Lessons from Real Life Experience: Importance of In-House Sequencing and Smart Ratio-Based Real-Time PCR Outperform Multiplex Ligation-Dependent Probe Amplification in Prenatal Diagnosis for Spinal Muscular Atrophy: Bench to Bedside Diagnosis.

Spinal muscular atrophy (SMA) is a rare, recessively inherited neurodegenerative disorder caused by the presence of pathogenic variants in the SMN gene. As it is the leading inherited cause of infant mortality, identification of SMN gene pathogenic variant carriers is important for diagnostic purposes with effective genetic counseling. Multiple ligation probe analysis (MLPA), a probe-based method, is considered as the gold standard for SMA carrier analysis. However, MLPA might give false-negative results in cases with variations in the probe-binding regions. Here, we present a case born to consanguineous SMA carrier parents. Prenatal diagnosis with MLPA failed to detect the compound heterozygous mutant state of the proband and she was born unfortunately with SMA phenotype. Further analysis with a real-time polymerase chain reaction kit was able to detect the compound heterozygous state of the patient and was confirmed with targeted next-generation sequencing technology.

Fibromuscular dysplasia as a cause of stroke in a 9-year-old girl.

Fibromuscular dysplasia is a rare, idiopathic and nonatheromatous disease. It is rarely encountered as a cause of stroke in children. We report a nine-year-old girl with stroke in whom extensive fibromuscular dysplasia of intracranial vessels was established. She also had familial combined hyperlipidemia as an additional risk factor. This case suggests that additional risk factors like hyperlipidemia in cases with fibromuscular dystrophy may facilitate the occurrence of stroke at early ages.

Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total absence of body fat since birth with predisposition to insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. Three CGL loci, AGPAT2, BSCL2, and CAV1, have been identified previously. Recently, mutations in polymerase I and transcript release factor (PTRF) were reported in five Japanese patients presenting with myopathy and CGL (CGL4). We report novel PTRF mutations and detailed phenotypes of two male and three female patients with CGL4 belonging to two pedigrees of Mexican origin (CGL7100 and CGL178) and one pedigree of Turkish origin (CGL180). All patients had near total loss of body fat and congenital myopathy manifesting as weakness, percussion-induced muscle mounding, and high serum creatine kinase levels. Four of them had hypertriglyceridemia. Three of them had atlantoaxial instability. Two patients belonging to CGL178 pedigree required surgery for pyloric stenosis in the first month of life. None of them had prolonged QT interval on electrocardiography but both siblings belonging to CGL7100 had exercise-induced ventricular arrhythmias. Three of them had mild acanthosis nigricans but had normal glucose tolerance. Two of them had hepatic steatosis. All patients had novel null mutations in PTRF gene. In conclusion, mutations in PTRF result in a novel phenotype that includes generalized lipodystrophy with mild metabolic derangements, myopathy, cardiac arrhythmias, atlantoaxial instability, and pyloric stenosis. It is unclear how mutations in PTRF, which plays an essential role in formation of caveolae, affect a wide variety of tissues resulting in a variable phenotype.

Two cases with megalencephalic leukoencephalopathy with subcortical cysts and MLC1 mutations in the Turkish population.

Megalencephalic leukoencephalopathy with subcortical cysts is a rare leukodystrophy that is characterized by macrocephaly and a slowly progressive clinical course. It is one of the most commonly reported leukoencephalopathies in Turkey. Mutations in the MLC1 gene are the main cause of the disease. We report two patients with megalencephalic leukoencephalopathy with subcortical cysts with confirmed mutations in the MLC1 gene. The mutation in the second patient was novel. We also review identified mutations in the Turkish population.

Two young sisters with spinocerebellar ataxia type 2 showing different clinical progression of disease.

Spinocerebellar ataxia type 2 is a neurodegenerative disease caused by a CAG repeat expansion in the ataxin-2 gene. Gain-of-toxic effects caused by expanded polyglutamine tracts are important for the disease pathogenesis and there is an inverse relationship between the number of CAG repeats and the age of onset and clinical severity. Previously, we reported an extended Turkish family with spinocerebellar ataxia type 2 with several affected members in three generations. Two sisters in this generation showed an earlier age of onset (5 and 7 years, respectively) than their father (30 years). In this paper, we present a further interesting finding regarding the disease onset and manifestation in the two sisters. Interestingly, the age of onset was delayed and the clinical severity of the disease was milder in the child who had more CAG repeats (84 vs. 70). This finding suggests that there are other factors contributing to the age of onset and clinical severity in spinocerebellar ataxia type 2 other than the increased CAG repeat.

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.

Oxidant status in children after febrile seizures.

To evaluate oxidant status in children after febrile seizures, 61 children were studied: 31 with and 30 without a febrile seizure. Erythrocyte malondialdehyde, glutathione peroxidase, and superoxide dismutase levels were assessed in all patients. Erythrocyte malondialdehyde and glutathione peroxidase levels were significantly higher and superoxide dismutase levels were significantly lower in the febrile seizure group. Febrile seizures may cause significant oxidative stress, and these changes in oxidant status may be a step along the way to cell damage subsequent to febrile seizures.

Dentatorubral pallidoluysian atrophy in a Turkish family.

Dentatorubral pallidoluysian atrophy is a neurodegenerative disease that generally presents in adulthood. Although rare, it can be observed in childhood due to extreme expansion of the triplet repeat size during spermatogenesis. The diagnosis in childhood is very difficult in the absence of family history. Here we describe a 12-year-old girl with dentatorubral pallidoluysian atrophy who presented with progressive myoclonic epilepsy and ataxia. Family history exhibited similarly affected cases on the paternal side. Molecular testing for dentatorubral pallidoluysian atrophy revealed abnormal "cytosine-adenine-guanosine" expansion in the atrophin-1 gene.

Differential diagnosis of muscular hypotonia in infants: the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI).

The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI) (OMIM 225400) is an inherited connective tissue disorder characterized by hypotonia and kyphoscoliosis at birth, joint hypermobility, and skin hyperelasticity and fragility. Biochemically, it is characterized by a deficiency of collagen lysyl hydroxylase (EC 1.14.11.4) due to mutations in PLOD1. This deficiency results in underhydroxylation of collagen lysyl residues and, hence, an abnormal pattern of lysyl pyridinoline (LP) and hydroxylysyl pyridinoline (HP) crosslinks excreted in the urine. Because of hypotonia and delay in gross motor development, a neuromuscular disease is usually suspected, and in most cases the diagnosis is considered only very late, after performing an invasive neuromuscular work-up with normal results. We report a 12-month-old boy with kyphoscoliosis and delayed gross motor development, in whom the differential diagnosis of kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI) was initially suspected and successively confirmed by the abnormal urinary ratio of total pyridinolines (LP to HP), and by mutation analysis. We advocate the analysis of urinary pyridinolines in all infants with severe hypotonia which is highly specific and sensitive, quick and inexpensive.

Acute cerebellitis with cerebellar swelling successfully treated with standard dexamethasone treatment.

Although cerebellitis is common in childhood but cerebellitis with cerebellar swelling is rarely reported. Pulsed high dose methylprednisolone treatment is the choice of treatment for cases who have non-progressive symptoms. An 8-year-old girl presented acutely with vertigo, headache, and vomiting. Brain magnetic resonance imaging showed marked bilateral cerebellar swelling with increased signal on T2-weighted imaging. Following treatment with standard dexamethasone dose, the clinical and radiological signs resolved in 1 week. We conclude that standard dexamethasone treatment should be used in mild cases of acute cerebellitis in order to avoid adverse reactions of pulsed high dose methylprednisolone treatment.

Recurrent attacks of status epilepticus as predominant symptom in 3-methylcrotonyl-CoA carboxylase deficiency.

A patient with isolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency with an unusual clinical presentation is described. The patient presented with clusters of seizures with two or three months disease free interval in the first year of life which then evolved into attacks of status epilepticus after the age of 12 months. MCC deficiency was suspected because of elevated C5-OH-carnitine in tandem mass spectrometry and elevated 3-hydroxy-isovaleric acid in urine organic acid analysis. Deficiency of MCC was confirmed in cultured fibroblasts and mutation analysis revealed a novel mutation in MCCB, p.S39F. Attacks of status epilepticus as a predominant symptom have not been described before in isolated MCC deficiency.

Multiple sulfatase deficiency in a Turkish family resulting from a novel mutation.

Multiple sulfatase deficiency (MSD) is an inherited lysosomal storage disease that affects post-translational activation of all of the sulfatases. Since biochemical and clinical findings are variable, the diagnosis is difficult in most of the cases. Missense, nonsense, microdeletion and splicing mutations in SUMF1 gene were found in all of the MSD patients analyzed. Here, we present clinical findings of two consanguineous patients with multiple sulfatase deficiency. They were found to be homozygous for a novel missense mutation c.739G > C causing a p.G247R amino acid substitution in the SUMF1 protein.

Vertebral artery dissection in a patient with Wildervanck syndrome.

Vertebral artery dissection as a cause of stroke is rarely reported in children. The association between vertebral artery dissection and Klippel-Feil syndrome is also very rare. We report on a case of vertebral artery dissection with posterior circulation involvement in a child with Klippel-Feil syndrome after a hard physical-training lesson. She was also diagnosed with Wildervanck syndrome, with additional clinical findings. Vertebral artery dissection should be considered in patients with Klippel-Feil syndrome who present with acute-onset neurologic signs. Movements such as hyperextension with rotation of the neck should be avoided in these cases.

Mycoplasma pneumoniae: nervous system complications in childhood and review of the literature.

Mycoplasma pneumoniae is an important pathogen which causes nervous system disorders during or after the course of a respiratory tract infection. The exact pathogenic mechanism which causes neurological disorders still remains unknown. Although meningoencephalitis and acute disseminated encephalomyelitis are common complications, there are few cases of acute transverse myelitis and isolated abducens nerve palsy associated with M. pneumoniae infection in childhood. The association between ocular myasthenia gravis and M. pneumoniae infection has not been described before. Here, we describe five patients with different nervous system complications associated with M. pneumoniae infection and discuss the pathological features of central nervous system involvement.

Long-standing fever and Angelman syndrome: report of two cases.

An 8-month-old girl and a 20-month-old boy who presented with motor and developmental delay and long-standing fever are presented. The patients were diagnosed as Angelman syndrome with fluorescence in situ hybridization (FISH) analysis. Despite extensive clinical and laboratory examinations, no inflammatory or infectious origin for the fever was found. It was considered that the long-standing fever observed in these cases was due to hypothalamic dysfunction for thermoregulation.

A case of Walker-Warburg syndrome resulting from a homozygous POMT1 mutation.

Walker--Warburg syndrome (WWS), the most severe alpha-dystroglycanopathy, is characterized by brain and eye anomalies, and congenital muscular dystrophy (CMD). So far at least four genes (POMT1, POMT2, Fukutin, and FKRP gene) have been implicated in WWS, accounting for about 30% of all cases. We report a male patient with WWS resulting from a homozygous nonsense mutation (R514X) in the POMT1 gene. The patient had congenital hydrocephalus which was detected at 29 weeks of gestation. A brain MRI obtained after birth revealed type II lissencephaly, hydrocephalus, and pontocerebellar hypoplasia. The case also exhibited severe ocular malformations and muscular hypotonia due to CMD.

The correlation of seizure characteristics and hippocampal volumetric magnetic resonance imaging findings in children with idiopathic partial epilepsy.

Cerebral volumetric measurements based on magnetic resonance imaging have been established as advanced morphometric techniques with anatomic and clinical utility in adults and children with epilepsy. This study investigated the cerebral and hippocampal volumes in children with idiopathic partial epilepsy to detect the factors correlated with volume reduction. Magnetic resonance imaging volumetric measurements were performed of the total cerebral and hippocampal formation volumes in 30 patients with idiopathic partial epilepsy between 3 to 18 years old. The cerebral and the total, right, and left hippocampal volumes of the study and control patients were detected using volumetric magnetic resonance imaging, and the volumes were compared between the 2 groups. In study patients, the correlation between volumetric findings and seizure characteristics was evaluated. The results suggested that children with idiopathic partial epilepsy had significant hippocampal volume reduction that was not influenced by the age of onset and the duration of epilepsy.

Spinocerebellar ataxia type 2 in a Turkish family.

Autosomal dominant spinocerebellar ataxias are neurodegenerative disorders that generally present in adulthood. Due to extreme expansion of the repeat size during spermatogenesis, they can also be observed in childhood. The diagnosis in childhood is very difficult in the absence of family history. Here we describe an 8-year-old girl with spinocerebellar ataxia type 2 who presented with progressive ataxia, cognitive deficits, and dysarthria. A detailed family history exhibited similarly affected cases on the paternal side. Molecular testing for spinocerebellar ataxia type 2 revealed abnormal "cytosineadenine-guanosine" expansion in all affected family members. The number of cytosine-adenine-guanosine repeats in the index case was 70. The mean size of expansion in the relatives of the patient was 42 (39-46). This finding explains the early onset of symptoms in the index case.

Basilar artery thrombosis in a child heterozygous for prothrombin gene G20210A mutation.

Prothrombin G20210A mutation is an important prothrombotic condition for venous thrombosis. Recently, some studies have also considered it to be a risk factor for arterial ischemic stroke in children. A 10-year-old boy with basilar artery thrombosis who was heterozygous for prothrombin G20210A mutation is described. In concordance with the previous literature, the present case suggests that prothrombin G20210A mutation may be a risk factor for arterial ischemic stroke in childhood.

Prevalence and characteristics of recurrent headaches in Turkish adolescents.

The objectives of this study were to determine the prevalence and characteristics of recurrent headaches and to investigate the sociodemographic differences between high school students with or without recurrent headaches from Izmir, Turkey. Multistep, stratified, cluster sampling method was used in this analytic, school-based cross-sectional study. Twenty-one schools were selected randomly, and 2384 preparatory, first-, second-, and third-grade high school students from 84 different classrooms constituted the study cohort. The prevalence of recurrent headaches was 45.7% (1090/2384). Female students had a significantly higher headache frequency than males (P = 0.000). No significant relationship was evident between age and headache (P = 0.065). Also, there were no significant differences between the adolescents with or without headache for variables such as parental divorce (P = 0.052), existence of a step parent (P = 0.32), people with whom the students live at home (P = 0.186), number of siblings (P = 0.37), and maternal and paternal educational levels (P = 0.62 and P = 0.15, respectively). Headache frequency was higher when the income level of the student's family was lower (P = 0.016). Among the students who had headaches, 53.3% had a medication, 37.3% were referred to a physician, and in 27.2% of them a diagnosis was established. School absenteeism with a ratio of 26.5% was a common problem among the students with headaches. These results indicate that approximately one half of Turkish high school students have recurrent headaches which reduce the quality of their lives.