Structural Brain Defects Research Articles

Fukutin-related protein is essential for mouse muscle, brain and eye development and mutation recapitulates the wide clinical spectrums of dystroglycanopathies

Mutations in fukutin-related protein (FKRP) cause a common subset of muscular dystrophies characterized by aberrant glycosylation of alpha-dystroglycan (α-DG), collectively known as dystroglycanopathies. The clinical variations associated with FKRP mutations range from mild limb-girdle muscular dystrophy type 2I with predominantly muscle phenotypes to severe Walker-Warburg syndrome and muscle-eye-brain disease with striking structural brain and eye defects. In the present study, we have generated animal models and demonstrated that ablation of FKRP functions is embryonic lethal and that the homozygous-null embryos die before reaching E12.5. The homozygous knock-in mouse carrying the missense P448L mutation almost completely lacks functional glycosylation of α-DG in muscles and brain, validating the essential role of FKRP in the functional glycosylation of α-DG. However, the knock-in mouse survives and develops a wide range of structural abnormalities in the central nervous system, characteristics of neuronal migration defects. The brain and eye defects are highly reminiscent of the phenotypes seen in severe dystroglycanopathy patients. In addition, skeletal muscles develop progressive muscular dystrophy. Our results confirm that post-translational modifications of α-DG are essential for normal development of the brain and eyes. In addition, both the mutation itself and the levels of FKRP expression are equally critical for the survival of the animals. The exceptionally wide clinical spectrums recapitulated in the P448L mice also suggest the involvement of other factors in the disease progression. The mutant mouse represents a valuable model to further elucidate the functions of FKRP and develop therapies for FKRP-related muscular dystrophies.

Mild POMGnT1 Mutations Underlie a Novel Limb-Girdle Muscular Dystrophy Variant

Mutations in protein-O-mannose-beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1) have been found in muscle-eye-brain disease, a congenital muscular dystrophy with structural eye and brain defects and severe mental retardation. To investigate whether mutations in POMGnT1 could be responsible for milder allelic variants of muscular dystrophy. Screening for mutations in POMGnT1. Tertiary neuromuscular unit. A patient with limb-girdle muscular dystrophy phenotype, with onset at 12 years of age, severe myopia, normal intellect, and decreased alpha-dystroglycan immunolabeling in skeletal muscle. A homozygous POMGnT1 missense mutation (c.1666G>A, p.Asp556Asn) was identified. Enzyme studies of the patient's fibroblasts showed an altered kinetic profile, less marked than in patients with muscle-eye-brain disease and in keeping with the relatively mild phenotype in our patient. Our findings widen the spectrum of disorders known to result from mutations in POMGnT1 to include limb-girdle muscular dystrophy with no mental retardation. We propose that this condition be known as LGMD2M. The enzyme assay used to diagnose muscle-eye-brain disease may not detect subtle abnormalities of POMGnT1 function, and additional kinetic studies must be carried out in such cases.

POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome

Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus...

Congenital microcephaly, juvenile retinal dystrophy and normal mentation in a mildly dysmorphic child

Congenital microcephaly, defined as a head circumference more than 2 standard deviations below the mean, results from a primary defect in neural tissue development (not bone development) and the resulting aberrant closure of the cranial sutures.1 It is therefore not surprising that most cases of congenital microcephaly are associated with mental retardation, various syndromes and chromosomal abnormalities.2–14 Motor and speech development are often delayed, and hyperactivity and mental retardation are common. In general, life expectancy is low, as is the prognosis for normal brain function.15–17 Multiple associations exist between microcephaly and abnormalities of the eye, such as Mirhosseini–Holmes–Walton (MHW) syndrome,2 Cohen syndrome,3 Seckel syndrome5 and Balci syndrome.6 All of these associations include various degrees of mental dysfunction, from severe retardation through structural brain defects to mild mental handicaps. We present a novel phenotypic variant: microcephaly with normal mentation and juvenile retinal dystrophy in an otherwise healthy boy with mildly dysmorphic features and normal brain structure.

Mutations in the Fukutin-Related Protein Gene ( FKRP) Cause a Form of Congenital Muscular Dystrophy with Secondary Laminin α2 Deficiency and Abnormal Glycosylation of α-Dystroglycan

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders presenting in infancy with muscle weakness, contractures, and dystrophic changes on skeletal-muscle biopsy. Structural brain defects, with or without mental retardation, are additional features of several CMD syndromes. Approximately 40% of patients with CMD have a primary deficiency (MDC1A) of the laminin alpha2 chain of merosin (laminin-2) due to mutations in the LAMA2 gene. In addition, a secondary deficiency of laminin alpha2 is apparent in some CMD syndromes, including MDC1B, which is mapped to chromosome 1q42, and both muscle-eye-brain disease (MEB) and Fukuyama CMD (FCMD), two forms with severe brain involvement. The FCMD gene encodes a protein of unknown function, fukutin, though sequence analysis predicts it to be a phosphoryl-ligand transferase. Here we identify the gene for a new member of the fukutin protein family (fukutin related protein [FKRP]), mapping to human chromosome 19q13.3. We report the genomic organization of the FKRP gene and its pattern of tissue expression. Mutations in the FKRP gene have been identified in seven families with CMD characterized by disease onset in the first weeks of life and a severe phenotype with inability to walk, muscle hypertrophy, marked elevation of serum creatine kinase, and normal brain structure and function. Affected individuals had a secondary deficiency of laminin alpha2 expression. In addition, they had both a marked decrease in immunostaining of muscle alpha-dystroglycan and a reduction in its molecular weight on western blot analysis. We suggest these abnormalities of alpha-dystroglycan are caused by its defective glycosylation and are integral to the pathology seen in MDC1C.

Fetal Alcohol Exposure: Effects on the Developing Brain

After completing this article, readers should be able to: 1. Describe the primary central nervous system effects of prenatal alcohol exposure. 2. Describe the relationship of fetal alcohol syndrome and mental retardation. 3. Delineate proposed mechanisms of alcohol’s adverse effects on the developing brain. 4. Identify key factors that increase the risk of alcohol-induced fetal brain damage. 5. Delineate proposed neuroprotective strategies to limit fetal brain damage. Fetal alcohol syndrome (FAS) was described initially in the American medical literature in 1973 by Jones and colleagues as a constellation of features in children born to alcoholic mothers. These features include facial and other physical anomalies, pre- and postnatal growth deficiency, and variable central nervous system (CNS) abnormalities. These latter may involve structural brain defects, cognitive abnormalities, delayed brain development, and signs of neurologic impairment, including lifelong behavioral and psychosocial dysfunction. In 1996, the Institute of Medicine further defined criteria for the diagnosis of FAS and also proposed a new term: Alcohol-related Neurodevelopmental Disorder (ARND). This latter term includes structural CNS and cognitive abnormalities in children in whom fetal exposure to alcohol has been confirmed. Unlike FAS, a diagnosis of ARND does not require the presence of facial or other physical abnormalities. In 2000, the American Academy of Pediatrics (AAP) Committee on Substance Abuse published these new definitions in Pediatrics (Figure⇓ ). Figure 1. Diagnostic classification of fetal alcohol syndrome (FAS) and alcohol-related birth defects (ARBD). Reprinted with permission from Pediatrics . 2000;106:358–361 The problem is enormous. FAS is estimated to occur in the United States at a rate of 1 to 3 per 1,000 live births and is higher in selected subgroups, such as Native Americans. The rate of ARND is estimated to be at least 10 times greater. Fetal alcohol exposure is estimated to be the leading cause of mental retardation in developed countries today. Although …

Separate and interactive effects of cocaine and alcohol dependence on brain structures and metabolites: quantitative MRI and proton MR spectroscopic imaging.

The effects of chronic cocaine and alcohol abuse on human brain structure and metabolites are not fully known. We studied controls (n = 13) and abstinent subjects dependent on cocaine (8), alcohol (12), and cocaine and alcohol (17) using quantitative MRI and proton MR spectroscopic imaging. Talairach-based techniques yielded tissue and CSF volumes and gray- and white-matter concentrations of N-acetylaspartate (NAA), creatine and choline metabolites in multiple brain regions. Alcohol dependents had lower gray-matter NAA concentrations and more sulcal CSF than non-alcohol dependents throughout the brain. They also had less subcortical gray matter and (regionally) less white matter. Cocaine dependents compared with non-cocaine dependents had higher posterior parietal white-matter creatine concentration. They also had less gray and white matter in the prefrontal lobes and in a region encompassing the temporal lobes and cerebellum. Structural white-matter deficits in cocaine dependents were greater with longer duration of cocaine use. Subjects with concurrent cocaine and alcohol dependence had less prefrontal white matter, especially in the anterior cingulate, than subjects dependent on only one substance. Chronically abused cocaine and alcohol each leave multiple metabolic and structural brain defects after long-term abstinence. Concurrent dependence on both substances may aggravate white-matter structural defects, primarily in frontal brain.

The WIF module

The Ryk (for related-to-tyrosine-kinase) receptor tyrosine kinases form a distinct subfamily of tyrosine kinases. They have an unusually short extracellular region 1 Hovens C.M. et al. Ryk, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11818-11822 Crossref PubMed Scopus (114) Google Scholar and unique substitutions in their catalytic domains 1 Hovens C.M. et al. Ryk, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 11818-11822 Crossref PubMed Scopus (114) Google Scholar , 2 Stacker S.A. et al. Molecular cloning and chromosomal localisation of the human homologue of a receptor related to tyrosine kinases (RYK). Oncogene. 1993; 8: 1347-1356 PubMed Google Scholar , 3 Tamagnone L. et al. The human ryk cDNA sequence predicts a protein containing two putative transmembrane segments and a tyrosine kinase catalytic domain. Oncogene. 1993; 8: 2009-2014 PubMed Google Scholar , 4 Dura J.M. et al. The Drosophila learning and memory gene linotte encodes a putative receptor tyrosine kinase homologous to the human RYK gene product. FEBS Lett. 1995; 370: 250-254 Abstract Full Text PDF PubMed Scopus (58) Google Scholar , 5 Oates A.C. et al. Embryonic expression and activity of doughnut, a second RYK homolog in Drosophila. Mech. Dev. 1998; 78: 165-169 Crossref PubMed Scopus (17) Google Scholar , 6 Halford M.M. et al. Genomic structure and expression of the mouse growth factor receptor related to tyrosine kinases (Ryk)s. J. Biol. Chem. 1999; 274: 7379-7390 Crossref PubMed Scopus (19) Google Scholar . The phylogenetic conservation of Ryk proteins from Caenorhabditis elegans and Drosophila to mammals strongly argues for an important and basic function of these proteins. Studies on mutants of the Drosophila derailed (drl) gene have shown that this Ryk protein plays a crucial role in cell-recognition processes controlling nervous system development and muscle development 4 Dura J.M. et al. The Drosophila learning and memory gene linotte encodes a putative receptor tyrosine kinase homologous to the human RYK gene product. FEBS Lett. 1995; 370: 250-254 Abstract Full Text PDF PubMed Scopus (58) Google Scholar . linotte (lio) mutants of the drl gene present structural brain defects in the adult central complex and mushroom bodies, indicating that this receptor tyrosine kinase is required for neuronal pathway selection 7 Moreau-Fauvarque C. et al. The receptor tyrosine kinase gene linotte is required for neuronal pathway selection in the Drosophila mushroom bodies. Mech. Dev. 1998; 78: 47-61 Crossref PubMed Scopus (56) Google Scholar , 8 Simon A.F. et al. The Drosophila putative kinase linotte (derailed) prevents central brain axons from converging on a newly described interhemispheric ring. Mech. Dev. 1998; 76: 45-55 Crossref PubMed Scopus (52) Google Scholar . Derailed mutants of the drl gene are defective in insertion of somatic muscles into the epidermis, suggesting that the mechanism for selecting sites for muscle attachment is biochemically similar to that used in axon pathfinding 9 Callahan C.A. et al. derailed is required for muscle attachment site selection in Drosophila. Development. 1996; 122: 2761-2767 PubMed Google Scholar . DNT, a second Ryk homologue in Drosophila, encoded by doughnut, is capable of a partial rescue of the muscle attachment defect of drl−/− embryos, suggesting that DNT and DRL proteins have overlapping biochemical activities 5 Oates A.C. et al. Embryonic expression and activity of doughnut, a second RYK homolog in Drosophila. Mech. Dev. 1998; 78: 165-169 Crossref PubMed Scopus (17) Google Scholar . The Ryk-homologue of C. elegans (gene C18B6.1) corresponds to the lin-18 gene that is required for cell–cuticle recognition 10 Serfas M.S. Tyner A.L. Ryk is expressed in a differentiation-specific manner in epithelial tissues and is strongly induced in decidualizing uterine stroma. Oncogene. 1998; 17: 3435-3444 Crossref PubMed Scopus (14) Google Scholar , 11 Ferguson E.L. et al. A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans. Nature. 1987; 326: 259-267 Crossref PubMed Scopus (255) Google Scholar . Mammalian Ryk proteins are found in most tissues but little is known about their function 11 Ferguson E.L. et al. A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans. Nature. 1987; 326: 259-267 Crossref PubMed Scopus (255) Google Scholar . Murine Ryk protein is induced in epithelial cells seeking a final place in a differentiated tissue, or during remodelling of the endometrium 10 Serfas M.S. Tyner A.L. Ryk is expressed in a differentiation-specific manner in epithelial tissues and is strongly induced in decidualizing uterine stroma. Oncogene. 1998; 17: 3435-3444 Crossref PubMed Scopus (14) Google Scholar , which suggests that mammalian Ryk proteins might also be involved in cellular recognition processes.

Central nervous system structure and function in Sturge-Weber syndrome: evidence of neurologic and radiologic progression.

Sturge-Weber syndrome is characterized by the presence of a port-wine nevus, epilepsy, stroke-like episodes, headache, and developmental delay. We studied 20 cases to test the hypothesis that decreased cerebral blood flow alters neurologic function by affecting cellular glucose metabolism. Group A consisted of 10 patients with a mean age of 1.75 years and early seizure onset (6.8 months), whereas group B was composed of older patients (mean age, 15.3 years) with later onset of seizures (3.7 years). Neurologic disease was more severe in group A, but group B had more widespread structural brain defects - shown on computed tomographic scans and magnetic resonance imaging - and metabolic brain defects shown on hexamethylpropyleneamine oxime and [18F] fluorodeoxyglucose single photon emission computed tomographic scans. Six group A cases had hypoperfusion at baseline and five of nine had worsening of perfusion and glucose metabolism 1 year later. A total of 119 stroke-like episodes occurred in six group A cases and eight group B cases; there were 65% fewer strokes in children treated with aspirin. The data suggest that progressive hypoperfusion and glucose hypometabolism are associated with neurologic deterioration in Sturge-Weber syndrome. Longitudinal studies are needed to better define the natural history of disease and to evaluate the safety and efficacy of aspirin therapy.

The receptor tyrosine kinase gene linotte is required for neuronal pathway selection in the Drosophila mushroom bodies

The linotte ( lio) mutant was first isolated as a memory mutant. The lio gene encodes a putative receptor tyrosine kinase (RTK), homologous to the human protein RYK. This gene has been independently identified in a screen for embryonic nervous system axonal guidance defects and called derailed ( drl). Here, we report that linotte mutants present structural brain defects in the adult central complex (CX) and mushroom bodies (MB). linotte and derailed are allelic for this phenotype, which can be rescued by a drl + transgene. The Lio RTK is expressed preferentially in the adult CX and MB. Our results suggest that, analogous to its role within the embryonic nervous system, the Lio RTK is involved in neuronal pathway selection during adult brain development.

Arm span as measurement of response to growth hormone (GH) treatment in a group of children with meningomyelocele and GH deficiency.

Children with meningomyelocele (MMC) frequently have impaired linear growth. A number have associated structural brain defects with resultant GH deficiency (GHD). Reproducible measurements of height or length in MMC patients are often hampered by lower limb contractures, spasticity, and scoliosis. Arm span has been proposed as a more reproducible measure of linear growth. Five MMC children documented to have GHD were treated with recombinant human GH (hGH) for 1-3 yr. Their height, arm span, and growth velocity were compared with 32 children with idiopathic GHD treated similarly with hGH. These measures are compared with normal children by being expressed as standard deviation scores. The results of this study indicate that arm span measurements in GHD MMC patients are almost identical to height measurements in idiopathic GHD patients both before and during hGH therapy. The physical condition of children with MMC makes reproducible longitudinal height measurements difficult. Routine determinations of arm span measurements for children with MMC will assist in recognizing growth failure as well as monitoring treatment results.

A higher control center of locomotor behavior in the Drosophila brain

In order to elucidate the behavioral significance of the central complex (CC), we have examined walking in 15 Drosophila mutant strains belonging to eight independent X-linked genes that affect the structure of the CC. Compared to four different wild-type strains, all are impaired either in a general or in a paradigm-dependent manner. Behavioral deficits concern walking activity, walking speed, or "straightness of walking" as measured in an object fixation task, in fast phototaxis, and in negative geotaxis. Behavioral deficits of three strains with mutations in different genes were studied in detail using mosaic analysis and high-speed cinematography. In all cases the focus for declining walking activity is located in the brain and is fully correlated with the respective defect of the CC. A high correlation between the degree of the behavioral impairment and the severity of the structural defect in two strains further adds to the evidence. Declining walking activity is not an unspecific side effect of structural brain defects, as steady walking is observed in structural mutants of the visual system and mushroom bodies. In mutant flies no-bridgeKS49 (nob), step size as a function of the stepping period is reduced. The focus of the resulting reduced average and maximum walking speeds resides in the brain and, again, the behavioral impairment fully correlates with the structural defects of the CC. While no indication is found for a role of the CC in setting up the basic stepping rhythm in straight walking (a respective phenotype in mutant central-complexKS181 flies resides in the ventral ganglion), a role in turning and start/stop maneuvers is suggested by aberrations in the stepping pattern of nob flies during such episodes.

Cell-specific immuno-probes for the brain of normal and mutant Drosophila melanogaster. I. Wildtype visual system.

We have screened antibodies for immunocytochemical staining in the optic lobes of the brain of Drosophila melanogaster. Seven polyclonal antisera and five monoclonal antibodies are described that selectively and reproducibly stain individual cells and/or produce characteristic staining patterns in the neuropile. Such antisera are useful for the cellular characterization of molecular and structural brain defects in visual mutants. In the wildtype visual system we can at present separately stain the following: the entire complement of columnar "T1" neurons; a small set of presumptive serotonergic neurons; some 3000 cells that contain and synthesize gamma-amino butyric acid (GABA); and three groups of cells that bind antibodies to Ca2+-binding proteins. In addition, small groups of hitherto unknown tangential cells that send fine arborizations into specific strata of the medulla, and two patterns of characteristic layers in the visual neuropile have been identified by use of monoclonal antibodies generated following immunization of mice with homogenates of the brain of Drosophila melanogaster.

Congenital structural brain defects in the deaf dalmatian.

Deafness in dalmatian dogs in known to be congenital. It has been reported that the condition is manifested in structural defects of the sensitive lamina of the organ of Corti. In a study of deaf puppies, examined as they became available, this was found to be in doubt. Moreover, a characteristic gross reduction of area was found in the structure of the acoustic cortex in affected puppies. Extension of the morphometric studies further showed that the acoustic pathways were generally attenuated in keeping with the changes in the cortex. Consideration is given to the probability that the condition develops centrally rather than peripherally. Thus instead of the central components failing to develop because of lack of evocative stimulus from the end organ it is envisaged that the peripheral organ regresses because of incomplete innervation by central outgrowth.