Elisa De Grandis

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

Immunological mechanisms in opsoclonus-myoclonus associated neuroblastoma

Opsoclonus-myoclonus syndrome is a rare paraneoplastic disorder, often associated with malignancies including neuroblastoma (NB), the most common solid tumor of childhood derived from the sympathetic nervous system. The pathogenesis of this syndrome is still undefined but is suspected to be the result of an autoimmune response. In this respect, different autoantibodies binding to neurons or cerebellar Purkinje cells have been detected in OMS-associated NB. In addition, immunohistochemical analysis of NB affecting children with OMS demonstrated the presence of interstitial or perivascular lymphoid infiltrates resembling secondary lymphoid follicles. Immunophenotyping of these lymphoid cells showed the existence of a mesh of CD21(+) follicular dendritic cells, numerous CD20(+) B lymphocytes in the germinal center and the mantle zone of the follicle and few CD3(+) T lymphocytes in a perifollicular area. Since information is lacking about the mechanism involved in ectopic lymphoid neogenesis of OMS-associated NB, we are currently investigating the role of different chemokines and their cognate receptors in the recruitment of lymphoid cells within tumor mass of OMS-associated NB. Here, we review some recent data about the pathogenesis of OMS-associated with NB.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype

Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve.

Childhood Thalidomide Neuropathy: A Clinical and Neurophysiologic Study

Thalidomide was recently reintroduced to treat several immune-mediated pathologies. Peripheral neuropathy is a significant side effect limiting its clinical use. Our aims include: (1) describing and identifying the incidence of clinical or electrophysiologic peripheral neuropathy in children, (2) determining whether peripheral neuropathy correlates with cumulative dose of thalidomide and with age, and (3) defining its reversibility rate. We studied 13 children manifesting immune-mediated pathologies treated with thalidomide at doses ranging from 25-100 mg/day. Clinical and neurophysiologic evaluation was performed before and after starting treatment. Seven children (53.8%) showed neurophysiologic signs of sensory peripheral axonal polyneuropathy. Five presented associated clinical symptoms, while the other two only presented subclinical, neurophysiologic signs of peripheral neuropathy. We found a significant correlation between the incidence of peripheral neuropathy and thalidomide cumulative dose (P = 0.02). We observed a lower incidence of peripheral neuropathy at a cumulative dose <20 gm, and a correlation with age (P < 0.01). The clinical and electrophysiologic recovery rate was 40%, and clinical improvement alone was observed in another 40%. Thalidomide induces dose-dependent and age-dependent peripheral neuropathy at a significant frequency in childhood (53.8%). In our experience a cumulative dosage at >20 gm and long-term administration for >10 months seem to increase the risk of peripheral neuropathy. We propose clinical and neurophysiologic follow-up every 3 months to identify and monitor possible side effects.

Response to rituximab in 3 children with opsoclonus-myoclonus syndrome resistant to conventional treatments.

We report the 1 year follow-up of 3 children affected by non-paraneoplastic Opsoclonus-Myoclonus Syndrome (OMS) resistant to conventional therapies (steroids, ACTH and intravenous immunoglobulins) who were treated with an anti CD20 monoclonal antibody (rituximab). Treatment response was recorded on the basis of an international score at 0, 3, 6, 9 and 12 months. Despite the long disease duration and the numerous previously administered treatments, all patients underwent rapid and persistent neurological recovery following rituximab administration, thus suggesting a potential role of this drug even in pre-treated patients.

Efficacious vitamin E treatment in a child with ataxia with isolated vitamin E deficiency

Vitamin E deficiency can cause a progressive spinocerebellar ataxia similar to Friedreich ataxia phenotype [2, 3]. Differential diagnosis between the two forms is based on serum level of vitamin E and is very important for prognosis because in patients with ataxia with isolated vitamin E deficiency (AVED) vitamin E supplementation allows a stabilization of the neurological conditions [3, 6] and may lead to clinical improvement [4]. We report the case of a young patient with AVED with a complete regression of ataxia after early and long-term vitamin E oral supplementation. Our case strongly suggests early recognition and treatment of vitamin E deficiency to improve disease outcome. AVED (OMIM #277460) is a rare autosomal recessive neurodegenerative disease caused by mutations in the αtocopherol transfer protein (TTPA) gene, which maps to locus 8q13.1-q13.3 on chromosome 8 [3]. The deficit reduces the capacity to incorporate α-tocopherol (the most biologically active form of vitamin E) into very low density lipoproteins secreted by the liver and therefore into plasma and tissues [1]; it affects particularly the nervous system, where neurons are more vulnerable to free-radical damage [5]. The disease was characterized clinically and the defective gene localized to proximal chromosome 8q by Ben Hamida et al. in 1993 [2]. Neurological findings include spinocerebellar degeneration and mild to moderate axonal sensory neuropathy (less severe than in Freidreich ataxia), with clinical picture of ataxia, areflexia, dysarthria, and impaired proprioception. AVED should be differentiated from other syndromes with vitamin E deficiency, which can be caused by intestinal and liver diseases, malabsorption or malnutrition [1]. An 8-year-old girl came to our attention for progressive ataxia since the age of 3 years. She was the only child of healthy consanguineous parents (3rd degree) with a family history of a not defined ataxia in the father’s line. Neurological examination disclosed spinocerebellar degeneration with clinical features of important trunkal ataxia, head tremor, dysmetria, areflexia, bilateral Babinski sign, pes cavus with retraction of Achilles tendon on left the side. Tests for cholestatic liver disease, fat malabsorption and abetalipoproteinemia showed no pathologic alterations. Brain and spine magnetic resonance imaging, fundus examination, electroencephalogram, electrocardiogram, as well as motor conduction velocity (MCV) on peroneal and median nerves resulted unrevealing. Alphafetoprotein (to rule out Ataxia-Telangiectasia) and molecular DNA analysis for Friedereich ataxia were both negative. Sensory conduction velocity (SCV) on sural and median nerves were suggestive of axonal sensory neuropathy and somatosensory evoked potentials (SEP) showed the alteration of bilateral somatosensory conduction. Alpha-tocopherol level was below the sensitivity of the test (normal values 0.5–2.0 mg/dl) and thus high-dose vitamin E supplementation was given at the dosage of 1200– 1500 mg/day until the serum concentration raised to 1.23 mg/dL. DNA analysis for the detection of the two most common mutations of the α-TTP gene in patients from Mediterranean population [6] showed homozygous 744delA mutation. After only six months we witnessed complete resolution of trunkal and limb ataxia as well as SCVand SEP normalization. Deep tendon reflexes remained abolished and the foot deformity persisted requiring surgical correction. We want to highlight the importance of the assay of vitamin E serum levels in Friedreich-like ataxia. In our case the truncating homozygous 744delA mutation caused the complete abolishment of α-TTP synthesis with a severe and early phenotype of the disease [1, 4]. However, early and high-dose oral supplementation could lead to complete L. Doria-Lamba (*) . E. De Grandis . E. Cristiani . I. Fiocchi . L. Montaldi . P. Grosso Operative Unit of Child Neuropsychiatry, Department of Neurosciences, Ophthalmology and Genetics, G Gaslini Institute, University of Genoa, L.go Gaslini 5, 16148 Genoa, Italy e-mail: lauradoria@ospedale-gaslini.ge.it Tel.: +39-010-5636702 Fax: +39-010-381303

Restless legs may be associated with the post-polio syndrome

Restless legs syndrome (RLS) has been described in association with a number of conditions including iron deficiency, neuropathy and Parkinsons disease. Here we report a patient who developed RLS concurrent with the development of classic post-polio syndrome (PPS), 40 years after recovery from an episode of paralytic poliomyelitis. PPS is still frequently encountered in neurological practice, and clinicians should be aware of the possibility of associated RLS.

Movement lateralization and bimanual coordination in children with Tourette syndrome.

Gilles de la Tourette syndrome is a childhood‐onset disorder characterized by persistent motor and vocal tics fluctuating in severity. Although structural changes observed in Gilles de la Tourette syndrome concern brain structures involved in voluntary motor control such as the basal ganglia, the frontoparietal cortex, and the corpus callosum, movement lateralization and bimanual coordination have been underinvestigated.

Alternating Hemiplegia of Childhood: Pharmacological treatment of 30 Italian patients

BACKGROUND Alternating Hemiplegia of Childhood (AHC) is a severe disorder. Several drugs have been administered as prophylaxis for paroxysmal attacks, however, no therapy is completely effective. METHODS Our aim is to review the pharmacological data related to the prophylactic and acute treatment of a cohort of 30 patients (16M, 14F, age range 5-42years) and to correlate them with the clinical and genetic data collected through the Italian Biobank and Clinical Registry for AHC. RESULTS Flunarizine was the most commonly used long-term treatment in the cohort; it reduced duration and frequency of attacks in 50% of patients and decreased intensity in 32.1%. In younger patients, flunarizine seemed significantly more effective in reducing intensity. We found no correlation between the effectiveness of flunarizine and genotype, or between developmental outcome and duration of treatment. In particular, 3 of our patients affected by E815K mutation presented rapid neurological deterioration despite ongoing treatment. Among the other administered prophylactic therapies, few proved to be effective (benzodiazepines, niaprazine, acetazolamide, melatonin, olanzapine, ketogenic diet). No clear rationale exists regarding their use, but these therapies may work by reducing the triggering factors. CONCLUSIONS The presented data are retrospective, but they are aimed at filling a gap given the rarity of the disease and the lack of randomized and controlled studies. Besides their usefulness in clarifying the pathophysiology of the disease, prospective studies involving larger cohorts of ATP1A3 mutated AHC patients are needed to provide a rationale for testing other molecules.

Paroxysmal features responding to flunarizine in a child with rapid-onset dystonia-parkinsonism

Mutations in the ATP1A3 gene, which encodes the α3 subunit of sodium-potassium ATPase, are related to rapid-onset dystonia-parkinsonism (RDP) and, recently, to alternating hemiplegia of childhood (AHC).1 Here we describe a patient with a de novo ATP1A3 mutation, previously linked to a severe infant variant phenotype for RDP, presenting a new early-onset variant overlapping between the 2 disorders.