HYPOTONIC INFANT: CLINICAL AND ETIOLOGICAL EVALUATION

Pediatri hekimlerinin özellikle yenidoğan döneminde sık karşılaştığı klinik tablolardan biriside hipotonidir. Hipotoniyi santral (beyin, beyin sapı ve servikal spinal bileşke) ve periferal hipotoni (ön boynuz hücreleri, periferik sinirler, nöromuskuler bileşke ve kaslar) olarak sınıflamak mümkündür. Ancak santral ve/veya periferal sinir sistemini etkileyebilen bazı multisistemik hastalıklar da klinik olarak hipotoni ile karşımıza çıkabilmektedirler. Hipotoniye neden olan durumların ortaya çıkartılmasında, nöroloji, genetik ve metabolizma bölümlerini içeren multidispliner yaklaşım gereklidir. Bu derlemede hipotoniye klinik yaklaşım ve sık görülen hipotoni nedenleri tartışılacaktır. Hypotonia is one of the frequent clinical finding that the pediatricians detected, especially in neonatal period. Hypotonia could be classified as central ( brain, brainstem and cervical spinal junction) and peripheral hypotonia (anterior horn cells, peripheral nerves, neuromuscular junction and muscles). However, multisystemic diseases that can affect central and/or peripheral nervous system may prove to a clinical hypotonia. Multidisciplinary approach is essential to detect the situations that can cause hypotonia, including neurology, genetic and metabolic disorders departments. In this study, the causes and the clinical approach to hypotonia were reviewed

ZONISAMIDE EXPERIENCE IN PATIENTS WITH REFRACTORY EPILEPSY

Amaç: Parsiyel epilepsisi bulunan, > 16 yaş hastalarda zonisamidin güvenilir ve etkin bir antiepileptik ilaç olduğu yapılan kontrollü çalışmalarla gösterilmiştir. Ancak literatürde zonisamidin çocuklarda kullanımı, etkinliği ve güvenilirliği ile ilgili yeterli sayıda çalışma bulunmamaktadır. Gereç ve yöntem: Ocak 2010-Aralık 2010 tarihleri arasında, diğer anti-epileptik ilaçlara yanıt alınamayan ve zonisamid tedavisi başlanan 10 dirençli epilepsi olgusunun tedavi sonuçları değerlendirilmiştir. Zonisamid, 2 mg/kg/gün ve 2 dozda başlanarak, haftalık 1-2 mg/kg/gün doz artışı yapılmış ve maksimum 12 mg/kg/gün dozunda kullanılmıştır. Bulgular: On hastanın (5 kız, 5 erkek) ortalama yaşı 9,7 yıl (min 4,7-max 17)'dir. 2/10 olgu idiyopatik, 3/10 olgu kriptojenik, 5/10 olgu semptomatik epilepsi olarak sınıflandırılmıştır. Tedavi süresi ortalama 6,9 aydır. Olguların 6/10'u jeneralize, 4/10'u parsiyel epilepsi hastasıdır. Jeneralize ve parsiyel epilepsi gruplarında birer olguda ≥ %50 tedavi yanıtı görüldü. Parsiyel epilepsi olarak sınıflandırılan 1 olgunun ise nöbetsiz olduğu tespit edilmiştir. Zonisamid tedavisi süresince sadece 1 olguda geçici iştahsızlık ve kilo kaybı görüldüğü saptanmıştır. Sonuç olarak, antiepileptik ilaçlara yanıt alınamayan, özellikle parsiyel epilepsisi bulunan olgularda zonisamid tedavisinin etkili ve güvenli bir tedavi seçeneği olduğunu düşünmekle beraber daha çok olguyu kapsayan çalışmalarla desteklenmesi gerektiği kanaatindeyiz. Objeçtive: It have shown with controlled studies that, zonisamide is a safe and effective antiepileptic drug in > 16 years of age patients with partial epilepsy. However, there is not enough study on the efficacy and safety of the use zonisamide with children, in literature. Material and method: The treatment results of 10 cases with refractory epilepsy, not responded to the other anti-epileptic drugs and zonisamide therapy was initiated, between January 2010-December 2010, were evaluated, The starting dose of zonisamide was 2 mg / kg / day, dose has been increased weekly by 1-2 mg / kg / day and a maximum of 12 mg / kg / day was used. Results: Ten patients (5 boys, 5 girls), mean age was 9.7 years (min 4.7-max 17 years). 2/ 10 of the cases idiopathic, 3 / 10 of the cases cryptogenic and 5 / 10 of the cases were classified as symptomatic epilepsy. The mean duration of treatment was 6.9 months. 6 / 10 of the cases were generalized and 4 / 10 of the cases were partial epilepsy patient. In each generalized and partial epilepsy groups, ≥ 50% treatment response was seen in one patients. One case who had been classified as partial epilepsy was found as seizure free. In only 1 case, temporary loss of appetite and weight loss was seen during zonisamide therapy. As a result, we thought that zonisamide is effective and safe treatment option, particularly in patients with partial epilepsy who did not respond to other antiepileptic drugs, but more studies are needed to support

IS ROLANDIC EPILEPSY ALWAYS A BENIGN DISEASE?

Rolandik epilepsi, çocukluk çağının sık görülen parsiyel epilepsisidir. Genellikle uykuda gelişen fokal ya da sekonder jeneralize nöbetler görülür. Elektroensefalografide, tek taraflı ya da bilateral sentro-temporal diken dalga deşarjlarının varlığı karakteristiktir. Olguların çoğunda, adolesan dönemde elektroensefalografik ve klinik bulguların normale dönmesi nedeniyle iyi seyirli olarak kabul edilmektedir. Nöbetlerin seyrek olarak görülmesi ve iyi prognozu nedeniyle anti-epileptik tedavi başlanması tartışmalıdır. Bu makalede Rolandik epilepsi bulguları ile izlenen, takipte uykunun elektriksel status epileptikusu, dil, ince motor ve kişisel sosyal alanlarda baskılanma bulguları gelişen bir olgu Rolandik epilepsi seyrinin her zaman iyi huylu olmayabileceğine dikkat çekmek amacıyla sunulmuştur Rolandic epilepsy is a common childhood partial epilepsy. Focal or secondary generalized seizures during sleep are usually developed. On electroencephalography, unilateral or bilateral presence of the centro-temporal spike-wave discharges are characteristic. In most cases, electroencephalographic and clinical findings are return to normal in adolescent period and is considered as a good prognosis. Due to the rare seizures and good prognosis treat with anti-epileptic therapy is controversial. In this study, we presented a patient with Rolandic epilepsy, who developed electrical status epilepticus during sleep, suppression of language, fine motor, and personal social areas to keep attention to the course of Rolandic epilepsy may not be always good-nature

TAY-SACHS HASTALIĞI BULUNAN BİR ERKEK ÇOCUĞUNDA MANYETİK REZONANS GÖRÜNTÜLEME BULGULARI

Tay-Sachs is a neurodegenerative lysosomal storage disease that is caused by the mutations in the HEXA gene. Decreased ß-hexosaminidase A activity leads to the accumulation of the GM2 gangliosides in neuron cytoplasms and causes progressive neurologic dysfunction. Magnetic resonance imaging findings drastically change during the progression of the disease. At the early stage of the disease T2 weighted images demonstrate hyperintense lesions in basal ganglia or non-specific findings. In the late phase of the disease cerebral and cerebellar atrophy, and basal ganglia and white matter T2 hyperintensities can be seen. In this paper, we reported a 17 month-old boy with Tay-Sachs disease whose clinical and magnetic resonance imaging findings progressed in 5 months period. Tay-Sachs HEXA genindeki mutasyonların neden olduğu nörodejeneratif bir lizozomal depo hastalığıdır. ß-heksosaminidaz A aktivitesinin düşüklüğü nedeniyle nöron sitoplazmalarında GM2 gangliozid birikimi ve bunun sonucunda da ilerleyici nörolojik disfonksiyon gelişir. Hastalığın progresyonu ile birlikte beyin manyetik rezonans görüntüleme bulguları da dramatik olarak değişir. Hastalığın erken dönemlerinde bazal ganglionlarda T2 ağırlıklı görüntülerde belirgin hiperintens lezyonlar ya da spesifik olmayan bulgular görülebilir. Hastalığı geç dönemlerinde ise serebral ve serebellar atrofi, bazal ganglion ve beyaz cevherde T2 hiperintens lezyonlar görülebilir. Bu makalede 5 aylık bir sürede klinik ve manyetik rezonans görüntüleme bulguları ilerleyen 17 aylık bir TAY-Sachs hastalığı olgusu sunulmuştu

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.Peer reviewe

Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning

Anti-GQ1b-negative Miller Fisher syndrome presented with one-sided horizontal gaze palsy

Miller Fisher syndrome classically presents with ophthalmoplegia, ataxia and areflexia. The syndrome may present rarely with atypical clinical features. Whether the central or peripheral nervous system is primarily involved remains controversial. Miller Fisher syndrome usually follows an infection, the most likely being Campylobacter jejuni. Mycoplasma pneumoniae has been reported rarely as the antecedent infectious agent in some patients

Nonketotic Hyperglycinemia and Acquired Hydrocephalus

Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism. Patients generally present in the neonatal period with lethargy, feeding difficulty, hypotonia, apnea, poorly controlled convulsions, and coma. Myoclonic seizures and burst suppression pattern on electroencephalography are major findings of disease, but development of hydrocephalus is not an expected finding. The present case is that of an infant with acquired hydrocephalus, psychomotor retardation, and myoclonic seizures in whom the final diagnosis was nonketotic hyperglycinemia. (C) 2009 by Elsevier Inc. All rights reserved