Catrinel Iliescu

Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs

BACKGROUND We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy.

Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C>T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T>C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5–10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

A multinational survey on actual diagnostics and treatment of subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.

Angelman syndrome patient management: 5 years of clinical experience

Abstract Angelman syndrome (AS) is a genetic condition characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behavior, and movement disorder. It is caused by a variety of genetic mechanisms that all interfere with the expression of the UBE3A gene on chromosome 15q11-13. The management of AS patients is complex and involves a multidisciplinary approach. Here, we present our experience in the diagnosis and treatment of children with AS.

DMD and West syndrome.

Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5-1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients.

Practical clues for diagnosing WWOX encephalopathy

The WW domain-containing oxidoreductase gene is implicated in autosomal recessive disorders of the central nervous system, expressed either as spinocerebellar ataxia or as a severe form with early-infantile epileptic encephalopathy. Here, we describe the electroclinical evolution of these disorders, adding new diagnostic clues based on a case study. The patient, a boy with early-onset epilepsy, presented with profound global developmental delay, persistent hypsarrhythmia, and epileptic spasms, associated with progressive cerebral atrophy without microcephaly. Metabolic disease was excluded. Whole-exome sequencing showed mutations in the WW domain-containing oxidoreductase gene. Our findings extend the phenotypic traits of this aggressive epileptic encephalopathy, with persistent epileptic spasms and hypsarhythmia as a part of the electroclinical phenotype, demonstrating that microcephaly is not mandatory for diagnosis, even when associated with progressive cerebral atrophy. These mutations might be more frequent than expected among early-onset epileptic encephalopathies. We present practical clues for the diagnosis of WWOX encephalopathy in order to avoid unnecessary investigations and ensure appropriate genetic counselling for the families.

OC-51 Tips and tricks in movement disorders in children – the paediatric neurologist perspective-

Movement disorders are neurological syndromes affecting either the voluntary movements, or implying abnormal postures and also a large category of involuntary movements. The movement disorders in children are difficult to classify and describe and most of the time need repeated video visualisation. In children the difficult part is to establish the main symptom, the dominant movement disorder, taking into consideration the variable pattern of symptoms with age and also in the context of the causative disease progression. The aim of the presentation is to help distinguish between different movement disorders, emphasising clinical clues and key-investigations which could offer a rapid aetiology orientation. Acute or chronic movement disorders, permanent or episodic, progressive or not will be exemplified through cases from the experience of a tertiary clinic of paediatric neurology. What would the algorithm of investigation of the ataxic child should be? What questions should be asked when facing a child with acute onset or at the other end of the spectrum – a progressive ataxia? Acute intoxication, opsoclonus-myoclonus, ataxia-telangiectasia, neuronal ceroid lipofuscinosis will be examples for these situation. The extrapyramidal, dyskinetic child will be presented in various instances – the chronic presentation being a sign in many neurometabolic conditions: Lesch-Nyhan, monocarboxylate transporter 8 deficiency, glutaric aciduria type 1, mitochondrial and neurotransmitters disorders will be a few examples of different situations. Conclusion The semiological recognition of the patterns of abnormal movements and the model of evolution help the etiological diagnostic, the history taken from patient and family and the videos being very useful for identifying correctly the abnormal movement. In approaching a child with movement disorder we should think simple, in well defined steps, starting from simple investigations and moving forward in an individualised manner. Early diagnosis might allow early treatment, anticipatory management of complications, sometimes improving outcome and ultimately the quality of life and also would allow in a number of cases genetic advise for the affected families.

P138 – 3000: Neonatal brachial plexus palsy – Romanian single centre experience over 6 years

Objective The aim of this poster is to analyze the cohort of patients with NBPP followed in the Pediatric Neurology Department, to identify specific clinical signs, investigations, outcome and to establish a protocol of diagnosis and follow-up for children with NBPP, according to the actual international recommendations adapted to the local needs. Methods The archive of Pediatric Neurology Clinic was retrospectively analyzed over a 6.5 years period (January 2007–July 2013), selecting the patients with NBPP. Clinical data, information about physical therapy, EMG and MRI results (if needed) were extract from the files and Active motor scale, Toronto score and protocol for obstetrical brachial plexus palsy (Hospital for Sick Children Seattle), were retrospectively applied. Also a questionnaire designed by us was applied for evaluation of present neurological status. Results A cohort of 28 cases evaluated in our clinic between Jan 2007-July 2013 was analyzed. 17 (60.7%) of the patients were boys and 11 (39.2%) were girls. 14 (50%) had right brachial plexus palsy, 12 (42.8%) had left brachial plexus palsy and 2 (7.1%) had bilateral involvement. 5 (17.8%) of them had reconstructive surgery. 11 (39.2%) had good to complete recovery with physical therapy. Conclusion A better information of the parents and doctors concerning the steps of evaluation of this diseases and importance of early diagnosis and compliance with the treatment protocol is critical for a better outcome and for avoiding permanent deficit. This is a pilot study, with a proposal of protocol for diagnosis and treatment, according to the international protocols in force, but prospective studies are mandatory to complete and refresh the existent data.

P25 – 2072 Diagnostic clues and difficulties in Dravet syndrome starting from 34 Dravet patients analysis within Romanian Research Group for Rare Genetic Epilepsies

Objectives: Antiepileptic drugs, such as carbamazepine, often increase the serum concentrations of serum lipids. Studies evaluating the effect of levetiracetam (LEV), a newer broad spectrum antiepileptic agent, on serum lipid levels are very limited. The aim of this study was to investigate prospectively the effect of LEV monotherapy on serum lipid profile in children with epilepsy. Material and methods: The study population consisted of 20 children (8 males, 12 females, aged 2 to 15 years old, mean age 6.5±4.16 years) with epilepsy treated with LEV monotherapy. None of the children were receiving any form of AED medication prior to LEV initiation. Serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), apolipoprotein AI (apo A-I), apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)] were evaluated in all children, before and at 2 and 6 months of LEV monotherapy. Results: TC and HDL-C were significantly increased at 6 (p=0.011 and p=0.012, respectively) months of LEV treatment. There were no significant alterations in LDL-C, TGs, apo A-I, apo B and Lp(a) levels during the study. Conclusions: LEV monotherapy may cause significant alterations in TC, and HDL-C levels in children with epilepsy, occurring early in the course of treatment. Long-term, large, prospective studies are required to clarify the possible effect of LEV on serum lipid profile, the underlying mechanisms involved and its clinical significance.