Evaluation of differential renal function in children - a comparative study between magnetic resonance urography and dynamic renal scintigraphy.

BACKGROUND: Urinary system anomalies, both congenital and acquired, constitute a relatively common clinical problem in children. The main role of diagnostic imaging is to determine early diagnosis and support therapeutic decisions to prevent the development of chronic renal disease. The aim of this study was to evaluate the utility of magnetic resonance urography (MRU) in assessment of urinary system in children, by comparing differential renal function calculated using MRU with dynamic renal scintigraphy (DRS). MATERIALS AND METHODS: The study group consisted of 46 patients aged 1 week to 17 years (median 7 (0.5; 13) years, 17 (37%) girls, 29 (63%) boys), who underwent dynamic renal scintigraphy due to various clinical reasons. All participants underwent MRU, which was used to measure differential renal function. Functional analysis was performed using dedicated external software (CHOP-fMRU and pMRI without prior knowledge of DRS results. MRU results acquired using pMRI were assessed for inter and intraobserver agreement. RESULTS: Statistical analysis of the results showed excellent agreement between MRU and DRS in measuring differential renal function with Pearson correlation coefficient 0.987 for CHOP-fMRU and 0.971 for pMRI, p < 0.001. Interclass correlation coefficient (ICC) for these programs was 0.987 (95% CI 0.976-0.993) and 0.969 (95% CI 0.945-0.983) respectively, p < 0.001. The Bland-Altman 95% limits of agreement for CHOP-fMRU results vs. DRS was - 6.29-5.50 p.p. and for pMRI results vs. DRS - 9.15-9.63 p.p. The differential renal function measurements calculated in pMRI showed excellent intraobserver and interobserver agreement with ICC 0.996 (95% CI 0.994-0.998) and 0.992 (95% CI 0.986-0.996) respectively, p < 0.001. CONCLUSIONS: The study showed no significant differences between magnetic resonance urography and dynamic renal scintigraphy in calculating differential renal function. It indicates high utility of MRU in the evaluation of urinary system in children.

DNAJC30 defect: a frequent cause of recessive Leber hereditary optic neuropathy and Leigh syndrome.

The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of Leigh syndrome, the most frequent paediatric mitochondrial disease. Herein, we characterize 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease. Moreover, the report of two additional patients with childhood- or adult-onset Leigh syndrome further evidences the association of DNAJC30 with Leigh syndrome, previously only reported in a single childhood-onset case.

NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy.

Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decrease in complex I enzymatic activity in muscle and fibroblasts. Complementation studies by expression of wild-type NDUFB8 in cells from affected individuals restored mitochondrial function, confirming NDUFB8 variants as the cause of complex I deficiency. Hereby we establish NDUFB8 as a relevant gene in childhood-onset mitochondrial disease.

Multiparametric MRI as a Noninvasive Monitoring Tool for Children With Autoimmune Hepatitis.

OBJECTIVES: Autoimmune hepatitis (AIH) is a progressive liver disease managed with corticosteroids and immunosuppression and monitored using a combination of liver biochemistry and histology. However, liver biopsy is invasive with risk of pain and bleeding. The aim of the present study was to investigate the utility of noninvasive imaging with multiparametric magnetic resonance imaging (MRI) (mpMRI) to provide clinically useful information on the presence and extent of hepatic inflammation, potentially guiding immunosuppression. METHODS: Eighty-one participants (aged 6-18), 21 healthy and 60 AIH patients, underwent multiparametric MRI to measure fibro-inflammation with iron-corrected T1 (cT1) at the Children's Memorial Health Institute in Warsaw alongside other clinical blood tests and liver biopsy at recruitment and after an average of 16-month follow-up (range 9-22 months). Correlation analyses were used to investigate the associations between cT1 with blood serum markers and histological scores. RESULTS: At recruitment, patients with AIH had a higher cT1 value than healthy controls (P < 0.01). cT1 correlated significantly with key histopathological features of disease. Treatment naïve AIH patients showed evidence of inflammation and heterogeneity across the liver compared to healthy controls.At follow-up, cT1 showed utility in monitoring disease regression as most patients showed significantly reduced fibro-inflammation with treatment (P < 0.0001) over the observational period. Six patients had histological fibrosis and clear fibro-inflammation on MR despite biochemical remission (normalized aspartate aminotransferase (AST), alanine aminotransferase (ALT), and immunoglobulin G [IgG]). CONCLUSIONS: Multiparametric MRI can measure disease burden in pediatric AIH and can show changes over time in response to therapy. Active disease can be seen even in biochemical remission in children.

NBAS deficiency due to biallelic c.2809C > G variant presenting with recurrent acute liver failure with severe hyperammonemia, acquired microcephaly and progressive brain atrophy.

Biallelic pathogenic variants in the neuroblastoma amplified sequence (NBAS) gene were firstly (2015) identified as a cause of fever-triggered recurrent acute liver failure (RALF). Since then, some patients with NBAS deficiency presenting with neurologic features, including a motor delay, intellectual disability, muscular hypotonia and a mild brain atrophy, have been reported. Here, we describe a case of pediatric patient diagnosed with NBAS deficiency due to a homozygous c.2809C > G, p.(Pro937Ala) variant presenting with RALF with severe hyperammonemia, acquired microcephaly and progressive brain atrophy. Not reported in the literature findings include severe hyperammonemia during ALF episode, and neurologic features in the form of acquired progressive microcephaly with brain atrophy. The latter raises the hypothesis about a primary neurologic phenotype in NBAS deficiency.

Vigabatrin - new data on indications and safety in paediatric epilepsy.

INTRODUCTION: Vigabatrin (VGB), a second-generation antiepileptic drug, is effective for the treatment of infantile spasms and focal seizures, primarily in tuberous sclerosis complex (TSC) patients. However, reports of adverse events of VGB, including VGB-associated visual field loss and brain abnormalities in neuroimaging, have raised concerns about the broader use of VGB and thus significantly limited its application. AIM OF THE STUDY: The goal of this review was to summarise the recent therapeutic guidelines, the use of VGB in focal seizures and new VGB applications as a disease-modifying treatment in TSC patients. Moreover, we discuss the current opinions on potential VGB-associated toxicity and the safety of VGB.

Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to EFNA5, BAHD1 and PPP2R5E as novel candidates for genes causing human Mendelian disorders.

BACKGROUND: Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients. METHODS: Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts. RESULTS: In all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter. CONCLUSION: SGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene-disease associations.

Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.

BACKGROUND: Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function. OBJECTIVES: To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease. METHODS: Whole exome sequencing was performed in both patients. The functional effect of prioritised variant in ELOVL1 (very-long-chain fatty acids (VLCFAs) elongase) was analysed by VLCFA profiling by gas chromatography-mass spectrometry in stably transfected HEK2932 cells and in cultured patient's fibroblasts. RESULTS: Probands shared novel heterozygous ELOVL1 p.Ser165Phe mutation (de novo in one family, while in the other family, father could not be tested). In transfected cells p.Ser165Phe: (1) reduced levels of FAs C24:0-C28:0 and C26:1 with the most pronounced effect for C26:0 (P=7.8×10-6 vs HEK293 cells with wild type (wt) construct, no difference vs naïve HEK293) and (2) increased levels of C20:0 and C22:0 (P=6.3×10-7, P=1.2×10-5, for C20:0 and C22:0, respectively, comparison vs HEK293 cells with wt construct; P=2.2×10-7, P=1.9×10-4, respectively, comparison vs naïve HEK293). In skin fibroblasts, there was decrease of C26:1 (P=0.014), C28:0 (P=0.001) and increase of C20:0 (P=0.033) in the patient versus controls. There was a strong correlation (r=0.92, P=0.008) between the FAs profile of patient's fibroblasts and that of p.Ser165Phe transfected HEK293 cells. Serum levels of C20:0-C26:0 FAs were normal, but the C24:0/C22:0 ratio was decreased. CONCLUSION: The ELOVL1 p.Ser165Phe mutation is a likely cause of IKSHD.

Mild phenotype of glutaric aciduria type 1 in polish patients - novel data from a group of 13 cases.

Glutaric aciduria type 1 is a neurometabolic disorder, caused by riboflavin-dependent glutaryl-CoA dehydrogenase deficiency. As its consequence, accumulation of the putatively neurotoxic metabolites (glutaric and 3-hydroxyglutaric acids) in body tissues, but especially within the brain, is observed. Estimated incidence of the disease is 1 in 110,000 newborns, The prevalence however may be higher, depending on a specific ethnic group, and result in phenotypic variation as well. In this paper we present clinical data of 13 patients of Polish nationality. They all present a mild phenotype and clinical course of glutaric aciduria type 1. Based on their clinical data, presented herein, we like to pay attention to the phenotypic and neuroimaging features important for the diagnosis of mild form of this disease. Moreover, we present novel molecular data, which may correlate with such a manifestation.

Clinical and molecular characteristics of newly reported mitochondrial disease entity caused by biallelic PARS2 mutations.

Most of the 19 mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) involved in mitochondrial protein synthesis are already linked to specific entities, one of the exceptions being PARS2 mutations for which pathogenic significance is not finally validated. The aim of the study was to characterize the PARS2- related phenotype.Three siblings with biallelic PARS2 mutations presented from birth with infantile spasms, secondary microcephaly, and similar facial dysmorphy. Mental development was deeply impaired with speech absence and no eye contact. A dilated cardiomyopathy and multiorgan failure developed in childhood at the terminal stage, together with mitochondrial dysfunction triggered by valproate administration.Brain MRI showed progressive volume loss of the frontal lobes, both cortical and subcortical, with widening of the cortical sulci and frontal horns of the lateral ventricles. Hypoplasia of the corpus callosum and progressive demyelination were additional findings. Similar brain features were seen in three already reported PARS2 patients and seemed specific for this defect when compared with other mt-aaRSs defects (DARS2, EARS2, IARS2, and RARS2).Striking resemblance of the phenotype and Alpers-like brain MRI changes with predominance of frontal cerebral volume loss (FCVL-AS) in six patients from three families of different ethnicity with PARS2 mutations, justifies to distinguish the condition as a new disease entity.

Leigh syndrome in individuals bearing m.9185T>C MTATP6 variant. Is hyperventilation a factor which starts its development?

Leigh syndrome (LS), subacute necrotizing encephalomyelopathy is caused by various genetic defects, including m.9185T>C MTATP6 variant. Mechanism of LS development remains unknown. We report on the acid-base status of three patients with m.9185T>C related LS. At the onset, it showed respiratory alkalosis, reflecting excessive respiration effort (hyperventilation with low pCO2). In patient 1, the deterioration occurred in temporal relation to passive oxygen therapy. To the contrary, on the recovery, she demonstrated a relatively low respiratory drive, suggesting that a "hypoventilation" might be beneficial for m.9185T>C carriers. As long as circumstances of the development of LS have not been fully explained, we recommend to counteract hyperventilation and carefully dose oxygen in patients with m.9185T>C related LS.

Spinal cord lesions in children and adolescents with multiple sclerosis - Magnetic resonance imaging.

PURPOSE: The purpose of our study was to determine the prevalence of spinal cord lesions revealed by magnetic resonance (MR) imaging in children and adolescents with clinically definite multiple sclerosis (MS). MATERIAL AND METHODS: We retrospectively evaluated the spinal cord magnetic resonance examinations in a group of MS patients consisting of 58 children (37 girls and 21 boys) aged from 7 to 17.8 years (mean 13.7 years). All children met the criteria of clinically definite MS and had typical MS lesions revealed in the brain imaging. RESULTS: Spinal cord lesions, regardless of localization, were identified in 36 (62%) patients. In 22 of 58 patients (38%) no lesions were observed. The plaques were found in the cervical spinal cord and the thoracic spinal cord in 30 out of 36 (86.1%) and in 31 out of 36 (88.6%) patients, respectively. Contrast enhancement was noticed in 10 out of 36 patients (27.7%) and was not correlated with the number of lesions present. We noticed a tendency to higher EDSS score in patients with lesions in more than 1 spinal cord region. Our study showed that spinal cord lesions are more frequently present in patients with complex neurological disability. CONCLUSION: The prevalence of spinal cord lesions in children and adolescents with MS is high. Therefore, spinal cord MRI should be included in diagnostic program of MS.

New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.

BACKGROUND: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD). METHODS: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family. RESULTS: Likely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria (MDC) scale (from 36 to 90 % for low and high probability, respectively). The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood (from 20 to 97 %). Molecular diagnosis was established in 30/47 (63.8 %) neonates and in 17/28 (60.7 %) patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria (3-MGA) as a discriminative feature. New MD-related candidate gene (NDUFB8) is under verification. CONCLUSIONS: We suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale.

Contrast enhancement pattern predicts poor survival for patients with non-WNT/SHH medulloblastoma tumours.

Recent studies revealed the biological heterogeneity of medulloblastoma, with the existence of at least four groups which are associated with several clinical and morphological features. We investigated for further correlations between molecular types, location of tumours, their contrast enhancement pattern and survival of patients. Altogether 76 tumours were analyzed and molecular subtypes were identified by immunohistochemistry using representative antibodies, detection of chromosome 6 monosomy and CTNNB1 mutation. The site of the tumour was assessed on diagnosis using Magnetic Resonance images and intra-operative surgical reports. In addition, the gadolinium enhancement pattern was also investigated in pre-treatment tumours. Cerebellar hemispheric location was associated with SHH tumours (p < 0.001), as opposed to midline location being typical for WNT and non-WNT/SHH tumours. Remarkably, for patients with non-WNT/SHH tumours, the extensive gadolinium enhancement pattern (present in >75% of tumour volume) predicted worse OS and EFS than for those with none/weak or heterogeneous enhancement (>10-75% of tumour volume), (both p < 0.001). Our analysis indicates that distribution of the medulloblastoma tumours location is related to the biological characteristics of tumour. Importantly, the enhancement pattern of the tumour may be a clinically useful prognostic marker for patients with non-WNT/SHH medulloblastomas.

MR imaging, apparent diffusion coefficient and histopathological features of desmoplastic infantile tumors-own experience and review of the literature.

PURPOSE: Desmoplastic infantile tumors are rare supratentorial brain lesions occurring in children under 18 months of age. We report characteristic neuroimaging with DWI and the histopathological features of these neoplasms. METHODS: Magnetic resonance (MR) examinations of nine patients, aged 0-18 months (median age 3.5 months), were retrospectively analyzed. Analysis of MR images included location and tumor size, signal intensity, contrast enhancement, presence of edema, and hemorrhage. Minimum and mean value of apparent diffusion coefficient (ADC) in the solid component of the tumor and contralateral normal-appearing white matter (NAWM) were measured, and ADC/NAWM ratios were calculated. All patients underwent tumor resection, and diagnosis of grade I desmoplastic tumors was confirmed. RESULTS: The tumors were located in the temporal lobe in seven patients, the parietal lobe in three, and in the frontal lobe in one case (in two children, tumors invaded more than one lobe). Suprasellar localization was observed in two patients; one child had multifocal brain lesions. In five cases, signal intensity of the solid component was hypointense on T2-WI. The measured minimum ADC value of solid tumor varied from 0.606 to 1.020 × 10(-3) mm(2)/s, with a mean value of 0.921 × 10(-3) mm(2)/s. The mean ADC value of NAWM was 1.121 × 10(-3) mm(2)/s. The mean ADC ratio was 0.858 × 10(-3) mm(2)/s. CONCLUSION: From our series, we can assume that restricted diffusion is observed not only in malignant but also in benign brain tumors. Diffusion signals and ADC values in these neoplasms appear to depend on their cellularity and components of the extracellular matrix.

Severe central and peripheral paraneoplastic demyelination associated with tumours of the ovaries.

PURPOSE: The aim of the study is to present MRI examinations of the brain and spinal cord, performed in girls with acute severe neurological presentation of paraneoplastic syndrome associated with ovarian teratomas. Paraneoplastic neurological syndrome (PNS) is a rare disorder caused by remote effects of malignancy in different organs. The pathogenesis of PNS concerns the autoimmune system and specific antibodies. PNS can be seen as encephalomyelitis, limbic encephalitis, progressive multifocal leukoencephalopathy, cerebellar ataxia, brainstem encephalitis, and paraneoplastic cerebellar degeneration. These symptoms are potentially reversible, if the underlying neoplasm is removed. METHODS: We presented three girls, aged 13, 17, and 18 years. They were all referred to the hospital because of an acute onset of severe disseminated encephalomyelitis. All MRI exams were performed on a 1.5 T scanner with a routine brain and spinal cord protocol, including TSE T2-WI and FLAIR sequences. In all cases, a contrast agent was injected in the standard dose. RESULTS: Neurological examination performed at the onset of the disease revealed hemiparesis, seizures, and consciousness disturbances. In one girl, visual field loss was also disclosed. They were all healthy before the onset of the disease. Brain and spinal cord MR imaging revealed multiple hyperintense lesions located supratentorially in the white matter of both hemispheres, in the pons, cerebellum, and spinal cord. Patients were treated with methyloprednisolone IV and IVIG. They all improved but significant sequelae were present. Two of them developed symptoms of acute demyelinating polyradiculoneuropathy within 2 months after the onset of encephalomyelitis. At the same time, brain MRI showed progression of the lesions. In two patients, anti-Yo antibodies were present in blood. Extensive examinations revealed bilateral ovarian teratomas in two patients, and left-sided ovarian teratoma in one case. Surgical resection of teratomas resulted in rapid clinical improvement. CONCLUSIONS: These cases show that in children and adolescents, acute demyelinating disease can be a manifestation of paraneoplastic neurological syndrome. Thus, PNS should always be considered in the differential diagnosis of encephalomyelitis. In female children and adolescents with suspected PNS, it is important to search for ovarian tumours.

Cervical spine MRI findings in patients with Mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked, recessive, lysosomal storage disorder caused by deficiency of iduronate-2-sulfatase (EC 3.1.6.13). The purpose of this report is to describe cervical spine magnetic resonance (MRI) findings in MPS II patients and to correlate them with clinical phenotype. Seven cervical spine MRI examinations from Polish MPS II patients (mean age 11.4 years, median age 8 years, range 5-30) were evaluated. Six patients were classified as neurological (85.7%) and 1 as attenuated (14.3%). Five patients were treated with idursulfase (range 110-260 weeks, mean 195, median 200), while 2 patients never received the treatment. The following features were assessed: periodontoid thickening, spinal stenosis, dens hypoplasia, myelopathy, and vertebral and intervertebral disc abnormalities. Mean age at evaluation was 11 years (range 5-30, median 8). Cervical spine MRI was abnormal in all the patients and the most frequent abnormalities found were dens hypoplasia (100%), periodontoid thickening (100%), disc abnormalities (100%) and spinal stenosis (43%). There was no clear correlation between MRI findings and patients' phenotypes.

Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation.

The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.

Attenuated adenylosuccinate lyase deficiency: a report of one case and a review of the literature.

We present a 9-year follow-up of a patient with an attenuated (type II) adenylosuccinate lyase deficiency with no obvious signs of disease progression and degradation. We also review the literature, focusing on attenuated phenotype, and we report a positive effect of a ketogenic diet on seizure control. The patient presented at the age of 5 months with a history of global developmental delay. Screening of urinary purine metabolites revealed elevation of succinyladenosine and succinylaminoimidazolecarboxamide riboside (a ratio of 2:1). Mutation analysis revealed a compound heterozygosity for missense mutations: p.R426H and p.D268H. She began to walk independently at the age of 3 years. From the age of 4 years, her communication skills improved and she presented fewer autistic features. Due to poor results in seizure control, the ketogenic diet was introduced at the age of 7 years, resulting in reduction of seizure frequency. Currently, at the age of 9 years, the girl is attending a special kindergarten and is functioning very well in her preschool group. She began to make statements that form a logical continuity and make progress in simple manual operations. The patient participates in therapies such as pet therapy, hippotherapy, speech therapy, physiotherapy, hydrotherapy, and music therapy.

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation: high outcome variation between two siblings.

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation is a rare disorder caused by mutations in the gene encoding a mitochondrial aspartyl-tRNA synthetase, DARS2. Clinical features include childhood or adolescent onset, slowly progressive ataxia, spasticity, and dorsal column dysfunction with or without mild cognitive decline. Magnetic resonance (MR) images show a characteristic leukoencephalopathy with multiple long tract involvement. MR spectroscopy shows elevated levels of lactate. We present strikingly different clinical courses and discrepant MR images findings for a pair of brothers. It cannot be excluded that in the cases presented, the different clinical outcome is related to a varicella infection in infancy in the younger brother.