Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Neuroradiological, neurophysiological and molecular findings in infantile Krabbe disease: two case reports.

Krabbe disease is an autosomal recessive neurodegenerative disorder due to a defect of the lysosomal enzyme ß-galactocerebrosidase (ß-GALC). Depending on the age of onset, the disease is classified into infantile and later-onset forms. We report neuroradiological, neurophysiological and molecular findings in two Greek patients with the infantile form of Krabbe disease. The index patients presented at the age of 3.5 and 6 months, respectively, due to developmental delay. Magnetic resonance imaging (MRI) of the first patient's brain demonstrated signs of leukodystrophy, while nerve conduction velocities (NCVs) were significantly decreased. The second patient's MRI at the age of 4 months was initially normal, but at 18 months demonstrated leukodystrophic alterations as well, whereas NCVs were also significantly delayed. In both patients, a severe decrease in ß-GALC, activity supported the diagnosis of Krabbe disease, while the final diagnosis was confirmed by molecular genetic testing. Two homozygous mutations of the GALC gene, the c.411_413delTAA [p.K139del] mutation in the first patient, and the c.749T>C [p.I250T] mutation in the second patient, were identified. At their last follow-up visit at the age of 4 and 6 years, respectively, both patients were bedridden and quadri-plegic, suffering from frequent respiratory tract infections and fed through a gastrostomy. Both mutations found in homozygosity in these two unrelated patients of Greek ancestry, could pinpoint a common origin. Genotyping of patients with Krabbe disease is important, in order to contribute to the creation of a European mutation database and to further study possible genotype-phenotype correlations of the disease.

Eponym: the Lemierre syndrome.

Fig. 1 Dr. Andre Lemierre Lemierre syndrome, also known as postanginal sepsis, is a severe complication of an acute oropharyngeal infection that results in septic thrombophlebitis of the ipsilateral internal jugular vein with subsequent septicemia, often complicated by metastatic infections. The usual agent in Lemierre syndrome is Fusobacterium necrophorum, a commensal bacillus of the oral cavity. After the advent of antibiotic therapy, especially in the 1960s and 1970s, when penicillin was frequently used to treat pharyngeal infections, Lemierre syndrome was often referred to as the "forgotten disease". Today with increasing antibiotic-resistant organisms and decreasing awareness of the syndrome, subsequent reemergence of this syndrome is becoming more common in clinical settings. The syndrome starts initially as an acute oropharyngeal infection followed by septicemia with intense fevers, rigors, swelling, and tenderness on the lateral aspect of the neck, parallel to the sternomastoid muscle (septic internal jugular vein thrombophlebitis), and multiple metastatic infections.

A patient with Lemierre syndrome.

Lemierre syndrome, also known as postanginal sepsis, is a severe complication of an acute oropharyngeal infection that results in septic thrombophlebitis of the ipsilateral internal jugular vein with subsequent septicemia, often complicated by metastatic infections (Syed et al., Laryngoscope 117:1605-1610, 2007). We present the case of a previously healthy 12-year-old boy with Lemierre syndrome, caused by streptococci (Abiotrophia defectiva), complicating a subcutaneous neck abscess. The patient had metastatic sequelae, was treated with antibiotics (clindamycin and vancomycin) and low molecular weight heparin, and had an uneventful outcome.

Coexistence of Constitutional Mismatch Repair Deficiency syndrome and Lynch syndrome in a family of seven : MSH6 mutation and childhood colorectal cancer - a case series.

PURPOSE: To present a case series of two fraternal twin girls who passed away from brain and colorectal cancers attributed to Constitutional Mismatch Repair Deficiency syndrome (CMMRD). A review of literature for CMMRD-related pediatric malignancies is also presented. METHODS: The two girls were diagnosed with cancer at the age of 11 and 13 respectively. The early onset of multiple malignancies in the family raised clinical suspicion for a potential genetic mutation. The presence of café-au-lait spots at clinical examination led to further investigations for neurofibromatosis. RESULTS: Neurofibromatosis type 1 testing was negative in both children. Genetic analysis turned out positive for biallelic MSH6 mutations in the two girls, leading to CMMRD syndrome diagnosis. Both parents and two out of three alive siblings were diagnosed with Lynch syndrome. CONCLUSIONS: Colorectal cancer is a very rare finding in childhood and should raise suspicion for CMMRD syndrome and should be followed by regular screening.

Tyrosine hydroxylase deficiency with severe clinical course.

Tyrosine hydroxylase (TH) deficiency is a rare autosomal recessive disorder mapped to chromosome 11p15.5. Its clinical expression varies with presentations as dopa-responsive dystonia (recessive Segawa's disease), dopa-responsive infantile parkinsonism, dopa-responsive spastic paraplegia, progressive infantile encephalopathy or dopa-non-responsive dystonia. We describe a 7-year-old boy with progressive infantile encephalopathy and non-responsiveness to dopamine. The patient demonstrated generalized hypotonia, pyramidal tract dysfunction and temperature instability after the second month of life. Dystonia, tremor and oculogyric crises complicated the clinical picture during the following months. Neurotransmitter analysis in CSF disclosed almost undetectable levels of HVA and MHPG, whereas serum prolactin was profoundly increased. Subsequent molecular analysis revealed homozygosity for a missense mutation (c.707T>C) in the TH gene. l-Dopa therapy in both high and low doses resulted in massive hyperkinesias, while substitution with selegiline exerted only a mild beneficial effect. Today, at the age of 7 years, the patient demonstrates severe developmental retardation with marked trunkal hypotonia, hypokinesia and occasionally dystonic and/or hyperkinetic crises. He is the third Greek patient with TH deficiency to be reported. Since all three patients carry the same pathogenetic mutation, a founder effect is suspected.

L-2-Hydroxyglutaric aciduria presenting with severe autistic features.

L-2-Hydroxyglutaric aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder characterized by psychomotor delay, ataxia, macrocephaly and typical neuroradiological findings of subcortical leucoencephalopathy. Recently, the disease causing gene has been discovered (L2HGDH) encoding L-2-hydroxyglutarate dehydrogenase. We present a 3-year-old boy with L-2-HGA, who demonstrated macrocephaly, noted already in utero with ultrasound. Cranial MRI demonstrated diffuse subcortical encephalopathy with increased signal of the subcortical white matter. Subsequent metabolic screening revealed increased levels of L-2-HGA, and genomic DNA analysis demonstrated two missense mutations in L-2-HGDG. Patient's further motor development was mildly impaired, whilst his speech development was profoundly impaired (first words at the age of 2 years). Since the age of 2 years he started demonstrating autistic repetitive behaviors and movements, increasing aloofness to his environment and limitations in the variety of spontaneous activity (CARS score: 44/60-severe autism). Autism has not so far been described in L-2-HGA and may be considered as an additional feature of the phenotypic spectrum.

Long-term response in biochemical markers of bone turnover during enzyme replacement therapy in a case-series of patients with Gaucher disease type I from Northern Greece.

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder characterized by severe skeletal complications. Bone complications are an important cause of morbidity of GD and are thought to result from imbalance in bone remodeling. The objective of this case series was to analyze the long-term effect of enzyme replacement therapy on chemokines MIP-1a and MIP-1b, cytokines IL-3, IL-6, IL-10, and IL-12, osteoprotegerin (OPG) and osteocalcin (BGP), chitotriosidase, quantitative ultrasound sonography (QUS), bone magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) in patients with GD in Northern Greece. In addition, the study aimed in investigating possible relationship between the above mentioned parameters. PATIENTS AND METHODS: Seven patients with GD type I (three males and four females) were included in the study. Mean age was 26.29 ± 15.34 years (range 7-47 years). Six patients were receiving enzyme replacement therapy (ERT), with 40-60 IU/kg of imiglucerase weekly, for a mean period of 36 months prior to study initiation. One patient started ERT after his inclusion in the study. The levels of MIP-1a, MIP-1b, IL-3, IL-6, IL-10, IL-12, OPG, BGP, chitotriosidase, bone imaging parameters assessed with two different techniques (QUS and DXA) and MRI data were estimated at baseline (T0) and after two years on ERT. RESULTS: Chitotriosidase, MIP-1a, and IL-6 levels decreased in all patients after two years of ERT (p =0.05). In contrast, OPG and BGP levels increased (p =0.04 and p =0.02, respectively). Bone mineral density (BMD) demonstrated a progressive improvement with regards to the Z-score in all patients (p =0.05). The decrease in the plasma levels of MIP-1a strongly correlated with a decrease in the plasma levels of chitotriosidase. Additionally, decreased plasma levels of IL-6 were correlated with increased Z-score both at baseline (T0) as well as two years later, in all patients. There was no correlation between MRI findings and any inflammatory biomarker. CONCLUSIONS: Measurement of serum markers in patients with GD under ERT could be used as an auxiliary tool in the monitoring of bone involvement, in combination with MRI imaging and BMD. However, larger studies involving higher numbers of GD patients are needed to confirm these conclusions. Hippokratia 2016, 20(2): 153-159.

Mobilization of circulating progenitor cells following brain injury in premature neonates could be indicative of an endogenous repair process. A pilot study.

BACKGROUND: Preclinical data and adult studies have showed an endogenous regeneration process following brain damage that involves mobilization of progenitor cells. This process is not well described in preterm neonates. The present study aims to investigate the mobilization of Circulating Progenitor Cells (CPCs) and their relation to biomarkers of brain injury in preterm neonates. METHODS: This is a prospective cohort study of preterm infants with gestational age (GA) <34 weeks. Serial cranial ultrasounds scans were performed in all neonates. Brain injury was defined by the presence of intraventricular hemorrhage grade III/IV, cystic periventricular leukomalacia or infarct. Peripheral blood samples were collected from all neonates on days(d) 1, 3, 9, 18 and 45 of life for the measurement of levels of CPCs [early and late Endothelial Progenitor Cells (EPCs), Haematopoietic Stem Cells (HSCs) and Very Small Embryonic-Like Stem Cells (VSELs)], Neuron-Specific Enolase (NSE), S100b, Erythropoietin (EPO) and Stromal Cell-Derived Factor-1 (SDF-1) . RESULTS: Ten out of the 23 preterm infants included in the study developed brain injury; the remaining thirteen infants served as controls. In the brain injury group a significant increase of HSCs (d9, d45), early EPCs (d3, d9, d18) and late EPCs (d1, d3, d9, d18, d45) was observed compared to controls. VSELs on d45 were significantly higher in controls. S100b on d1, EPO on d1, SDF-1 on d3 and NSE on d18 were significantly increased in the brain injury group. Moreover, CPCs were significantly related to S100b, NSE, EPO and SDF-1 levels at multiple time points. CONCLUSIONS: The observed pattern of CPCs mobilization and its association with biomarkers following brain injury in preterm neonates indicate the existence of an endogenous brain regeneration process. Enhancement of this process with exogenous progenitor cell transplantation might be a powerful therapeutic strategy to restore brain damage and improve the neurodevelopmental outcome in premature infants. Hippokratia 2015; 19 (2):141-147.

Characteristics and prognosis of epilepsy in children with cerebral palsy.

The aims of the study were to describe the prevalence and characteristics of epilepsy in a population of patients with cerebral palsy in a university referral center and to determine the rate of relapse caused by discontinuation of antiepileptic drugs after a 3-year seizure-free period. A total of 178 consecutive patients with cerebral palsy and epilepsy were prospectively followed for 9.2 +/- 2.4 years after onset of seizures and compared to a control group of 150 epileptic patients without cerebral palsy (median follow-up period, 10.5 years). The overall prevalence of epilepsy was 36.1%. Patients with atonic-diplegic, dystonic, tetraplegic, and hemiplegic cerebral palsy had a higher incidence of epilepsy (87.5%, 87.1%, 56.5%, and 42%, respectively). In all, 134 (75.3%) patients were seizure free for more than 3 years and could discontinue therapy, whereas 44 patients (24.7%) were still on antiepileptic drugs. Eighteen of 134 patients relapsed after a 3-year seizure-free period and subsequent discontinuation of antiepileptic drugs, thus giving a relapse rate of 13.4%. First seizures occurred during the first year of life in 69.7% of the patients with epilepsy and cerebral palsy. Complete control of seizures could be achieved in 65.2% of the patients with cerebral palsy and epilepsy; however, regardless of the prognosis of seizures, epilepsy was a major prognostic factor regarding both the presence of mental retardation and the motor development of children with cerebral palsy.

Plantar response profile of high-risk infants at one year of life.

To clarify the plantar reflex profile at 1 year of life in different categories of neurodevelopmental abnormalities, plantar responses were examined prospectively in 204 high-risk infants, of whom 58 developed cerebral palsy, 22 had developmental retardation without motor disturbance, and 124 were normal at a follow-up examination at 3 years of age. The plantar response was extensor in 82.3% of infants subsequently found to be neurologically normal at the first month of life, becoming flexor at the age of 9 and 11 months in 68.5% and 86.3%, respectively. Twenty-one (42.9%) of 49 patients with various types of spastic cerebral palsy demonstrated a combined extensor response (ie, dorsiflexion of the great toe with fanning of the remaining toes) as early as the first month of life. Children with spastic quadriplegia and hemiplegia more frequently demonstrated a combined extensor response compared to diplegic patients. The combined extensor plantar response remains a reliable prognostic clinical tool that contributes to an earlier diagnosis of spastic cerebral palsy as early as the first month of life.

Adrenocorticotropic hormone and vigabatrin treatment of children with infantile spasms underlying cerebral palsy.

Nine infants with an underlying static encephalopathy (confirmed as cerebral palsy in a later follow-up examination) and newly diagnosed infantile spasms were entered in an open study with adrenocorticotropic hormone (ACTH) and vigabatrin as the initial therapy regimen. The ACTH was discontinued after 4-6 weeks and the infants were maintained on vigabatrin alone. Following an initial response with complete suppression of spasms in all patients, a long term response maintained for a mean of 19.2 months was confirmed in all but one child. Tolerability appeared excellent with 7 of 9 patients reporting no side effects; vigabatrin related hypotonia presented in all patients and turned out to be a 'positive' side-effect on the abnormally increased muscle tone of these infants. Given the very poor prognosis of infantile spasms especially in such conditions as cerebral palsy, the combination of ACTH and vigabatrin appears to be an interesting therapy advance with very few side effects.

Deficiency in complex IV (cytochrome c oxidase) of the respiratory chain, presenting as a leukodystrophy in two siblings with Leigh syndrome.

Two siblings with Leigh syndrome presenting at the age of 6 months with clinical and radiological features suggestive of a leukodystrophy are reported. A deficiency in complex IV of the respiratory chain (cytochrome c oxidase) was demonstrated in muscle mitochondria of both patients. To our knowledge, this is the first familial case of Leigh syndrome due to cytochrome c oxidase deficiency, presenting clinically and radiologically with signs of a leukodystrophic process. We suggest that respiratory chain enzyme defects should be considered in the differential diagnosis of cases suggestive of a leukodystrophy.

Single dose immunoglobulin therapy for childhood Guillain-Barré syndrome.

To establish the efficacy of intravenous immunoglobulins (IVIG) in the treatment of acute Guillain-Barré syndrome (GBS), we treated nine consecutive pediatric cases (age 2.5-13.5 years) fulfilling the criteria for GBS with a single dose of IVIG (Sandoglobulin; 2 g/kg/BW). None of the patients experienced any IVIG related side-effects. The mean time required to improve by at least one grade on the functional GBS scale after IVIG treatment was 3.5 days, while the mean period to regain ambulation was 11.2 days. Full mobilization without evidence of relapse in the follow-up period (mean 14.5 months) was noted in all but one patient who relapsed after 5 months. We conclude that the early use of a single IVIG dose may prevent further progression of the disease, thus shortening the clinical course of childhood GBS. The most beneficial IVIG dose regimen remains to be determined by controlled trials.

Using postural reactions as a screening test to identify high-risk infants for cerebral palsy: a prospective study.

To clarify the predictive value of the seven more commonly used postural reactions (PR) in the 1st year of life regarding the diagnosis of cerebral palsy (CP), we prospectively examined 204 high-risk infants of whom 58 developed CP, 22 had developmental retardation (DR) and 124 were normal at follow-up at 3 years of age. Abnormalities of five or more PR from the 1st month of life were correlated with spastic CP, while five or six abnormal PR were also correlated with athetoid CP. Three or less abnormal PR correlated with a normal outcome. All seven PR tested were significantly abnormal in children with spastic CP from the 1st month compared to normal children. Athetoid children demonstrated abnormalities of the Peiper-Isbert (P-I) reaction and Vojta reaction from the 1st month and of the vertical, horizontal and Collis vertical suspension from the 3rd month. Children with DR had significantly abnormal Collis horizontal and Collis vertical suspension, Vojta reaction and traction response from the 1st month and Peiper-Isbert reaction from the 3rd month. Ataxic children demonstrated significantly abnormal traction response from the 1st month, Collis horizontal reaction from the 7th month and Peiper-Isbert reaction from the 11th month. We conclude that the examination of PR is a useful quantitative and qualitative diagnostic screening tool for high-risk infants from the 1st month of life.

L-2-Hydroxyglutaric aciduria presenting as status epilepticus.

L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare organic aciduria with a slowly progressive course regarding CNS involvement. We present a 13.5-year-old female patient who presented at the Emergency Department with a generalized status epilepticus, which promptly responded to intravenous phenytoin. CT and MRI demonstrated subcortical white matter alterations. The neurological examination revealed mild mental retardation, macrocephaly and ataxic gait with cerebellar signs. Repeated urinary organic acid analysis demonstrated increased excretion of 2-hydroxyglutaric acid which was of the L-configuration. The constellation of macrocephaly in a patient with mental retardation, cerebellar tract involvement and subcortical white matter signal alterations on MRI should alert the physician to the possibility of L-2-HGA. Although rare, epileptic seizures or even status epilepticus can be among the presenting symptoms in organic acidurias with a slow course, such as L-2-HGA.

Early infantile Krabbe disease: deceptively normal magnetic resonance imaging and serial neurophysiological studies.

Early infantile Krabbe disease is a progressive neurodegenerative disease caused by deficiency of lysosomal enzyme galactocerebroside beta-galactosidase, with onset before the age of 6 months. We present serial clinical, radiological and neurophysiological findings of a patient with early infantile Krabbe disease, presenting at the third day of life with hypotonia, macrocephaly and neonatal seizures. The patient had a deceptively normal initial magnetic resonance imaging examination at the age of 3 months, with progression of the white matter disease over the following 9 months, showing a clinical picture of profound hypotonia with pyramidal and pseudobulbar signs, as well as mild optic atrophy. Assay of galactocerebroside beta-galactosidase activity in leukocyte culture disclosed a marked deficiency of the enzyme (0.00 nmol/mg protein per h with normal values > 0.7 nmol/mg protein per h), thus confirming the diagnosis of Krabbe disease. Nerve conduction velocity and evoked potential studies, as well as the electroencephalogram, were abnormal at the age of 6 months, while serial neurophysiological studies at the age of 12 and 18 months demonstrated the progressive nature of the disease.

Protracted course of N-acetylaspartic aciduria in two non-Jewish siblings: identical clinical and magnetic resonance imaging findings.

Canavan disease (CD) or N-acetylaspartic aciduria (NAA) is a severe, progressive, autosomal recessive leukodystrophy, occurring mainly among Ashkenazi Jewish individuals. We report clinical and MRI findings in two, non-Jewish, Greek siblings, 7 and 5 years, respectively, with a protracted form of NAA. The constellation of identical clinical course and identical MRI findings with involvement of the basal ganglia, the brainstem, the dentate nucleus and the subcortical white matter in both siblings, as well as the absence of the three commonest mutations found in both Jewish and non-Jewish CD patients, give support to the existence of a protracted form of NAA with a milder clinical course, presumably genetically determined.

Serial magnetic resonance imaging findings in mucopolysaccharidosis IIIB (Sanfilippo's syndrome B).

Sanfillippo B syndrome (mucopolysaccharidosis (MPS) III, type B) is characterized by mild expression of the characteristic 'Hurler' phenotype and a severe central nervous system involvement. We report three patients with Sanfilippo B syndrome, referred to our clinic because of peculiar facies, delay in language development and behavioral problems, at the ages of 4, 3 and 5 years, respectively. At presentation they manifested clinical features of MPS, severe developmental retardation, radiological features of dysostosis mutiplex, as well as neurophysiological findings suggestive of carpal tunnel syndrome and sensorineural hearing impairment. Due to marked urinary excretion of heparan sulfate, as well as deficiency of alpha-N-acetylglucosaminidase in leukocytes, the diagnosis of Sanfilippo B syndrome was made. Serial brain magnetic resonance imaging (MRI) at different ages demonstrated white matter abnormalities, cortical atrophy and ventricular enlargement in all three patients, while other findings included thickening of the diploe in two patients and callosal atrophy, basal ganglia involvement, cerebellar changes and dilatation of venous sinuses in one patient. Although the combination of the above MRI findings is highly suggestive of a MPS, they carry a little predictive value in the different clinical stages of MPS IIIB.

Plantar grasp reflex in high-risk infants during the first year of life.

For most primitive reflexes, retention of the reflex beyond the period when it should no longer be elicited suggests a pathologic process within the central nervous system. However, for certain primitive reflexes, such as the plantar grasp reflex, a negative response within the first months of life is suggestive of a neurologic abnormality. From the results of one prospective and one retrospective study, it is clearly indicated that the absence of the plantar grasp reflex from 3 months of age and on correlates with the development of spastic cerebral palsy. The specific combination of presence or absence of specific primitive reflexes, postural reactions, or both may accurately predict a specific type of cerebral palsy or neurodevelopmental abnormality.