CAUSE OF RECURRENT RHABDOMYOLYSIS, CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY AND NOVEL PATHOGENIC MUTATION

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal inherited metabolic disorder in which the beta-oxidation of the long chain fatty acids is defective. The clinical presentation may be in various forms; it presents itself in the severe form during neonatal and infantile periods and as the less severe myopathic form in the school age and adolescence. While the severity of the rhabdomyolysis attacks varies, occasionally the clinical course may be complicated with acute renal failure. Acylcarnitine analysis may help in the diagnosis of CPT II, but its normality does not indicate the absence of the disease. If there is strong suspicion, genetic analysis should be performed on the cases. In this article, we present a 15-year-old male patient who had two rhabdomyolysis attacks triggered by infection and starvation. Acylcarnitine analysis of the case was normal, CPT II deficiency was considered when the history was evaluated, and CPT II gene c.137A>G (p.Gln46Arg) homozygous novel pathogenic mutation was detected. CPT II deficiency is one of the most common causes of metabolic rhabdomyolysis in patients with recurrent episodes of rhabdomyolysis

FAMILIAL ATYPICAL HEMOLYTIC UREMIC SYNDROME WITH POSITIVE p.S1191L (c.3572C > T) MUTATION ON THE CFH GENE: A SINGLE-CENTER EXPERIENCE

The atypical hemolytic uremic syndrome (aHUS) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and acute kidney injury (AKI), which can exhibit a poor prognosis. Complement factor H (CFH) gene mutations play a key role in this disease, which may be sporadic or familial. We studied 13 people from the same family, investigated for gene mutations of the familial aHUS after a family member presented to our emergency clinic with the aHUS and reported a family history of chronic renal failure. The p.S1191L mutation on the CFH gene was heterozygous in six people from the patient's family with the aHUS. One of these family members is our patient with acute kidney injury, and the other two are followed at the Nephrology Clinic, Medeniyat University, Goztepe Training and Research Hospital, Istanbul, Turkey, due to chronic renal failure. The other three family members showed no evidence of renal failure. The index case had a history of six sibling deaths; three died of chronic renal failure. Plasmapheresis and fresh frozen plasma treatment were administered to our patient. When the patient showed no response to this treatment, eculizumab (ECZ) therapy was started. The study demonstrated that thorough family history should be taken in patients with the aHUS. These patients may have the familial type of the disease, and they should be screened genetically. Eculizumab should be the first choice in the treatment with plasmapheresis. It should be kept in mind that the use of ECZ as prophylaxis in posttransplant therapy is extremely important for preventing rejection

A CASE OF SOTOS SYNDROME CAUSED BY A NOVEL VARIANT IN THE NSD1 GENE: A PROPOSED RATIONALE TO TREAT ACCOMPANYING PRECOCIOUS PUBERTY

Sotos syndrome is characterized by overgrowth, macrocephaly, distinctive facial features, and learning disabilities and is associated with alterations in the nuclear receptor binding SET domain protein 1 (NSD1) gene. Due to the advanced bone age, the eventual adult height is usually at the upper limit of normal. In this case report, a 6-year and 10-month old boy who presented with Sotos syndrome was described. He also had increased testicular volumes with advanced bone age. The stimulated levels of gonadotropins revealed central precocious puberty and brain magnetic resonance imaging (MRI) showed a pineal cyst. A heterozygous duplication variant [NM_022455.4:c.4560dup; p.(His1521Thrfs*9)] in the NSD1 was identified. Triptorelin acetate treatment was started. The aim was to report the novel duplication variant in the NSD-1 in a patient with Sotos syndrome accompanied by a pineal cyst and central precocious puberty, and also to discuss the rationale for treating precocious puberty

A Novel Mutation of HINT1 Gene in an Adolescent Female with Axonal Neuropathy and Neuromyotonia

HINT1 gene mutations cause an axonal neuropathy with some specific findings including presence of neuromyotonia, autosomal recessive inheritance, onset in the first decade, and primary motor involvement. In this case report, we described an 18-year-old female patient who presented to the clinic with gait instability and muscle stiffness. A homozygous novel c.180_181delAT (p.Ser61Profs*8) variant in the HINT1 gene was found by clinical exome analysis. Parents were heterozygous for the same variant. The patient was diagnosed with autosomal recessive axonal neuropathy with neuromyotonia. The presence of neuromyotonia must be evaluated in patients with hereditary axonal neuropathies as this can help the diagnosis prior to genetic testing

Functional characterization of KCNMA1 mutation associated with dyskinesia, seizure, developmental delay, and cerebellar atrophy

KCNMA1 located on chromosome 10q22.3, encodes the pore-forming α subunit of the ‘Big K+’ (BK) large conductance calcium and voltage-activated K + channel. Numerous evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with different symptoms, such as paroxysmal non kinesigenic dyskinesia with gain of function and ataxia with loss of function. Functional classifications revealed two major patterns, gain of function and loss of function effects on channel properties in different cell lines. In the literature, two mutations have been shown to confer gain of function properties to BK channels: D434G and N995S. In this study, we report the functional characterization of a variant which was previously reported the whole exome sequencing revealed bi-allelic nonsense variation of the cytoplasmic domain of calcium-activated potassium channel subunit alpha-1 protein. To detect functional consequences of the variation, we parallely conducted two independent approaches. One is immunostaining using and the other one is electrophysiological recording using patch-clamp on wild-type and R458X mutant cells to detect the differences between wild-type and the mutant cells. We detected the gain of function effect for the mutation (NM_001161352.1 (ENST00000286628.8):c.1372C > T;Arg458*) using two parallel approaches. According to the result we found, the reported mutation causes the loss of function in the cell. It should be noted that in future studies, it can be thought that the functions of genes associated with channelopathies may have a dual effect such as loss and gain

Clinical and molecular findings in 6 Turkish cases with Krabbe disease

© 2022, Turkish National Pediatric Society. All rights reserved.Background. Krabbe disease is a rare lysosomal storage disorder with a neurodegenerative course that occurs because of the deficiency of the beta-galactocerebrosidase (GALC) enzyme activity. The genetic basis of Krabbe disease consists of biallelic mutations in the GALC gene, but the genetic spectrum in the Turkish population is poorly defined. We aimed to present a Turkish case-series with infantile-onset Krabbe disease, define the clinical and molecular findings and compare the genetic spectrum with the mutations previously reported in the literature. Methods. Six cases, who were referred to our clinic between 2015-2019, with a definite diagnosis of infantile-onset Krabbe disease were included in the study. The family history, clinical information, biochemical and radiological examinations of the patients were screened and evaluated. All encoded exons and exon-intron regions of the GALC gene were sequenced using next generation sequencing technology. Multiplex ligation-dependent probe amplification analysis was used for deletion type mutations that could not be detected by sequence analysis. Results. GALC gene sequence analysis revealed four known mutations including c.1394C>T (p.Thr465Ile), c.411_413delTAA (p.Lys139del), c.820G>C (p.Glu274Gln), and 30 kilobase deletion mutation among the exons 11-17 (IVS10del30kbp). Moreover, the c.1623G>A (p.Trp541Ter) variant, which was not previously reported in the literature, was detected in two cases. Conclusions. We believe that the demonstration of the genetic spectrum of infantile-onset Krabbe disease in Turkish patients will be an important contribution to the GALC mutation data in our country. More importantly, two novel variants were defined. This knowledge may enable early detection and treatment with the advent of a carrier or newborn screening tests