Goran Krakar

Evolutive leukoencephalopathy in congenital cytomegalovirus infection.

Congenital cytomegalovirus infection is the most common infectious cause of congenital brain injury. Type and severity of congenital cytomegalovirus infection–related brain abnormalities depend on the developmental stage of the central nervous system at the time of fetal infection. The aim of this study was to follow the course of leukoencephalopathy in a patient with congenital cytomegalovirus infection. We describe brain magnetic resonance imaging (MRI) findings of a boy with symptomatic congenital cytomegalovirus infection performed at the age of 3 weeks, 13 months, and 4 and 7 years. Neonatal brain MRI showed most of characteristic findings in congenital cytomegalovirus infection with most prominent white matter abnormalities and cortical dysplasia. MRI follow-up images showed that cortical dysgenesis remained unchanged and static, whereas white matter abnormalities evolved over the years. We propose that leukoencephalopathy in congenital cytomegalovirus infection is not only nonprogressive or static but even evolutive and suggests both underlying disruption and delay of myelination.

Host genetics and susceptibility to congenital and childhood cytomegalovirus infection: a systematic review.

Aim To summarize available evidence on the role of host genetics in the susceptibility to congenital and childhood cytomegalovirus (CMV) infections by conducting a systematic review of published studies. Methods We searched online databases (PubMed, Web of Science, Scopus and HuGe Navigator) for relevant studies with well-defined inclusion and exclusion criteria and assessed the risk of bias using novel Confounding-Selection-Information bias score (CSI). Results 5105 studies were initially identified, but only 5 met all the inclusion criteria and were analyzed in detail. Polymorphisms of the toll-like receptors (TLRs) and mannose-binding lectin (MBL) genes were shown to have an impact on the CMV infection in infants. Polymorphisms of the TLR2 (rs3804100, rs1898830), TLR4 (rs4986791), and TLR9 (rs352140) were shown to have a role in congenital CMV infection. Low MBL levels were associated with CMV infection in Chinese individuals, a finding that was not replicated in Caucasians. The overall credibility of evidence was weak. Conclusions Based on currently available very limited amount of evidence, it is uncertain whether congenital and childhood CMV infections are under host genetic control. Additional primary studies are needed with more specific research hypotheses that will enable gradual understanding of specific mechanisms of the CMV pathogenesis. More genetic studies in the future will facilitate better understanding of host susceptibility and likely enable novel preventative and curative measures.

PP15.5 – 2646: Value of multiple T2-hyperintensities on brain MRI as a diagnostic criterion for neurofibromatosis 1 in children: Comparison of the diagnostic accuracy of T2-hyperintensities versus the National Institutes of Health criteria

Objective Neurofibromatosis 1 (NF1) is autosomal dominant inherited disorder often difficult to diagnose in children besause of its age-dependent presentation. The early diagnosis using National Intitutes of Health (so called NIH-criteria) cannot be made on the basis of routine clinical and ophthalmological examinations in all children, especially in patients of early age and in sporadic cases. T2-hyperintensities on brain MRI has been suggested as a new diagnostic sign. The aim of this study was to compare the degree of diagnostic accuracy T2-hyperintensity versus diagnostic accuracy NIH diagnostic changes. Methods We performed a cross-sectional study of 162 children with NF1 from Croatian Neurofibromatosis Association Database and 163 control children between the ages of 2 and 18 years who underwent brain MRI during twenty year period. In this study we used the basic reference standard – NIH diagnostic criteria for NF1 to determine or exclude a definitive clinical diagnosis of NF1. Results Multiple T2-hyperintensities on brain MRI had excellent diagnostic accuracy with the area under the ROC curve of 0.849, estimated on the whole group subjects aged 2–18 years. The diagnostic accuracy of T2-hyperintensities for NF1 were highest in the youngest age (2–8 years). At that age diagnostic accuracy of multiple T2-hyperintensities was significantly higher than diagnostic accuracy of majority of NIH-diagnostic signs – neurofibromas, freckling in the axillary or inguinal region, Lisch nodules, optic gliomas, a distinctive osseous lesions (p Conclusion Significant higher levels of multiple T2-hyperintensities in comparison to most of the NIH diagnostic criteria, especially in the early childrens age, confirm of justifiableness of their inclusion in the major NF1 diagnostic criteria and the need to revise the current NIH diagnostic criteria NF1 in children.

PP04.11 – 3037: Moyamoya in children

Objective Moyamoya is progressive occlusive cerebral arteriopathy of unknown etiology, a common cause of cerebral ischemic stroke in children. It is characterized by progressive constriction (and finally, occlusion) of the terminal part of internal carotid artery and proximal parts of the middle and anterior cerebral arteries, resulting in collateral circulation in the thalamus and basal ganglia. Blood vessels, representing collateral flow in areas of the brain hypoperfusion distal to the stenosis, on the DSA look like “cigarette smoke”, which in Japanese is called “moyamoya”. The highest incidence of the disease was found in Japan. Methods In this paper, we will present nine patients, five boys and four girls, different age (2–10 years, peak 5–6 years) and with different clinical picture (transient hemiparesis in 5/9 children, convulsions in 4/9 children, headaches in 2/9 and dizziness in 1 child), admitted to our clinic. Results By processing (Transcranial color doppler, MRI/MRA and DSA) in all progressive occlusive cerebrovascular arteriopathy was proven (Moyamoya disease in 6/9 and Moyamoya syndrome in 3/9 children). Six of the nine patients underwent neurosurgical revascularization with variable outcome. One patient in young age had extremely progressive course of the disease, developing tetraparesis, epilepsy, blindness, motor aphasia and dysphagia, renal failure and death. Other patients had a better outcome: 3/6 operated have orderly development, and the two have mild cognitive deterioration. Conclusion Regardless differences between idiopathic and syndromal (associated) forms, angiographic characteristics, clinical features and outcome are the same. Unfavorable outcome have small children with bilateral ischemic infarcts and fixed neurologic deficit. The clinical presentation and neurological status at the moment of diagnosis are most important prognostic factors and predictors of long term outcome. It is important to make a diagnosis on time and prevent serious permanent neurological damage.

Congenital myotonic dystrophy: case report

Miotonička distrofi ja tip 1 (DM1) ili Steinertova bolest druga je po učestalosti mišićna distrofi ja u djetinjstvu, odmah nakon progresivnih mišićnih distrofi ja Duchenne i Becker. Incidencija u općoj populaciji iznosi 1:8000 u Europi (1), 1:30 000 u Hrvatskoj (2). U našoj zemlji visoka prevalencija miotoničke distrofi je od 18/100 000 stanovnika nađena je u Istri (3). Nasljeđuje se autosomno dominantno, gen je lociran na dugom kraku 19. kromosoma (19q13), a genski produkt je mio tonin proteinska kinaza. Bolest nastaje zbog dinamičke mutacije, tj. patološkog umnažanja sljedova identičnih trinukleotida CTG unutar nekodirajuće sekvencije gena za miotonin protein kinazu (DMPK) na dugom kraku 19. kromosoma (19q13.3). U zdravih osoba broj ponavljanja tripleta CTG iznosi 5-34 i on ostaje stabilan tijekom generacija. Kod bolesnih osoba slijed je produljen i sadržava od 50 do nekoliko tisuća trinukleotida CTG, a težina kliničke slike i vrijeme javljanja bolesti koreliraju s veličinom produljenog slijeda. Osobe s brojem tripleta 35-49 koji su nositelji premutacijskog alela, zdravi su prenositelji bolesti (4). Mutacija se češće prenosi preko majke, a svaka sljedeća generacija nosi molekulski i klinički težu mutaciju (fenomen anticipacije).

Identical mutation associated with distinct clinical phenotypes of Friedreich’s ataxia: case report

Friedreich’s ataxia (FA or FRDA) is an autosomal recessive spinocerebellar disorder that has a slow, degenerative course. It aff ects one per 50 000 people and is the most frequent inherited ataxia. Friedreich’s ataxia is characterized by progressive gait and limb ataxia, with no diff erence regarding race and gender. Genetically, it is identifi ed by expression of the unstable guanidine adenine adenine trinucleotide (GAA) repeat expansion in the fi rst intron of the FXN gene on chromosome 9. Most patients are homozygous for the expansion of GAA triplet repeat within the FXN gene. A great majority of patients with FA (about 94%) are homozygous for the GAA trinucleotide, while only a small percentage (about 6%) are compound heterozygotes for GAA expansion and frataxin point mutation responsible for the formation of abnormal protein as a possible source of diff erent clinical presentation (1). The expanded GAA repeat is thought to result in frataxin defi ciency by interfering with transcription of the gene by adopting an unstable helical structure. The larger the number of repeats, the more profound is the reduction in frataxin expression (2). The age at disease onset, severity, progression speed, and neurologic involvement vary with the number of repetitive GAA sequences (3). The broad clinical spectrum includes late-onset FA (LOFA) and FA with retained refl exes (FARR).

P17.19 Menkes disease – a case report of a male infant

Background: Menkes disease is a rare X linked lethal disease of copper metabolism, characterized by extreme hypotonia, seizures, sparse, brittle and colorless hair, brain atrophy with cerebrovascular malformations and profound deterioration during first years of life. Disease is a consequence of multiple focal involvement of the grey matter due to copper maldistribution. The defective gene is predicted to encode ATP7A, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Biochemical characteristics are low serum copper and low ceruloplasmin. The aim: We present an 18 months old male infant with cavernous hemangioma of the face and inherited PAI mutation, in whom the diagnosis of Menkes disease was established at the age of 6 months. Methods and results: Patient presented at the age of 2 months with dysmorphia, cavernous haemangioma of the left side of the head, hypotonia and seizures. Brain US showed large area of hyperechogenicity with calcifications of a left side while CT and MRI showed suspected cerebral venous angiomatosis peridurally. At the age of 4, 5 months, child had convulsive status and suspicion of ischemic insult. (CT and MRI showed possible acute ischemic infarction (venous?) of the right cerebral temporoparietal region as well as vascular anomalies of the left side of the brain depicted also on previous CT/MRI). EEG showed spike-low wave temporo-parieto-occipitally billaterally. (fig ). Seizures were stabilized by vigabatrin. Repeated MRI/MR-angiography showed large arteriovenous malformation (AVM), fistula type, arising from the anterior cerebral artery (Fig ). Genetic analysis showed heterozygosity for point mutation C677T gene for MTHFR, genotype CT and homozygosity for 5G/5G in PAI-1 gene (as his mother). Diagnosis of Menkes disease was made at the age of six months, due to dominant clinical features of hypotonia, dysmorphia and sparse, brittle and colorless hair, accompanied by low values of serum copper and ceruloplasmin. Genetic analysis is in progress. Conclusion: This is a rare case of Menkes disease with inherited PAI 1 mutation and complex brain AVM. Dysmorphia, hair changes, seizures and extreme hypotonia in infant with brain AVM is very suspect for Menkes disease. It is important to evaluate serum copper and ceruloplasmin to confirm diagnosis. Genetic analysis and counseling is important.