Alessandro Iodice

ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients

Introduction ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated. Methods We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders. Results We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence. Conclusion Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.

Expanding phenotype of PRRT2 gene mutations: A new case with epilepsy and benign myoclonus of early infancy.

BACKGROUND Mutations in the gene PRRT2 have been identified in a variety of early-onset paroxysmal disorders. To date associations between PRRT2 mutations and benign myoclonus of early infancy have not been reported. CLINICAL REPORT We describe a baby affected by PRRT2 mutation and benign infantile epilepsy, with an episode of focal status epilepticus. During follow-up he developed benign myoclonus of early infancy. DISCUSSION We hypothesize a pathogenic role of PRRT2 mutation in inducing benign myoclonus of early infancy, similarly to that at the origin of other PRRT2-related paroxysmal movement disorders, such as paroxysmal kinesigenic dyskinesia. CONCLUSIONS Currently the function of PRRT2 is poorly understood, even if a marked pleiotropy and variable penetrance of its mutations are well known. Our case concurs in expanding the broad clinical spectrum of PRRT2-related disorders.

CMV-associated axonal sensory-motor Guillain-Barré syndrome in a child: Case report and review of the literature.

BACKGROUND Guillain-Barré syndrome is the most frequent cause of flaccid paresis in Western countries. Moreover, CMV infection is the most common antecedent viral infection in adult patients and the presence of specific IGM antiganglioside antibodies is often identified. Instead, Guillain-Barré syndrome following CMV infections is rarely reported in childhood and often presents severe symptoms at onset and longer recovery times. MATERIAL AND METHODS One year of clinical, electrophysiological and serological follow-up of a 9-year old child with axonal sensory-motor Guillain-Barré syndrome following CMV infection is reported. Moreover, the literature data on paediatric sensory-motor axonal GBS and GBS secondary to CMV infection and antiganglioside antibodies are reviewed. RESULTS Our patient presented with paraesthesias and a pattern of weakness showing proximal predominance and affecting the upper limbs more than the lower limbs. At nadir, unilateral facial palsy was also present and he was unable to walk. Electroneurography showed motor-sensory axonal damage. Both anti-CMV and anti-GM2 IgM were positive. After early treatment with IVIG and IV methylprednisolone the patient recovered deambulation. Six months later, his neurological examination was normal and electroneurography showed normal data. CONCLUSION The sensory-motor axonal form of Guillain-Barré syndrome following CMV infection may present a good prognosis and a prompt full recovery also in children, if adequate treatment is started in time.

KCNQ2 encephalopathy: A case due to a de novo deletion

KCNQ2 encephalopathy is characterized by severely abnormal EEG, neonatal-onset epilepsy and developmental delay. It is caused by mutations (typically missense) in the KCNQ2 gene, encoding the voltage gated potassium channel Kv7.2 and leading to a negative-dominant effect. We present one case experiencing recurrent neonatal seizures with changing hemispheres of origin, reminiscent of epilepsy of infancy with migrating focal seizures. At 9months of age the patient is still seizure-free on carbamazepine, although he is developing a spastic-dystonic tetraplegia with severe dysphagia. He harbors a de novo deletion (c.913_915del [p.Phe305del)]), only described once in a couple of severely affected twins, and leading to the deletion of a phenylalanine residue in the pore domain of the channel. In conclusion, our case is the second described with encephalopathy due to this specific deletion (the one and only deletion so far reported in KCNQ2 encephalopathy). Thus, deletion is a newly described mechanism highlighting how not only missense mutations but also deletions in the channel hot spots can lead to a severe phenotype. Furthermore he presented ictal EEG features similar to epilepsy of infancy with migrating focal seizures not previously described.

Long-term follow-up in spastic paraplegia due to SPG56/CYP2U1: age-dependency rather than genetic variability?

We read with great interest the paper by Leonardi et al. [1] which presented an Italian family harboring a novel homozygous mutation in SPG56/CYP2U1 with pigmentary degenerative maculopathy as a prominent feature. SPG56, due to CYP2U1 mutation, is a rare autosomal recessive early-onset complicated form of hereditary spastic paraplegia with spasticity in the upper limbs, rare dystonic postures, cognitive impairment and subclinical neuropathy [2]. The phenotypic spectrum of SPG56 has been recently expanded: 18 subjects have currently been reported with increasing clinical and neuroradiological heterogeneity [1–6]. We would like to present a further case with two novel mutations in in CYP2U1 gene and pigmentary degenerative maculopathy to highlight how the phenotypic variability so far reported might also be age-dependent and not only related to genetic heterogeneity. This 34-year-old patient was the first daughter of healthy non-consanguineous Caucasian parents. During the long-term follow-up started since the first year of age, she underwent different genetic and neurometabolic investigations. We finally identified thanks to targeted re-sequencing TruSeq Custom Amplicon panel (MiSeq Illumina platform) formed by 21 idiopathic intracranial calcification genes two novel heterozygote mutations in SPG56/CYP2U1 gene: a c.1288?1G[A splicing mutation (exon 3) and a c.1545_1546delTTAC frameshift mutation (exon 5). The segregation of the mutations in the family was confirmed by DNA analysis of the parents. To prove pathogenicity of the mutations we conducted studies through the Next Generation Sequencing of the cDNA of CYP2U1 extracted from patient fibroblasts, evidenced the absence of the allele containing the 4 bp deletion and a significative exon 3 skipping. Until 14 years of age, our patient did not show the described pigmentary maculopathy on the retina, although she had already developed macular haemorrhagic lesions. Moreover, delayed flashing lights and P100 in visualevoked potentials only appeared after 10 years of age. Differently from our case and the case reported by Leonardi et al. [1], in other descriptions ophthalmological examinations were unremarkable [3, 4], probably because subjects were in the pediatric age, whereas in the cases reported by Tesson et al. no information about ophthalmological features were available [1]. In our patient, normal developmental milestones were reported until 14 months, when her motor skills began to deteriorate rapidly for the first 3 years and subsequently slowed down in progression. Since 16 months of age, she developed four limbs spasticity, more remarkable in the lower limbs, with ‘‘bottom to top’’ progression. After the age of 4 years appeared dysarthria and focal dystonic postures of the upper limbs probably due to the basal ganglia involvement. In the time of the last evaluation at 34 years old, she was on a wheelchair due severe spasticity with joint contractures especially in a lower limbs and presented swallowing difficulties. These appear to be & Alessandro Iodice alle.iodice@gmail.com

Symptomatic and presumed symptomatic focal epilepsies in childhood: An observational, prospective multicentre study

To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2–5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance.

Infantile neuroaxonal dystrophy and PLA2G6-associated neurodegeneration: An update for the diagnosis

Infantile neuroaxonal dystrophy is a rare neurodegenerative disorder characterized by infantile onset of rapid motor and cognitive regression and hypotonia evolving into spasticity. Recessively inherited mutations of the PLA2G6 gene are causative of infantile neuroaxonal dystrophy and other PLA2G6-associated neurodegeneration, which includes conditions known as atypical neuroaxonal dystrophy, Karak syndrome and early-onset dystonia-parkinsonism with cognitive impairment. Phenotypic spectrum continues to evolve and genotype-phenotype correlations are currently limited. Due to the overlapping phenotypes and heterogeneity of clinical findings characterization of the syndrome is not always achievable. We reviewed the most recent clinical and neuroradiological information in the way to make easier differential diagnosis with other degenerative disorders in the paediatric age. Recognizing subtle signs and symptoms is a fascinating challenge to drive towards better diagnostic and genetic investigations.

Steroids efficacy in the acute management of seizure clusters in one case of PCDH19 female epilepsy

We read with great interest the paper entitled ‘‘Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy’’ by Higurashi et al. [1]. Clusters of febrile and afebrile seizures, mainly focal motor or hypomotor with affective symptoms, are typical of PCDH19 female epilepsy (PCDH19-FE) [2]. After first reporting on the excellent efficacy of corticosteroids in acute cluster termination in one

Neurovisual Assessment in Children with Ataxia Telangiectasia

Abstract Aim Visual impairment is present in almost all patients with ataxia telangiectasia (AT) and, due to their early onset, constitute an important disabling aspect of the syndrome: the quality of vision is limited by dyspraxia and oculomotor abnormal movements. The purpose of this observational study was to describe visual disorders, notably oculomotor impairment, in a sample of children with AT. Methods Fifteen AT patients (mean age 12 years and 4 months) underwent a neurovisual evaluation, particularly focused on oculomotor functions (fixation, smooth pursuit, saccades, and abnormal ocular movements). We compared the visual profile obtained with that described using the International Cooperative Ataxia Rating Scale (ICARS) subscale of oculomotor dysfunction. Results Refractive errors were seen in eight patients and strabismus in three. Major oculomotor findings were fixation abnormalities (6/15), saccadic impairment (15/15), and abnormal smooth pursuit (14/15). Abnormal ocular movements were seen in 13/15 (saccadic intrusion in 8 and nystagmus in 5). Using ICARS scale, 13/15 children presented gaze‐evoked nystagmus, 4/15 a clearly saccadic pursuit, and 11/15 dysmetria of saccades. Discussion We propose a clinical neurovisual evaluation, which could be integrated with ICARS scores in the study of oculomotor involvement in AT pediatric patients. We strongly recommend the empowerment of visual functions to slow down progressive global disability of these patients.

Restless Legs Syndrome in NKX2-1-related chorea: An expansion of the disease spectrum

BACKGROUND Molecular technologies are expanding our knowledge about genetic variability underlying early-onset non-progressive choreic syndromes. Focusing on NKX2-1-related chorea, the clinical phenotype and sleep related disorders have been only partially characterized. METHODS We propose a retrospective and longitudinal observational study in 7 patients with non-progressive chorea due to NKX2-1 mutations. In all subjects sleep and awake EEG, brain MRI with study of pituitary gland, chest X-rays, endocrinological investigations were performed. Movement disorders, pattern of sleep and related disorders were investigated using structured clinical evaluation and several validated questionnaires. RESULTS In patients carrying NKX2-1 mutations, chorea was mainly distributed in the upper limbs and tended to improve with age. All patients presented clinical or subclinical hypothyroidism and delayed motor milestones. Three subjects had symptoms consistent with Restless Legs Syndrome (RLS) that improved with Levodopa. CONCLUSIONS Patients with NKX2-1 gene mutations should be investigated for RLS, which, similarly to chorea, can sometimes be ameliorated by Levodopa.