Electro-clinical features and long-term outcomes in guanidinoacetate methyltransferase (GAMT) deficiency.

OBJECTIVE: To evaluate clinical characteristics and long-term outcomes in patients with guanidinoacetate methyltransferase (GAMT) deficiency with a special emphasis on seizures and electroencephalography (EEG) findings. METHODS: We retrospectively analyzed the clinical and molecular characteristics, seizure types, EEG findings, neuroimaging features, clinical severity scores, and treatment outcomes in six patients diagnosed with GAMT deficiency. RESULTS: Median age at presentation and diagnosis were 11.5 months (8-12 months) and 63 months (18 months -11 years), respectively. Median duration of follow-up was 14 years. Global developmental delay (6/6) and seizures (5/6) were the most common symptoms. Four patients presented with febrile seizures. The age at seizure-onset ranged between 8 months and 4 years. Most common seizure types were generalized tonic seizures (n = 4) and motor seizures resulting in drop attacks (n = 3). Slow background activity (n = 5) and generalized irregular sharp and slow waves (n = 3) were the most common EEG findings. Burst-suppression and electrical status epilepticus during slow-wave sleep (ESES) pattern was present in one patient. Three of six patients had drug-resistant epilepsy. Post-treatment clinical severity scores showed improvement regarding movement disorders and epilepsy. All patients were seizure-free in the follow-up. CONCLUSIONS: Epilepsy is one of the main symptoms in GAMT deficiency with various seizure types and non-specific EEG findings. Early diagnosis and initiation of treatment are crucial for better seizure and cognitive outcomes. This long-term follow up study highlights to include cerebral creatine deficiency syndromes in the differential diagnosis of patients with global developmental delay and epilepsy and describes the course under treatment.

Predictors of eventual requirement of phenylalanine-restricted diet in young infants with phenylalanine hydroxylase deficiency initially managed with sapropterin monotherapy.

BACKGROUND: Phenylalanine (Phe)-restricted diet is associated with lower quality of life for patients with phenylketonuria (PKU), and a concern for caregivers of recently-diagnosed infants. Sapropterin is an oral drug used as an alternative or adjunct to dietary treatment. We have observed that some of the young infants initially managed successfully with sapropterin monotherapy have required dietary treatment in long-term follow-up. We aimed to determine the baseline factors associated with future initiation of dietary treatment in these patients. METHODS: Data were obtained retrospectively from the medical records of 80 PKU patients started on sapropterin monotherapy before 3 months of age between 2011 and 2021. RESULTS: The patients were followed for a median of 3.9 years (Q1-Q3: 2.5-5.75 years). Sapropterin was tapered down and discontinued in 5 patients (6.3%) as their Phe levels remained below 360 µmol/L without treatment. Sapropterin monotherapy was sufficient in 62 patients (77.5%), while 13 (16.2%) required dietary treatment. Phe and tyrosine (Tyr) levels, and Phe:Tyr ratios differed significantly among the patients maintained on sapropterin monotherapy and those started on dietary treatment, but the Phe:Tyr ratio at diagnosis was the most important independent baseline variable (OR: 1.61, 95% CI: 1.15-2.27, p = 0.006), with Phe:Tyr ratio at diagnosis >5.25 associated with dietary treatment (sensitivity: 90.0%, specificity: 81.8%). Genotypic phenotype value (GPV), unavailable at baseline, was also associated with dietary treatment (median GPV 9.2 vs. 3.8, p = 0.006), but some genotypes were not specific to the final treatment modality. DISCUSSION: We propose that the Phe:Tyr ratio at diagnosis is an important indicator to predict dietary requirement in young infants initially managed with sapropterin monotherapy.

Organic acidemias in the neonatal period: 30 years of experience in a referral center for inborn errors of metabolism.

OBJECTIVES: Neonatal-onset organic acidemias (OAs) account for 80% of neonatal intensive care unit (NICU) admissions due to inborn errors of metabolism. The aim of this study is to analyze clinical features and follow-up of neonates diagnosed with OAs in a metabolic referral center, focusing on perinatal characteristics and the impact of first the metabolic crisis on long-term outcome. METHODS: Perinatal features, clinical and laboratory characteristics on admission and follow-up of 108 neonates diagnosed with OAs were retrospectively analyzed. Global developmental delay, abnormal electroencephalogram (EEG) or brain magnetic resonance imaging (MRI), chronic complications, and overall mortality. Associations between clinical findings on admission and outcome measures were evaluated. RESULTS: Most prevalent OA was maple syrup urine disease (MSUD) (34.3%). Neonates with methylmalonic acidemia (MMA) had significantly lower birth weight (p<0.001). Metabolic acidosis with increased anion gap was more frequent in MMA and propionic acidemia (PA) (p=0.003). 89.1% of OAs were admitted for recurrent metabolic crisis. 46% had chronic non-neurologic complications; 19.3% of MMA had chronic kidney disease. Abnormal findings were present in 26/34 of EEG, 19/29 of MRI studies, and 32/33 of developmental screening tests. Metabolic acidosis on admission was associated with increased incidence of abnormal EEG (p=0.005) and overall mortality (p<0.001). Severe hyperammonemia in MMA was associated with overall mortality (33.3%) (p=0.047). Patients diagnosed between 2007-2017 had lower overall mortality compared to earlier years (p<0.001). CONCLUSIONS: Metabolic acidosis and hyperammonemia are emerging predictors of poor outcome and mortality. Based on a large number of infants from a single center, survival in neonatal-onset OA has increased over the course of 30 years, but long-term complications and neurodevelopmental results remain similar. While prompt onset of more effective treatment may improve survival, newer treatment modalities are urgently needed for prevention and treatment of chronic complications.

Single Institutional Experience with GM1 Gangliosidosis: Clinical and Laboratory Results of 14 Patients

Background: GM1 gangliosidosis is an autosomal recessive lysosomal storage disease caused by biallelic mutations in the GLB1 gene. Neurodegeneration, hypotonia, visceromegaly, macular cherry-red spots, skeletal dysplasia, and coarse and dysmorphic face are the major clinical features. Aims: To evaluate the demographic and clinical data of patients with GM1 gangliosidosis in a single center. Study Design: A retrospective clinical study. Methods: This study included patients followed at Hacettepe University Ihsan Dogramaci Children's Hospital Pediatric Metabolism Unit with the diagnosis of GM1 gangliosidosis between 1988 and 2021. Hospital records of the patients were reviewed for demographic, clinical, and laboratory findings. Results: Fourteen patients were included in the study and 10 (71.4%) were male. The age at onset of clinical symptoms was between 0 and 5 months, and the median time to diagnosis after the first symptom was 4.3 (0-13) months. Motor delay (54%) was the most common initial symptom. The median follow-up period was 14.8 (0.4-92.2) months. Twelve patients (85.7%) died, and all deaths occurred before the age of 24 months. The median survival was 21.3 (95% confidence interval, 15.5-24.9) months. Higher leukocyte beta-galactosidase activity correlated with later age at onset (ρ = 0.575), later age at diagnosis (ρ = 0.618), and longer diagnostic delay (ρ = 0.702) (ρ < 0.05). Conclusion: Median survival in patients with GM1 gangliosidosis is less than 24 months. Beta-galactosidase enzyme activity may be associated with clinical onset and time of diagnosis in these patients.

Recommendations on phenylketonuria in Turkey.

BACKGROUND: Phenylketonuria (PKU), is an autosomal recessive disease leading to the conversion defect of phenylalanine (Phe) into tyrosine. Severe neurocognitive and behavioral outcomes are observed in untreated cases. The present paper aims to review clinical experiences and expert recommendations in diagnosis, treatment, and follow-up of pediatric PKU patients in Turkey. METHODS: Two advisory board meetings were held in the year 2016 and 2017 with contributions of four leading experts in this field, and an online update meeting was held for final decisions about statements, and conclusions in January 2021. Considering management gaps in diagnosis, treatment, and follow-up of PKU, discussion points are defined. The Committee members then reviewed the Turkish and general literature and the final statements were formulated. RESULTS: The diagnostic cut-off for dried blood spots should remain at 2 mg/dl. Treatment cut-off value is acceptable at 6 mg/dl. Compliance with an ideal follow-up list is strongly recommended. Total protein intake should not be limited. Age-related safe levels of protein intake should be encouraged with an additional 40% from L-amino acids supplements, a 20% compensatory factor to account for the digestibility and utilization of amino acids from the supplement, and a further 20% compensation to optimize Phe control. Cognitive impairment and intelligence quotient evaluations should be performed at least twice before 3 years of age. In pregnant women, the target Phe level should be < 5 mg/dl, and they should be followed-up weekly in the first trimester, then every 2 weeks after organogenesis. Novel pharmacological treatments are promising, but some of them have limitations for our country. CONCLUSIONS: Early diagnosis and treatment initiation; determination and standardization of diagnostic and treatment thresholds; treatment modalities and follow-up parameters are significant steps in treating PKU in the long term. PKU follow-up is a dynamic process with uncertainties and differences in clinical practice.

Autism spectrum disorder in patients with inherited metabolic disorders-a large sample from a tertiary center.

BACKGROUND: There is increased awareness regarding the co-occurrence of autism spectrum disorder (ASD) and inherited metabolic disorders (IMD), and this is crucial for the management of both diagnoses in clinical practice. We aimed firstly to report twenty-two patients with a dual diagnosis of IMD and ASD who are still being followed up in the child metabolism outpatient clinic; secondly to evaluate the time of both IMD and ASD diagnosis and the clinical progress of their metabolic disorders to underline treatable conditions. METHODS: Among the patients admitted to the Pediatric Metabolism outpatient clinic because of IMD, twentytwo of them who had a diagnosis of ASD were included in the study. Data of the patients were collected from their medical records. The most recent progress of the patients concerning their metabolic disorder was obtained from the patients` files. RESULTS: Six cases with Phenylketonuria, 2 cases with partial Biotinidase Deficiency, 3 cases with Cerebral Creatine Deficiency Syndrome (CCDS), 5 cases with Mucopolysaccharidosis (MPS) Type-3b, 2 cases with MPS Type-3a, 1 case with MPS Type 4, 2 cases with Hypervalinemia and 1 case with Maple Syrup Urine Disease were all diagnosed as also having ASD. The diagnoses of CCDS and MPS Type 3 were after the diagnosis of ASD. Phenylketonuria and Mucopolysaccharidosis were the most common diagnoses in our study. In addition, rare entities such as MPS Type 3b and Type 4 and Hypervalinemia were also reported to co-occur with autism. CONCLUSIONS: Considering the co-occurrence of both disorders and implementing intervention strategies accordingly will certainly be beneficial in clinical practice and particularly in countries with a high rate of consanguinity.

COVID-19-related anxiety in phenylketonuria patients.

BACKGROUND: Phenylketonuria (PKU) is an inherited disorder of amino acid metabolism, the treatment of which often requires a special diet to prevent adverse neuropsychiatric outcomes. In the COVID-19 pandemic, which has had a substantial effect on the whole world since the beginning of 2020, PKU patients represent a vulnerable population because they may be dependent on special nutritional products, have limited access to routine care and display increased levels of anxiety. METHODS: For this reason, an online questionnaire assessing the anxiety levels and various personal opinions and practices regarding the pandemic was sent to the PKU patients managed at our clinic, who were 12 years of age or older. Ninety-eight patients responded to the questionnaire. Median age of the participants was 19 years. RESULTS: Most patients were compliant with the hygiene and social distancing recommendations regarding the spread of COVID-19. Of the patients, 61.2% felt more anxious since the pandemic. The most common concern was the possibility of not being able to obtain special nutritional products (58.2%). Anxiety level was significantly higher in females. CONCLUSIONS: These data suggest that food security is an important issue of concern in PKU patients. In line with the changing world after the pandemic, different strategies should be considered in the management of patients with inborn errors of metabolism, including PKU.

Prevalence of cerebrotendinous xanthomatosis in cases with idiopathic bilateral juvenile cataract in ophthalmology clinics in Turkey.

PURPOSE: To determine the prevalence of cerebrotendinous xanthomatosis (CTX) in patients with idiopathic bilateral juvenile cataract in Turkey. METHODS: In this multicenter, epidemiologic observational study, patients with idiopathic bilateral juvenile cataract (aged ≥1 year at study entry) were identified from the records of 31 ophthalmology clinics. The Mignarri suspicion index determined in all potential CTX patients; blood samples were collected, and genetic testing for CYP27A1 gene mutation was performed. Cholestanol levels of the patients were measured, and those with a level of ≥3.75 µg/mL (threshold value) underwent genetic testing for mutations in the CYP27A1 gene. RESULTS: CTX was diagnosed in 7 of 452 patients (1.55%) with bilateral juvenile cataract. There was no significant difference between patients with a Mignarri score of <100 (n = 8) and those with a score of ≥100 (n = 19) with respect to cholestanol levels and genetic test results. Genetic testing was undertaken in 27 patients based on elevated cholestanol levels. Of these 27, 7 (26%) had CYP27A1 gene mutations. Of these 7 patients with genetically confirmed CTX, 5 (71%) were in the group with higher Mignarri score (≥100). CONCLUSIONS: CTX is a treatable condition, and early detection is crucial for avoiding irreversible neurological manifestations. Screening using the Mignarri suspicion index and cholestanol blood levels can be helpful in identifying suspected cases of CTX.

Clinical and molecular characteristics of carnitineacylcarnitine translocase deficiency with c.270delC and a novel c.408C>A variant.

BACKGROUND: Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare, autosomal recessive, and highly lethal fatty acid oxidation (FAO) disorder caused by defective acylcarnitine transport across the mitochondrial membrane. CACTD is characterized by severe episodes of hypoglycemia and hyperammonemia, seizures, cardiomyopathy, liver dysfunction, severe neurological damage, and muscle weakness. Herein, we described the clinical features, biochemical, and molecular findings of three patients with CACTD, presented with poor feeding, hypoglycemia, liver dysfunctions, and hyperammonemia, but died despite intensive treatment. CASES: All cases had similar signs and symptoms like poor feeding and respiratory failure associated with liver dysfunction. Urinary organic acid profiles in the presence of hypoglycemia and hyperammonemia led us to the possible diagnosis of one of fatty acid ß-oxidation defects. Results of the molecular analyses were compatible with CACTD. In addition to known mutation (c.270delC;p.Phe91Leufs*38) we detected a novel one (c.408C > A;p.Cys136*). CONCLUSIONS: All three cases died despite a very intensive therapy. Based on our experience with these three cases, it can be said that CACTD has a relatively poor prognosis, molecular studies are of most importance in suspected cases for the final diagnosis and such studies might be of help while giving genetic counselling and guidance to parents for future pregnancies.

A new UHPLC-MS/MS method for the screening of urinary oligosaccharides expands the detection of storage disorders.

BACKGROUND: Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders. METHODS: The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation. RESULTS: The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/ß-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS. CONCLUSION: This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.

Creatine Transporter Deficiency Presenting as Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is the most common disability-causing neurodevelopmental disorder in childhood. Although inborn errors of metabolism (IEM) are rare causes of ASD, they are significant for several reasons, including implications in genetic counseling and determination of prognosis. In this article, we present a 6-year-old boy who presented to us with ASD and was diagnosed with creatine transporter deficiency. Physical and neurologic examination of this patient had not previously raised suspicion of IEM, but twin pregnancy, prematurity, NICU stay due to necrotizing enterocolitis, transient infantile hypotonia, gross-motor delay, breath-holding spells, and a single febrile seizure complicated the history. MRI revealed mild T2-hyperintensity in posterior periventricular white matter. Further evaluation with magnetic resonance spectroscopy, which showed a decreased creatine peak, led to diagnostic investigations for disorders of creatine metabolism, revealing increased urinary creatine:creatinine ratio and a de novo, novel hemizygous frameshift variant in SLC6A8 Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM. In this case report, we present challenges and pitfalls in the diagnostic journey for creatine transporter deficiency and underline the significance of a thorough history and physical examination in the evaluation of a child with ASD.

Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients.

INTRODUCTION: Glutaric aciduria type 1 (GA1) is a rare and inherited autosomal-recessive metabolic disorder that occurs in the deficiency of glutaryl-co-enzyme A dehydrogenase (GCDH) enzyme encoded by GCDH gene. In this study, we aim to retrospectively investigate the clinical, biochemical, and neuroradiological parameters and examine the spectrum of GCDH gene variants in Turkish patients with glutaric aciduria type 1. METHODS: This is a descriptive cross-sectional study. The study was conducted in fifty-three patients from 39 unrelated Turkish families who were diagnosed with GA1 based on their clinical presentation, neuroimaging, and biochemical measurements, at the department of pediatric metabolism of a university hospital between June 1998 and August 2019. Pathogenic variants screening of GCDH gene was performed by direct DNA sequence analysis in forty-six patients with GA1. Pathogenicity of the novel variants was predicted via computational programs. RESULTS: A total of 53 patients were diagnosed with GA1. Of those, 32 (60.3%) had encephalopathic crisis and 33 (62.3%) had macrocephaly. Twenty different pathogenic variants were detected, 7 of which are novel (p.Glu57Lys, p.Ser145Profs*79, p.Ser246Glyfs*96 p.Ala293Val, p.His348Gln, p.His417Tyr, p.Asp418Val). The p.Arg402Trp, p.Pro248Leu and p.Leu340Phe variants were the most common in Turkish patients, with a frequency of 21.2%, 18.2% and 12.1% respectively. CONCLUSION: This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the GCDH gene. The identification of common variants and hot spot regions of the GCDH gene is important for genetic counselling and the prenatal diagnosis of Turkish patients with GA1.

Two cases of Vici syndrome presenting with corpus callosum agenesis, albinism, and severe developmental delay.

BACKGROUND: Vici syndrome is a rare autosomal recessive disease with phenotypically heterogeneous presentation. Characteristic features of the disease are oculocutaneous albinism, corpus callosum agenesis, cataract, cardiomyopathy, and immunodeficiency. CASE: Here we report two Turkish patients with Vici syndrome. One of these patients had a novel mutation in EPG5 and presented with idiopathic thrombocytopenic purpura (ITP) and maculopapular rashes similar to Stevens-Johnson syndrome, which has been previously reported in only a few cases in the literature. CONCLUSION: Vici syndrome presents with a typical phenotype which may facilitate diagnosis for infants with multisystemic disorders. ITP and maculopapular rashes might be added to the spectrum of findings of patients with Vici syndrome.

Expanding the clinical spectrum of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency with Turkish cases harboring novel HMGCS2 gene mutations and literature review.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHS) deficiency is a very rare autosomal recessive inborn error of ketone body synthesis and presents with hypoketotic hypoglycemia, metabolic acidosis, lethargy, encephalopathy, and hepatomegaly with fatty liver precipitated by catabolic stress. We report acute presentation of two patients from unrelated two families with novel homozygous c.862C>T and c.725-2A>C mutations, respectively, in HMGCS2 gene. Affected patients had severe hypoketotic hypoglycemia, lethargy, encephalopathy, severe metabolic and lactic acidosis and hepatomegaly after infections. Surprisingly, molecular screening of the second family showed more affected patients without clinical findings. These cases expand the clinic spectrum of this extremely rare disease.

Predictors of acute metabolic decompensation in children with maple syrup urine disease at the emergency department.

Acute metabolic decompensation (AMD) of maple syrup urine disease (MSUD) must be promptly recognized and treated. In this study, we aimed to identify simple variables associated with AMD in children with MSUD for use in emergency settings. Data were collected retrospectively from 115 emergency visits of 29 children with MSUD over a 4-year period in a major referral hospital. Variables in visits with and without AMD were compared using t test, Mann-Whitney U test, and chi-square test. Logistic regression was used to identify independent variables associated with decompensations. Cut-off values of laboratory variables were determined with receiver operating characteristic curves and correlations with Spearman's rank correlation. Most important variables independently associated with AMD were poor feeding, malaise, anion gap, and especially uric acid, which correlated with leucine levels. Vomiting, dehydration, neurological signs, ketonuria, and ketoaciduria were also associated with AMD. Although sodium, chloride, and glucose were lower in AMD, they had little diagnostic value.Conclusion: In children with MSUD, uric acid and anion gap are key markers for AMD. Poor feeding and malaise are clues before the onset of neurological symptoms. These simple parameters can help determine the presence of AMD in emergency settings.What is Known:• In maple syrup urine disease, acute metabolic decompensations are characterized by gastrointestinal and neurological findings.• Diagnosis requires detection of significantly elevated leucine, which may take a long time or not be available.What is New:• Poor feeding, malaise, hyperuricemia, and high anion gap are parameters that can help diagnose acute decompensations in children with maple syrup urine disease at emergency departments.• Uric acid may be a biomarker for acute decompensations because of its high sensitivity, specificity, and its strong correlation with leucine.

Oral health status of children with phenylketonuria.

Background Diet plays an integral role in the maintenance of oral health, but dietary modifications due to medical problems such as phenylketonuria (PKU) can have adverse effects on oral health. This descriptive study was performed to evaluate the oral health status of children with PKU. Methods One hundred and ninety-seven patients with PKU aged between 1 and 22 years were evaluated. Clinical evaluations were performed by one experienced dentist regarding dental caries, gingival health and dental erosion. Categorical variables were assessed with descriptive statistics. Differences in feeding frequencies and sociodemographic characteristics were compared regarding dental caries using chi-square (χ2) tests. Results One hundred and thirty-two patients (67%) had dental caries. The mean plaque index (PI) and gingival index (GI) values were 1.37 ± 0.58 and 1.40 ± 0.64, respectively, which shows moderate plaque accumulation and moderate gingival inflammation. Of the patients, 85.3% did not brush their teeth regularly and 90.4% had never visited a dentist before. No statistically significant differences were found in dental caries according to feeding frequencies (p = 0.448). Conclusions Despite the high prevalence of caries in patients with PKU, most had never seen a dentist. Physicians must encourage patients with PKU and their parents to have regular dental visits to maintain an optimal general and oral health.

Genotypes and estimated prevalence of phosphomannomutase 2 deficiency in Turkey differ significantly from those in Europe.

Phosphomannomutase 2 deficiency (PMM2-CDG) is an autosomal recessive congenital disorder of glycosylation, characterized by multisystem phenotypes, mostly including neurological involvement. In Turkey, due to high rates of consanguinity, many patients with autosomal recessive disorders have homozygous variants and these diseases are more common, compared to Europe. However, published reports of PMM2-CDG from Turkey are scarce. Here, we describe clinical and molecular characteristics of PMM2-CDG patients diagnosed in three centers in Turkey, using data obtained retrospectively from hospital records. We also analyzed an in-house exome database of 1,313 individuals for PMM2 variants and estimated allele, carrier and disease frequencies, using the Hardy-Weinberg law. Eleven patients were identified from 10 families, displaying similar characteristics to previous publications, with the exception of the first report of epilepsia partialis continua and increased prevalence of sensorineural hearing loss. p.Val231Met was the most common variant, and was homozygous in four patients. This novel genotype results in a neurological phenotype with subclinical visceral involvement. Exome database analysis showed an estimated prevalence of 1:286,726 for PMM2-CDG, which is much lower than expected (1:20,000 in Europe) because of the lack of predominance of the common European p.Asp141His allele, associated with a severe phenotype (allele frequency of 1:2,622 compared to 1:252 in gnomAD). These data suggest that prevalence, phenotypes and genotypes of PMM2-CDG in Turkey differ significantly from those in Europe: Milder phenotypes may be more common, but the disease itself rarer, requiring a higher clinical suspicion for diagnosis. The association of sensorineural hearing loss with PMM2-CDG warrants further study.

Molecular Etiology of Isolated Congenital Cataract Using Next-Generation Sequencing: Single Center Exome Sequencing Data from Turkey.

Congenital cataract, which refers to lenticular opacity diagnosed at birth or more commonly during the first year of life, is one of the leading causes of childhood blindness. Molecular understanding of the disease pathogenesis has evolved thanks to many studies based on modern technologies. In this study, we aimed to identify and discuss the molecular etiology of nonsyndromic or nonmetabolic bilateral congenital cataract by whole-exome sequencing (WES). Patients with bilateral congenital cataract presumed to be isolated after metabolic and genetic evaluation were enrolled in the study. All patients underwent detailed ophthalmological examination and bilateral cataract surgery. DNA samples of the probands, parents, and available affected family members were analyzed by WES. Variants were validated and confirmed by Sanger sequencing in all probands and in available affected family members. A total of 4 patients (3 girls and 1 boy) were recruited. Two patients had nuclear, 1 patient had total, and 1 patient had combined lamellar and sutural cataract. One family had consanguinity. A heterozygous c.215+1G>A mutation in CRYBA1, heterozygous c.432C>G (p.Tyr144Ter) mutation in CRYGC, heterozygous c.70A>C (p.Pro24Thr) mutation in CRYGD, and a heterozygous c.466G>A (p.Gly156Arg) mutation in CRYBB3 were detected. All these mutations were confirmed by Sanger sequencing in selected affected individuals. The current study identified all causative mutations of congenital cataract in the crystalline genes. The results confirmed that WES is a very useful tool in the investigation of the diseases with heterogeneous genetic background.