Lucija Lujić

Cytochrome c Oxidase Partial Deficiency-Associated Leigh Disease Presenting as an Extrapyramidal Syndrome:

Leigh disease is a subacute neurodegenerative disorder characterized by symmetric necrotic lesions in the basal ganglia, cerebellum, thalamus, brain stem, and optical nerves and caused by altered oxidative phosphorylation. We describe the clinical, biochemical, neuroimaging, and molecular studies of a 19-year-old boy with early-onset Leigh disease manifesting as severe extrapyramidal disorder with generalized dystonia and choreoathetosis. He was born of healthy parents after an uneventful pregnancy and delivery. At the age of 2½ years, after a minor respiratory infection, he developed unstable, broad-based gait and tremor of the hands. These symptoms persisted for the next several years, when ataxia became more prominent. Difficulty in swallowing, dysarthria, trunk dystonia, and marked dyskinesia of the arms and hands gradually developed. Nystagmus, transient ptosis, and strabismus also appeared. Abnormal laboratory findings included elevated plasma and cerebrospinal fluid lactate and pyruvate, with an abnormal lactate/pyruvate ratio. Cranial computed tomography and magnetic resonance imaging demonstrated signs of cerebellar atrophy, bilateral and symmetric hypodensities in the lentiform nucleus and thalamus, and transient hyperintensities of cerebral peduncles in T2-weighted sequences suggestive of Leigh disease. Muscle biopsy revealed isolated fiber atrophy, necrotic fibers undergoing phagocytosis, and no ragged-red fibers. The measured catalytic activity of cytochrome c oxidase in skeletal muscle homogenates demonstrated a partial cytochrome c oxidase deficiency. No abnormalities in the mitochondrial genome and in the SURF-1 gene were found. The boy is currently receiving levodopa therapy, creatine monohydrate, and a high dosage of thiamine and lipoic acid, his condition is stabilized, and extrapyramidal symptoms are less pronounced. (J Child Neurol 2001; 16:616-619).

The burden of paediatric stroke and cerebrovascular disorders in Croatia

Pediatric stroke is significantly less common than stroke in adults, but represents a major challenge to public health authorities. The aim of this retrospective study was to identify the total and annual number of children younger than 18 years with arterial ischaemic stroke and transient ischaemic attack referred to the Childrens Hospital Zagreb, which is a major national centre specialised for the treatment and prevention of stroke in children. We reviewed the medical records of the Department of Neuropediatrics database at the Childrens Hospital Zagreb between 1998–2005 in order to provide demographic and clinical characteristics and neuroimaging findings in children with arterial ischaemic stroke. In the 7-year period, we identified a total of 124 children from different geographic areas of Croatia with a confirmed diagnosis of transient ischaemic attack (N = 77), and arterial ischaemic stroke (N = 47). Perinatal and childhood arterial ischaemic stroke were equally represented (23 and 24 children, respectively). The average number of new cases identified each year was 18 cases (range: 12–21), seven arterial ischaemic stroke and 11 transient ischaemic attack cases. Male predominance was found in children with arterial ischaemic stroke with a male:female ratio of 1·76:1, and was slightly higher in childhood arterial ischaemic stroke compared with perinatal arterial ischaemic stroke (2:1 and 1·56:1, respectively). In contrast, transient ischaemic attack was more frequently found in girls, and more likely identified in older children compared with younger children with arterial ischaemic stroke. Obtained data will contribute to better understanding of paediatric stroke in Croatia and will provide a base for the establishment of the national referral center and national pediatric stroke registry.

Ataxia Telangiectasia and Juvenile Idiopathic Arthritis

We report, to the best of our knowledge, the first case of a child with typical ataxia telangiectasia (A-T) who developed juvenile idiopathic arthritis (JIA). The patient was a 15-year-old boy with A-T who presented with noninfectious polyarthritis. A-T is a rare, autosomal recessive disorder characterized by cerebellar atrophy, oculocutaneous telangiectasia, immunodeficiency, radiosensitivity, and predisposition to cancer. The gene responsible for A-T is the A-T mutated (ATM) gene. Clinical manifestations of the disorder are the result of lacking ATM protein, which is involved in DNA repair, apoptosis, various checkpoints in the cell cycle, gene regulation, translation, initiation, and telomere maintenance. There are a few articles that describe deficiency of the DNA repair enzyme, ATM, in rheumatoid arthritis, but the connection between the absence of ATM protein and JIA has not been presented or studied yet. JIA is a heterogeneous group of diseases characterized by arthritis of unknown origin with onset before the age of 16 years. It is the most common childhood chronic rheumatic disease and causes significant disability. Because immunodeficiency can be part of A-T, infectious arthritis can occur, but chronic autoimmune arthritis in these patients is rare. We report a rare case of a 15-year-old boy with A-T and JIA. This case shows a possible relationship between altered function of ATM protein and the pathogenesis of JIA.

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.

C0414: Prevalence of Hyperhomocysteinemia and its Association with C677T MTHFR Polymorphism, Vitamin B12 and Folate Levels in Croatian Children with Cerebrovascular Accidents

Mild hyperhomocysteinemia is well documented as a risk factor for stroke in eldery but in paediatric population results are still inconclusive. The aim of the study was to determine frequency of increased total plasma homocysteine (tHcy) levels, its relationship with levels of serum folate and vitamin B12 as well as with presence of C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene in children with cerebrovascular accidents (CVAs) with either ischemic stroke (IS) or transient ischemic attack (TIA). Levels of tHcy, folate, vitamin B12 and presence of the MTHFR C667T polymorphism were determined by standard methods in 124 patients aged below 18 years admitted at the Department of Neuropediatrics in Children‘s Hospital Zagreb under diagnosis of IS and TIA. Increased levels of tHcy were recorded in 16/124 (12.9%) patients. Low folate levels were found in 42/124 (33.9%) patients whereas all of patients had regular levels of vitamin B12. MTHFR C667T polymorphism was observed in 38/124 (30.6%) patients (TT and CT genotype in 9 (7.3%) and 29 (23.4%) of cases, respectively). The polymorphism was observed in 7/16 patients with hyperhomocysteinemia, and 16/42 patients with low folate levels. Furthermore, decreased folate levels were recorded in 6/16 patients with hyperhomocysteinemia, whereas concomitant presence of increased tHcy, decreased folates and MTHFR C667T polymorphism were recorded in 3/16 patients. By testing interconnectivity between all observed parameters, significant association was found between decreased folate levels and the presence of the MTHFR C667T polymorphism (TT and CT genotype) (c2 = 3934, p = 0.047, contingency coefficient = 0.278). No significant association between hyperhomocysteinemia and the polymorphism or decreased folate levels was observed. We found out relatively high incidence of decreased folate levels as well as MTHFR C667T polymorphism in children with CVAs, but without proportional increase in homocysteine levels. In approximately 40% of patients the reason for decreased folate levels is presence of MTHFR polymorphism and only 18% (1/5) of them will develop hyperhomocysteinemia. Therefore it could be presumed that these are not main factors responsible for hyperhomocisteinemia. Moreover, overall prevalence of hyperhomocysteinemia (~13%) makes this group of risk factors less significant in aethiology of children CVAs

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.

109Transcranial‐duplex‐Doppler US findings and neurodevelopmental outcome of infants with perinatal cerebral infarction

Objectives