Homozygous exonic and intragenic NRXN1 deletion presenting as either West syndrome or autism spectrum disorder in two siblings

Neurexins (NRXNs) are cell-adhesion molecules that play critical roles in establishing and maintaining synaptic connections. Humans have three NRXN genes (NRXN1, NRXN2, NRXN3) and heterozygous intragenic microdeletions involving NRXN1 have been associated with autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, seizures, schizophrenia, and bipolar disorder. Bi-allelic loss in NRXN1 produces a recessive and severe phenotype. We would like to describe the clinical, electroencephalographic, and genetic findings of two siblings, one with a neurodevelopmental disorder with infantile spasms and the other with autism spectrum disorder, having homozygous exonic NRXN1 deletion. A suspicious variant was not detected in the whole exome-sequencing but copy number variation analysis revealed NRXN1 exon 2–5 homozygous deletion (chr2:51149007–51255411; 106.404 kb) in both siblings. Neurodevelopmental disorder with infantile spasms and autism spectrum disorder in two siblings with homozygous NRXN1 deletion display intrafamilial phenotypic variation. Bi-allelic/homozygous NRXN1 exonic deletions are responsible for a spectrum from significant intellectual disability to epileptic encephalopathy, even within the same family. Array comparative genomic hybridization should be the first genetic testing in epileptic encephalopathy although we reached the diagnosis with next-generation sequencing and later copy number variation analysis

Interacting with AP1 complex mutated synergin gamma (SYNRG) reveals a novel coatopathy in the form of complicated hereditary spastic paraplegia

Background: Today, it is known that about 80 genes are involved in the etiology of hereditary spastic paraplegia. However, there are many cases whose etiology could not be determined by extensive genetic tests such as whole-exome sequencing, clinical exome. Methods: Candidate genes were determined, since no clinically illuminating variant was detected in the whole-exome sequencing analysis of three patients, two of whom were siblings, with a complex hereditary spastic paraplegia phenotype. Results: The p.Leu1202Pro variant in the SYNRG gene in the 1st and 2nd cases, and the p.Gly533* variant in the 3rd case were homozygous. Discussion: We suggest that the SYNRG gene interacting with AP-1 (adaptor-related protein) from the AP complex family may cause the complex hereditary spastic paraplegia phenotype with extensive clinical spectrum. It may be important to evaluate SYNRG gene variants in patients with hereditary spastic paraplegia whose etiology has not been clarified

A genetic mimic of cerebral palsy: Homozygous NFU1 mutation with marked intrafamilial phenotypic variation

Background: Genetic defects in the NFU1, an iron-sulfur cluster scaffold protein coding gene, which is vital in the final stage of assembly for iron sulfur proteins, have been defined as multiple mitochondrial dysfunctions syndrome I. This disorder is a severe autosomal recessive disease with onset in early infancy. It is characterized by disruption of the energy metabolism, resulting in weak-ness, neurological regression, hyperglycinemia, lactic acidosis, and early death.Patient description: This report documents the case of a 27-month-old girl, who showed clinical signs and symptoms of spastic paraparesis with a relapsing-remitting course. The patient had a sister with a severe phenotype who died at the age of 16 months.Results: Magnetic resonance imaging revealed hyperintensity of the cerebral white matter that was more prominent in the frontal regions, with milder involvement in the posterior periventricular regions. There was also evidence of partial cystic degeneration and cavitation in the frontal regions. In addition, she had hyperglycinemia. Homozygous NM_001002755.4:c.565G>A (p.Gly189Arg) mutation was identified in the NFU1 gene; this had not previously been reported as homozygous.Conclusion: Hyperglycinemia and cavitating leukodystrophy are suggestive of an NFU1 mutation diagnosis. An intrafamilial phenotypic variation has not been published in NFU1-associated disorders before. Presenting with spasticity as a rare phenotype, NFU1 mutations could be considered a genetic mimic of cerebral palsy

Basal ganglia calcifications is not inconsequential in pediatric cases

Introduction. Basal ganglia calcification (BGC) in pediatric population is rare and is considered as a pathological finding. Various causes may be responsible for BGC including hypoparathyroidism, various infectious, toxicities or hereditary disorders. Aim. We aimed to present a 8 year old boy presented with generalized seizure and bilateral small amount of globus pallidum calcifications on neuroimaging studies leading to the diagnosis of idiopathic hypoparathyroidism, which is a treatable cause of seizure. Description of the case. A 8-year-old boy presented to our emergency department with generalized seizure for the first time in his life. There was no history of previous head trauma and his family history was unremarkable. Neurological examination revealed no pathological findings. Radiological imaging studies revealed only bilateral small amount of globus pallidus calcifications. He was referred to the pediatric endocrinology department for further evaluation of the hypocalcemic convulsion, where laboratory investigations revealed idiopathic hypoparathyroidism as the cause of hypocalcemic convulsion with exclusion of the other causes. Conclusion. Even a small amount of BGC in pediatric patients may be the sign of primary hypoparathyroidism and should be evaluated with serum electrolyte levels for early diagnosis and for the prevention of multisystemic complications of hypoparathyroidism

Çocuk nöroloji polikliniğine nöromüsküler belirtilerle başvuran hastaların laboratuvar bulgularının, klinik özelliklerinin ve tanı oranlarının değerlendirilmesi

Objective: Our aim is to evaluate how many patients with neuromuscular manifestations get a definite diagnosis and which methods are used in the pathway to diagnosis as well as to assess patient characteristics.Methods: Patients aged 0-18 years old with neuromuscular manifestations (e.g., weakness, hypotonia, creative kinase elevation) who were admitted to Okmeydani Training and Research Hospital between January 2017 and July 2019 were included. Retrospectively, patient demographics, clinical signs, laboratory tests, diagnoses, clinical follow-up were recorded.Results: Forty-five patients aged 67.8 +/- 59.6 months were included in the study. Thirteen (29%) patients were female, and 32 (71%) were male. Creatine kinase levels were increased in 26 (58%) patients (median: 3211 IU/L). Twenty-four patients underwent electromyography; seven patients had neuropathy and nine patients muscular pathologies. Three (0.07%) patients underwent muscle biopsy and had nonspecific myopathic changes. Twenty-six (58%) patients out of 45 had a definite diagnosis, and 21 of these diagnoses were genetically confirmed. Seven patients had been subjected to next generation sequencing, and five of these were diagnosed with dystrophinopathy, hypokalemic periodic paralysis, mental retardation autosomal dominant type 9, Ullrich muscular dystrophy, and calpainopathy. Altogether, the most common diagnoses were dystrophinopathy, spinal muscular atrophy, and chronic inflammatory demyelinating polyneuropathy.Conclusion: After a patient history is taken, a physical examination is conducted, and serum creotine kinase levels are measured, establishment of diagnosis is possible through targeted genetic tests for diseases like dystrophinopathy. However, for patients who cannot be diagnosed with this approach, neuromuscular panels and whole exome sequencing can provide a diagnosis.Amaç: Bu çalışmada amacımız, nöromüsküler hastalıkları düşündüren semptom ve bulgularla başvurançocuk hastaların ne kadarının kesin tanı aldığının, bu hastalarda hangi yöntemler ile tanıya ulaşıldığının vehasta özelliklerinin değerlendirilmesidir.Yöntem: Okmeydanı Eğitim ve Araştırma Hastanesi Çocuk Nöroloji Polikliniği’ne Ocak 2017-Temmuz 2019tarihleri arasında nöromüsküler belirtilerle (örn: güçsüzlük, hipotoni, kreatin kinaz yüksekliği) başvuran0-18 yaş arası hastalar değerlendirmeye alındı. Retrospektif olarak hastaların demografik verileri, klinikbulguları, laboratuvar testleri, tanıları, izlemleri kayıt altına alındı.Bulgular: Çalışmaya dahil edilen 45 hastanın yaş ortalaması 67,8±59,6 ay idi. On üç (%29)’ü kız, 32(%71)’si erkekti. Kreatin kinaz seviyeleri 26 (%61) hastada yüksekti ve medyanı 3211 IU/L idi. Elektromiyografiyapılan 24 hastadan yedisinde nöropati, dokuz hastada kasa ait patolojiler saptandı. Kas biyopsisi yapılanüç (%0,07) hastada non spesifik miyopatik değişiklikler izlendi. Kırkbeş hastadan 26 (%58)’sına kesin tanıkonulabildi, bunlardan 21 (%47)’inin tanısı genetik olarak kesinleştirildi. Yedi hastada yeni nesil dizilemeanalizi uygulandı ve beşi distrofinopati, hipokalemik periyodik paralizi, otozomal dominant mental retardasyon tip 9, Ullrich müsküler distrofi, calpainopati tanılarını aldı. Tüm hastalarda en sık tanılar distrofinopati, spinal müsküler atrofi ve kronik inflamatuvar demiyelinizan polinöropatiydi.Sonuç: Öykü, fizik muayene ve serum kreatin kinaz seviyesi sonrasında, örneğin distrofinopati gibi bir gruphastalıkta hedefe yönelik genetik testler ile tanıya ulaşılabilir. Ancak bu şekilde tanıya ulaşılamayan hastalarda nöromüsküler hastalık panelleri ve tüm ekzom dizileme gibi ileri moleküler genetik incelemeleretkili bir şekilde tanıya ulaşmayı sağlayabilir