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A K Percy

Publications and source records attributed to A K Percy.

At least 19 recordsLinked to original sources
PubMed2006

Early progressive encephalopathy in boys and MECP2 mutations.

MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.

Cerebral Cortex↗
PubMed2002

Clinical and genetic heterogeneity in benign hereditary chorea.

BACKGROUND: Benign hereditary chorea (BHC) is an autosomal dominant disorder that can be distinguished from Huntington disease by its early onset, stable or only slightly progressive course, and absence of mental deterioration. The variation in clinical features is such that its very existence has been doubted. The authors recently described the localization of a gene responsible for BHC on chromosome 14q in a large Dutch family. OBJECTIVE: To report results of extensive clinical and linkage analyses for this Dutch family and six other families with BHC. RESULTS: Three of the seven families had linkage to a region on chromosome 14q13.1-q21.1. HOMOG analysis showed odds of 10 x 10(11) in favor of locus heterogeneity. Haplotype analyses for the linked families resulted in a reduction of the critical interval for the BHC gene to 8.4 cM between marker D14S49 and marker D14S278. Clinically, these three families had a homogeneous picture with early-onset chorea, sometimes accompanied by slight ataxia in walking, but without dystonia, myoclonic jerks, or dysarthria. The severity of the choreatic movements tended to abate in adolescence or early adulthood. In the unlinked families, symptoms and signs were more heterogeneous as to age at onset and the occurrence of myoclonic jerks or dystonia. CONCLUSIONS: BHC is a clinically and genetically heterogeneous disorder, with one well-defined clinical syndrome mapping to chromosome 14q.

Adolescent↗
PubMed2001

Distal infantile neuroaxonal dystrophy--a new familial variant with perineuronal argyrophilic bodies.

We report on two sisters with an infantile onset of dyskinetic movements, tonic spasms, seizures and apneic spells. The condition deteriorated to a hypotonic "burnt out" stage by the age of 3 years in the older sister and to a stable dyskinetic condition by the age of 2.5 years in the younger one. A skin biopsy from the older sister revealed myelinated nerve fibers crowded with neurofilaments. The extensive investigation for neurometabolic disorder, magnetic resonance imaging of the brain, and ophthalmological and neurophysiological examinations were not especially revealing. The older sister died at the age of 3 years. The autopsy revealed no apparent loss of nerve cells in the brain and no sign of storage disease. However, silver-stained coarse granules, immunopositive for neurofilament polypeptide, were found around nerve cell bodies in the cortex and in the basal ganglia. Electron microscopy revealed perineuronal membrane-bound profiles filled with filaments. Silver-stained axonal torpedoes were found in the cerebellum, but there were no spheroids. The substantia nigra, the locus ceruleus and the nucleus basalis of Meynert showed extensive perineuronal and perivascular swelling. Homovanillic acid was severely reduced, while 5-hydroxyindoleacetic acid and hydroxymethylphenyl glycol were normal in the cerebrospinal fluid of the severely affected, autopsied case. The two cases are considered to represent a new form of infantile neuroaxonal dystrophy, characterized by the degeneration of perineuronal terminals in the cerebral cortex and in the basal ganglia, as well as by axonal degeneration in the cerebellum and peripheral nerves.

Brain↗
PubMed2001

Rett syndrome: clinical correlates of the newly discovered gene.

The recent identification of mutations in the gene, MECP2, in girls with Rett syndrome (RS) firmly establishes the molecular genetic basis of this X-linked dominant disorder. This discovery, with ramifications far beyond establishing the gene for RS, represents a dramatic conclusion to an intensive, decade-long search. MECP2 encodes a methyl-CpG-binding protein (MeCP2) involved in transcriptional silencing of a yet to be defined number and type of genes. The clinical spectrum of resultant disorders extends well beyond RS. Indeed, the clinical phenotypes for MECP2 mutations range from mild disability in the mother of a girl with RS to rapidly progressive encephalopathy in her brother. Further, the recent identification of MECP2 mutations in boys with phenotypes quite different from RS adds yet another element to the mix. Within the classic RS group, clinical severity varies remarkably, depending at least in part on the degree of non-random X-inactivation. Those with clinical patterns in the border zones of RS remain to be examined fully for less severe mutational events. Further, the pathobiology of RS and the role of transcriptional silencing as a disease-producing mechanism could be a prototype for other disorders of neurodevelopment. Thus, the identification of mutations in MECP2 creates completely new vistas as to fundamental neurobiologic processes, to disease mechanisms in the neurodevelopmental disabilities, and to potential new therapeutic strategies for RS and related disorders.

Adolescent↗
PubMed2001

Neuropathology of occipital horn syndrome.

Occipital horn syndrome, formerly known as Ehlers-Danlos syndrome type IX or X-linked cutis laxa, is an allelic variant of Menkes' syndrome. Although the clinical symptomatology and systemic pathology findings have been well described in occipital horn syndrome, the neuropathology has not previously been reported. A kindred affected by the X-linked occipital horn syndrome is followed at the University of Alabama at Birmingham. A severely mentally retarded dysmorphic man, who died at the age of 26 years, never gained the ability to walk or talk. Among other findings at autopsy, the patient had the skeletal anomalies previously described with occipital horn syndrome. Neuropathologic findings included neovascularization and extreme reduplication of the cerebral arteries, in conjunction with cystic medial degeneration; bilateral cerebellar hypoplasia; focal cortical dysplasia, and cerebellar heterotopias. These findings are similar to those seen in the brains of patients with Menkes' syndrome, which is not surprising, given the known phenotypic overlap and the proven allelism of occipital horn syndrome with classic Menkes' syndrome.

Adolescent↗
PubMed2000

Cocaine inhibits NGF-induced PC12 cells differentiation through D(1)-type dopamine receptors.

In utero cocaine exposure can adversely affect CNS development. Previous studies showed that cocaine inhibits neuronal differentiation in a dose-dependent fashion in nerve growth factor (NGF)-stimulated PC12 cells. Cocaine binds with high affinity to several neurotransmitter transporters, resulting in elevated neurotransmitter levels in nerve endings. To determine if cocaine inhibits neurite outgrowth through the effects of these neurotransmitters, we applied dopamine, norepinephrine, serotonin, and acetylcholine to NGF-induced PC12 cells. Dopamine was the only neurotransmitter to inhibit neurite outgrowth significantly in a dose-dependent pattern without affecting cell viability. Norepinephrine and acetylcholine did not affect neurite outgrowth, while serotonin enhanced it. Furthermore, GBR 12909, a potent dopamine transporter (DAT) inhibitor, yielded similar effects. We then showed PC12 cells express D(1) and D(2) receptors and DAT proteins. Dopamine uptake measured over time was significantly blocked by cocaine and GBR 12909 which may result in elevated extracellular dopamine. The role of dopamine receptors in PC12 differentiation was further examined by using D(1) and D(2) specific receptor agonists. Only the D(1) agonist, SKF-38393, had a significant dose-dependent inhibitory effect. In addition, a D(1) antagonist produced significant recovery of neurite outgrowth in cocaine-treated cells. These findings suggest that cocaine inhibitory effects on neuronal differentiation are mediated through its binding to the dopamine transporter, resulting in increased dopamine level in the synapses. Subsequently, up regulation of D(1) receptors alters NGF signaling pathways.

Animals↗
PubMed2000

Enlarged parietal foramina: association with cerebral venous and cortical anomalies.

OBJECTIVE: To evaluate a series of patients with enlarged parietal foramina for associated brain anomalies. BACKGROUND: Enlarged parietal foramina are usually considered a benign calvarial defect. METHODS: Ten patients with enlarged parietal foramina were identified. Seven patients were evaluated with neuroimaging: two by cranial CT and five by CT and/or MRI. Three patients who underwent MRI also underwent MR angiography or MR venography. RESULTS: Six of seven patients had cranial imaging showing a persistent falcine venous sinus. Three of six patients had variations of occipital cortical infolding. One patient had focal encephalomalacia in close proximity to the persistent falcine venous sinus and one had a previously undiagnosed atretic occipital encephalocele. CONCLUSION: This constellation of findings suggests that aberrant vascular evolution during fetal development may affect cerebrovascular, brain, or skull development. Individuals with enlarged parietal foramina (>5 mm) warrant imaging of underlying brain parenchyma and vasculature.

Adult↗
PubMed2000

Cocaine inhibition of neuronal differentiation in NGF-induced PC12 cells is independent of ras signaling.

In utero exposure to cocaine may result in altered neuronal development. Our previous studies demonstrated cocaine inhibits neurite outgrowth in NGF-induced PC12 cells through dopamine, by activation of D1 receptors. This study examined where cocaine interferes in the NGF signaling cascade. GSrasl cells that inducibly express activated forms of Ras upon treatment with dexamethasone were used. Morphological differentiation was quantified by counting cells bearing neurite-like processes after 72 h exposure to either dexamethasone or NGF alone, or with cocaine, dopamine or SKF-38393. Cocaine, dopamine, and the D1 agonist inhibited neurite-like process outgrowth in both dexamethasone and NGF-induced GSras1 cells. GAP-43 expression, used as a measure for biochemical differentiation was severely diminished in NGF and dexamethasone-induced GSras1 cells treated with cocaine. These results suggest that cocaine, dopamine and activation of D1 receptors affect the NGF signaling downstream, independent of ras expression, leading to altered neuronal differentiation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Genetics of Rett syndrome: properties of the newly discovered gene and pathobiology of the disorder.

The recent identification of mutations in the gene methyl-Cpg-binding protein-2 (MECP2) in girls with Rett syndrome (RS) has firmly established the molecular genetic basis of this unique, X-linked, dominant disorder and provides a dramatic conclusion to an intensive, decade-long search. This finding has ramifications far beyond establishing the gene for RS. Recent data indicate that the clinical phenotypes for MECP2 mutations range from mild disability in the mother of a girl with RS to rapidly progressive encephalopathy in her brother. Further, the pathobiology of MECP2 could be a prototype for other disorders of neurodevelopment. MECP2 encodes a methyl-CpG-binding protein (MeCP2), which is critical for transcriptional silencing of an as yet unknown number and type of genes responsible for the pathobiology of RS. As such, this discovery opens up completely new vistas as to fundamental neurobiologic processes, to disease mechanisms in the neurodevelopmental disabilities, and to potential new therapeutic strategies for RS and related disorders.

Child↗
PubMed2000

Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes.

We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease-causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.

DNA Mutational Analysis↗
PubMed2000

Decreased cerebrospinal fluid levels of beta-phenylethylamine in patients with Rett syndrome.

To clarify the mechanism of brain impairment in Rett syndrome, we measured the cerebrospinal fluid levels of beta-phenylethylamine (PEA) in 17 patients with Rett syndrome. Findings were compared with those obtained in age-matched controls and diseased controls. The cerebrospinal fluid level of PEA was significantly lower in patients with Rett syndrome than in the controls (31% of control values). The alteration in the cerebrospinal fluid level of PEA may reflect dopamine system impairment in Rett syndrome.

Adult↗
PubMed1999

Paul Dyken Lecture of the Southern Pediatric Neurology Society. Inherited neurodegenerative disease: the evolution of our thinking.

The past 3 decades have witnessed impressive progress in our understanding of inherited neurometabolic diseases, promoted by the rapid development and application of molecular genetic strategies. Such progress has required the juxtaposition of clinical evaluations and basic science techniques. The central role of careful and complete assessment of affected children cannot be overemphasized and in no way has been diminished by technologic advances. Indeed, enhanced clinical and laboratory evaluations have led to important conceptual advances. Molecular genetics has elucidated those disorders with known metabolic defects through functional cloning and explained the variability of disease expression based on specific mutational events. Alternatively, positional cloning has identified molecular defects for those disorders with clear phenotypic patterns, but lacking a defined metabolic abnormality. Regarding heterogeneous expression, disorders with clearly different phenotypes can arise from different mutations within the same gene. The multiple variants of beta-hexosaminidase deficiency (Tay-Sachs disease) are, arguably, the best examples. Conversely, disorders with similar phenotypes are explainable by quite different mutational events. In addition, the identification of specific diseases exhibiting both biochemical abnormalities and disturbed organogenesis has blurred conventional dogma regarding separation of genetic disorders into strict metabolic and structural categories. Disorders of peroxisomal function and the neuronal ceroid lipofuscinoses are prototypes for the points noted above and raise important issues regarding our approaches to children with these disorders. These issues include a high index of suspicion for an inherited neurometabolic disease and an open mind to possible interrelations with other known and seemingly dissimilar conditions.

Child↗
PubMed1999

Rett syndrome: 1H spectroscopic imaging at 4.1 Tesla.

Rett syndrome, a neurodevelopmental disorder predominantly affecting girls, is characterized by regression of psychomotor development, communication dysfunction, and hand stereotypies. Brain morphologic studies demonstrate increased neuronal packing density and reduced dendritic arborizations, suggesting an arrest or interruption of normal maturation. Numerous neurotransmitter systems have been implicated. Among these, cerebrospinal fluid glutamate levels are elevated and glutamate receptors, particularly in putamen, are reduced. Therefore, 1H spectroscopy at 4.1 Tesla was used to evaluate glutamate, creatine, and N-acetylaspartate in six girls with Rett syndrome and four normal sibling controls. The ratio of creatine to N-acetylaspartate was significantly elevated in white matter, primarily reflecting reduced N-acetylaspartate levels, and normal in gray matter. The glutamate to N-acetylaspartate ratio was elevated in gray matter and normal in white matter. These findings are consistent with previous neuropathologic and neurochemical findings and indicate the feasibility of imaging these metabolites in vivo.

Aspartic Acid↗