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  • Author: Velibor Tasic x
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Abstract

Krabbe disease (KD) (globoid cell leukodystrophy) is a degenerative, lysosomal storage disease, caused by a severe loss of galactocerebrosidase (GALC) enzymatic activity. The inheritance is autosomal recessive. KD affects the white matter of the central and peripheral nervous systems.

We present a 3 year old boy in whom the disease had an ‘infantile’ or ‘classic’ presentation, with spasticity, irritability, and developmental delay. In addition the boy showed progressive severe motor and mental deterioration, difficulties in swallowing and decerebration.

Molecular analysis revealed that the child is a compound heterozygote: p.Asp187Val (c.560A>T) and p.Ile250Thr (c.749T>C). The father was the carrier of p.Asp187Val (c.560A>T), while the mother was the carrier of the p.Ile250Thr (c.749T>C) in exon 6 of the GALC gene.

The clinical course in this compound heterozygote is severe and the patient passed away at the age of 3 years. Genotype-phenotype relations are discussed in this Macedonian patient with KD.

Abstract

The 4th meeting on rare diseases in South Eastern Europe (SEE) was held in Skopje, at the Macedonian Academy of Sciences and Arts (MASA) on the 14th of November 2015. The focuses were metabolic, rare brain diseases as well as the rare dysmorphic syndrome. The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. The talk on an iminosugar-based pharmacological chaperone compound as a drug candidate for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B) was enlightening. To date, there is no treatment available to be offered to patients, but chaperones lead mutated proteins to adopt a native-like conformation and to successfully traffic to their normal cellular destination. DORPHAN is developing an iminosugar-based pharmacological chaperone compound for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB.

A talk on recent developments in the laboratory diagnosis of mucopolysaccharidoses (MPS) was particularly interesting, covering the laboratory diagnosis of the MPS diseases by a strategy of clinical examination, biochemical analysis of urine samples, enzyme tests and genetic characterization of underlying mutations. New techniques were developed, including analysis of urinary glycosaminoglycans with tandem mass spectrometry, miniaturized enzyme tests or novel synthetic substrates for enzyme assays using mass spectrometry detection of products using dried blood spots. Feasibility and cost-effectiveness of these methods in newborn screening programs have been demonstrated.

Neuromuscular RDs, and especially familial amyloid polyneuropathy (FAP) were a topic of the Bulgarian colleagues. Diagnosis, screening and the role of microglia were also topics of particular interest. In summary, this year RD meeting was exciting and productive on a wide range of diseases and on a novel insights on diagnosis and treatment. New methods are expanding our capabilities for a fast and precise diagnosis. Novel knowledge offers better distinction on whom to treat with which medications (e.g. steroid dependent nephrotic syndrome). Novel diseases or variants are published (segmental overgrowth). The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. Namely, the Health Fund of Macedonia for the first time treats the patients with Gaucher′s disease. We are hopeful that the number of patients treated for Gaucher′s disease and the number of treated patients with other treatable RDs diseases will continue to grow.

Abstract

Nephrotic syndrome is defined as the association of massive proteinuria, hypoalbuminaemia, edema, and hyperlipidemia. It is separated to steroid-sensitive or steroid-resistant (SRNS) forms in respect to the response to intensive steroid therapy. SRNS usually progresses to end-stage renal failure. According to the North American Pediatric Renal Trials and Collaborative Studies SRNS constitutes the second most frequent cause of ESRD in the first two decades of life. Unfortunately, there is no curative treatment for majority of patients. Majority of the SRNS patients have the histologic picture of focal segmental glomerulosclerosis. Interestingly, the risk of recurrence in the kidney graft in patients with hereditary SRNS is lower than in those who do not have genetic background. The etiology and pathogenesis of SRSN has remained enigma for decades. The discovery of 39 dominant or recessive SRNS genes enabled better understanding of the function of the glomerular podocytes and slit membrane. Hildebrandt′s group has shown that 85% of the SRNS cases with onset by 3 months of age and 66% with onset by 1 year of age can be explained by recessive mutations in one of four genes only (NPHS1, NPHS2, LAMB2, or WT1). The same group used modern diagnostic techniques such as the next generation sequencing and tested a large international cohort of SRNS patients (n = 1783 families). The diagnostic panel included 21 genes with a recessive mode of inheritance and 6 genes with a dominant mode of inheritance. Single-gene cause was detected in 29.5% (526 of 1783) of the families with SRNS that manifested before 25 years of age. The identification of causative single-gene mutations may have important therapeutic consequences in some cases. This is very important for patients who carry mutations in a gene of coenzyme Q10 biosynthesis (COQ2, COQ6, ADCK4, or PDSS2). In these patients the treatment with coenzyme Q10 may be indicated. Also, patients with recessive mutations in PLCE1 may respond fully to the treatment with steroids or cyclosporine A. The patients with CUBN may benefit the treatment with vitamin B12. The detection of causative mutations may also be very important for familial genetic counseling and for prenatal diagnosis.

Abstract

The fifth SEE meeting on rare diseases (RDs) was held in Macedonian Academy of Sciences and Arts (MASA) the November 11th, 2016. Several lectures dealt with mucopolysaccharidosis, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatment (ERT), its availability, effects (or the lack of it) on the brain, and further prospects of eventual gene treatment were comprehensively exposed and discussed. Special accent was on Gaucher, Morquio IVA, Hunter and the audience was given new knowledge on the complexities of diagnosis and treatment. A block of lectures on rare renal diseases was also impressive. From renal stones, their molecular and genetic mechanisms to different forms of CAKUT the use of NGS and other molecular methods in diagnosis of RDs. Mitochondrial diseases, the novelties and importance of early discovery were comprehensively exposed. Special lecture was given on the complement system. Endocrine disruptors, microprolactinomas were also the topic of the meeting. A rather reach session of posters was also presented.

Abstract

Pediatric kidney diseases were in the focus of the World Kidney Day 2016. Macedonian pediatric nephrologists gave their contribution with public appearance in kindergartens, primary and secondary schools, with interactive lectures and discussion with the youngest about the kidney function, healthy life style and simple measures to prevent kidney and urinary tract diseases. Besides promotive appearance in the media, series of lectures were presented in front of the health professionals. The aim was to attract the attention of the professionals for early diagnosis and prevention of kidney disease. The action starts in utero, followed by early postnatal imaging and assessment, conservative treatment and in selected cases surgical treatment. The emphasis is on the multidisciplinary and comprehensive approach to children and adolescents with kidney diseases.

Abstract

The sixth SEE meeting on rare diseases (RDs) was held in MASA the November 10th, 2017. A block of lectures on rare renal diseases started the meeting: nephrotic syndrome, Alport syndrome, atypical HUS, hypophosphatemic rickets, CAKUT were presented in all complexities. Their molecular and genetic mechanisms were discussed. The discovery of a dozen of newly genes in CAKUT, congenital overgrowth, spodilocostal dysplasia, precocious puberty has been done with collaboration of Macedonian and foreign researchers. NGS and other molecular methods in diagnosis of RDs have been presented by several presenters. The mitochondrial diseases, the novelties and importance of early discovery were comprehensively presented and discussed. The genetics and treatment of persistent neonatal hypoglcaemia were of special interest. Dysmorphic syndromes (Klippel Feil) were also presented. A session of oral electronic posters was reach and inspiring. Several lectures dealt with mucopolisaccaridoses, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatement (ERT), its availability, effects (or the lack of it on the brain), intratecal ERT administration and further prospects of eventual gene treatment were comprehensively exposed and discussed. The main purposes of this traditional meeting are hopefully fulfilled: increased number of patients with RDs treated and cutting edge presentations got.

Abstract

Rare renal diseases (RRD) are an important category of rare disease (RD) as they can do great damage to the patients, families and society. The patient may undergo years even decades of numerous investigations including invasive procedures and yet not have definitive and precise diagnose and therefore, no opportunity for appropriate treatment. The great progress in molecular genetic techniques characterized many Mendelian diseases on molecular level. This gave the possibility for appropriate prevention and treatment interventions, genetic counseling and prenatal diagnosis. Herein, we summarize the current status of RRD in Macedonia. The research interest of Macedonian clinicians and scientists is focused on the genetics of congenital anomalies of the kidney and urinary tract (CAKUT), steroid resistant nephrotic syndrome, nephrolithiasis and nephrocalcinosis, cystic diseases and cilliopathies with collaborations with eminent laboratories in Unites States and Europe. This collaboration resulted in detection of new genes and pathophysiological pathways published in The New England Journal of Medicine and in other high impact journals. Macedonian health professionals have knowledge and equipment for diagnosis of RRD. Unfortunately the lack of finances is great obstacle for early and appropriate diagnosis. Participation in the international registries, studies and trials should be encouraged. This would result in significant benefit for the patients, health professionals and science.

Abstract

Background: Bardet-Biedl syndrome (BBS) is a multisystem genetic disorder characterized with central obesity, pigmentary retinopathy, polydactyly, mental retardation, and hypogenitalism. Renal abnormalities have been recognized as a cardinal feature of the disease with serious prognostic implication. The aim of this study was to analyze the renal status in children with BBS and to implement appropriate interventions in those with progressive course

Patients and methods: The diagnosis of BBS was established on the basis of criteria proposed by Beales et al. (J Med Genet 1999). Imaging of the kidneys and urinary tract was performed with ultrasound study, Tc99mDMSA scan and a cystographic study. Twenty four hour urine collections were obtained for estimation of proteinuria and creatinine clearance. Blood pressure was monitored at clinical visits or as 24-hour ambulatory monitoring.

Results: There were 4 children (2 males, 2 females). All four children displayed abnormal kidney ultrasound and Tc99mDMSA scan resembling dysplastic kidney(s). Two of them had overt proteinuria (glomerulo-tubular pattern). Three children had normal blood pressure and glomerular filtration rate (GFR): 107, 145 and 95 ml/min/1.73m2, and the fourth had hypertension and progressive worsening of the GFR at 65 ml/min/1.73m2. Conclusion: Children with BBS should undergo imaging studies of the kidneys and urinary tract at initial work up; in those with renal dysplasia proteinuria, GFR and blood pressure should be regularly monitored to slow down progression to terminal renal failure.

Abstract

Wildervanck syndrome (WS) combines features of Klippel-Feil syndrome (KFS), sixth nerve palsy, and deafness. This is a case of a 23 year old woman, diagnosed with KFS (a triad of short neck, low posterior hairline and restricted neck movements) at the age of 20 days. The manifestations of the WS in this patient are severe: she has torticollis, and an extremely severe scoliosis. In addition, she is short (-3 SD; parental target height + 0.8SD) and has mixed sensorineural and conductive deafness. She also has ptosis, strabismus and a high myopia. Radiologically, there are multiple coalitions of cervical vertebrae. Intelligence is unaffected (IQ 95), but deafness, strabismus and high myopia forced her early out of school. Karyotype is 46, XX. In brief, this is a patient with severe WS and additional anomalies. Short and/or reduced parental target height is a part of WS.

Abstract

Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) represent several types of malformations with occurrence of 1 in about 500 live births.

Objective: Small for gestation age (SGA) may influence in prevalence of CAKUT and progression of chronic kidney disease (CKD) in children. The aim of this study was to elaborate our experiences with detected CAKUT in a cohort of SGA born children in Macedonia.

Methods: Our cohort consisted of 100 SGA born children investigated for associated congenital anomalies of urinary tract. We analyzed anthropometric and clinical birth data in children with diagnosed CAKUT and estimated the stage and time of onset of CKD by biochemical and imaging technics.

Results: We revealed 7 (7.0%) SGA born children with congenital anomalies of the urinary tract. Their mean birth weight was very low 1855 gr (-3.93 SDS) and the birth length 45.57cm (-2.17 SDS), as well. A significant growth failure with reduced weight and BMI were noticed at the time of diagnosis. A diagnosis of CAKUT in 4/7 was established in the first few months of life, but in others 3 later in early childhood. Three children revealed with unilateral kidney agenesis, 2 had hypo-dysplastic kidneys and in 2 children was found vesicoureteral reflux. Normal glomerular filtration rate was estimated in 2 children with CAKUT. Stage 2 CKD with GFR 60-90 ml/minx1.73m2 had 3 children, 1 patient was graded in stage 3 and one child needed kidney transplantation, stage 5 CKD.

Conclusions: We presented 7 SGA born children with CAKUT. An early recognition, assessment and treatment of these anomalies might improve their quality of life.