Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.

The mitochondrial phosphate carrier is critical for adenosine triphosphate synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. Variants in the SLC25A3 gene coding mitochondrial phosphate carrier lead to failure in inorganic phosphate transport across mitochondria. The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases. The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene. Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency.

Sepiapterin Reductase Deficiency Misdiagnosed as Neurological Sequelae of Meningitis.

Introduction: Sepiapterin reductase deficiency (SRD) is an exceedingly rare neurotransmitter disease caused by an enzyme error involved in the synthesis of tetrahydrobiopterin (BH4). It has been described in nearly 60 cases so far. The clinical manifestations include motor and speech delay, axial hypotonia, dystonia, weakness, oculogyric crises, diurnal fluctuation, and improvement of symptoms during sleep. Molecular genetic analysis can demonstrate pathogenic mutations in the SPR gene, allowing for a definitive diagnosis. Levodopa/carbidopa and 5-hydroxytryptophan are used for treatment. Case Presentation: We present a 19-year-old male patient who was evaluated for dysarthria, axial hypotonia, limb dystonia, and movement disorder. The parents described the current patient's history with febrile seizures since 9 months of age, as well as speech and neuromotor developmental retardation, which indicated that the disease began in infancy. The basal metabolic work-up was normal except for hyperprolactinemia. The definitive diagnosis of SRD was confirmed by whole exome sequencing (WES) analysis, which revealed a homozygous pathogenic mutation c.655C>T (p.Arg219*) (rs779204655) in the SPR gene. After treatment, we noted significant improvements in dystonia, axial hypotonia, and dysarthria. Conclusion: WES analysis offers a more expeditious and dependable method for diagnosing difficult cases exhibiting neurodevelopmental problems and thus renders the possibilities of early management.

A Rare Treatable Cause of Cardiomyopathy: Primary Carnitine Deficiency.

Introduction: Primary carnitine deficiency (PCD) is a rare autosomal recessive disorder caused by loss of function mutations in the solute carrier family 22 member 5 (SLC22A5) gene that encodes a high-affinity sodium-ion-dependent organic cation transporter protein (OCTN2). Carnitine deficiency can result in acute metabolic decompensation or, in a more insidious presentation, cardiomyopathy. Cardiomyopathy associated with PCD often presents with life-threatening heart failure. This presentation also usually includes skeletal muscle myopathy. Early recognition of this disorder and treatment with carnitine can avoid life-threatening complications related to cardiomyopathy. Case Presentation: Herein, we present a 10-month-old male patient with PCD, which was diagnosed while investigating the etiology of dilated cardiomyopathy and confirmed by molecular genetic analysis. Conclusion: Homozygous c.254_265 insGGCTCGCCACC (p.I89Gfs) pathogenic variant of the SLC22A5 gene was detected. With oral L-carnitine supplementation, the free carnitine level increased up to 14 µmol/L and the symptoms disappeared. LVEF increased by 45-70%. We would like to emphasize that this problem is a combination of the metabolic decompensation and the cardiac phenotypes, which are usually separated to either phenotype.

Long-term clinical evaluation of patients with alpha-mannosidosis - A multicenter study.

BACKGROUND: Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the MAN2B1 gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly. This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics. METHOD: Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded. RESULTS: Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16-208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4-181) months. Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%). Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease. Homozygous c.2477C>A (p.Ser826Ter) and homozygous c.967G>A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C>A (p.Ser826Ter). CONCLUSION: The present study identified two novel MAN2B1 variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.

Hereditary spastic paraplegia type 35 in a Turkish girl with fatty acid hydroxylase-associated neurodegeneration.

OBJECTIVES: The fatty acid 2-hydroxylase gene (FA2H) compound heterozygous or homozygous variants that cause spastic paraplegia type 35 (SPG35) (OMIM # 612319) are autosomal recessive HSPs. FA2H gene variants in humans have been shown to be associated with not only SPG35 but also leukodystrophy and neurodegeneration with brain iron accumulation. CASE PRESENTATION: A patient with a spastic gait since age seven was admitted to the paediatric metabolism department. She was born to consanguineous, healthy Turkish parents and had no family history of neurological disease. She had normal developmental milestones and was able to walk at 11 months. At age seven, she developed a progressive gait disorder with increased muscle tone in her lower limbs, bilateral ankle clonus and dysdiadochokinesis. She had frequent falls and deteriorating school performance. Despite physiotherapy, her spastic paraplegia was progressive. Whole exome sequencing (WES) identified a homozygous NM_024306.5:c.460C>T missense variant in the FA2H gene, of which her parents were heterozygous carriers. A brain MRI showed a slight reduction in the cerebellar volume with no iron deposits. CONCLUSIONS: Pathogenic variants of the FA2H gene have been linked to neurodegeneration with iron accumulation in the brain, leukodystrophy and SPG35. When patients developed progressive gait deterioration since early childhood even if not exhibited hypointensity in the basal ganglia detected by neuroimaging, FA2H-related neurodegeneration with brain iron accumulation should be ruled out. FA2H/SPG35 disease is characterised by notable clinical and imaging variability, as well as phenotypic diversity.

Evaluation of clinical, laboratory, and molecular genetic features of patients with biotinidase deficiency.

Biotinidase deficiency (BD) is an autosomal recessive inherited metabolic disorder which results from the inability of biotin-dependent carboxylase enzymes to function due to the release and absorption of biotin, leading to neurological and cutaneous findings. In the present study, evaluation of demographic characteristics, clinical findings, laboratory results, molecular genetic characteristics, and genotype-phenotype correlations of cases with BD. Two hundred forty-seven cases were included in the study who were admitted to the Department of Pediatric Metabolism of Ankara Bilkent City Hospital after being identified with potential BD through the Newborn Screening Program (NBS), during family screening or based on suspicious clinical findings, or following the detection of a pathogenic variant in a BTD genetic analysis during the period of October 2020 and February 2022. The medical files of the cases were reviewed retrospectively. An analysis of the admission routes of all cases to our clinic revealed 89.5% NBS, 5.7% family screening, and 4.9% suspicious clinical findings suggestive of BD. Complete enzyme deficiency was identified in 19.8%, partial enzyme deficiency in 55.1%, and heterogenous enzyme deficiency in 9.7%. The most common pathogenic variants were c.1270G > C (p.Asp424His), c.410G > A (p.Arg137His), and c.38_44delGCGCTGinsTCC (p.Cys13Phefs*36) in BTD gene. The c.1270G > C variant was most common in patients with cutaneous symptoms. The c.410G > A and c.38_44delGCGCTGinsTCC variants were more common in the patients with neurological symptoms. The mean activity level in patients with the c.1270G > C homozygous variant was statistically significantly higher than the mean activity level in the c.1270G > C compound heterozygous patients and the activity level of patients without the c.1270G > C variant. The mean activity level in c.410G > A homozygous patients was statistically significantly lower than the mean activity level of the c.410G > A compound heterozygous patients and the activity level of patients without the c.410G > A variant. In the course of our study, four new pathogenic variants were detected, namely: c.190G > A (p.Glu64Lys), c.249 + 5G > T, c.228delA (p.Val77*), and c.682A > G (p.Ile228Val).     Conclusions: The present study has determined the clinical and genetic spectrum of a large group of patients with BD in a single center. The frequent mutations in our study were similar to those reported in literature, and four novel variants were also described. What is Known: • Biotinidase deficiency is an autosomal recessive, treatable inborn error of metabolism. Two hundred ninety-four pathogenic variants in the BTD gene have been identified and the c.1270G > C variant is the most frequent BTD gene mutation in both Turkey and around the world. What is New: • Four new pathogenic variants (c.190G > A, p.Glu64Lys; c.249 + 5G > T; c.228delA, p.Val77*; and c.682A > G, p.Ile228Val) have been identified. It is believed that the c.38_44delGCGGCTGinsTCC variant is more commonly seen in individuals with ocular issues; however, further genotype-phenotype correlations are needed.

Assessment of the diagnosis, treatment, and follow-up of a group of Turkish pediatric glycogen storage disease type 1b patients with varying clinical presentations and a novel mutation.

OBJECTIVES: Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, different from GSD type 1a. Treatment with granulocyte-colony stimulating factor (G-CSF) is often required in the management of neutropenia and inflammatory bowel disease. Recently, an alternative treatment option to G-CSF has been preferred, like empagliflozin. To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b). METHODS: A retrospective analysis of the clinical course of eight patients with GSD type 1b whose diagnosis was confirmed by molecular testing. RESULTS: The mean age at referral was four months. The diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies. One patient presented with an atypical clinical finding in the form of hydrocephalus at the time of first admission. The first symptom was abscess formation on the scalp due to neutropenia in another patient. Other patients had hypoglycemia at the time of admission. All patients presented suffered from neutropenia, which was managed with G-CSF, except one. Hospitalizations for infections were frequent. One patient developed chronic diarrhea and severe infections, which have been brought under control with empagliflozin. CONCLUSIONS: Neutropenia is an essential finding in GSD 1b and responsible for complications. The coexistence of hypoglycemia and neutropenia should bring to mind GSD 1b. Empagliflozin can be a treatment option for neutropenia, which is resistant to G-CSF treatment.

Out-of-pocket health expenditures in patients living with inborn errors of metabolism.

AIM: The implementation of newborn screening programs for inborn errors of metabolism has advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. We aimed to determine out-of-pocket health expenditures of patients with inborn errors of metabolism during follow-up and treatment processes and to determine the economic burden on the families. MATERIALS AND METHODS: A total of 232 patients who voluntarily agreed to participate in the study and were regularly followed up in the Department of Pediatric Metabolism with the diagnosis of Inborn Errors of Metabolism between April 2022 and July 2022 were included. Questionnaires were asked about the demographic characteristics of patients, use of health services, follow-up, treatment procedures, frequency of controls and health expenditures. RESULTS: The average out-of-pocket expenditure of the households in the last month was 1039.22 ± 1030.08 (minimum: 20, maximum: 5000) Turkish Liras. When we consider the catastrophic health expenditure rate as expenditure exceeding 40% of household income, we found that 9.9% (23 people) of parents included in the study made catastrophic health expenditures. The rate of catastrophic expenditure of patients with a diagnosis of Amino Acid Metabolism Disorders was found to be higher than that of patients with a diagnosis of Vitamin and Cofactor Metabolism Disorders. Similarly, patients with a diagnosis of lysosomal storage diseases had more expenditures than patients with a diagnosis of vitamin and cofactor metabolism disorders. When we compared the rate of catastrophic health expenditure of the patients with urea cycle disorders and the patients with a diagnosis of vitamin and cofactor metabolism disorders, the former had more expenditure than the latter (p < 0.05). There was no significant difference between other disease groups in terms of catastrophic expenditure. The rate of catastrophic expenditures of the households living as large family type were higher than the families living as nuclear family type (p < 0.01). A statistically significant difference was found between the rates of catastrophic expenditures of the families living in Ankara and those who were admitted from other provinces for follow-up and treatment (p < 0.001). However, there was no difference between the rates of catastrophic expenditure of the patients who received any treatment and those who were followed up without treatment (p > 0.05). CONCLUSION: Due to the high rate of consanguineous marriages in our country, the development of newborn screening programs, the increase in awareness about metabolic diseases and the improvement in diagnostic methods, the frequency of metabolic diseases is increasing, and mortality and morbidity rates are significantly reduced with early diagnosis and treatment opportunities. It is necessary to carry out more comprehensive studies to determine and prevent the socioeconomic effects of out-of-pocket health expenditures of patients living with Inborn Errors of Metabolism.

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.

Two Patients Diagnosed as Succinate Dehydrogenase Deficiency: Case Report.

Introduction: Succinate dehydrogenase deficiency, also known as mitochondrial complex II deficiency, is a rare inborn error of metabolism, accounting for approximately 2% of mitochondrial disease. Mutations in the four genes SDHA, B, C,and D have been reported resulting in diverse clinical presentations. The vast majority of clinically affected individuals reported in the literature harbor genetic variants within the SDHA gene and present with a Leigh syndrome phenotype, clinically defined as a subacute necrotizing encephalopathy. Case Report: Herein, we report the first case of a 7-year-old child who was diagnosed as having succinate dehydrogenase deficiency. The affected child presented at 1 year of age with encephalopathy and developmental regression following viral illnesses. MRI changes supported a clinical diagnosis of Leigh syndrome and c.1328C>Q and c.872A>C SDHA variants were identified as compound heterozygous. Mitochondrial cocktail treatment including L-carnitine, riboflavin, thiamine, biotin, and ubiquinone was started. Mild clinical improvement was observed after treatment. He is now unable to walk and speak. The second patient, a 21-year-old woman, presented with generalized muscle weakness, easy fatigability, and cardiomyopathy. Investigations revealed increased lactate level of 67.4 mg/dL (4.5-19.8) with repeatedly increased plasma alanine levels 1,272 µmol/L (200-579). We administered carnitine, coenzyme, riboflavin, and thiamine for empirical therapy with the suspicion of mitochondrial disease. Clinical exome sequencing revealed compound heterozygous variants NM_004168.4:c.1945_1946del (p.Leu649GlufsTer4) at exon 15 of the SDHA gene and NM_004168.4:c.1909-12_1909-11del at intron 14 of SDHA gene. Discussion and Conclusion: There are several very different presentations including Leigh syndrome, epileptic encephalopathy, and cardiomyopathy. Some cases present following viral illness; this feature is not specific to mitochondrial complex II deficiency and occurs in many other mitochondrial disease presentations. There is no cure for complex II deficiency, though some reported patients showed clinical improvement following riboflavin therapy. Riboflavin is not the only therapeutic intervention that is available to patients with an isolated complex II deficiency and various other compounds have shown promise in the treatment of symptoms, including L-carnitine and ubiquinone. Treatment alternatives such as parabenzoquinone EPI-743 and rapamycin are under study in the treatment of the disease.

The First Case of 4H Syndrome with Type 1 Diabetes Mellitus.

4H syndrome is a rare progressive hypomyelinating leukodystrophy. Hypomyelination, hypodontia, and hypogonadotropic hypogonadism are the 3 classic features of 4H syndrome. Biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K gene cause 4H leukodystrophy. Herein, we present clinical features in two siblings with 4H syndrome. The first patient (16 years) presented hypogonadotropic hypogonadism, euthyroid Hashimoto's thyroiditis and type 1 diabetes mellitus. The second patient (13.5 years) showed normal physical, biochemical and hormonal examination at presentation. It was learned that he was followed up for epilepsy between the ages of 6 months and 6 years, his epilepsy medication was discontinued at the age of 6, and he did not have seizure again. T2-weighted magnetic resonance images showed increased signal intensity secondary to hypomyelination at patients. They were subsequently found to have homozygous mutation in the POLR3A gene. 4H syndrome may present with neurological and non-neurological findings in addition to classic features of 4H syndrome. Progressive neurological deterioration may occur and endocrine dysfunction may be progressive. Although multipl endocrine abnormalities associated with this disorder have been reported to date, a case accompanied by type 1 DM has not been seen in the literature. We do not know exactly whether this is coinsidans or the expansion of the phenotype. So that reporting such cases helps to determine the appropriate genotype-phenotype correlation in patients.

ALG11-CDG: novel variant and review of the literature.

OBJECTIVES: Asparagine-dependent glycosylation 11-congenital disorders of glycosylation (ALG11-CDG) is a rare autosomal recessive N-glycosylation defect with multisystem involvement particularly neurological symptoms such as epilepsy and neuromotor developmental delay. CASE PRESENTATION: A 31-month-old male patient admitted to our center with complaints of axial hypotonia, drug-resistant myoclonic seizures, microcephaly and deafness. The electroencephalography (EEG) showed a burst-suppression pattern without hypsarrhythmia. Basal metabolic investigations were unremarkable. Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features in brain MRI images taken during our follow-up. Compound heterozygous mutations of the ALG11 gene were found by whole exome sequencing (WES) analysis. It was determined that the c.476T>C mutation is a novel mutation. CDG type 1 pattern was detected with the examination of carbohydrate-deficient transferrin (CDT) by capillary zone electrophoresis. CONCLUSIONS: In patients with a possible congenital defect of glycosylation, a screening test such as CDT analysis is suggested. To discover novel mutations in this rare disease group, expanded genetic analysis should be performed.

CLN3-Associated NCL Case with a Preliminary Diagnosis of Niemann Pick Type C.

Introduction: Neuronal ceroid lipofuscinoses (NCLs) are a broad class of inherited lysosomal storage disorders. Known mutations in at least 13 different genes can result in NCL with variable ages of onset, symptoms, and pathologic findings. Generally, these patients experience cognitive and motor decline, seizures, visual impairment, and premature death. Pathologically, NCL patients display heterogeneous histologic abnormalities, but consistently exhibit neuronal loss, reactive gliosis, and lysosomal accumulation of autofluorescent storage material or lipopigment. Juvenile-onset NCL has been classically referred to as Batten disease. By far the most prevalent NCL is CLN3-associated disease. It is an autosomal recessive condition that is usually caused by mutations in the ceroid-lipofuscinosis, neuronal 3 (CLN3) gene. CLN3 encodes battenin, a ubiquitously expressed transmembrane protein of unknown function that is associated with cellular homeostasis and neuronal survival. The initial clinical symptom of CLN3-associated NCL is central vision loss, which is usually detected between 4 and 9 years of age. Seizures typically begin early in the second decade of life, and affected individuals rarely live beyond their mid-20ies. Case Presentation: Herein, we describe a 16-year-old patient with CLN3-related juvenile NCL with a preliminary diagnosis of Niemann Pick Type C disease. The proband showed characteristic clinical signs, including epilepsy, ataxia, psychomotor regression, dementia, and visual impairment with an unusual elevation of lyso-sphingomyelin-509 (Lyso-SM-509; 812 nmol/L, normal 1-33 nmol/L). A homozygous NM_001042432.2(CLN3):c.233dup (p.Thr80fs) variant was detected at exon 4 of CLN3. Diagnosis of NCL was difficult due to the pronounced elevation of LysoSM-509. Discussion: LysoSM-509 is a biomarker which is elevated especially in Niemann Pick Type C. We can consider that a high LysoSM-509 level might be also an indicator of NCL, especially NCL type 3.

Multiplexed cell-based diagnostic devices for detection of renal biomarkers.

The number of synthetic biology-based solutions employed in the medical industry is growing every year. The whole cell biosensors being one of them, have been proven valuable tools for developing low-cost, portable, personalized medicine alternatives to conventional techniques. Based on this concept, we targeted one of the major health problems in the world, Chronic Kidney Disease (CKD). To do so, we developed two novel biosensors for the detection of two important renal biomarkers: urea and uric acid. Using advanced gene expression control strategies, we improved the operational range and the response profiles of each biosensor to meet clinical specifications. We further engineered these systems to enable multiplexed detection as well as an AND-logic gate operating system. Finally, we tested the applicability of these systems and optimized their working dynamics inside complex medium human blood serum. This study could help the efforts to transition from labor-intensive and expensive laboratory techniques to widely available, portable, low-cost diagnostic options.

Homozygous SLC20A2 mutations cause congenital CMV infection-like phenotype.

BACKGROUND: Idiopathic basal ganglia calcification, also known as Fahr's disease, it is a neurological disease characterized by intracranial calcification caused by heterozygous SLC20A2 mutations. Patients with calcifications can either be asymptomatic or show a wide spectrum of neuropsychiatric symptoms, including parkinsonism, tremor, dystonia, ataxia, and seizures. OBJECTIVES: The aim of this study was to investigating the clinical implications of the SLCA20A2 gene and identifying a new phenotype through a family. METHODS: Two siblings with growth retardation, bilateral cataracts, microcephaly, and convulsion were included in the study. The MRI showed cerebral atrophy, corpus callosum hypoplasia, microcalcifications. Chromosomal microarray analysis was performed to identify the existence of copy number variation. The whole exome sequencing analysis of the individual IV-I was performed, and Sanger sequencing was performed for segregation. RESULTS: Whole exome sequencing revealed a homozygous NM_006749.5:c.1794 + 1G > A of the SLC20A2 gene. The Sanger sequencing confirmed the affected siblings were homozygous and the parents were heterozygous. CONCLUSIONS: SLC20A2 gene heterozygous mutations were associated with the adult-onset phenotype, while homozygous SLC20A2 mutations in the two affected siblings we reported in our study resulted in a severe clinic including growth retardation, bilateral cataracts, microcephaly, and convulsion. We showed that biallelic mutations in the SLC20A2 gene that cause the Fahr's disease lead to more severe phenotypes contrary to what is known. The two siblings, showing similar phonotypic and genotypic characteristics, would be the youngest cases in the pediatric age group published in the literature.

Novel sphingosine-1-phosphate lyase mutation causes multisystemic diseases: case report.

BACKGROUND: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) caused by inactivating mutations in the human SGPL1 gene results in congenital nephrotic syndrome, adrenal insufficiency, ichthyosis, immunodeficiency, and a wide range of pathological neurological features. We present a novel mutation in the SGPL1 gene causing hypocalcemia, primary adrenal insufficiency (PAI), nephrotic syndrome, subclinical hypothyroidism, lymphopenia, ptosis, and pathologic neuroimaging findings. CASE: A Turkish male infant presented with bruising at 2 months of age and was diagnosed with hypocalcemia, PAI, and subclinical hypothyroidism. At the age of 15 months, he was admitted to the hospital with ptosis. Other systemic manifestations included persistent lymphopenia and nephrotic syndrome. Magnetic resonance imaging (MRI) of the brain and orbit demonstrated asymmetric contrast enhancement in the left cavernosal sinus, orbital apex, and thinning at the bilateral optic nerve. Whole exome sequencing (WES) revealed a homozygous c.1432C > G (p.Gln478Glu) variant in the SGPL1 gene (NM_003901.4), which has not previously been reported in the literature. CONCLUSIONS: Novel mutations in SGPL1 are still being identified. This case reminded us that SPLIS should not be considered for patients with nephrotic syndrome alone. Still, PAI may also include patients with neurological disorders, hypocalcemia, and pathological neuroimaging findings such as thinning at the bilateral optic nerve.