Objective To assess clinical and neurocognitive function in children who have undergone liver transplantation for classical maple syrup urine disease (MSUD). Study design A total of 35 patients with ...classical MSUD (age 9.9 ± 7.9 years) underwent liver transplantation between 2004 and 2009. Six patients donated their liver to recipients without MSUD (“domino” transplant). We analyzed clinical outcomes for our cohort and 17 additional cases from the national United Network for Organ Sharing registry; 33 patients completed IQ and adaptive testing before transplantation, and 14 completed testing 1 year later. Results Patient and graft survival were 100% at 4.5 ± 2.2 years of follow-up. Liver function was normal in all patients. Branched-chain amino acid levels were corrected within hours after surgery and remained stable, with leucine tolerance increasing more than 10-fold. All domino transplant recipients were alive and well with normal branched-chain amino acid homeostasis at the time of this report. Patient and graft survival for all 54 patients with MSUD undergoing liver transplantation in the United States during this period were 98% and 96%, respectively. One-third of our patients were mentally impaired (IQ ≤ 70) before transplantation, with no statistically significant change 1 year later. Conclusion Liver transplantation is an effective long-term treatment for classical MSUD and may arrest brain damage, but will not reverse it.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Objective
To report clinical and immunological investigations of contactin‐associated protein‐like 2 (Caspr2), an autoantigen of encephalitis and peripheral nerve hyperexcitability (PNH) previously ...attributed to voltage‐gated potassium channels (VGKC).
Methods
Clinical analysis was performed on patients with encephalitis, PNH, or both. Immunoprecipitation and mass spectrometry were used to identify the antigen and to develop an assay with Caspr2‐expressing cells. Immunoabsorption with Caspr2 and comparative immunostaining of brain and peripheral nerve of wild‐type and Caspr2‐null mice were used to assess antibody specificity.
Results
Using Caspr2‐expressing cells, antibodies were identified in 8 patients but not in 140 patients with several types of autoimmune or viral encephalitis, PNH, or mutations of the Caspr2‐encoding gene. Patients' antibodies reacted with brain and peripheral nerve in a pattern that colocalized with Caspr2. This reactivity was abrogated after immunoabsorption with Caspr2 and was absent in tissues from Caspr2‐null mice. Of the 8 patients with Caspr2 antibodies, 7 had encephalopathy or seizures, 5 neuropathy or PNH, and 1 isolated PNH. Three patients also had myasthenia gravis, bulbar weakness, or symptoms that initially suggested motor neuron disease. None of the patients had active cancer; 7 responded to immunotherapy and were healthy or only mildly disabled at last follow‐up (median, 8 months; range, 6–84 months).
Interpretation
Caspr2 is an autoantigen of encephalitis and PNH previously attributed to VGKC antibodies. The occurrence of other autoantibodies may result in a complex syndrome that at presentation could be mistaken for a motor neuron disorder. Recognition of this disorder is important, because it responds to immunotherapy. Ann Neurol 2011
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, ...we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CODAS syndrome is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. Using whole-exome and Sanger sequencing, we identified four LONP1 ...mutations inherited as homozygous or compound-heterozygous combinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n = 8; Mennonite-German from Canada, n = 1; mixed European from Canada, n = 1). LONP1 encodes Lon protease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stress responses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAA+ domain at residues near the ATP-binding pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When expressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1 c.2161C>Gp.Arg721Gly) homo-oligomerizes poorly in vitro. Lymphoblastoid cell lines generated from affected children have (1) swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology; (2) aggregated MT-CO2, the mtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial proteostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of the mitochondrial Lon protease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
De novo glycosphingolipid (GSL) biosynthesis defects cause severe neurological diseases, including hereditary sensory and autonomic neuropathy type 1A (HSAN1A), GM3 synthase deficiency, and ...hereditary spastic paraplegia type 26 (HSPG26), each lacking effective treatment. Recombinant adeno-associated virus (AAV)-mediated gene therapy has emerged as a powerful treatment for monogenic diseases and might be particularly suitable for these neurological conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the ...efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.
...Objective
We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.
Methods
Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials,
n
= 102 patients; postmarketing surveillance,
n
= 665 reported adverse event AE cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated.
Results
The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients.
Conclusions
Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This study reports the association of a mutant form of contactin-associated protein-like 2 (CASPR2) and epilepsy, cortical dysplasia, and developmental decay among children in an Old Order Amish ...population. It suggests that mutant CASPR2 causes epilepsy and influences cortical architecture.
This study reports the association of a mutant form of contactin-associated protein-like 2 (CASPR2) and epilepsy, cortical dysplasia, and developmental decay among children in an Old Order Amish population.
Most epileptic disorders can be traced to an abnormality of cortical architecture, channel-mediated currents, neuronal growth and differentiation, or cerebral metabolism.
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In most cases, however, the underlying biologic complexity of epilepsy precludes the identification of the genetic cause, and 65 to 79 percent of recurrent seizure syndromes remain unexplained.
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Microarray analysis of DNA samples can be a powerful tool for revealing a genetic lesion in well-defined families. We have used this approach in Old Order Amish families, some members of which have a clinical and neuropathological phenotype that we designate as the cortical dysplasia–focal epilepsy (CDFE) syndrome. We identified . . .
We present the quasi-stellar object (QSO) luminosity function (LF) of the completed 2dF–SDSS LRG and QSO (2SLAQ) survey, based on QSOs photometrically selected from Sloan Digital Sky Survey (SDSS) ...imaging data and then observed spectroscopically using the 2dF instrument on the Anglo-Australian Telescope. We analyse 10 637 QSOs in the redshift range 0.4 < z < 2.6 to a g-band flux limit of 21.85 (extinction-corrected) and an absolute continuum magnitude of Mg(z= 2) < −21.5. This sample covers an area of 191.9 deg2. The binned QSO LF agrees with that of the brighter SDSS main QSO sample, but extends ∼2.5 mag fainter, clearly showing the flattening of the LF towards faint absolute magnitudes. 2SLAQ finds an excess of QSOs compared to the 2dF QSO Redshift Survey at g > 20.0, as found previously by Richards et al. The LF is consistent with other previous, much smaller, samples produced to the depth of 2SLAQ. By combining the 2SLAQ and SDSS QSO samples, we produce a QSO LF with an unprecedented combination of precision and dynamic range. With this we are able to accurately constrain both the bright and faint ends of the QSO LF. While the overall trends seen in the evolution of the QSO LF appear similar to pure luminosity evolution, the data show very significant departures from such a model. Most notably we see clear evidence that the number density of faint QSOs peaks at lower redshift than bright QSOs: QSOs with Mg > −23 have space densities which peak at z < 1, while QSOs at Mg < −26 peak at z > 2. By fitting simple LF models in narrow Mg intervals, we find that this downsizing is significant at the 99.98 per cent level. We show that LF models which follow the pure luminosity evolution form i.e. M*g≡M*g(z), but with a redshift-dependent bright-end slope and an additional density evolution term, Φ*≡Φ*(z), provide a much improved fit to the data. The bright-end slope, α, steepens from α≃−3.0 at z≃ 0.5 to α=−3.5 at z≃ 2.5. This steepening is significant at the 99.9 per cent level. We find a decline in Φ* from z≃ 0.5 to 2.5 which is significant at the 94 per cent level.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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