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.

Evaluation of the efficacy and associated complications of regional citrate anticoagulation in neonates: experience from a fourth level neonatal intensive care unit.

Continuous kidney replacement therapy (CKRT) use has increased in recent years, but anticoagulation is a challenge for neonates. Regional citrate anticoagulation (RCA) is rarely preferred in neonates because of citrate accumulation (CA) and metabolic complications. We aimed to demonstrate the efficacy and safety of RCA in neonates. We retrospectively analyzed the medical records of 11 neonates treated with RCA-CKRT between 2018 and 2023. The initial dose of RCA was 2.1-3 mmol/l, and then, its dose was increased according to the level of ionized calcium (iCa+2) in the circuit and patients. The total/iCa+2 ratio after-treatment > 2.5 was indicated as CA. We evaluated to citrate dose, CA, circuit lifespan, and dialysis effectivity. The median gestational age was 39 (36.4-41.5) weeks, the median body weight (BW) was 3200 (2400-4000) grams, and the mean postnatal age was 4 (2-24) days. The most common indication for CKRT was hyperammonemia (73%). All neonates had metabolic acidosis and hypocalcemia during CKRT. Other common metabolic complications were hypophosphatemia (90%), hypokalemia (81%), and hypomagnesemia (63%). High dialysate rates with a median of 5765 ml/h/1.73 m2 allowed for a rapid decrease in ammonia levels to normal. Four patients (36.3%) had CA, and seven (63.7%) did not (non-citrate accumulation, NCA). Mean BW, median postnatal age, biochemical parameters, coagulation tests, and ammonia levels were similar between the CA and NCA groups. Low pH, low HCO3, high lactate, and SNAPPE-II scores could be associated with a higher T/iCa ratio. CONCLUSION:  RCA was an efficient and safe anticoagulation for neonates requiring CKRT. Metabolic complications may occur, but they could be managed with adequate supplementation. WHAT IS KNOWN: • Continuous kidney replacement therapy (CKRT) has become popular in recent years due to its successful treatment of fluid overload, electrolyte imbalance, metabolic acidosis, multi-organ failure, and hyperleucinemia/hyperammonemia associated with inborn errors of metabolism. • The need for anticoagulation is the major difficulty in neonatal CKRT. In adult and pediatric patients, regional citrate anticoagulation has been shown to be effective. WHAT IS NEW: • RCA is an effective and safe anticoagulation method for neonates who require CKRT. • Electrolyte imbalances and metabolic acidosis could be managed with adequate supplementation and appropriate treatment parameters such as citrate dose, blood flow rate, and dialysate flow rate.

Characteristics of continuous venovenous hemodiafiltration in the acute treatment of inherited metabolic disorders.

BACKGROUND: Continuous kidney replacement therapies (CKRT) have been reported to be an effective approach to removing toxic metabolites in inborn errors of metabolism (IEM). The present study evaluates efficiency and complications of CKRT in children with IEM. METHODS: Patients diagnosed with IEM who underwent CKRT in pediatric and neonatal intensive care units were analyzed. CKRT were initiated in patients with persistently high blood ammonia levels (≥ 500 µmol/L), blood ammonia levels > 250 µmol/L in the presence of moderate encephalopathy, high blood leucine levels (≥ 1500 µmol/L), and blood leucine levels < 1500 µmol/L in the presence of deteriorating neurological status or persistent metabolic acidosis. RESULTS: Of 22 patients enrolled, nine (40.9%) Maple syrup urine disease (MSUD), eight (36.4%) urea cycle disorders (UCD), and five (22.7%) organic acidemias (OA). Median age was 72.3 [9.9-1040.8] days. In total, 28 dialysis sessions were analyzed [16 (57.1%) continuous venovenous hemodialysis, and 12 (42.9%) continuous venovenous hemodiafiltration]. A significant decrease was noted in leucine levels (from 1608.4 ± 885.3 to 314.6 ± 109.9 µmol/L) of patients with MSUD, while ammonia levels were significantly decreased in patients with UCD and OA (from 1279.9 ± 612.1 to 85.1 ± 21.6 µmol/L). The most frequent complications of CKRT were thrombocytopenia (60.7%), hypotension (53.6%), and hypocalcemia (42.9%). Median age of patients with hypotension treated with vasoactive medications was significantly lower than median age of those with normal blood pressure. CONCLUSION: CKRT is a reliable approach for effective and rapid removal of toxic metabolites in children with IEM, and CKRT modalities can be safely used and are well-tolerated in infants.

Does Metformin Treatment in Pediatric Population Cause Vitamin B12 Deficiency?

BACKGROUND/AIM: There have been no studies to date examining the effect of metformin treatment on vitamin B12 status in children and adolescents. In this prospective study, the effects of metformin on blood vitamin B12, serum methylmalonic acid (MMA), homocysteine and holo-transcobalamin-II (holo-TC-II) levels were assessed in pediatric age group. MATERIALS AND METHODS: This prospective study was conducted at the Pediatric Endocrinology and Adolescent Department between January 2017 and March 2019. Metabolic syndrome and polycystic ovary syndrome diagnosed patients with insulin resistance and/or impaired glucose tolerance, patients with type 2 diabetes mellitus (DM) treated with metformin were enrolled in study. Blood vitamin B12, MMA, homocysteine, holo-TC-II levels and hemogram values were evaluated. RESULTS: Twenty-four patients were enrolled in study. Among these, 15 (62.5%) were female. The mean age of patients was 13.7±2.3 (10-19) years. Sixteen patients were diagnosed with metabolic syndrome and 8 patients were type 2 DM. At 6-month follow-up of all patients, there was no statistically significant difference in terms of vitamin B12, homocysteine, MMA and holo-TC-II levels. A 0.6% decline in vitamin B12 levels were revealed. At 12-month follow-up of 11 patients (45.8%) (6 Type 2 DM, 5 metabolic syndrome), no statistically significant difference was determined in vitamin B12, homocysteine, MMA and holo-TC-II levels. There were 6% decline in vitamin B12 levels and 10.9% increase in homocysteine levels, 5.4% decrease was detected in holo-TC-II level. CONCLUSION: Although no significant changes in the serum vitamin B12, homocysteine, MMA or holo-TC-II levels with metformin therapy were detected, long-term prospective studies with high-dose metformin treatment in pediatric population are needed to confirm our results.

Inherited metabolic disorders in the neonatal intensive care unit: Red flags to look out for.

BACKGROUND: We aimed to assess symptoms, laboratory findings, and radiological abnormalities in patients diagnosed with inherited metabolic disorders (IMDs) in the neonatal intensive care unit. METHODS: A total of 6,150 newborns treated in a third-level neonatal intensive care unit between 2012 and 2020 in Turkey were screened, of which 195 consulted with a suspicion of metabolic disease based on their clinical, laboratory, or radiological findings were included in the present study. RESULTS: The prevalence of IMDs in the patients was 1:94.6. Those consulted in the department of pediatric metabolism were divided into two groups, with the 65 diagnosed with IMDs assigned as Group I, and the 130 patients who were not diagnosed with IMDs as Group II. The most common IMDs were organic acidemias (29.23%) and urea cycle disorders (UCDs) (26.15%). The rates of consanguinity marriage (75.3% vs 37.6%, P < 0.001), siblings diagnosed with an IMD (27.6% vs 3.8%, P < 0.001), and sibling death (56.9% vs 14.6%, P < 0.001) were higher in Group I than in Group II. Hyperammonemia (61.5% vs 18.4%, P < 0.001) was the most common laboratory finding in Group I, and anemia (Group I 60.0% vs 43.0% P = 0.033), metabolic acidosis (53.8% vs 36.9%, P = 0.028) and respiratory alkalosis (16.9% vs 1.5%, P < 0.001) were all higher in Group I. CONCLUSIONS: This retrospective study found that the results of clinical findings and basic laboratory tests could be strong indicators of IMDs, although extensive newborn screening tests and advanced biochemical and genetic tests should be carried out for the diagnosis of IMDs in newborns.

Pros and Cons of Telemedicine for Inherited Metabolic Disorders in a Developing Country During the COVID-19 Pandemic.

Introduction: The COVID-19 pandemic has led to considerable changes in the health care system. Experts suggested that individuals protect themselves through social isolation during the pandemic, and consequently, the importance of telemedicine came to be understood for patients with chronic diseases. Telemedicine started to be used in developing countries where the appropriate infrastructure was lacking earlier. The present study investigates the level of satisfaction of patients with inherited metabolic disorders (IMDs) with telemedicine. Methods: This prospective study was conducted by making use of a new video appointment program that ensures the privacy of the patients in video-based consultations. The sociodemographic characteristics of the patients, their clinical status, their views on the telemedicine system, and their levels of satisfaction were questioned. Results: Overall, 174 patients were included in the study. The most common diagnoses were aminoacidopathies, lipid metabolism disorders, biotinidase deficiency, and lysosomal/peroxisomal diseases. More than half of the parents (67.6%) who lived in another city reported accommodation issues when coming to the hospital, and most believed telemedicine would save them time (93.1%) and money for travel (81.6%). The lack of laboratory and radiological tests (83.9%) was stated as the main disadvantage by most parents. Almost all the parents (96.6%) stated that they would opt for telemedicine if it became available in daily practice. The overall satisfaction rate was 94.6 (±10.1)/100. Conclusions: The present research is the most extensive cohort study to date assessing telemedicine in patients with IMDs and it highlights the importance of telemedicine, especially in developing countries during the COVID-19 pandemic.

Continuous venovenous hemodiafiltration in the treatment of newborns with an inborn metabolic disease: a single center experience

Background/aim: Most inborn metabolic diseases are diagnosed during the neonatal period. The accumulation of toxic metabolites may cause acute metabolic crisis with long-term neurological dysfunction and death. Renal replacement therapy (RRT) modalities allow the efficient removal of toxic metabolites. In this study, we reviewed our experience with continuous venovenous hemodiafiltration (CVVHDF) as RRT for newborns with an inborn metabolic disease. Materials and methods: Patients diagnosed with an inborn metabolic disease and who received CVVHDF treatment at our neonatal intensive care unit between January 2014 and December 2017 were included in this study. Their demographic and clinical data were collected, and the efficacy and safety of CVVHDF was evaluated. Results: A total of nine continuous RRT (CRRT) sessions as CVVHDF were performed in eight newborns with a diagnosis of urea cycle defect (n = 5), maple syrup urine disease (n = 2), or methylmalonic acidemia (n = 1). The mean age at admission was 10 ± 8.6 days (range: 3­28 days). The mean plasma levels of ammonium were 1120 ± 512.6 mg/dL and 227.5 ± 141.6 mg/dL before and at the end of the treatment, respectively. Plasma levels of leucine were 2053.5 ± 1282 µmol/L and 473.5 ± 7.8 µmol/L before and at the end of the treatment, respectively. The CVVHDF duration was 32.3 ± 11.1 h (median: 37 h; range: 16­44 h), and the mean length of hospitalization was 14.6 ± 12.9 days. The mean duration of CVVHDF was 32.3 ± 11.1 h (range: 16­44 h). Circuit clotting was the most common observed complication (37.5%) and the survival rate was 50%. Among surviving patients, two developed severe and two developed mild mental and motor retardation. Conclusion: CVVHDF is a CRRT modality that can be used to treat newborns with an inborn metabolic disease. Early diagnosis, commencement of specific medical therapy, diet, and extracorporeal support, if needed, are likely to result in improved short and long- term outcomes.

TMEM70 deficiency: long-term outcome of 48 patients.

OBJECTIVES: TMEM70 deficiency is the most common nuclear-encoded defect affecting the ATP synthase. In this multicentre retrospective study we characterise the natural history of the disease, treatment and outcome in 48 patients with mutations in TMEM70. Eleven centers from eight European countries, Turkey and Israel participated. RESULTS: All 27 Roma and eight non-Roma patients were homozygous for the common mutation c.317-2A > G. Five patients were compound heterozygotes for the common mutation and mutations c.470 T > A, c.628A > C, c.118_119insGT or c.251delC. Six Arab Muslims and two Turkish patients were homozygous for mutations c.238C > T, c.316 + 1G > T, c.336 T > A, c.578_579delCA, c.535C > T, c.359delC. Age of onset was neonatal in 41 patients, infantile in six cases and two years in one child. The most frequent symptoms at onset were poor feeding, hypotonia, lethargy, respiratory and heart failure, accompanied by lactic acidosis, 3-methylglutaconic aciduria and hyperammonaemia. Symptoms further included: developmental delay (98%), hypotonia (95%), faltering growth (94%), short stature (89%), non-progressive cardiomyopathy (89%), microcephaly (71%), facial dysmorphism (66%), hypospadias (50% of the males), persistent pulmonary hypertension of the newborn (22%) and Wolff-Parkinson-White syndrome (13%). One or more acute metabolic crises occurred in 24 surviving children, frequently followed by developmental regression. Hyperammonaemic episodes responded well to infusion with glucose and lipid emulsion, and ammonia scavengers or haemodiafiltration. Ten-year survival was 63%, importantly for prognostication, no child died after the age of five years. CONCLUSION: TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood.

Neuronal ceroid lipofuscinosis type 11 diagnosed patient with bi-allelic variants in GRN gene: case report and review of literature.

OBJECTIVES: Neuronal ceroid lipofuscinosis type 11 (NCL11) is a rare disease that presents with progressive cognitive decline, epilepsy, visual impairment, retinal atrophy, cerebellar ataxia and cerebellar atrophy. We present herein a case of NCL11 in a patient diagnosed with neuromotor developmental delay, epilepsy, bronchiolitis obliterans and hypothyroidism. CASE PRESENTATION: A 4-year-old male patient was admitted to our clinic with global developmental delay and a medical history that included recurrent hospitalizations for pneumonia at the age of 17 days, and in months 4, 5 and 7. Family history revealed a brother with similar clinical findings (recurrent pneumonia, hypothyroidism, hypotonicity, swallowing dysfunction and neuromotor delay) who died from pneumonia at the age of 22 months. Computed tomography of the thorax was consistent with bronchiolitis obliterans, while epileptic discharges were identified on electroencephalogram with a high incidence of bilateral fronto-centro-temporal and generalized spike-wave activity but no photoparoxysmal response. Cranial MRI revealed T2 hyperintense areas in the occipital periventricular white matter and volume loss in the white matter, a thin corpus callosum and vermis atrophy. A whole-exome sequencing molecular analysis revealed compound heterozygous c.430G>A (p.Asp144Asn) and c.415T>C (p.Cys139Arg) variants in the GRN gene. CONCLUSIONS: The presented case indicates that NCL11 should be taken into account in patients with epilepsy and neurodegenerative diseases.

Two Turkish patients with Primary Coenzyme Q10 Deficiency-7: case report and literature review.

OBJECTIVES: Primary Coenzyme Q10 Deficiency-7 (OMIM 616276) results from bi-allelic pathogenic variants in the COQ4 gene. Common clinical findings include hypotonia, seizures, respiratory distress, and cardiomyopathy. In this report, we present two patients diagnosed with Primary Coenzyme Q10 Deficiency-7 along with a review of previously published cases, with the aim being to provide a better understanding of the clinical and laboratory manifestations of the disease. CASE PRESENTATION: A 3-month-and-22-day-old male was admitted to our outpatient clinic due to poor feeding and restlessness. He was born following an uneventful pregnancy to a nonconsanguineous marriage. A physical examination revealed hypotonia, a dolichocephaly, periorbital edema, and long eyelashes. Blood tests revealed metabolic acidosis and elevated serum lactate levels, while the genetic analysis revealed a variant previously reported as pathogenic, c.437T>G (p.Phe146Cys), in the COQ4 gene. Genetic tests were also conducted on both mother and father, and it revealed heterozygous variant, 0.437T>G (p.Phe146Cys), in the COQ4 gene. As a result of these findings, the patient was diagnosed with neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome (Primary Coenzyme Q10 Deficiency-7). A 1-year-old male was admitted to our clinic with complaints of hypotonia, seizures, and feeding difficulties. He was born following an uneventful pregnancy to a nonconsanguineous marriage. On his first day of life, he was admitted to the neonatal intensive care unit due to poor feeding and hypotonia. A physical examination revealed microcephaly, a high palate, poor feeding, weak crying, hypotonia, bilateral horizontal nystagmus, and inability to maintain eye contact. Laboratory findings were within normal limits, while a whole exome sequencing analysis revealed a homozygous variant previously reported as pathogenic, c.458C>T (p.A153V), in the COQ4 gene. The patient was diagnosed with Primary Coenzyme Q10 Deficiency-7. CONCLUSIONS: Primary Coenzyme Q10 Deficiency-7 should be considered in the differential diagnosis of infants presenting with neurological and dysmorphic manifestations.

Metabolic etiologies in children with infantile epileptic spasm syndrome: Experience at a tertiary pediatric neurology center.

OBJECTIVE: Infantile epileptic spasm syndrome (IESS), including West syndrome (WS) and infantile spasm (IS), causes a challenging prognosis, particularly when associated with metabolic etiologies. METHODS: This study, conducted at a tertiary pediatric neurology center, explored the prevalence and clinical features of inborn errors of metabolism in 112 children with IESS over 10 years. RESULTS: Most patients presented with seizures, primarily flexor spasms, and the median age at onset was 5 months. Comprehensive clinical evaluation and neuroimaging revealed structural-acquired causes as the most common etiology. Notably, inborn errors of metabolism were identified in 5.4 % of cases, with six distinct diagnoses including nonketotic hyperglycinemia, pyridoxine-dependent epilepsy, primary coenzyme Q10 deficiency 7, congenital disorder of glycosylation type IIM, 6-pyruvoyl tetrahydrobiopterin synthase deficiency, and argininosuccinate lyase deficiency. The prevalence of inborn errors of metabolism in this cohort was consistent with global variations reported in the literature. Genetic testing, including karyotype analysis and whole exome sequencing, was performed in a subset of cases with no clear diagnosis, revealing abnormalities in approximately 50 % of cases. Adrenocorticotropic hormone emerged as the most frequently prescribed antiseizure medication. CONCLUSION: This study provides insight into the diagnostic challenges associated with IESS and highlights the importance of metabolic investigations, especially in cases without a clear etiology. The findings emphasize the need for further genetic and metabolic studies to enhance prognostic accuracy and guide potential treatment options for children with IESS, particularly in populations with high rates of consanguinity.

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.

Is Ultrasonography a Reliable Approach for the Evaluation of Carpal Tunnel Syndrome in Patients With Mucopolysaccharidosis?

BACKGROUND: One of the most common causes of carpal tunnel syndrome (CTS) in childhood is mucopolysaccharidosis (MPS). While ultrasonography (US) can aid in the diagnosis of CTS in adult patients, there is limited experience of this in the pediatric group. We aimed to investigate the results of wrist ultrasonography, which may be a candidate alternative to electrophysiological examination. METHODS: The participants were evaluated for symptoms, physical examination findings, electrophysiological tests and grayscale US. CTS was diagnosed in accordance with the American Academy of Orthopedic Surgeons Management of Carpal Tunnel Syndrome: Evidence-Based Clinical Practice Guideline. RESULTS: Included in the study were 27 MPS patients aged 4.5-32 years and 30 healthy control subjects aged 4.3-26 years. Of the 54 wrists in the MPS group, 30 were diagnosed with CTS. The median cross-sectional area (CSA) at the proximal carpal tunnel, the CSA at the forearm, and the wrist-forearm ratio (WFR) were higher in the wrists of the MPS with CTS group than in those without CTS and the healthy control subjects. The WFR cutoff of ≥1.35, 56.6% (95% CI: 437.4-74.5) sensitivity, and 89.8% (95% CI: 81.0-95.5) specificity were consistent with a diagnosis of CTS (receiver operating characteristics analysis, area under the curve = 0.775, 95% CI: 0.673-0.877). CONCLUSION: Although the US provides results with unsatisfactory specificity and sensitivity, it is a candidate for further investigation for the diagnosis of CTS because it is an innovative, noninvasive, and more accessible method. WFR value may produce more meaningful results than wrist or forearm nerve area measurements.

Literature review and outcome of classic galactosemia diagnosed in the neonatal period.

BACKGROUND: The aim of this study was to evaluate the features and outcome of classic galactosemia diagnosed in the neonatal period. METHODS: A retrospective study was carried out on 22 newborns with classic galactosemia who were followed-up in a tertiary neonatal intensive care unit from January 2005 to January 2011. RESULTS: During the study period, 22 (18 boys, 4 girls) newborns were diagnosed with classic galactosemia. The median gestational age was 38 weeks (31 - 42) with a median age of 13 (3 - 23) days on admission. Major presenting symptoms were hepatomegaly (n = 22, 100%), jaundice [n = 19, 86%; including (n = 14, 63%) indirect and (n = 8, 36%) direct hyperbilirubinemia], vomiting (n = 17, 77%), and nuclear cataract (n = 15, 68%). Liver dysfunction (n = 22, 100%), Escherichia coli sepsis (n = 10), purpura fulminans (n = 1), hemophagocytosis (n = 1), and long QT syndrome (n = 1) were also noted. Cataract resolved in 11 (73%) patients with galactose-restricted diet in the first months. Four patients were operated for cataracts. Neurodevelopmental evaluation showed mild psychomotor retardation in one patient, learning disabilities in five, and developmental delay in three. None died from galactosemia or its complications. Patients who were diagnosed before 17 days did not require cataract operation. CONCLUSIONS: Early diagnosis of galactosemia and treatment with a galactose-restricted diet could partially prevent and recover complications of the disease, but not all of them. Cataracts can develop even in the first few weeks of life. Early diagnosis seems important in the prevention of severe cataracts. Therefore, newborn screening for galactosemia should improve morbidity.

IGAm: A novel index predicting long-term survival in patients with early-diagnosed inherited metabolic disorders.

OBJECTIVES: The childhood mortality rate for IMDs is approximately 25 % in populations with no expanded newborn screening program. Although the factors that increase mortality risk are known, an index predicting long-term survival has yet to be established. METHODS: Two hundred sixty patients who were hospitalized during the first month of their life were screened, and 94 patients diagnosed with IMDs were included in the study. Clinical and laboratory data were assessed to identify any independent prognostic factors for overall survival. RESULTS: Among the 38 patients with IMDs in the exitus group, the presence of dysmorphism, extremity abnormalities, respiratory distress, cyanosis, elevated transaminases, elevated INR, hypoglycemia, hypoalbuminemia, metabolic acidosis, electrolyte imbalance and anemia were associated with poorer survival. Elevated INR (Hazard Ratio [HR]: 0.17, 95 % CI: 0.03-0.87, p=0.034), hypoglycemia (HR: 0.48, 95 % CI: 0.25-0.91, p=0.026) and hypoalbuminemia (HR: 0.09, 95 % CI: 0.03-0.26, p<0.001) were the independent prognostic factors for survival after adjusting for confounding factors. For the prediction of survival, INR, glucose, and albumin were used to structure a novel index (IGAm = INR-Glucose-Albumin metabolic index). The median survival was shorter in the IGAm-high group (2 or 3 points) than in the IGAm-low group (p<0.001). Harrell's c-index was 0.73 for the IGAm index. CONCLUSIONS: The devised novel IGAm index can predict long-term survival in patients with IMDs, with a high IGAm index being associated with higher mortality in patients with IMDs.

A different approach to the evaluation of the genotype-phenotype relationship in biotinidase deficiency: repeated measurement of biotinidase enzyme activity.

OBJECTIVES: In the present study, we aimed to evaluate the genotype-phenotype relation in patients with biotinidase enzyme deficiency based on repeated biotinidase enzyme measurements. METHODS: The hospital file information of patients with biotinidase, enzyme deficiency was assessed retrospectively, and the relationship between the BTD gene mutations analysis results and biotinidase enzyme activity following the first and repeated enzyme activity assessments was analyzed. RESULTS: One-hundred-ten patients were included. In the first enzyme evaluation, profound biotinidase enzyme deficiency was identified in 15 (13.6 %), partial biotinidase enzyme deficiency in 63 (57.3 %), and heterozygous biotinidase enzyme deficiency in 32 (29.1 %) of the patients. The BTD genetic analysis revealed 42 (38.2 %) homozygous, 42 (38.2 %) heterozygous, and 26 (23.6 %) compound heterozygous variants. The most common homozygous variant, p.Asp444His, was evaluated with 130 repeated enzyme measurements and was consistent with a partial biotinidase enzyme deficiency in 55.4 % of cases, heterozygous biotinidase enzyme deficiency in 43.8 % of cases, and profound biotinidase enzyme deficiency in one (0.8 %) case. Clinical symptoms developed in 17 patients during follow-up, of which 70.6 % were related to neurodevelopment. The most common variant was homozygous p.Asp444His (29.4 %) among the patients who developed symptoms. CONCLUSIONS: This is the first study to date to evaluate the genotype-phenotype relationship in patients with biotinidase deficiency through repeated measurements of biotinidase enzyme activity. The study reveals that biotinidase enzyme activity alone is inadequate for diagnosing biotinidase enzyme deficiency or evaluating disease severity, as genetic investigations are also required for a definitive diagnosis of biotinidase enzyme deficiency.

A Rare Contiguous Gene Deletion Leading to Trichothiodystrophy Type 4 and Glutaric Aciduria Type 3.

Introduction: Trichothiodystrophy type 4 and glutaric aciduria type 3 are rare autosomal recessive disorders caused by biallelic variants in the MPLKIP and SUGCT genes on chromosome 7p14, respectively. Trichothiodystrophy type 4 is characterized by neurologic and cutaneous abnormalities. Glutaric aciduria type 3 is a rare metabolic disorder with inconsistent phenotype and elevated urinary excretion of glutaric acid. Case Presentation: Here, we report on an infant presenting with hypotonia, failure to thrive, microcephaly, dysmorphic features, brittle hair, hypertransaminasemia, and recurrent lower respiratory tract infections. Microarray analysis revealed a homozygous microdeletion involving the MPLKIP and SUGCT genes, which are located close to each other. Conclusion: Copy number variations should be considered in patients with coexisting clinical expression of different genetic alterations. To the best of our knowledge, our patient is the second case with co-occurrence of trichothiodystrophy type 4 and glutaric aciduria type 3, resulting from a contiguous gene deletion.

ALG1-CDG: A Patient with a Mild Phenotype and Literature Review.

ALG1-congenital disorder of glycosylation (ALG1-CDG) is an autosomal recessive multisystem disease. We here present a patient with a mild phenotype of ALG1-CDG. A 15-month-old female was referred with hypotonia, failure to thrive, and developmental delay. At 8 months of age, failure to thrive, feeding difficulties and developmental delay became apparent, and an epileptic seizure was observed at 11 months of age. Progressive deterioration and swallowing difficulty were observed. A brain MRI revealed a widening of the cerebrospinal fluid spaces and ventricular system, and decreased protein C, protein S and antithrombin III levels were identified. The isoelectric focusing showed a type 1 pattern. A homozygous c.1076C>T (p.Ser359Leu) variant was found in the ALG1 gene. CDG should be taken into consideration in patients presenting with unexplained multisystem involvement.