Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation?

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) cleaves the phosphodiester bond between a covalently stalled topoisomerase I (Topo I) and the 3' end of DNA. Stalling of Topo I at DNA strand breaks is induced by endogenous DNA damage and the Topo I-specific anticancer drug camptothecin (CPT). The H493R mutation of Tdp1 causes the neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy (SCAN1). Contrary to the hypothesis that SCAN1 arises from catalytically inactive Tdp1, Tdp1-/- mice are indistinguishable from wild-type mice, physically, histologically, behaviorally, and electrophysiologically. However, compared to wild-type mice, Tdp1-/- mice are hypersensitive to CPT and bleomycin but not to etoposide. Consistent with earlier in vitro studies, we show that the H493R Tdp1 mutant protein retains residual activity and becomes covalently trapped on the DNA after CPT treatment of SCAN1 cells. This result provides a direct demonstration that Tdp1 repairs Topo I covalent lesions in vivo and suggests that SCAN1 arises from the recessive neomorphic mutation H493R. This is a novel mechanism for disease since neomorphic mutations are generally dominant.

Neurologic phenotype of Schimke immuno-osseous dysplasia and neurodevelopmental expression of SMARCAL1.

Schimke immuno-osseous dysplasia (OMIM 242900) is an uncommon autosomal-recessive multisystem disease caused by mutations in SMARCAL1 (swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), a gene encoding a putative chromatin remodeling protein. Neurologic manifestations identified to date relate to enhanced atherosclerosis and cerebrovascular disease. Based on a clinical survey, we determined that half of Schimke immuno-osseous dysplasia patients have a small head circumference, and 15% have social, language, motor, or cognitive abnormalities. Postmortem examination of 2 Schimke immuno-osseous dysplasia patients showed low brain weights and subtle brain histologic abnormalities suggestive of perturbed neuron-glial migration such as heterotopia, irregular cortical thickness, incomplete gyral formation, and poor definition of cortical layers. We found that SMARCAL1 is highly expressed in the developing and adult mouse and human brain, including neural precursors and neuronal lineage cells. These observations suggest that SMARCAL1 deficiency may influence brain development and function in addition to its previously recognized effect on cerebral circulation.

The mitochondrial myopathy encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome: a review of treatment options.

Mitochondrial encephalomyopathies are a multisystemic group of disorders that are characterised by a wide range of biochemical and genetic mitochondrial defects and variable modes of inheritance. Among this group of disorders, the mitochondrial myopathy, encephalopathy, lactic acidosis with stroke-like episodes (MELAS) syndrome is one of the most frequently occurring, maternally inherited mitochondrial disorders. As the name implies, stroke-like episodes are the defining feature of the MELAS syndrome, often occurring before the age of 15 years. The clinical course of this disorder is highly variable, ranging from asymptomatic, with normal early development, to progressive muscle weakness, lactic acidosis, cognitive dysfunction, seizures, stroke-like episodes, encephalopathy and premature death. This syndrome is associated with a number of point mutations in the mitochondrial DNA, with over 80% of the mutations occurring in the dihydrouridine loop of the mitochondrial transfer RNA(Leu(UUR)) [tRNA(Leu)((UUR))] gene. The pathophysiology of the disease is not completely understood; however, several different mechanisms are proposed to contribute to this disease. These include decreased aminoacylation of mitochondrial tRNA, resulting in decreased mitochondrial protein synthesis; changes in calcium homeostasis; and alterations in nitric oxide metabolism. Currently, no consensus criteria exist for treating the MELAS syndrome or mitochondrial dysfunction in other diseases. Many of the therapeutic strategies used have been adopted as the result of isolated case reports or limited clinical studies that have included a heterogeneous population of patients with the MELAS syndrome, other defects in oxidative phosphorylation or lactic acidosis due to disorders of pyruvate metabolism. Current approaches to the treatment of the MELAS syndrome are based on the use of antioxidants, respiratory chain substrates and cofactors in the form of vitamins; however, no consistent benefits have been observed with these treatments.

Spectrum of pediatric neuromyelitis optica.

OBJECTIVE: Our goal was to describe the spectrum of clinical phenotypes, laboratory and imaging features, and treatment in pediatric patients with neuromyelitis optica. PATIENTS AND METHODS: The study consisted of a retrospective chart review of patients followed in a pediatric multiple sclerosis center with a diagnosis of neuromyelitis optica spectrum disorder. RESULTS: Nine patients with neuromyelitis optica spectrum disorders were included, all of whom were female. There were 4 black children, 2 Latin American children, 2 white children, and 1 child of mixed Latin American/white heritage. Median age at initial attack was 14 years (range: 1.9-16 years). Median disease duration was 4 years (range: 0.6-9 years). Tests for neuromyelitis optica immunoglobulin G were positive for 7 patients. Eight patients had transverse myelitis and optic neuritis, and 1 patient had longitudinally extensive transverse myelitis without optic neuritis but had a positive neuromyelitis optica immunoglobulin G antibody titer. Cerebral involvement on MRI was found in all subjects, 5 of whom were symptomatic with encephalopathy, seizures, hemiparesis, aphasia, vomiting, or hiccups. Immunosuppressive therapy reduced attack frequency and progression of disability. CONCLUSIONS: Pediatric neuromyelitis optica has a diverse clinical presentation and may be difficult to distinguish from multiple sclerosis in the early stages of the disease. The recognition of the broad spectrum of this disease to include signs and symptoms of brain involvement is aided by the availability of a serum biomarker: neuromyelitis optica immunoglobulin G. Early diagnosis and immunosuppresive treatment may help to slow the accumulation of severe disability.

Visceral endoderm function is regulated by quaking and required for vascular development.

The quaking (qkI) gene produces three major alternatively spliced variants (qkI-5,-6,-7) that encode for proteins that share the RNA binding, KH domain. Previous studies utilizing the qk(k2) allele, which contains an N-ethyl-N-nitrosourea (ENU)-induced point mutation in the KH domain, demonstrate that this functional region of qkI is required for embryonic vascular development. In the current studies we demonstrate that qk(l-1)/qk(l-1) mutants, which lack the QKI-5 splice variant, also died at midgestation due to vascular remodeling defects. In addition, although all three QKI isoforms were expressed in the visceral endoderm of wildtype yolk sacs, qkI-6 and qkI-7 transcript and protein expression were suppressed in qk(k2)/qk(k2) and qk(l-1)/qk(l-1) mutant yolk sacs, suggesting that the KH-domain of QKI-5 was required for qkI-6 and qkI-7 expression. Further studies revealed that the cellular role of qkI is to regulate visceral endoderm function, including the local synthesis of retinoic acid (RA) and the subsequent control of endothelial cell proliferation, matrix production, and visceral endoderm survival. Although these defects were rescued by exogenous RA, visceral endoderm function or vascular remodeling were not restored. Thus, we conclude that qkI regulates visceral endoderm function, which is critical for vascular remodeling.

Schimke immuno-osseous dysplasia: a cell autonomous disorder?

SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like protein 1) encodes a SWI/SNF ATP-dependent chromatin remodeling protein. Mutations in SMARCAL1 cause the autosomal-recessive multisystem disorder Schimke immuno-osseous dysplasia (SIOD); this suggests that the SMARCAL1 protein is involved in the development or maintenance of multiple organs. Disease within these many tissues could arise by a cell autonomous or a cell non-autonomous mechanism. Consistent with a cell autonomous mechanism, we did not find any disease recurrence in transplanted organs or protection of other tissues by the organ grafts. In order to better understand the role of SMARCAL1 during normal development and in the pathogenesis of SIOD, we characterized the spatial and temporal expression of the murine homolog (Smarcal1). The Smarcal1 mRNA and protein were expressed throughout development and in all tissues affected in patients with SIOD including the bone, kidney, thymus, thyroid, tooth, bone marrow, hair, eye, and blood vessels. Significantly, the expression profile of Smarcal1 in the mouse has led us to reexamine and identify novel pathology in our patient population resulting in changes in the clinical management of SIOD. The expression of Smarcal1 in affected tissues and the non-recurrence of disease in grafted organs lead us to hypothesize a cell autonomous function for SMARCAL1 and to propose tissue-specific mechanisms for the pathophysiology of SIOD.

Congenital disorder of glycosylation (CDG)-Ih patient with a severe hepato-intestinal phenotype and evolving central nervous system pathology.

We present the clinical, molecular, and biochemical diagnosis of a patient with congenital disorder of glycosylation (CDG)-Ih. We report significant brain dysfunction in this multisystem disease, further expanding its complex clinical spectrum.

Quaking is essential for blood vessel development.

For nearly 40 years functional studies of the mouse quaking gene (qkI) have focused on its role in the postnatal central nervous system during myelination. However, the homozygous lethality of a number of ENU-induced alleles reveals that quaking has a critical role in embryonic development prior to the start of myelination. In this article, we show that quaking has a previously unsuspected and essential role in blood vessel development. Interestingly, we found that quaking, a nonsecreted protein, is expressed in the yolk sac endoderm, adjacent to the mesodermal site of developing blood islands, where the differentiation of blood and endothelial cells first occurs. Antibodies against PE-CAM-1, TIE-2 and SM-alpha-actin reveal that embryos homozygous for the qk(k2) allele have defective yolk sac vascular remodeling and abnormal vessels in the embryo proper at midgestation, coinciding with the timing of embryonic death. However, these mutants exhibit normal expression of Nkx2.5 and alpha-sarcomeric actin, indicating that cardiac muscle differentiation was normal. Further, they had normal embryonic heart rates in culture, suggesting that cardiac function was not compromised at this stage of embryonic development. Together, these results suggest that quaking plays an essential role in vascular development and that the blood vessel defects are the cause of embryonic death.