Olcay Güngör

A compound heterozygous EARS2 mutation associated with mild leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL)

Mitochondrial glutamyl-tRNA synthetase is a major component of protein biosynthesis that loads tRNAs with cognate amino acids. Mutations in the gene encoding this enzyme have been associated with a variety of disorders related to oxidative phosphorylation. Here, we present a case of leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) presenting a biphasic clinical course characterized by delayed psychomotor development and seizure. High-throughput sequencing revealed a novel compound heterozygous mutation in mitochondrial glutamyl-tRNA synthetase 2 (EARS2), which appears to be causative of disease symptoms.

A novel homozygous HOXB1 mutation in a Turkish family with hereditary congenital facial paresis

Hereditary congenital facial paresis (HCFP) is characterized by isolated dysfunction of the facial nerve (CN VII) due to congenital cranial dysinnervation disorders. HCFP has genetic heterogeneity and HOXB1 is the first identified gene. We report the clinical, radiologic and molecular investigations of three patients admitted for HCFP in a large consanguineous Turkish family. High-throughput sequencing and Sanger sequencing of all patients revealed a novel homozygous mutation p.Arg230Trp (c.688C>T) within the HOXB1 gene. The report of the mutation brings the total number of HOXB1 mutations identified in HCFP to four. The results of this study emphasize that in individuals with congenital facial palsy accompanied by hearing loss and dysmorphic facial features, HOXB1 mutation causing HCFP should be kept in mind.

Novel mutation in SUCLA2 identified on sequencing analysis

Succinate‐CoA ligase, ADP‐forming, beta subunit (SUCLA2)‐related mitochondrial DNA depletion syndrome is caused by mutations affecting the ADP‐using isoform of the beta subunit in succinyl‐CoA synthase, which is involved in the Krebs cycle. The SUCLA2 protein is found mostly in heart, skeletal muscle, and brain tissues. SUCLA2 mutations result in a mitochondrial disorder that manifests as deafness, lesions in the basal ganglia, and encephalomyopathy accompanied by dystonia. Such mutations are generally associated with mildly increased plasma methylmalonic acid, increased plasma lactate, elevated plasma carnitine esters, and the presence of methylmalonic acid in urine. In this case report, we describe a new mutation in a patient with a succinyl‐CoA synthase deficiency caused by an SUCLA2 defect.

A case of congenital insensitivity to pain with anhidrosis.

To the Editor, Congenital insensitivity to pain with anhidrosis (CIPA) syndrome is a rare autosomal recessive disease which is also known as hereditary sensory and autonomic neuropathy type 4 (1). The prominent characteristics of the disease include fever due to anhidrosis, absence of sense of pain, painless ulcers in the structures inside the mouth and extremities, self-harm behavior, mild to severe mental retardation, myelination defect in the sural nerve biopsy and loss of small myelinized fibers. Infection in the fingers and toes, lips and tongue and scarring is observed commonly. Keratoderma palmoplantaris is a typical finding in the advanced period (1, 2). Other problems include chronic bone and joint infections. Inability to sense pain and absence of hidrosis in the patients arise from absence of sympathetic nerve supply of the afferent neurons of pain and eccrine sweat glands due to tissue damage. These neurons originate from neural crest cells and are localized in the dorsal root ganglion. The cell is stimulated by the “Nerve Growth Factor” (NGF) and TRKA receptors. TRKA is a tyrosine kinase receptor with high affinity and is activated by NGF. In patients with congenital insensitivity to pain with anhidrosis syndrome, mutations in the TRKA (NTRK1) gene which codes the TRKA receptor have been defined. Since congenital insensitivity to pain with anhidrosis syndrome is a rare disease, a child with this syndrome is presented here to draw attention to early diagnosis. A 10 year-old male patient presented to the pediatric emergency department with fever, ulcers on the skin which did not heal and erythema on the left amputated extremity. It was learned that the complaint of fever recurred intermittently since the delivery and he was frequently hospitalized because a focus of infection could not be found, his left foot was amputated because of chronic osteomyelitis approximately one year ago, multiple ulcers occured on his feet, hands, fingers and toes, knees and elbows from the time he started to walk, some of these ulcers healed, but some healed with much difficulty and even did not heal and some fingers were lost because the ulcers did not heal, he never sweated from the time of delivery and did not feel pain when he was exposed to any trauma. He had frequent hospitalizations because of skin infection and fever, recurrent febrile convulsions and follow-up with a diagnosis of keratoderma in dermatology clinics where he was referred because of skin lesions in his personal history. He had no additional pathology in his familial history. On physical examination, his consciousness was open, he had no interest for the environment, he did not speak and there was no eye contact, he had mental retardation. His weight and height were compatible with his peers. Pulse rate: 96/min, blood pressure: 115/70 mmHg, fever: 39°C, respiratory rate: 28/min, oxygen saturation: 99%. Oral hygiene was poor, varying degrees of eruptions were present in the tooth, cracked and eroded lesions were present in the tongue and lips and tissue loss was present in the distal parts of the fingers (Figure 1). Eroded and ulcerated lesions were present between various fingers and toes from place to place. Hyperkeratotic swollen lesions with irregular surface were observed especially around the knees and elbows. The left lower extremity was amputated in the middle of the tibia and there was erythema, induration and increased warmth on the amputation area (Figure 2). There was an sharply circumscribed ulcerated lesion with dimensions of 2×3 cm on an erythematous background sunken from the surface (Figure 3). Cranial nerve examination and muscle strength were found to be normal. Muscle tonus was mildly reduced. Deep tendon reflexes were normoactive. He was insensitive against deep and superficial pain stimuli. No marked pathology was found on the examination of the other systems. Laboratory findings were as follows: WBC 16 800/mm3, absolute neutrophil count 10 300/mm3, absolute lymphocyte count 4 400/mm3, Hb 9.5 g/dL, MCV 77.9 fL/mm3, RDW 15.9%, platalet count 362 000/mm3, erythrocyte sedimentation rate 77 mm/h, C-reactive protein 97.3 mg/dL, blood glucose 87 mg/dL, BUN 8 mg/dL, creatinine 0.3 mg/dL, uric acid 2.2 mg/dL, creatinine kinase 55 U/L. Serum electrolytes were within the normal limits. Chormosome analysis of the patient was found to be 46 XY. Electromyography, cranial magnetic resonance imaging, serum vitamin B12, folic acid, zinc levels were found to be normal. Serum immunoglobulins were compatible with the age. The pilocarpin iontophoresis test was found to be negative. He had moderate mental retardation according to the “Wechsler Intelligence Scale for Children”. The patient was hospitalized in the ward because of congenital insensitivity to pain and soft tissue infection. Antibiotic treatment was started after obtaining samples for blood culture and wound site culture. Figure 1. Tissue loss and deformations in the distal parts of the fingers, contracture and unhealing wounds in the fingers Figure 2. Hyperemia in the skin in the distal part of the left amputated lower exremity Figure 3. Ulcerated necrotic lesion in the periphery on the right patella which has not healed for a long time Pain is a warning, preventive or therapeutic, protective function against damage. When a patient with congenital insensitivity to pain with anhidrosis seriously injures himself/ herself, injury is generally not recognized and permanent wounds occur as a result. Hydrosis is an important function to keep the body temperature within normal limits in warm environments. Anhidrosis leads to recurrent febrile convulsions due to disruption in maintanence of the body temperature and hyperthermia. In patients with congenital insensitivity to pain with anhidrosis syndrome, absense of sense of pain and heat is related with absence of nerve supply of the fibers which conduct the sense of pain and of the eccrine sweat glands (3). Insensitivity to pain and anhidrosis were prominent characteristics in our patient. In patients with congenital insensitivity to pain with anhidrosis, oral lesions, tissue loss in the fingers, tongue and lips, wound site infection, acute and chronic osteomyelitis, finger amputations and joint abnormalities are frequently found because of self harm behavior (1). In these patients, the pilocarpin iontophoresis test is negative. In the literature, nerve supply of the eccrine sweat glands have been found histopathologically in some patients despite a negative pilocarpine iontophoresis test (2). However, Sztriha et al. (1) showed that the present nerve fiber were dysfunctional with immunohistochemical staining methods. Our patient had a clinical history of anhidrosis and the pilocarpin iontophoresis test was found to be negative. Findings including hypotonia, absence of deep tendon reflexes or decreased deep tendon reflexes are expected in patients with congenital insensitivity to pain with anhidrosis (1). Loss of muscle fibers, variability in their size, appearance of a central nucleus, endomisial fibrosis and presence of vacuolar formation are known in patients with CIPA. It is thought that changes in muscle and deep tendon reflexes are related with chronic neuropathic and myopathic changes (4, 5). In patients with congenital insensitivity to pain with anhidrosis, mental retardation is observed frequently. Although microcephaly is an expected finding, enlargement in the ventricles and hydrocephaly have been found in some patients (6). Our patient had mental retardation, but magnetic resonance imaging findings were found to be normal. When the nerve growth factor (NGF)-TRKA system does not function fully, the nerve fibers which are related with the sense of pain and which provide specific nerve supply to the eccrine sweat glands are absent in the organism or do not function (3). It is known that the nerve growth factor has a regulatory role in neuroimmune and endocrine interaction and it has been found in periosteal osteoprogenitor cells. Changes in the functions of these cells may be a facilitating factor in skeletal involvement in patients with CIPA. Many and varying types of mutations have been found in the TRKA gene. The disease is most probably inherited with autosomal dominant inheritance, but it has also been shown to be inherited by “unipaternal” disomy (1, 3). Thus, this should be kept in mind when giving genetic counseling service to patients with CIPA.

A new mutation in an infant with Krabbe disease accompanied by enlargement of the optic nerves

Krabbe disease is a lysosomal disorder resulting in the accumulation of galactocerebroside and psychosine in macrophages; the condition is associated with demyelination and dysmyelination of the cerebral white matter [1]. A 7-month-old male infant was admitted to our clinic because of hyperirritability that had developed when he was 3 months of age and persisted thereafter. A neurological examination indicated excessive irritability without any accompanying abnormal visual tracking or fixation. The patient had also exhibited poor head control since he was 3 months of age, as well as reduced appendicular and truncal tone. Magnetic resonance imaging (MRI) of the brain revealed bilateral enlargement of the proximal prechiasmatic optic nerves and slight hypertrophy of the chiasmatic optic nerves (Fig. 1). T2weighted images revealed that the dentate nuclei were hyperintense, accompanied by abnormal T2 prolongation at the posterior limbs of the capsules and in the deep periventricular white matter. Single-voxel MR spectroscopy showed that the N-acetylaspartate level was reduced, and that of choline elevated, in the white matter of the centrum semiovale (Fig. 2). The b-galactosylcerebrosidase level was 6.5 nmol/17 h/mg protein (normal 18–115 nmol/17 h/mg protein). Next-generation sequencing of the GALC gene revealed a novel homozygous c.943delG mutation in the proband (our patient). This was predicted to cause a substitution of glutamate 315 by asparagine (p.E315Nfs*10), resulting in a truncated protein. To the best of our knowledge, this mutation has not been reported before. Given the nature of the change caused by the mutation, it is very likely to be disease causing. The Polyphen-2 and Mutation Taster applications predicted that the mutation was disease causing with high probabilities. The Integrative Genomics Viewer display showing the novel homozygous GALC mutation in the proband is shown in Fig. 3. Krabbe disease is caused by various mutations that generally cause galactosylceramide b-galactosidase deficiencies [2]. Optic nerve hypertrophy (in particular hypertrophy of the prechiasmatic and chiasmatic nerves) was previously observed in early-onset (infantile) Krabbe disease patients [3]. Such nerve enlargement has extensive diagnostic implications; the differential diagnoses include retinoblastoma, medulloepithelioma, postviral optic neuritis, juvenile xanthogranuloma, leukemia, histiocytic or granulomatous infiltration, nerve sheath meningioma, and optic nerve glioma with dural ectasia [1, 3]. During differential diagnosis, it is also necessary to consider neurofibromatosis (NF) type 1. The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck.com/certificate/MC9ocq.

Intracranial Saccular Aneurysm in a Child With Only Persistent Headache

Headache is one of the common symptoms of intracranial aneursym. A 5-year-old child lately presented to our pediatric emergency department with persistent headache. Brain magnetic resonance imaging revealed a 7×8 mm rounded lesion with slowly heterogeneous low signal in T2 sequence consistent with a partial occluded aneurysm, in the right medial frontal lobe that close to anterior cerebral artery. Intracranial aneurysms are rare in children and they are noncommon without complications as our case.

Exome sequencing identifies a novel homozygous CLN8 mutation in a Turkish family with Northern epilepsy

Neuronal ceroid lipofuscinosis (NCL), one of the most common neurodegenerative childhood-onset disorders, is characterized by autosomal-recessive inheritance, epileptic seizures, progressive psychomotor deterioration, visual impairment, and premature death. Based on the country of origin of the patients, the clinical features/courses, and the molecular genetics background of the disorder, 14 distinct NCL subtypes have been described to date. CLN8 mutation was first identified in Finnish patients, and the condition was named Northern Epilepsy (NE); however, the severe phenotype of the CLN8 gene was subsequently found outside Finland and named ‘variant late-infantile’ NCL. In this study, five patients and their six healthy relatives from a large Turkish consanguineous family were enrolled. The study involved detailed clinical, radiological and molecular genetic evaluations. Whole-exome sequencing and homozygosity mapping revealed a novel homozygous CLN8 mutation, c.677T>C (p.Leu226Pro). We defined NE cases in Turkey, caused by a novel mutation in CLN8. WES can be an important diagnostic method in rare cases with atypical courses.

Acute Mercury Poisoning in a Group of School Children.

Objective Elemental mercury is a toxic liquid element that is used widely in the home, medicine, agriculture, and industry. It is readily vaporized and inhaled at room temperature. Thereby, inhalation can cause acute or chronic poisoning. Mercury can be found in environmental naturally find but some dangers sources give rise to contaminations. It can be very dangerous to all living organisms, especially children. Methods This study presents the features of mercury poisoning in a group of pediatric cases. Data were obtained for 29 pediatric cases exposed to elemental mercury in a high school chemistry laboratory in Turkey. Patients with a blood mercury level exceeding 10 μg/L or a urine mercury level exceeding 15 μg/L were considered to have mercury poisoning. The patients were treated with 2,3-dimercaptopropane sulfonic acid or D-penicillamine. Results Twenty-nine children with mercury poisoning were admitted to the hospital. The median duration of exposure was 58 (range, 15–120) minutes. Ten (29%) children were asymptomatic. Physical and neurological examinations were normal in 19 (65.5%) children. The most common presenting complaint was headache. The most common neurological abnormality, partly dilated/dilated pupils, was present in 9 (31%) children. Mercury levels were measured in blood samples every 5 days, and the median blood mercury level was 51.98 (range, 24.9–86.4) μg/L. There was a positive correlation between the duration of exposure and maximum blood/urine mercury levels (P = 0.001). Conclusions Elemental mercury exposure is potentially toxic; its symptomatology varies, especially in children. Secure storage of mercury and other toxic substances and provision of information about this subject to individuals who might be exposed to mercury and their families might help to prevent mercury poisoning.

Williams-Beuren Syndrome with Mirror Movements

To the Editor: Williams-Beuren Syndrome (WBS) is a rare neurodevelopmental disorder caused by deletion of chromosome 7 at q11.23. It is characterized by distinctive facies, congenital cardiovascular malformations, intellectual disabilities, and various other manifestations [1, 2]. Here, we present a child with WBS who presented with abnormal involuntary hand movements. An 8-y-old boy presented with history of simultaneous, involuntary movements of left hand along with voluntary movements of the opposite hand for about 7 y. He had difficulty in writing, drawing, pushing buttons, using scissors and eating because of involuntarily movements of the left hand. The perinatal history was unremarkable. The parents described developmental delay in his motor, social and language skills since infancy. He was diagnosed with supravalvular aortic stenosis at the age of 3. His weight, height, and head circumference were on 50th percentile. Dysmorphic facial features including puffy eyes, full cheeks, flat midface, epicanthic folds, narrow and high palate, wide mouth with thick lips, and long philtrum were noted in physical examination (Fig. 1). During examination, involuntary, simultaneous movement of the left hand whenever the right hand was moved were noted. Routine blood and metabolic tests and brain and cervical vertebra magnetic resonance imaging were normal. Fluorescent in situ hybridization study revealed deletion of 7q11.23 region and he was diagnosed with WBS. Neurologic problems in WBS vary and include mental retardation, delayed developmental milestones, and visual spatial deficits [1, 2]. To the best of our knowledge, only two cases about the co-existence of mirror movements with

Thalamic T2 hypointensity: a diagnostic clue for Tay–Sachs disease

A 15-month-old male infant was admitted to our clinic due to complaints of hyperirritability that had persisted since he was 6 months old. The infant exhibited axial hypotonia, visual fixation, and tracking, as well as very limited spontaneous movements, and no head control. Tendon reflexes were to elicit. The patient was unable to exhibit head control since he was 4 months of age, and required support when sitting until 10 months of age. Brain magnetic resonance imaging (MRI) revealed a bilateral low intensity signal in the thalamus, and a bilateral moderately high intensity signal in the white matter and basal nuclei (Fig. 1a–c). In control MRI of the patient when compared to normal patients at the same age, T2 hypointensity became evident in thalamus (Figs. 2, 3). Serum was also analyzed for hexosaminidase A by a fluorometric method defined by O’Brien et al. [1]. According to laboratory tests, the patient’s leukocyte Beta-hexosaminidase A activity was 30.1 nmol/ mg protein/h (control range = 153–371 nmol/mg protein/ h), while the total leukocyte Beta-hexosaminidase activity was 1240.1 nmol/mg protein/h (control range = 734–1628 nmol/mg protein/h) and leukocyte beta-hexosaminidase A activity was 2.4 % of total hexosaminidase (normal value: 63–75 %). Based on these values, Tay– Sachs disease was diagnosed. Tay–Sachs disease, which also known as GM2 gangliosidosis, is disorder that results from hexosaminidase A deficiency. The disease, which shows early onset in infancy, is characterized by macrocephaly, convulsions, hypersensitivity to sound, and bilateral red spots on the eyes’ fundus. The main MRI findings in Tay–Sachs disease are bilateral high intensity signals on the T2 images of the patients’ cortex and basal ganglia. Over time, such signals are reported to evolve in the white matter of patients with this and related illnesses [2]. Bilateral T2 hypointensity at the thalamus is accepted as an indication of lysosomal storage diseases, and is observed in Tay–Sachs and Sandhoff diseases (GM2 gangliosidosis), Krabbe disease, metachromatic leukodystrophy (MLD), and neuronal ceroid lipofuscinosis (NCL) [3]. Fourteen types of NCL are available, and in types of infantile, late onset and juvenile NCL thalamic hypointensity can be visible on T2-weighted MRI images [4]. It is possible to clinically distinguish Tay– Sachs and Sandhoff disease based on the presence or absence of hepatosplenomegaly, since this condition is only observed in Sandhoff disease. A diagnosis of Sandhoff disease can be further confirmed by assay of beta-hexosaminidase activities; in this condition, there is deficiency of both the hexosaminidase A and B isozymes. NCL shows similar features to Tay–Sachs diseases, but is accompanied by severe cerebral atrophy. In Krabbe disease, the T2 hypointensity tends to be more extensive, affecting the cerebellum, central white matter, and basal ganglia, along with the thalamus [5]. Observation of T2 thalamic hypointensity is an important indication of lysosomal & Olcay Güngör drolcaygungor@gmail.com