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.

Early diagnostic clues of mucolipidosis type II: Significance of radiological findings.

Mucolipidosis type-II (ML-II) is an ultra-rare disorder caused by deficiency of N-acetylglucosaminyl-1-phosphotransferase enzyme due to biallelic pathogenic variants in GNPTAB gene. There are a few known about the natural history of ML-II. In this study, we presented the natural course of 24 patients diagnosed with ML-II. Mean age at diagnosis was 9.3 ± 5.7 months. All patients had coarse face, developmental delay, and hypotonia. The mean survival time was 3.01 ± 1.4 years. The oldest patient was 6.5 years old. Twelve patients died due to lung infection and respiratory failure. We observed early and significant radiological findings of ML-II were different from typical dysostosis multiplex such as femoral cloaking, rickets-like changes, and talocalcaneal stippling. These are significant findings observed in the fetal or newborn period which is considered to be highly characteristic of ML-II and disappears in the first year. Cloaking, rickets-like changes, and stippling were not observed in patients older than three months of age and this suggests that these findings disappear within the first year. These radiological features can be used as important clues for diagnosis. We detected eight different pathogenic variants in GNPTAB gene, three of them were novel.

Actions speak louder than words: Home visits and its effect on dietary adherence in patients with phenylketonuria.

AIM: Phenylketonuria (PKU) is an inherited metabolic disorder in which accumulation of phenylalanine (Phe) leads to poor neurological outcomes without treatment. Dietary therapy is the main treatment and nonadherence is associated with elevated blood Phe levels and correspondingly poor neuropsychiatric outcomes. This study aimed to examine the effect of home visits on blood Phe levels in PKU patients. METHODS: Sixty-five paediatric PKU patients who were on low-phenylalanine diet were visited monthly at home for 6 months. At each visit, dietary education was provided, patients' height and weight were measured and blood samples were collected. RESULTS: Twenty-eight (43.1%) patients had classic PKU and 37 (56.9%) had moderate PKU. Blood Phe levels decreased statistically significant at first, second, fifth, and sixth months compared with screening visit. Blood Phe levels in moderate PKU patients decreased significantly at the last visit unlike classic PKU patients. A significant decrease in blood Phe levels was observed in patients older than 10 years. Anthropometric parameters improved. CONCLUSIONS: Dietary nonadherence is the main treatment failure in PKU. Home visits for education are a promising way to improve treatment outcomes by providing quality education, better assessment, and correction of mistakes but they should be ongoing and supported by different interventions that address patients' special needs.

Perspectives of adult patients with lysosomal storage diseases on the transition from pediatric to adult healthcare in Turkey.

AIM: In many countries, adult clinics specifically dedicated to adult patients with lysosomal storage diseases (LSDs) do not exist. In Turkey, these patients are managed either by pediatric metabolic specialists or adult physicians who do not specifically specialize in LSDs. In this study, we aimed to identify the unmet clinical needs of these adult patients and their suggestions. METHODS: The focus group participants were 24 adult LSD patients. Interviews were conducted in person. RESULTS: A total of 23 LSD patients and parents of a patient with mucopolysaccharidosis type-3b with intellectual deficit were interviewed, with 84.6% of patients diagnosed after the age of 18 years and 18% of patients diagnosed before the age of 18 years desiring management by adult physicians. Patients with particular physical characteristics or severe intellectual deficit declined the transition. Patients reported structural problems in the hospital and social problems associated with pediatric clinics. They made suggestions to facilitate the possible transition. CONCLUSION: With improved care, more patients with LSDs survive into adulthood or receive the diagnosis in adulthood. Children with chronic diseases need to transition to the care of adult physicians when they reach adulthood. Thus, there is an increasing need for adult physicians to manage these patients. In this study, most LSD patients accepted a well-planned and organized transition. Problems were related to stigmatization and social isolation in the pediatric clinic or adult issues with which pediatricians are not familiar. There is a need for adult metabolic physicians. Thus, health authorities should adopt necessary regulations for training of physicians in this field.

Expanding the phenotypic landscape of Gaucher disease type 3c with a novel entity - Transient neonatal cholestasis.

Gaucher disease (GD) is the most frequent lysosomal storage disorder due to biallelic pathogenic variants in GBA gene. Only homozygous D409H variant has been associated with the cardiovascular phenotype which is also known as Gaucher disease type 3c. In this descriptive study, we presented phenotypic heterogeneity and a novel clinical finding among 13 patients with GD type 3c. Patients presented with varying degrees of cardiac valve and/or aortic calcifications (84,6%) and corneal opacities (76,9%) in addition to visceral (100%), hematological (92,3%), neurological (92,3%), and skeletal (30%) manifestations. Also, cervical dystonia (38,4%) and psychiatric disorders (46,1%) were not infrequent entities with respect to neurological involvement in GD type 3c. In this report, we highlight transient neonatal cholestasis (38,4%) as a novel finding in GD type 3c. Neonatal cholestasis is a finding associated with Gaucher type 2, but transient neonatal cholestasis has not been reported in GD patients, so far. The clinical features of GD type 3c are highly heterogeneous, from disease severity or age of onset to disease progression. Also, we concluded that phenotypic spectrum may be associated with age at onset of clinical symptoms. As, patients presenting in infancy or childhood had mainly visceral and hematological involvement and patients presenting in adolescence and adulthood had mainly cardiac, neurological involvement, and psychiatric behavioral disorders. Identifying the heterogeneous clinical course of these patients in this fatal disease, may lead a sufficient understanding of the pathophysiology which will enable targeted therapeutic interventions.

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT). PROCEDURE: In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center. RESULTS: A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant. CONCLUSIONS: Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.

Clinical spectrum of early onset "Mediterranean" (homozygous p.P131L mutation) mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive mitochondrial disorder characterized by cumulative and progressive gastrointestinal and neurological findings. This retrospective observational study, aimed to explore the time of presentation, diagnosis and clinical follow-up of 13 patients with a confirmed MNGIE disease of Mediterranean origin. The mean age of symptom onset was 7 years (6 months-21 years) and the average diagnosis age was 15.4 years ±8.4. Four of 13 patients (30%) died before 30 years at the mean age of 19.7 years ±6.8. Cachexia and gastrointestinal symptoms were observed in all patients (100%). The mean body mass index standard deviation score at diagnosis was 4.8 ± 2.8. At least three subocclusive episodes were presented in patients who died in last year of their life. The main neurological symptom found in most patients was peripheral neuropathy (92%). Ten patients (77%) had leukoencephalopathy and the remaining three patients without were under 10 years of age. The new homozygous "Mediterranean" TYMP mutation, p.P131L (c.392 C > T) was associated with an early presentation and poor prognosis in nine patients (69%) from five separates families. Based on the observations from this Mediterranean MNGIE cohort, we propose that the unexplained abdominal pain combined with cachexia is an indicator of MNGIE. High-platelet counts and nerve conduction studies may be supportive laboratory findings and the frequent subocclusive episodes could be a negative prognostic factor for mortality. Finally, the homozygous p.P131L (c.392 C > T) mutation could be associated with rapid progressive disease with poor prognosis.

A rare cause of microcephaly, thin corpus callosum and refractory epilepsy due to a novel SLC1A4 gene mutation.

L-serine is an important amino acid that ensures neuronal differentiation and development. The SLC1A4 gene encodes proteins that transport amino acids such as serine, alanine, threonine and glutamate into neurons. Pathogenic variants in SLC1A4 gene interneuron transport of L-serine impaired and a severe global developmental delay occurs, characterized by microcephaly and refractory seizures. In this article, we would like to describe the demographic, clinical, electroencephalography (EEG) and magnetic resonance imaging (MRI) features of a patient with a novel pathogenic variant in the 6th exon of the SLC1A4 gene (p.Gly374Arg) detected by whole-exome sequencing, which is extremely rare (there have been twenty patients reported in the literature). It is emphasized that SLC1A4 gene variants should be kept in mind if the patients have microcephaly, global developmental delay, refractory seizures, and there are no abnormalities in basal metabolic investigations, and the thin corpus callosum and myelination delay is seen on the MRI.

Diagnostic value of plasma lysosphingolipids levels in a Niemann-Pick disease type C patient with transient neonatal cholestasis.

OBJECTIVES: Niemann-Pick disease type C (NPC) is a lysosomal storage disease due to impaired intracellular lipid trafficking caused by biallelic pathogenic variants in NPC1 or NPC2 genes. NPC is classified according to the age of onset of neurological manifestations. Cholestatic liver disease can be transient or lead to liver failure. Accompanying neurological findings can be observed at any age. In this report, an infant with a homozygous pathogenic variant in NPC1 gene whose diagnosis was eventually confirmed by specific biomarkers is described. CASE PRESENTATION: A sixteen-day-old male was admitted to hospital with prolonged jaundice. He had mild hepatosplenomegaly, conjugated hyperbilirubinemia, elevated liver transaminases, and mild hypoalbuminemia. Cholestasis resolved spontaneously and patient was readmitted due to progressive hepatosplenomegaly without any neurologic findings when he was 8 months old. Molecular investigations detected homozygous c.1123A > C (p.Thr375Pro) pathogenic variant in NPC1 gene. NPC-specific lysosomal biomarkers such as Lysosphingomyelin and Lysosphingomyelin-509 were elevated, confirming the diagnosis. CONCLUSIONS: The clinical features of NPC are highly heterogeneous, from disease severity or age of onset to disease progression. Patients presenting with transient neonatal cholestasis and should be regularly followed for neurodevelopmental status and visceromegaly. In the case of variants of unknown significance in NPC1 gene, lysosomal biomarkers play an important role when genetic analyses are inconclusive.

Evaluation of bone health in patients with mucopolysaccharidosis.

INTRODUCTION: This study aimed to evaluate the relationship between clinical findings, height and weight standard deviation scores, 25-hydroxyvitamin D3 (25(OH)D3) level, and dual-energy X-ray absorptiometry (DXA) results in patients diagnosed with mucopolysaccharidosis (MPS), where effective current treatments such as enzyme replacement therapy (ERT) can be accessed. MATERIALS AND METHODS: 25(OH)D3 level was measured in 126 patients with MPS (17 with MPS I, 14 with MPS II, 18 with MPS III, 33 with MPS IVA, and 44 with MPS VI; 24-524 months). DXA was performed in 45 of these patients (8 with MPS I, 4 with MPS II, 4 with MPS III, 12 with MPS IVA, and 17 with MPS VI; 62-197 months; all patients were under 18 when DXA was performed) to assess bone mineral density (BMD) of the lumbar spine. RESULTS: In total, 67.5% patients had a short stature, and 50% of them were underweight for their age. Of the patients, 13.5% were immobile, 28.6% had 25(OH)D3 deficiency, and 30.2% had an insufficient level of 25(OH)D3. BMD z score of 45 patients was - 2.5 ± 1.7. In 40% patients, it was < - 2. However, after correction for height-for-age z score (HAZ), HAZ-adjusted BMD z score was - 0.1 ± 0.9. In 2.2% patients, it was < - 2. CONCLUSION: The low BMD z score prevalence reported with DXA was misleadingly higher in children with MPS and short stature. To prevent exposure to unnecessary antiresorptive treatments in these children, the effect of severe short stature and bone geometry on DXA measurements should be considered; further studies on bone health are warranted.

Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report.

OBJECTIVES: Aldolase A deficiency also known as glycogen storage disease (GSD) XII, is an ultra rare autosomal recessively inherited GSD, associated with hemolytic anemia and rhabdomyolysis. CASE PRESENTATION: Here, we first report a patient with dermatological findings, hemodialysis requirement for rhabdomyolysis, and a novel likely pathogenic c.971C>T (p.A324V) mutation in the ALDOA gene. CONCLUSIONS: Episodes of rhabdomyolysis can be triggered by febrile illnesses and catabolic processes. Diagnosis should be confirmed by the mutation analysis of ALDOA gene. Treatment includes management of hemolytic anemia and administration of antipyretics during febrile episodes to avoid hemolysis and rhabdomyolysis.

Morquio A syndrome and effect of enzyme replacement therapy in different age groups of Turkish patients: a case series.

BACKGROUND: This case series includes longitudinal clinical data of ten patients with Morquio A syndrome from south and southeastern parts of Turkey, which were retrospectively collected from medical records. All patients received enzyme replacement therapy (ERT). Clinical data collected included physical appearance, anthropometric data, neurological and psychological examinations, cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat examinations, endurance in the 6-min walk test and/or 3-min stair climb test, joint range of motion, and skeletal investigations (X-rays, bone mineral density). RESULTS: At the time of ERT initiation, two patients were infants (1.8 and 2.1 years), five were children (3.4-7.1 years), and three were adults (16.5-39.5 years). Patients had up to 4 years follow-up. Most patients had classical Morquio A, based on genotypic and phenotypic data. Endurance was considerably reduced in all patients, but remained relatively stable or increased over time in most cases after treatment initiation. Length/height fell below normal growth curves, except in the two infants who started ERT at ≤ 2.1 years of age. All patients had skeletal and/or joint abnormalities when ERT was started. Follow-up data did not suggest improvements in skeletal abnormalities, except in one of the younger infants. Nine patients had corneal clouding, which resolved after treatment initiation in the two infants, but not in the other patients. Hepatomegaly was reported in seven patients and resolved with treatment in five of them. Other frequent findings at treatment initiation were coarse facial features (N = 9), hearing loss (N = 6), and cardiac abnormalities (N = 6). Cardiac disease deteriorated over time in three patients, but did not progress in the others. CONCLUSIONS: Overall, this case series with Morquio A patients confirms clinical trial data showing long-term stabilization of endurance after treatment initiation across ages and suggest that very early initiation of ERT optimizes growth outcomes.

Clinical and molecular findings in 37 Turkish patients with isolated methylmalonic acidemia

Background/aim: Isolated methylmalonic acidemia (MMA) is caused by complete or partial deficiency of the enzyme methylmalonyl- CoA mutase (mut0 or mut­ enzymatic subtype), a defect of its cofactor adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. While onset of the disease ranges from the neonatal period to adulthood, most cases present with lethargy, vomiting and ketoacidosis in the early infancy. Major secondary complications are; growth failure, developmental delay, interstitial nephritis with progressive renal failure, basal ganglia injury and cardiomyopathy. We aimed to demonstrate clinical and molecular findings based on long-term follow up in our patient cohort. Materials and methods: The study includes 37 Turkish patients with isolated MMA who were followed up for long term complications 1 to 14 years. All patients were followed up regularly with clinical, biochemical and dietary monitoring to determine long term complications. Next Generation Sequencing technique was used for mutation screening in five disease-causing genes including; MUT, MMAA, MMAB, MMADHC, MCEE genes. Mutation screening identified 30 different types of mutations. Results: While 28 of these mutations were previously reported, one novel MMAA mutation p.H382Pfs*24 (c.1145delA) and one novel MUT mutation IVS3+1G>T(c.752+1G>T) has been reported. The most common clinical complications were growth retardation, renal involvement, mental motor retardation and developmental delay. Furthermore, one of our patients developed cardiomyopathy, another one died because of hepatic failure and one presented with lactic acidosis after linezolid exposure. Conclusion: We have detected two novel mutations, including one splice-site mutation in the MUT gene and one frame shift mutation in the MMAA gene in 37 Turkish patients. We confirm the genotype-phenotype correlation in the study population according to the long-term complications.

A rare cause of hepatomegaly and dyslipidemia: lysosomal acid lipase deficiency.

BACKGROUND: Lysosomal acid lipase deficiency (LAL-D), also known as cholesteryl ester storage disease or Wolman disease, is a multi-systemic autosomal recessive genetic disorder caused by mutations in the lysosomal acid lipase gene (LIPA). CASE: A 14-year-old female patient was diagnosed as LAL-D with the findings of hepatomegaly, splenomegaly, elevated liver enzyme levels, and abnormal lipid profile. Her sister had similar laboratory and ultrasonographic findings. Both siblings had a homozygous c.894 G > A mutation in the LIPA gene, and their parents were heterozygous for this mutation. CONCLUSIONS: This case is one of the similar reports in the literature regarding clinical, biochemical, and genetic findings. It is well-known that LAL-D has overlapping clinical manifestations, and early diagnosis is quite challenging. Therefore, most patients die in the first year of life. After the determination of novel mutations in LAL-D patients, it is thought that LAL-D can present with heterogeneous signs and symptoms.

Mutations Within the Transcription Factor PROP1 in a Cohort of Turkish Patients with Combined Pituitary Hormone Deficiency

Objective: Mutations of the genes encoding transcription factors which play important roles in pituitary morphogenesis, differentiation and maturation may lead to combined pituitary hormone deficiency (CPHD). PROP1 gene mutations are reported as the most frequent genetic aetiology of CHPD. The aim of this study was to describe the phenotypes of Turkish CPHD patients and define the frequency of PROP1 mutations. Methods: Fifty-seven CPHD patients from 50 families were screened for PROP1 mutations. The patients were affected by growth hormone (GH) and additional anterior pituitary hormone deficiencies. Results: All patients had GH deficiency. In addition, 98.2% had central hypothyroidism, 45.6% had hypogonadotropic hypogonadism, 43.8% had adrenocorticotropic hormone deficiency and 7.1% had prolactin deficiency. Parental consanguinity rate was 50.9% and 14 cases were familial. Mean height standard deviation score (SDS) and weight SDS were -3.8±1.4 and -3.1±2.0, respectively. Of 53 patients with available pituitary imaging, 32 (60.4%) showed abnormalities. None had extra-pituitary abnormalities. Eight index patients had PROP1 gene mutations. Five sporadic patients were homozygous for c.301_302delAG (p.Leu102CysfsTer8) mutation, two siblings had exon 2 deletion, two siblings had complete gene deletion and two siblings were homozygous for the novel c.353A>G (p.Q118R) mutation. The frequency of the PROP1 mutations was 16% in our cohort. Mutation rate was significantly higher in familial cases compared to sporadic cases (42.8% vs 11.6%; p<0.01). Conclusion: Phenotype of patients regarding hormonal deficiencies, pituitary morphology, presence of extra-pituitary findings, family history of CPHD and parental consanguinity are important for deciding which pituitary transcription factor deficiency should be investigated. PROP1 mutation frequencies vary in different populations and its prevalence is high in Turkish CPHD patients.

Congenital erythropoietic porphyria with erythrodontia: A case report.

BACKGROUND: The causes for intrinsic tooth discoloration can be separated into two categories as systemic and local. Systemic causes are either genetic or drug-induced effects. The development of dentition can also be affected by a number of systemic factors and metabolic diseases such as porphyria. Congenital erythropoietic porphyria (CEP), also known as Gunther's disease, is a metabolic disease caused by a transformation in the gene that codifies uroporphyrinogen-3 synthesis, leading to porphyrin aggregation in urine, skin, bone, and dentin. CASE REPORT: A 21-month-old girl with erythrodontia was referred to Paediatric Dentistry Department in September 2017. A physical examination revealed blisters on her face, nose, hands, and feet. Laboratory findings showed highly elevated urine total uroporphyrin and total coproporphyrin I and III levels. Next-generation sequencing multigene panel testing for porphyria demonstrated a homozygous c.10C>T (p.L4F) mutation in the UROS gene. For curative therapy, the patient was admitted to the allogeneic bone marrow transplantation program. CONCLUSION: Congenital erythropoietic porphyria most commonly presents in the first few years of life. Manifestations can include reddish-colored urine, skin blistering, scarring, and erythrodontia. A timely diagnosis can prevent undesirable skin findings of the disease and death due to hematological involvement before a curative allogeneic bone marrow transplantation is performed.

Clinical features of 27 Turkish Propionic acidemia patients with 12 novel mutations.

Kör D, Seker-Yilmaz B, Bulut FD, Kilavuz S, Öktem M, Ceylaner S, Yildizdas D, Önenli-Mungan N. Clinical features of 27 Turkish Propionic acidemia patients with 12 novel mutations. Turk J Pediatr 2019; 61: 330-336. Propionic acidemia (PA) is an inherited metabolic disease caused by the deficiency of one of the four biotin-dependent enzymes propionyl-CoA carboxylase (PCC), and is characterized by coma and death in unrecognized patients, additionally late diagnosis leads to severe developmental delay and neurological sequels. Manifestations of PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure. Mutations in PCCA-PCCB genes cause the clinically heterogeneous disease of PA. In this study, we investigate the mutation spectrum of PCCAPCCB genes and phenotypic features of 27 Turkish patients with PA from the South and Southeast parts of Turkey. We report 12 novel PA mutations, five affecting the PCCA gene and 7 affecting the PCCB gene.

Four Gaucher disease type II patients with three novel mutations: a single centre experience from Turkey.

Gaucher disease is the most common lysosomal storage disorder due to glucosylceramidase enzyme deficiency. There are three subtypes of the disease. Neurological involvement accompanies visceral and haematological findings only in type II and type III Gaucher patients. Type II is the acute progressive neuronopathic form which is the most severe and rare subtype. Clinical findings are recognized prenatally or in the first months of life and followed by death within the first two years of age. Among our 81 Gaucher patients, we identified 4 (4,9%) type II patients in our metabolic centre. This rate is significantly higher than the rate reported in the literature (<1%). Three of the patients had novel mutations, one of them was a collodion baby and the other one was mistyped as type III due to its atypical presentation at the beginning and he was treated with ERT for 8 months. In this report, we present our type II Gaucher patients with three novel mutations and one perinatal lethal form with generalized ichthyosis which is a very rare disorder. Additionally, we would like to highlight the phenotypic heterogeneity not only between the subtypes, also even in the same type.

Coexistence of 2 rare autosomal recessively inherited disorders manifesting with immune deficiency; IL-12 receptor ß1 and biotinidase deficiencies.

Dogruel D, Bulut FD, Yilmaz M, Önenli-Mungan N, Altintas DU. Coexistence of 2 rare autosomal recessively inherited disorders manifesting with immune deficiency; IL-12 receptor ß1 and biotinidase deficiencies. Turk J Pediatr 2018; 60: 584-587. In this report, we described an infant with both partial biotinidase and IL-12Rß1 deficiencies as these two entities are rare and unrelated inherited disorders. One-month-old girl was diagnosed as partial biotinidase deficiency with newborn screening programme. Mutation analysis revealed a compound heterozygous mutation BTD: c.1330G > C (p.Val444Leu) / c.196_197dupCATC (p.Leu69HisfsTer24). At the age of 6 months, a nodule on her left axilla with purulent discharge was noticed which was related to BCG vaccination. A mutational analysis revealed a homozygous c.783+1G > A mutation on IL-12Rß1 gene. Interferon-gamma and anti-tuberculosis treatment were initiated together and the nodule with purulent discharge regressed dramatically. Here, we want to emphasize consideration of coexistence of two rare autosomal recessively inherited diseases in a patient due to the high rate of consanguinity in our country.

Turkish case of ethylmalonic encephalopathy misdiagnosed as short chain acyl-CoA dehydrogenase deficiency.

Ethylmalonic encephalopathy is a very rare autosomal recessively inherited inborn error of metabolism; characterized by encephalopathy, recurrent petechiae without bleeding diathesis, chronic diarrhea, and orthostatic acrocyanosis. Here, we describe a case of ethylmalonic encephalopathy with late onset neurologic symptoms and a confusing family history of two deceased brothers with the wrong suspicion of short chain acyl-CoA dehydrogenase deficiency.