Muge Ayanoglu

Genetic Landscape of Congenital Myasthenic Syndromes from Turkey: Novel Mutations and Clinical Insights

Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. This underlines the importance of genetic diagnosis. Here, the authors report on cases with genetically proven congenital myasthenic syndromes from Turkey. The authors retrospectively reviewed their experience of all patients with congenital myasthenic syndromes, referred over a 5-year period (2011-2016) to the Child Neurology Department of Dokuz Eylül University, Izmir, Turkey. In addition, PubMed was searched for published cases of genetically proven congenital myasthenic syndromes originating from Turkey. In total, the authors identified 43 (8 new patients, 35 recently published patients) cases. Defects in the acetylcholine receptor (n = 15; 35%) were the most common type, followed by synaptic basal-lamina associated (n = 14; 33%) and presynaptic syndromes (n = 10; 23%). The authors had only 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n = 1; 2%). Knowledge on congenital myasthenic syndromes and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.

Myelin Oligodendrocyte Glycoprotein Antibody Persistency in a Steroid-Dependent ADEM Case.

Myelin oligodendrocyte glycoprotein (MOG) is a candidate target antigen in demyelinating central nervous system diseases, including acute disseminated encephalomyelitis (ADEM), neuromyelitis optica, and multiple sclerosis. It may give prognostic information regarding monophasic or recurrent course of the disease. MOG antibodies have been shown to be positive in high titers during the first episode of ADEM with rapidly decreasing to undetectable limits after recovery. However, persistent MOG antibodies are considered as a predicting factor for multiple sclerosis, optic neuritis relapses, and incomplete recovery of ADEM. Here we report a unique case with persistent MOG antibodies presented with multiphasic ADEM-like attacks. A 6-year-old girl was consulted with encephalopathy, gait disturbance, and oculomotor nerve palsy. Periventricular white matter lesions were seen on cranial magnetic resonance imaging studies. ADEM was diagnosed and treated with steroid. During follow-up, she experienced repeated episodes after steroid therapy termination. We were able to search MOG antibody at the ninth attack. The positivity of this antibody remained. It was thought to be associated with steroid-dependent course, and azathioprine and intravenous human immunoglobulin treatment were added. Patients with persistent MOG antibodies may benefit from addition of immunosuppressant agents, which may decrease the number of attacks.

Importance of acrocyanosis in delayed walking

We present a four-year-old wth ethylmalonic encephalopathy who presented with delayed walking. She had bilateral hyperintense lesions in the basal ganglia. Molecular analysis revealed a homozygous c.3G>T mutation in the ETHE1 gene. She did not have typical findings of the disease including recurrent petechia, chronic diarrhea and acrocyanosis was very subtle and orthostatic. She benefited from riboflavine and Q10 treatments. We suggest that acrocyanosis should be questioned and examined in patients with motor delay.

Expanding spectrum of scn1a-related phenotype with novel mutations

Mutations in the genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes, with most of the mutations occurring in SCN1A gene. It is one of the most well-researched epilepsy genes. The SCN1A gene, which seems to be a relevant regulator of excitability of the CNS, is implicated in various epilepsy phenotypes through various genetic mechanisms ranging from common variants to rare monogenic variants. It is known that SCN1A gene is tightly linked to severe myoclonic epilepsy of infancy (SMEI). However, its phenotypic spectrum is expanding. Here, we report clinical and genetic findings of 10 patients with SCN1A mutations where two of them were found to have novel mutations. Our findings support understanding and updating knowledge on the correlation between phenotype distribution and location and type of mutations in SCN1A-related disorders.

Williams Syndrome with Infantile Spasms.

To the Editor : A 7-mo-old girl was admitted with 1 mo history of symmetric extensor type of jerks in clusters followed by stiffening just after waking up. After the start of sudden jerks, psychomotor development got arrested. She was born at 38 wk of gestation by spontaneous vaginal delivery with a birth weight of 2400 g. She was the first child of healthy nonconsanguineous parents. In the newborn period she was diagnosed with supravalvular aorta stenosis with mild pulmonary stenosis. Her head circumference was 43 cm (50–75p). On physical examination dysmorphic facial features including elfin face, puffy eyes, full cheeks, flat midface, epicanthal folds and long philtrumwas noted. Complete blood cell count, biochemical and metabolic tests were normal. Cranial magnetic resonance imaging showed normal findings except thin splenium of corpus callosum. Interictal sleep electroencephalography revealed hypsarrhythmia pattern. She was treated with adrenocorticotropic hormone. She was seizure free after the third dose. Control electroencephalography showed bilateral parietal and occipital epileptic discharges. Despite she was seizure free after the third dose of ACTH, due to the ongoing EEG abnormalities, levetiracetam treatment was continued. Fluorescent in situ hybridization study revealed deletion of 7q11.23 region. She was diagnosed with Williams syndrome. After the cessation of spasms, her psychomotor development also improved. Williams syndrome is a contiguous gene deletion syndrome resulting from the submicroscopic deletion on chromosome 7q11.23 [1]. It is characterized by stenosis of large vessels (supravalvular aorta stenosis with or without pulmonar stenosis), elfin face, dental abnormalities, growth retardation and hypercalcemia during infancy [1, 2]. The central nervous system features of Williams syndrome include motor and mental retardation with behavioral disorders [2–4]. Seizures, especially infantile spasms are not specific features of Williams syndrome. There are few cases of Williams syndrome with seizures including apnea which correlates with ictal activity on EEG and tonic clonic seizures in a patient with larger deletions towards to the telomere [3–5]. 7q11.23-21.11 region is distal to the specific deletion region (7q11.23) of Williams syndrome. This 7q11.23-21.11 region includes a part or whole of the MAGI2 (Membrane Associated Guanylate Kinase, WW And PDZ Domain Containing 2) gene which is found to be associated with infantile spasms in patients with Williams syndrome [1, 3]. There are also two cases with Williams syndrome and infantile spasms that only have microscopic interstitial deletion without deletion inMAGI2 gene [2, 6].We could not test whetherMAGI2 gene was involved in our case. In conclusion, cases with Williams syndrome should be carefully followed up for the development of infantile spasms which can deteriorate pre-existing neurologic conditions.

An infant with hypomotor seizures and cutaneous lesions.

A 2-month-old infant presented to the emergency department with 1 day history of multiple hypomotor seizures characterized by diminished activity with indeterminate level of consciousness. Some of the seizures evolved to include version of head and eyes to the right side suggesting a focal onset. She was previously a healthy infant. Skin examination revealed a 4 9 5 cm congenital melanocytic nevus in the medial surface of right ankle with multiple satellite nevi (Fig. 1). Neurologic examination and interictal electroencephalography were normal. Magnetic resonance imaging of the brain revealed hyperintense lesions in left medial temporal lobe, brainstem and bilateral cerebellar hemispheres on T1-weighted images (Fig. 2). There were no lesions in the leptomeninges and spinal cord. The patient was diagnosed as neurocutaneous melanosis based on clinical and radiologic findings. Phenobarbital was started at a dose of 5 mg/kg/day. The frequency of seizures decreased by at least half with phenobarbital treatment, but addition of levetiracetam at a dose of 20 mg/ kg/day completely stopped the seizures. The patient is now 6 months old. She has no seizures and developmental milestones are appropriate for her age. Neurocutaneous melanosis is a rare phakomatosis characterized by giant or multiple, nonmalignant-pigmented cutaneous nevi with leptomeningeal melanosis or parenchymal involvement [1]. The disease has a predilection for leptomeninges, anterior temporal lobes and cerebellum. Most of the patients become symptomatic by 2 years of age [1]. Neurologic findings include increased intracranial pressure, hydrocephalus and epileptic seizures [2]. Although the interictal electroencephalography of our case was normal, hypomotor seizures with no automatisms were typical for temporal lobe regions in this age group. The paramagnetic properties of melanin contribute to the classic magnetic resonance imaging findings. The lesions are typically hyperintense on T1-weighted and fluid-attenuated inversion recovery sequences and hypointense on T2-weighted sequences [3]. Patients who are neurologically asymptomatic have a better prognosis. Patients should be followed for lesion enlargement, mass effect, nodular enhancement, necrosis and hemorrhage because there is risk of malignant degeneration. In conclusion, the present case shows importance of skin examination because a number of neurocutaneous syndromes are associated with seizures. Increasing knowledge about rare neurocutaneous syndromes is also essential. U. Yiş (&) M. Ayanoğlu A. İ. Polat S. H. Kurul Division of Child Neurology, Department of Pediatrics, School of Medicine, Dokuz Eylül University, İzmir, Turkey e-mail: ulyis@yahoo.com