -related disease., Methods: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques., Results: Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16., Conclusions: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.