Safety and recommendations for vaccinations of children with inborn errors of metabolism.

Inborn errors of metabolism (IEM) are genetic disorders due to a defective metabolic pathway. The incidence of each disorder is variable and depends on the respective population. Some disorders such as urea cycle disorders (UCD) and organic acidurias, pose a high risk for a metabolic crisis culminating in a life-threatening event, especially during infections; thus, vaccines may play a crucial role in prevention. However, there are different triggers for decompensations including the notion that vaccines themselves can activate fever and malaise. Additionally, many of the IEM include immunodeficiency, placing the patients at an increased risk for infectious diseases and possibly a weaker response to immunizations. Since metabolic crises and vaccine regimens intersect in the first years of life, the question whether to vaccinate the child occupies parents and medical staff. Many metabolic experts hesitate to vaccinate IEM patients, disregarding the higher risk from the direct infections. In this paper we summarize the published data regarding the safety and recommendations for vaccinations in IEM patients, with reference to the risk for decompensations and to the immunogenic component.

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.

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.

Investigation of the motor system in two siblings with Canavan's disease: a combined transcranial magnetic stimulation (TMS) - diffusion tensor imaging (DTI) study.

Canavan's disease (CD) is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to spongiform degeneration of the white matter and severe impairment of psychomotor development. We present the cases of two non-Jewish sisters with CD that have a milder and protracted clinical course compared to typical CD. MRI imaging revealed bilateral high-signal-intensity areas in the thalami and the internal capsule and MR spectroscopy showed typical findings for CD (a marked increase in N-acetylaspartate (NAA) levels). FA values of the right and left corticospinal tracts at the level of the posterior limb of the internal capsule, and the centrum semiovale were found to be significantly reduced compared to healthy controls. From a neurophysiological point of view, the peripheral motor system was normal. In contrast, cortical stimulation at maximal intensity failed to elicit facilitated or resting MEPs and silent periods (SPs) in upper and lower limbs, providing evidence for significant upper motor pathway dysfunction.

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.

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.

Update on transcobalamin deficiency: clinical presentation, treatment and outcome.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

Endothelial activation and inflammation biomarkers in children and adolescents with sickle cell disease.

Sickle cell disease pathogenesis is a complex interplay of multiple factors associated with vascular endothelial activation, intense oxidative stress, and increased sickle cell adhesion. The aim of this study was to determine and compare three panels of plasma circulating biomarkers at 'steady state' and during veno-occlusive crises (VOC) in a cohort of children and adolescents with SCD and healthy controls. The following biomarkers were assessed: acute phase reactants, endothelial factors, and adhesion molecules. Forty-one SCD pediatric patients and 28 healthy children were enrolled. Patients at 'steady state' presented significantly elevated plasma levels of endothelin-1 (ET-1), soluble-VCAM-1 (sVCAM-1), soluble P-selectin (sP-selectin), and d-dimers compared to the control group. ET-1, sP-selectin, platelet-derived growth factor (PDGF), von Willebrand factor (vWf), d-dimers, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) seems to represent additional, but not independent, prognostic markers of VOC crisis. Elevated plasma levels of sP-selectin, ET-1, and sVCAM-1 were associated with VOC frequency. The present study provides preliminary evidence of a possible association between these biomarkers and the endothelial activation at steady state and VOC in childhood SCD. Further prospective studies are required to confirm the potential independent prognostic value of these markers in different stages of pediatric SCD.

Brain and spinal MR imaging findings in mucopolysaccharidoses: a review.

MPS represents a group of rare hereditary disorders characterized by multisystem involvement due to intralysosomal GAG accumulation. Among various tissues, both the central and peripheral nervous system are affected in almost all types of the disease. Thus, brain and spinal MR imaging are valuable tools for the assessment of neurologic involvement, and there is evidence that they might be reliable markers demonstrating disease severity and efficacy of treatment options currently used in patients with MPS. We aimed to review the most prominent MR imaging features of patients with MPS, paying attention to the physiopathologic mechanisms responsible for these alterations. Along with the description of neuroimaging findings, existing data in relation to their correlation with the severity of neurologic involvement is discussed, while another topic of great importance is the effect of various therapeutic regimens in the progression of brain and spinal MR imaging alterations. Finally, recent data concerning MR spectroscopy studies in MPS are also critically discussed.

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.

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.

The serotonergic system: its role in pathogenesis and early developmental treatment of autism.

Autism is a severe childhood disorder already presenting in the first 3 years of life and, therefore, strongly correlated with neurodevelopmental alterations in prenatal, as well as postnatal period. Neurotransmitters hold a pivotal role in development by providing the stimulation needed for synapses and neuronal networks to be formed during the critical period of neuroplasticity. Aberrations of the serotonergic system modify key processes in the developing brain and are strongly implicated in the pathophysiology of developmental disorders. Evidence for the role of serotonin in autism emerges from neuropathological, imaging and genetic studies. Due to its developmental arrest, autism requires early intervention that would, among others, target the disrupted serotonergic system and utilize brain plasticity to elicit clinically important brain changes in children.

Mesangioproliferative glomerulonephritis in an infant with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurobehavioral disorder characterized mainly by neonatal hypotonia, dysmorphic features, hypogonadism, mental retardation and behavioral problems. The PWS has not been associated with renal complications. We report the case of an infant with Prader-Willi syndrome due to loss of the paternal copy of chromosome 15q11.2-13, who presented with severe proteinuria and microscopic hematuria. Renal biopsy revealed mesangioproliferative glomerulonephritis (MPGN). The early onset of the primary MPGN in this infant make us consider a possible association between the deficiency of the paternally expressed genes from the 15q11-q13 region and the renal disease.

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.

Episodic ataxia type 2 showing ictal hyperhidrosis with hypothermia and interictal chronic diarrhea due to a novel CACNA1A mutation.

Autosomal dominant episodic ataxia type 2 (EA2) results from mutations of the CACNA1A gene. We describe EA2 with unusual features in a father and daughter with a novel CACNA1A mutation coding for Y248C. Both patients showed severe cerebellar atrophy in MRI and clinical signs of progressive spinocerebellar atrophy type 6. Most disabling were the very frequent episodes of ataxia with migraine (with aura in the father and without aura in the daughter) and nystagmus in our patients. Additionally, they suffered from ictal hyperhidrosis with acute hypothermia of the extremities. Lastly, the father presented with interictal chronic diarrhea not associated to a known primary gastrointestinal disorder. Both ictal hyperhidrosis and interictal diarrhea ameliorated upon acetazolamide intake, the typical treatment for EA2. The significance of these findings is discussed and the phenotype correlated to previously reported cases.

MR spectroscopy and serial magnetic resonance imaging in a patient with mitochondrial cystic leukoencephalopathy due to complex I deficiency and NDUFV1 mutations and mild clinical course.

We present clinical, magnetic resonance imaging and MR spectroscopic findings of a female patient, first admitted at the age of 9 months for regression of motor milestones and signs of mild spastic diplegia. Magnetic resonance imaging (MRI) demonstrated periventricular white matter abnormalities with sparing of the subcortical white matter. Subsequent MRIs, performed at the ages of 13 and 16 months, demonstrated progression of the white matter changes, progressive white matter rarefaction and cystic degeneration, and additional involvement of the corpus callosum; only the subcortical white matter remained spared. Proton MR spectroscopy revealed lactate elevation in the white matter. Blood lactate and lactate/pyruvate ratio were mildly elevated. Subsequent analysis of mitochondrial function in muscle tissue showed decreases in substrate oxidation and in ATP and CrP production rates. Complex I activity was seriously decreased, whereas mild decreases of complex II and IV activities were also noted. Analysis of the NDUFV1 gene revealed compound heterozygosity for two point mutations, each of them carried by one parent. The further clinical course of the patient was uphill; she slowly regained all previously lost motor milestones. In conclusion, diffuse white matter changes on MRI are compatible with mitochondrial encephalopathy and not necessarily associated with a severe clinical course.

Scarlet Fever and hepatitis: a case report.

Scarlet fever is a streptococcal infection with a good prognosis. Complications are well described. Hepatitis is a rare complication. We describe a 6-year old boy with scarlet fever, jaundice and elevated liver transaminases.

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.