Warburg micro syndrome type 1 associated with peripheral neuropathy and cardiomyopathy

The Warburg micro syndrome (WARBM) is a genetically heterogeneous syndrome linked to at least 4 loci. At the clinical level, WARBM is characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, corpus callosum hypoplasia, severe mental retardation, and hypogonadism. In some families additional clinical features have been reported. The presence of uncommon clinical features (peripheral neuropathy, cardiomyopathy) may result in misdirected molecular diagnostics. Using the next generation sequencing approach (NGS), we were able to diagnose WARBM1 syndrome by detection of a new mutation within the RAB3GAP1 gene. We have detected some DNA variants which may be responsible for cardiomyopathy. We did not find any obvious pathogenic mutation within a set of genes known to be responsible for hereditary motor and sensory neuropathy (HMSN). We conclude that: (i) in clinically delineated syndromes, a classical single-gene oriented approach may be not conclusive especially in the presence of rare clinical features, (ii) peripheral neuropathy and cardiomyopathy are rare additional symptoms coexisting with WARBM1, (iii) a pleiotropic effect of a single point mutation is sufficient to be causative for WARBM1 and (iv) more WARBM-affected patients should be reported to delineate a complete phenotype

Choroba Alexandra w badaniu rezonansu magnetycznego i spektroskopii protonowej HMRS : opis trzech przypadków

Background: Alexander's disease is a rare genetic leukodystrophy connected with mutation of the GFAP gene. Infantile, juvenile, and adult subtypes are described. Case reports: We analyzed MR images in three and HMRS in two cases of Alexander's disease. The examinations were performed with a 1.5T scanner in the SE, FSE, and FLAIR sequences in T1,T2 W I before and after gadolinium injection. Single voxel HMRS was performed. M RI showed extensive abnormal signal in the white matter of the frontal lobes, in external capsules, basal ganglia, posterior limbs of the internal capsules, and the hilus of dentate nuclei. Focal contrast enhancement was seen near the frontal horns. HMRS revealed increased Cho/Cr and mI/Cr ratios and decreased NAA/Cr ratio. The presence of lactate was also observed. Conclusions: MR is useful in imaging typical forms of Alexander's disease. Genetic investigation is necessary for definitive diagnosis. HMRS demonstrates metabolic abnormalities of white matter

Brain and cerebellar hemidysplasia in a case with ipsilateral body dysplasia and suspicion of CHILD syndrome

A b s t r a c t CHILD syndrome is an acronym fo

Alexander disease - astrogliopathy considered as leukodystrophy - experience of an institution

Alexander Disease (ALXDRD) is an autosomal dominant leukodystrophy caused by mutation in one allele of GFAP gene, encoding glial fibrillary acidic protein (GFAP). Most cases occur due to de novo. There are three clinical subtypes of ALXDRD: infantile, juvenile and adult form, but congenital form is also outlined. The disease's spectrum comprises of macrocephaly, progressive pyramidal signs, and seizures in congenital and infantile subtypes. Neuropathologically are enormous number of Rosenthal fibers (RF) mainly around vessels, in subependymal and subpial regions are found. The diagnosis is based on the typical findings on MRI: diffuse white mater lesions with frontal regions preponderance and possibly on the detection of the gene mutation. Here we present six Polish children affected of Alexander disease with congenital (1), infantile (4) and juvenile (1) form. Five of them were previously misdiagnosed as cerebral palsy or unspecific developmental delay; two patients had MRI because of another suspicion, before specific diagnosis was established. Molecular analysis performed in four cases confirmed mutations of GFAP gene; all mutation were de novo. The role of astroglia in brain is shortly reviewed

Dlaczego neurolog dziecięcy MUSI zawsze mierzyć obwód głowy - opis przypadku deficytu transportera glukozy typu 1 (Glut1-DS)

Introduction. The deficit of the type 1 glucose transporter (Glut1-DS) belongs to the neurometabolic disorders that can be effectively treated, in this case with ketogenic diet. By limiting glucose supply to the brain the deficit of glucose transporter 1 leads to cerebral energy deficiency. Glut1-DS manifests with a wide range of neurological symptoms that usually start in early childhood, including cognitive impairment, epilepsy and permanent and/or paroxysmal motor disorders, often provoked by physical activity, fasting or hyperthermale. Aim. We present the case of a 6,5-year-old patient with Glut1- -DS who, despite presenting typical symptoms, remained undiagnosed for years. Family history was positive of intellectual disability in first degree relative. The child suffered from psychomotor development delay, motor coordination difficulties, motor disorders and epilepsy with focal and absence seizures of early onset. However, the significant symptom of secondary microcephaly remained unnoticed for years. Conclusion. Secondary microcephaly is a valuable symptom which can guide towards the diagnosis. The early diagnosis of Glut1 deficiency syndrome enables prompt introduction of the ketogenic diet crucial for the child’s development and improvement of both the patients and their families’ quality of life.Wstęp. Deficyt transportera glukozy typu 1 (Glut1-DS.) należy do tych nielicznych neurometabolicznych schorzeń, które mogą być skutecznie leczone, w tym wypadku dietą ketogenną. Deficyt transportera 1, poprzez redukcję transportu glukozy do OUN, prowadzi do deficytu energetycznego mózgu. Schorzenie to charakteryzuje się wieloma objawami ze strony układu nerwowego, najczęściej z początkiem w okresie wczesnego dzieciństwa. Należą do nich zaburzenia poznawcze, padaczka, dysfunkcje ruchowe o przewlekłym charakterze lub występujące napadowo, często prowokowane wysiłkiem, głodzeniem czy zwyżką ciepłoty ciała. Cel. Celem pracy było przedstawienie przypadku 6,5 letniej pacjentki z Glut1-DS, u której rozpoznanie było opóźnione pomimo obecności typowych dla tego schorzenia objawów klinicznych. Wywiad rodzinny był obciążony występowaniem niepełnosprawności intelektualnej u krewnego I stopnia. U dziecka obserwowano nieprawidłowy rozwój poznawczy, niezgrabność ruchową oraz padaczkę z napadami ogniskowymi oraz nieświadomości o wczesnym początku. Jednakże, istotny objaw diagnostyczny, jakim było małogłowie wtórne, długo nie był rejestrowany. Wnioski. Małogłowie wtórne jest istotnym objawem ukierunkowującym diagnostykę. Wczesne rozpoznanie Glut1-DS. umożliwia wprowadzenie skutecznego leczenia dietą ketogenną, co prowadzi do poprawy rozwoju dziecka i tym samym do polepszenia jakości życia pacjenta i jego rodziny

A current view of mitochondria damage and the diversity of lipopigment inclusions in neuronal ceroid lipofuscinose type 2 from rectal biopsy

Neuronal ceroid lipofuscinoses (NCLs) are a growing group of neurodegenerative storage diseases, in which specific features are sought to facilitate the creation of a universal diagnostic algorithm in the future. In our ultrastructural studies, the group of NCLs was represented by the CLN2 disease caused by a defect in the TPP1 gene encoding the enzyme tripeptidyl-peptidase 1. A 3.5-year-old girl was affected by this disease. Due to diagnostic difficulties, the spectrum of clinical, enzymatic, and genetic tests was extended to include analysis of the ultrastructure of cells from a rectal biopsy. The aim of our research was to search for pathognomonic features of CLN2 and to analyse the mitochondrial damage accompanying the disease. In the examined cells of the rectal mucosa, as expected, filamentous deposits of the curvilinear profile (CVP) type were found, which dominated quantitatively. Mixed deposits of the CVP/fingerprint profile (FPP) type were observed less frequently in the examined cells. A form of inclusions of unknown origin, not described so far in CLN2 disease, were wads of osmophilic material (WOMs). They occurred alone or co-formed mixed deposits. In addition, atypically damaged mitochondria were observed in muscularis mucosae. Their deformed cristae had contact with inclusions that looked like CVPs. Considering the confirmed role of the c subunit of the mitochondrial ATP synthase in the formation of filamentous lipopigment deposits in the group of NCLs, we suggest the possible significance of other mitochondrial proteins, such as mitochondrial contact site and cristae organizing system (MICOS), in the formation of these deposits. The presence of WOMs in the context of searching for ultrastructural pathognomonic features in CLN2 disease also requires further research

Pelizaeus-Merzbacher disease in patients with molecularly confirmed diagnosis

Pelizaeus-Merzbacher disease (PMD) is X-linked hypomyelinating leukodystrophy caused by mutations of the PLP1 gene, which codes the proteolipid protein 1. The result of mutations is abnormal myelination – hypomyelination and dysmyelination of cerebral white matter, and in some form of the disease hypomyelinating peripheral neuropathy. DNA samples from 68 patients suspected of PMD due to the clinical course and hypomyelination at magnetic resonance imaging (MRI) were analyzed. Medical history and detailed clinical course of PMD patients were also analyzed. Different mutations of the PLP1 gene were detected in 14 boys from 11 families (~20%). Amongst the molecularly confirmed patients, 13 presented classical PMD forms but clinical phenotypes varied in the severity even amongst siblings. One patient presented a severe connatal form. One mother, obligate carrier, presented complicated SPG2 (spastic paraparesis). There was no phenotype-genotype correlation in our material. In many cases PMD was suspected with a delay of many years, sometimes only after birth of another affected child in the family. Pelizaeus-Merzbacher disease was most frequently misdiagnosed as cerebral palsy

The spectrum of PLP1 gene mutations in patients with the classical form of the Pelizaeus-Merzbacher disease.

Uterine and umbilical blood flow measurements are reviewed in terms of studies carried out in uncomplicated human pregnancies. The review includes the perspective of how those estimates of flow fit with current knowledge of human fetal O2 consumption and uterine O2 and glucose consumption. From the consideration of both the O2 data and the flow measurements, we conclude that the best estimates for mean umbilical blood flow at term range between 120 and 145 ml•min-1•(kg fetus)-1. The uterine flow estimate from physiologic data would equate to ~270 ml•min-1•(kg fetus)-1. This estimate, based upon estimates of uterine O2 and glucose consumption, is much higher than some estimates made by imaging techniques. The reasons for this discrepancy are not yet established. However, given the enormous variability in uterine flow measurements made with imaging techniques, it is clear that more research into improvement in these non-invasive approaches is still required and all current estimates of uterine flow must be regarded as rather crude trials

Leukoencephalopathy with vanishing white matter due to homozygous EIF2B2 gene mutation. First Polish cases

Leukoencephalopathy with vanishing white matter (VWM), also called childhood ataxia with central nervous system hypomyelination (CACH), is an autosomal recessive disease caused by mutations in any of the five genes encoding subunits of the eukaryotic translation initiation factor elF2B. Neuropathological findings comprise a severe, cavitating orthochromatic leukodystrophy with only small amounts of myelin breakdown products, and predominantly involving the cerebral hemispheric white matter. Within the white matter abnormal oligodendroglial cells are present with abundant "foamy" cytoplasm. In some regions oligodendroglial cells are increased in numbers. We present three siste rs, 18, 11 and 8 years old, with the early to late childhood phenotype. The first signs of the disease were gait disturbances at 4, 2 and 6 years of age, respectively. Neurological examination showed mild tremor of hands and head, truncal ataxia, dysarthria, and hypotonia, after several years followed by spasticity. The course of the disease was slowly progressive. Intellectual abilities are relatively spared. The MRI showed diffusely abnormal white matter of the cerebral hemispheres. The FLAIR images revealed rarefaction of the affected white matter with some stripe-like structures, suggesting the presence of remaining tissue strands. The abnormalities were most pronounced with the middle sister, who had the earliest onset of the disease. A homozygous point mutation in the EIF2B2 gene was found, 638A>G. Both the parents were found to be carriers of this mutation. This is the first description of a Polish family with VWM

Wczesnoniemowlęca encefalopatia padaczkowa 19 z dyskinezami uwarunkowana nową mutacją w genie GABRA1 – pierwszy przypadek w polskiej populacji

Background: Dominant, heterozygous mutations in the GABRA1 gene on chromosome 5q34 cause a heterogeneous, constantly growing group of neurological disorders. Aim: The aim of the study was to report on an individual with profound psychomotor retardation, extrapyramidal symptoms and epilepsy due to a new mutation in GABRA1 gene (c.799C>A). Material and Methods: The child with unremarkable family and perinatal history, fetal and perinatal primary microcephaly, delayed psychomotor development in a profound degree as well as with impaired global physical development and a failure to thrive. From the first months of life dyskinesias, bruxism, upward eye deviation and oropharyngeal movements were present. However, on sleep EEG generalized spike and wave discharges were present. Whole-exome sequencing (WES) was carried out in the proband. Results: WES results detected disease-causing novel mutation in the GABRA1 gene, the first case in the Polish population. Conclusions: Our observation expands the spectrum of syndromes of EIEE19 associated with GABRA1 gene mutations. This mutation (c.799 C>A) has not been described previously in the literature.Wstęp: Dominujące, heterozygotyczne mutacje w genie GABRA1 zlokalizowanym na chromosomie 5q34 powodują zróżnicowaną, stale powiększającą się grupę zaburzeń neurologicznych. Cel pracy: Celem pracy jest przedstawienie fenotypu pacjenta z opóźnieniem rozwoju psychoruchowego w stopniu głębokim, objawami pozapiramidowymi oraz padaczką, uwarunkowanych nowo powstałą mutacją w genie GABRA 1 (c.799C>A). Materiał i Metody: Dziecko z nieobciążonym wywiadem rodzinnym, płodowo-okołoporodowym, pierwotnym małogłowiem, opóźnionym rozwojem psychoruchowym w stopniu głębokim jak również z zaburzonym rozwojem fizycznym. Od pierwszych miesięcy życia obserwowano: dyskinezy, bruksizm, zwroty gałek ocznych ku górze, ruchy orofaryngealne. W zapisie EEG we śnie stwierdzono zmiany napadowe uogólnione iglica fala. W celu identyfikacji genów odpowiadających za fenotyp przeprowadzono sekwencjonowanie całego eksomu (WES). Wyniki: Badanie metodą WES wykazało mutację w genie GABRA1, odpowiadającą za chorobę – pierwszy przypadek w polskiej populacji. Wnioski: Opis naszego przypadku poszerza spektrum objawów EIEE19 powiązanych z mutacjami w genie GABRA1. Mutacja (c.799C>A) nie została jak dotychczas opisana w literaturze