Background/aim:Pompe disease (acid maltase deficiency, glycogen storage disease type II, OMIM #606800) is an autosomal recessive disorder characterized by lysosomal acid-α-glucosidase deficiency. The infantile-onset type of the disease is mainly characterized by cardiomegaly, hypotonia, and a high mortality rate. This study aimed to create a national consensus about infantile-onset Pompe disease (IOPD) to raise awareness among clinicians and standardize diagnosis and treatment approaches in Türkiye. Materials and methods:The Gazi University Division of Metabolic Diseases and Nutrition developed this expert opinion consensus and expanded it to include metabolism specialists across Türkiye. A systematic literature review was performed, and the Delphi method was used to evaluate the results. Results:Seventeen conclusive questions were produced about clinical presentation, diagnosis, and treatment, and 14 reached a consensus. Consensus was reached that general hypotonia is one of the most important findings, and agreement was also achieved on the starting dose of treatment for presymptomatic patients. The contributors agreed that gene therapy is a good treatment option for IOPD in the future. Conclusion:The topics related to this consensus will help physicians in Türkiye and elsewhere with high incidence rates of IOPD, especially regarding diagnosis and treatment decisions.

Objective Central nervous system (CNS) complications can be seen in patients with leukemia, depending on the disease itself and the chemotherapeutic agents used. This study focused on CNS complications during treatment in children with acute leukemia in a single pediatric institution Methods We retrospectively analyzed the clinical reports of 115 children with acute leukemia. Results A total of 115 children’ clinical records with acute leukemia over a four-year period, were reviewed. Acute CNS complications developed in 23.1% of AML patients and in 13.5% of ALL patients. CNS complication developed most frequently during the induction phase of the treatment (66.7%). Seizures were the most common symptom (9 patients, 50%), followed by hemiparesis (4 patients, 22.2%) and headache (4 patients, 22.2%). Six patients (33.3%) had chemotherapy-induced toxic leukoencephalopathy, two (11.1%) had Wernicke's encephalopathy, and one patient (5.6%) each had sinus vein thrombosis, posterior reversible encephalopathy syndrome, and CNS infection. Sequelae occurred in three patients (16.7%) and only one patient (5.6%) died due to a CNS complication. Conclusion CNS complications in children with leukemia may present with a wide variety of symptoms. Despite the long-term use of chemotherapeutic agents, their side effects are still not fully clarified. Systemic evaluation of the patients and a multidisciplinary approach are important.

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 extra- neurologic 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 p = 0.069), peripheral neuropathy (p p = 0.234) and psychiatric manifestations (p 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.

Çocuklarda Nörometabolik ve Nörodejeneratif Hastalıklarda Öykü, Muayene ve Temel Yaklaşımlar Cengiz HAVALI Kalıtsal Metabolizma Hastalıklarında Laboratuvar İncelemeleri Mehmet Şerif CANSEVER Çocuklarda Temel Radyolojik Görüntüleme Yöntemleri ve Beyin Görüntülemesinde Uygun Yaklaşım Seçimi Derya BAKO Çocuklarda Beyin Manyetik Rezonans Görüntüleme Özge YAPICI Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklara Manyetik Rezonans Görüntüleme Temelli Radyolojik Yaklaşım Derya BAKO Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Manyetik Rezonans Spektroskopi Sinan GENÇ Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklara Genetik Yaklaşım Orhan GÖRÜKMEZ Mitokondriyal Hastalıklarda Heteroplazmi Dinamikleri ve Moleküler Genetik Testlerin Kullanımı Ali TOPAK Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Kardiyak Değerlendirme Mete Han KIZILKAYA Çocukluk Çağı Nörodejeneratif ve Nörometabolik Hastalıklarda Göz Bulguları Asiye EKİNCİ Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Hematolojik Bulgular Bilgen IŞIK Nöroenflamasyon Eren ÇAĞAN Nörodejeneratif Hastalıklar ve İmmün Sistem Eren ÇAĞAN Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Kök Hücre Nakli Bilgen IŞIK Çocukluk Çağı Nörometabolik ve Nörodejeneratif Hastalıklarda Gen Tedavisi Özlem GÖRÜKMEZ OLGU 1 Cengiz HAVALI OLGU 2 Mine Çiğdem ŞENOĞLU OLGU 3 Sevil DORUM OLGU 4 Esra SARIGEÇİLİ OLGU 5 Dilek GÜNEŞ OLGU 6 Rabia TÜTÜNCÜ TOKER OLGU 7 Pembe SOYLU ÜSTKOYUNCU, Songül GÖKAY OLGU 8 Fatma KAYA OLGU 9 Beyza Belde DOĞAN OLGU 10 Sebile KILAVUZ OLGU 11 Ayfer SAKARYA GÜNEŞ OLGU 12 Sevim TÜRAY OLGU 13 Ayşe Ergül BOZACI OLGU 14 Didem SOYDEMİR OLGU 15 Aliye GÜLBAHÇE OLGU 16 Ayfer SAKARYA GÜNEŞ OLGU 17 Elif Perihan ÖNCEL OLGU 18 Emine GÖKSOY OLGU 19 Pınar ÖZBUDAK OLGU 20 Hülya İNCE OLGU 21 Serçin TAŞAR OLGU 22 Habibe KOÇ UÇAR, Berrak BİLGİNER GÜRBÜZ OLGU 23 Rabia TÜTÜNCÜ TOKER OLGU 24 Gülhan KARAKAYA MOLLA OLGU 25 Ayşenur METİN OLGU 26 Gülşah KALAY OLGU 27 Canan ÜSTÜN OLGU 28 Zeynep Beyza KUŞKU OLGU 29 Özgen HÜR OLGU 30 Beyza Belde DOĞAN OLGU 31 Cumali ALAN OLGU 32 Pınar ÖZBUDAK OLGU 33 Serkan KIRIK OLGU 34 Ayşe Nur COŞKUN OLGU 35 İpek DOKUREL ÇETİN OLGU 36 Sevim TÜRAY OLGU 37 Mutluay ARSLAN OLGU 38 Selen HAS ÖZHAN OLGU 39 Hilal AYDIN OLGU 40 Gül YÜCEL OLGU 41 Esra ÜLGEN TEMEL OLGU 42 İlknur CANKURT OLGU 43 Beyza Belde DOĞAN OLGU 44 Çağatay GÜNAY OLGU 45 Aliye GÜLBAHÇE OLGU 46 Dilek GÜNEŞ OLGU 47 Asburce OLGAC OLGU 48 Mehtap KAĞNICI OLGU 49 Nazlı Balcan KARACA OLGU 50 Halil ÇELİK OLGU 51 Esra SARIGEÇİLİ OLGU 52 Serap BİLGE OLGU 53 Hakan ERÇELEBİ OLGU 54 Gül YÜCEL OLGU 55 Asburce OLGAC OLGU 56 Emine Gülben YURDAGÜL OLGU 57 Berrak BİLGİNER GÜRBÜZ, Habibe KOÇ UÇAR OLGU 58 Fatih Mehmet Akif ÖZDEMİR OLGU 59 Özge TOPTAŞ DEDEOĞLU OLGU 60 Fatih Mehmet Akif ÖZDEMİR OLGU 61 Şeyma Nur KARATAŞ OLGU 62 Sevil DORUM, Cengiz HAVALI OLGU 63 Gamze AYVAZOĞLU Nörometabolik Hastalıklar ve Karaciğer Nilüfer ÜLKÜ ŞAHİN OLGU 64 Didem SOYDEMİR

Although hyperuricemia is a widely studied condition with well-known effects on the kidneys, hypouricemia is usually considered a biochemical abnormality of no clinical significance despite the fact that it can be a sign or major finding of serious metabolic or genetic diseases affecting kidney health. In this study, we aimed to investigate and emphasize the clinical significance of hypouricemia. Patients were evaluated retrospectively for persistent hypouricemia defined as serum uric acid concentrations of < 2 mg/dL on at least 3 different occasions. According to the blood and urine uric acid (UA) levels, the patients were classified as having hypouricemia due to UA underproduction vs. overexcretion. Demographic, clinical, and genetic characteristics were noted for analysis. Fourteen patients (n = 14; M/F 8/6) with persistent hypouricemia were identified. Hypouricemia due to underproduction was the cause of 42.8

BACKGROUND:Arginase-1 deficiency is a rare, autosomal recessively inherited disorder of the urea cycle. In this study, we describe the clinical and molecular details of six patients who were diagnosed with argininemia, and we describe two of the patients with hyperargininemia who carried two novel variations of the Arginase-1 gene. METHODS:The clinical and demographic characteristics of the patients were retrospectively evaluated. RESULTS:The ages of the six patients ranged from 1 day to 20 years, and each patient had consanguineous parents. Neuromotor retardation and spastic paraparesis were found in all patients except one, who was diagnosed prenatally. Hyperargininemia was present in all patients. Urinary orotic acid excretion was increased in four of the six patients. The diagnosis was confirmed by genetic analysis in all the patients. Elevated liver enzymes were detected in three patients and blood urea nitrogen levels were normal in each of the six patients. CONCLUSIONS:In this study, we describe the two patients with hyperargininemia who carried two novel variations of the ARG1 gene. Also, we present a patient with normal neurodevelopment who was diagnosed prenatally and treated at an early stage of the disease.

Amaç: Üre döngüsü bozuklukları (ÜDB), vücut için toksik olan amonyağın kanda birikimi sonucu ortaya çıkan doğumsal metabolizma bozukluklarıdır. Çalışmamızda ÜDB hastalarımızın klinik, laboratuvar, genetik ve radyolojik özellikleri değerlendirilmiştir. Yöntem: Çalışmamızda 12 ÜDB tanılı hastanın klinik, laboratuvar, genetik ve radyolojik özellikleri retrospektif olarak değerlendirildi. Bulgular: Dört (%33) hasta yenidoğan döneminde akut metabolik kriz ile başvurmuştu. Hastalardan biri (sitrullinemi tip I) intrauterin tanı almıştı ve doğar doğmaz tedavisi başlanmıştı. Hastaların başvuru yaşları 0 gün ile 12 yaş arasında değişmekteydi. Yenidoğan başlangıçlı 4 hastadaki en sık şikâyet, doğumdan sonraki ilk 6 gün içinde ortaya çıkan sepsis benzeri klinik, kusma ve koma tablosuydu. Yenidoğan dönemi dışında tanı alan hastalarda ise koma, zekâ geriliği, yürüme gecikmesi, spastisite (arjininemi), büyüme geriliği (LPİ), proteinli gıdalardan kaçınma (LPİ, OTC eksikliği) baskındı. Geç başlangıçlı hastaların başvuru yaşı 2 yaş ile 12 yaş arasında değişmekteydi. Yedi geç başlangıçlı hastadan sadece bir tanesi normal büyüme ve mental gelişim gösterdi. Sonuç: ÜDB sadece yenidoğan dönemi değil, yaşamın her döneminde karşımıza çıkabilir. Klinik şüphe varlığında tanıya yönelik testler hızlıca planlanmalıdır. Erken tanı mortalite ve morbiditeyi önemli düzeyde etkilemektedir.

Neurotransmitter disorders are a group of neurometabolic syndromes caused by disturbances of neurotransmitter metabolism. The primary aim of this retrospective study is to present patients with disturbances of monoamine neurotransmitter metabolism. Cerebrospinal fluid (CSF) neurotransmitter measurements and genetic analysis were performed on five patients. Five patients who had various movement disorders and motor and cognitive disabilities were included. Four patients were diagnosed with sepiapterin reductase (SR) deficiency, and one was diagnosed with aromatic L-amino acid decarboxylase (AADC) deficiency. Different treatment responses appeared in patients with SR and AADC deficiency. The responses to drug treatment ranged from good to weak in our patients. The diagnosis process is challenging in patients with SR and AADC deficiency, which present similar clinical features to other neurological and metabolic diseases. Investigations of neurotransmitters in CSF and analysis of related genes are essential to differentiate disturbances of monoamine neurotransmitter metabolism from other neurometabolic diseases. For patients with monoamine neurotransmitter disorders, drugs that target these disturbances should be combined as necessary to produce the appropriate response.

Alkaptonuria (AKU) is an inborn error of metabolism caused by the deficiency of homogentisate 1,2-dioxygenase (HGD) as a result of a defect in the HGD gene. HGD enzyme deficiency results in accumulation of homogentisic acid (HGA) in the body, which in turn leads to multisystemic clinical symptoms. The present study aimed to investigate the presenting symptoms, age at diagnosis, and clinical and genetic characteristics of AKU patients followed-up in different centers in Turkey. In this cross-sectional, multicenter, descriptive study, medical records of 66 AKU patients were retrospectively evaluated. Patients? data regarding demographic, clinical and genetic characteristics were recorded. HGD database (http://hgddatabase.cvtisr.sk/) was used to identify HGD gene variants. Of the patients, 37 (56.1%) presented with isolated dark urine and 29 (43.9%) were diagnosed based on the clinical symptoms or family screening. One of these patients was on follow-up for 2 years due to Parkinsonism and was diagnosed with AKU on further analyses. Signs of ochronosis such as joint pain, low back pain and renal stones developed in childhood in 7 patients. Eight patients were diagnosed with depression via psychiatric evaluation. There were 14 (21.2%) patients operated on for ochronosis. The most frequent mutation observed in the patients was c.175delA, which was followed by c.674G > A and c.1007-2A > T mutations. Four novel mutations (c.189G > A, c.549+1G > T, c.1188+1G > A, and c.334 T > G) were identified in the patients included in the study. In addition to the known signs such as dark urine and skin pigmentation, symptoms involving different systems such as neurological findings and depression can also be encountered in AKU patients. The presence of a change in urine color needs to be questioned in patients presenting with different symptoms such as arthralgia/arthritis, renal stones or low-back pain, particularly in childhood, when skin ochronosis is not pronounced, and further examination should be performed.

Trichohepatoenteric syndrome (THES) is a very rare autosomal recessive genetic disorder, which is characterized by intractable diarrhea during infancy, dysmorphic features, immunodeficiency, and a failure to thrive. There are still significant difficulties for patients and clinicians in terms of the management of THES, even though its molecular basis has been uncovered in the last decade. In this article, we have presented two cases relating to siblings that have been diagnosed with the condition. Concerning one of the patients, we described a novel variation (c.2114 + 5G > A) in the TTC37 gene and a mild clinical course; meanwhile, the other one was clinically diagnosed with THES at 17 years of age, but they had seizures and died suddenly. These cases expand the spectrum of clinical findings in relation to THES.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

Background Familial renal glycosuria (FRG) is a rare renal tubular disorder characterized by a variable loss of glucose in the urine despite normal blood glucose levels, which is seen in a condition in which other tubular functions are preserved. In this study, the molecular and clinical characteristics of pediatric FRG cases due to SLC5A2 gene variants were defined. Methods Demographic features, diagnostic tests, and molecular analyses of patients with a diagnosis of FRG cases due to SLC5A2 gene variants were retrospectively analyzed between 2016 and 2019. Results The data of 16 patients who were clinically and genetically diagnosed with FRG in a 4-year period were analyzed. Seven (44%) of the cases were female and 9 (56%) were male. The median age at diagnosis was 6 years old (2 months old to 17 years old). Neuromotor development was found to be appropriate for the age in each case. Systemic blood pressure was evaluated as normal. A homozygous pathogenic variant in the SLC5A2 gene was detected in 14 patients in the genetic examination. A heterozygous variant was detected in one patient. In the other patient, two different heterozygous pathological variants were found in the SLC5A2 gene. Conclusions It was revealed that growth and development were normal in children with glucosuria due to variations in the SCL5A2 gene. Renal function tests and urinary amino acid excretion were also within normal values. In our case series, the most common genetic variation in the SCL5A2 gene was the A219T (c.655G>A) variant.

Purpose: Pathogenic variants of the WWOX gene have been linked to sexual differentiation disorders, spinocerebellar ataxia, and epileptic encephalopathy (EE). We evaluated the clinical and molecular data from six newly diagnosed patients with WWOX-related EE.Methods: Clinical and molecular findings in six patients with EE were investigated, and biallelic pathogenic variants in the WWOX gene were identified. Clinical exome sequencing and Sanger sequencing were performed.Results: Three variations, as well as two novel mutations, in the WWOX gene were detected.Conclusion: Pathogenic WWOX mutations are associated with early-onset EE. Here, we report the case of six children with WWOX-related EE.

Peroxisomal disorders are a heterogeneous group of diseases caused by mutations in a large number of genes. One of the genetic disorders known to cause this situation is ACBD5 (Acyl-CoA binding-domain-containing-5) gene mutations that have been described in recent years. Here, we report two siblings with a novel homozygous nonsense variation (c.1297C>T, p.Arg433*) in ACBD5 (NM_145698.4) gene using Clinical Exome Sequencing (Sophia Genetics).

American Journal of Medical Genetics Part AVolume 182, Issue 7 p. 1541-1546 ISSUE INFORMATIONFree Access Table of Contents, Volume 182A, Number 7, July 2020 First published: 20 June 2020 https://doi.org/10.1002/ajmg.a.61236AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume182, Issue7July 2020Pages 1541-1546 RelatedInformation

BACKGROUND:Glutaric Aciduria Type 3 (GA-3) is a rare metabolic disease which is inherited autosomal recessively and characterized by isolated glutaric acid excretion. To date, a limited number of cases have been reported in the literature. We present two patients with GA3 who were diagnosed with the isolated increased level of glutaric acid in urine.CASE:Glutaric aciduria type 1 and type 2 were excluded by genetic analysis and other laboratory and clinical findings. One of our patients had a homozygous mutation p.Arg322Trp (c.964C > T) of SUGCT (NM_001193311) gene. To the best of our knowledge this mutation has not been reported in the literature previously. Symmetrical periventricular and deep cerebral white matter abnormalities were detected on his brain magnetic resonance imaging (MRI).CONCLUSION:We present two patients with GA-3 and a novel mutation in the SUGCT gene. Our findings expand the spectrum of causative mutations and clinical findings in GA-3.

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.

Background Peroxisomal biogenesis disorders (PBDs) include a miscellaneous group of diseases which cause serious multisystem disease. Mutations of 13 different PEX genes lead to PBDs including Zellweger syndrome (ZS). Different types of mutations of PEX1 and PEX10 genes are correlated with broad-range phenotypes of PBDs. Case presentation Patient 1 is a 4-month-old boy who was affected by myoclonic seizures, poor oral feeding since birth. The patient was hypotonic and had hepatosplenomegaly. Patient 2 is a 2-month-old boy who presented with decreased movement, severe hypotonia and failure to thrive. The laboratory studies of the patients revealed increased plasma very-long-chain fatty acids (VLCFAs). The genetic analyses of patient 1 demonstrated the first homozygous missense mutation in the PEX10 gene. A novel homozygous missense mutation was found in the PEX1 gene in patient 2. Conclusions This report highlights that the detected homozygous missense mutations of PEX10 and PEX1 genes and the substitutions of specific amino acids lead to the severe form of PBDs.

Objectives: To describe the clinical, metabolic and genetic characteristics of the floppy infants diagnosed at a tertiary care center. Methods: A retrospective analysis was performed on the medical files of 90 floppy infants diagnosed in the pediatric metabolism department of our tertiary care center. Baseline descriptives, prenatal and perinatal data, results of genetic and metabolic tests as well as neuroradiological imaging findings were overviewed. Results: Our series was comprised of 42 (46.7%) females and 48 (53.3%) males. Consanguineous marriages were detected in 60 (66.7%) cases. There was no history of prenatal comorbidity or birth-related trauma or infections. Gestational age was ≥ 37 weeks in 78 (87%) infants. The average body weight was 2521.2 ± 839.4 grams (range: 1510-4300). The average height and head circumference were 48.9 ± 0.9 cm and 33.9 ± 0.7 cm, respectively. The etiology of hypotonia was found to be central in 89 (98.8%) infants. The most frequent diseases diagnosed were vitamin B12 deficiency (14.4%), dystrophinopathy (7.7%), spinal muscular atrophy (5.5%), gangliosidosis (3.3%), peroxisomal disease (3.3%), Pompe disease (3.3%), and Zellweger disease (3.3%). Conclusions: The floppy infant still constitutes a diagnostic challenge in spite of the technological advances in genetic, molecular and metabolic test methods. The priority and selection of diagnostic measures need to be determined on an individualized basis, and multidisciplinary and collaborative work is mandatory to set the diagnosis cost-effectively without delay. An algorithm based and individualized approach may provide a high diagnostic yield for the clinician.