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B T Darras

Publications and source records attributed to B T Darras.

At least 19 recordsLinked to original sources
PubMed2006

A novel mutation in two families with limb-girdle muscular dystrophy type 2C.

The authors present three unrelated North American patients with limb-girdle muscular dystrophy type 2C. Muscle biopsies suggested gamma-sarcoglycan deficiencies for all three patients. Patients 1 and 2 had a novel homozygous E263K missense mutation on exon 8 of gamma-sarcoglycan (SGCG). Patient 3 had del521T on her maternal allele and an exon 6 deletion on her paternal allele. Patients 1 and 2 are of Puerto Rican ancestry, suggesting the presence of a founder mutation in that population.

Adolescent↗
PubMed2006

Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease).

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Two of the patients had prolonged evaluations before the diagnosis was made. All patients had Gowers signs and two had pes planus. In patients with proximal muscle weakness the presence of asymmetrical weakness, upper motor neuron signs, or both, may be compatible with spinal muscular atrophy type III. The diagnosis of spinal muscular atrophy should be considered when other possibilities have been excluded.

Brain↗
PubMed2003

XL PCR for the detection of large trinucleotide expansions in juvenile Huntington's disease.

Juvenile Huntington's disease (HD) becomes clinically manifest before 20 years of age. The diagnosis of HD is based on family history, characteristic clinical findings, and the detection of an expansion of a CAG polyglutamine tract in the Huntingtin gene. Juvenile HD is characterized by paternal anticipation and large CAG expansions that may be missed using routine molecular analysis. We have developed an easy, rapid, and reliable modified PCR method using XL (Extra Long) PCR that allowed us to diagnose one of the youngest children reported with juvenile HD. Without this innovation we would not have been able to demonstrate the large CAG expansion. This assay could become part of a standard protocol for HD testing in molecular diagnostic laboratories.

Age of Onset↗
PubMed2002

Primary gamma-sarcoglycanopathy (LGMD 2C): broadening of the mutational spectrum guided by the immunohistochemical profile.

An important step in the diagnostic evaluation of a patient with recessive limb-girdle muscular dystrophy is the immunohistochemical analysis of the components of the sarcoglycan complex in a muscle biopsy specimen. Even though a primary mutation in any of the four sarcoglycan genes (alpha-, beta-,gamma-, delta-sarcoglycan) may cause secondary deficiencies in all the other sarcoglycan proteins, more specific immunohistochemical patterns have emerged with the potential to guide and abbreviate the necessary molecular genetic investigations. In gamma-sarcoglycan mutations, the pattern consists of absent or prominently reduced gamma-sarcoglycan immunoreactivity in combination with reduced but detectable immunoreactivity for the other components, with preservation of delta-sarcoglycan. In five consecutive patients, this pattern was able to predict primary gamma-sarcoglycan mutations. Five different mutations were found, including a recurrent novel splice mutation, a large deletion of the entire gene and a novel missense mutation (Leu90Ser). The mutation Cys283Tyr, previously restricted to Gypsy populations was found in compound heterozygosity with del521T, common in north Africa. The variety of known and novel mutations found indicates that the immunohistochemical profile of gamma-sarcoglycan mutations is not restricted to a particular mutation or type of mutation, but rather is a general reflection of the effect of gamma-sarcoglycan mutations on the composition of the sarcoglycan complex. Complete immunohistochemical analysis with all available sarcoglycan antibodies, therefore, is a useful tool to guide the molecular genetic investigations that are necessary to arrive at the correct genetic diagnosis in a given case.

Adolescent↗
PubMed2001

Detection of mutations in the dystrophin gene via automated DHPLC screening and direct sequencing.

BACKGROUND: Currently molecular diagnostic laboratories focus only on the identification of large deletion and duplication mutations (spanning one exon or more) for Duchenne Muscular Dystrophy (DMD) yielding 65% of causative mutations. These mutations are detected by an existing set of multiplexed polymerase chain reaction (PCR) primer pairs. Due to the large size of the dystrophin gene (79 exons), finding point mutations (substitutions, deletions or insertions of one or several nucleotides) has been prohibitively expensive and laborious. The aim of this project was to develop an effective and convenient method of finding all, or most, mutations in the dystrophin gene with only a moderate increase in cost. RESULTS: Using denaturing high performance liquid chromatography (DHPLC) screening and direct sequencing, 86 PCR amplicons of genomic DNA from the dystrophin gene were screened for mutations in eight patients diagnosed with DMD who had tested negative for large DNA rearragements. Mutations likely to be disease-causative were found in six of the eight patients. All 86 amplicons from the two patients in whom no likely disease-causative mutations were found were completely sequenced and only polymorphisms were found. CONCLUSIONS: We have shown that it is now feasible for clinical laboratories to begin testing for both point mutations and large deletions/duplications in the dystrophin gene. The detection rate will rise from 65% to greater than 92% with only a moderate increase in cost.

Automation↗
PubMed2001

Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X-linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function.

Adult↗
PubMed2001

Exclusion of growth factor gene mutations as a common cause of Sotos syndrome.

Sotos syndrome is characterized by somatic overgrowth, i.e., macrocephaly and tall stature. Because the cause and pathogenesis of Sotos syndrome remain unknown, we selected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) as possible genes mutated in Sotos syndrome. In seven patients with the classic phenotype, we excluded mutations in these growth factor genes. It is possible that these three genes are not involved in the cause of Sotos syndrome, or alternatively, mutations could not be identified in the small number of patients studied.

Abnormalities, Multiple↗
PubMed2001

Magnetic resonance spectroscopy and magnetic resonance imaging findings in Krabbe's disease.

Two twins with late infantile globoid cell leukodystrophy of Krabbe's disease were studied with conventional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy. Brain MRI demonstrated brain atrophy with extensive bilateral symmetric abnormal T2 signal in the posterior periventricular white matter, parietal lobes, corona radiata, centrum semiovale, and splenium of the corpus callosum. Magnetic resonance imaging-guided proton magnetic resonance spectroscopy revealed prominent peaks from choline-containing compounds, total creatine, and inositols. The N-acetylaspartate peak was markedly reduced, and the choline-to-N-acetylaspartate ratio was abnormally high; in one of the twins, lactic acid was also detected. The constellation of magnetic resonance spectroscopy findings is indicative of extensive demyelination, gliosis, and loss of axons in the involved white matter; the latter two events occur in the later stages of globoid cell leukodystrophy. In conjunction with brain MRI, these magnetic resonance spectroscopy findings may alert clinicians to the possibility of leukodystrophy in children with progressive encephalopathy.

Aspartic Acid↗
PubMed2000

A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy.

Multiple epiphyseal dysplasia (MED) is a degenerative cartilage condition shown in some cases to be caused by mutations in genes encoding cartilage oligomeric matrix protein or type IX collagen. We studied a family with autosomal dominant MED affecting predominantly the knee joints and a mild proximal myopathy. Genetic linkage to the COL9A3 locus on chromosome 20q13.3 was established with a peak log(10) odds ratio for linkage score of 3.87 for markers D20S93 and D20S164. Reverse transcription-PCR performed on the muscle biopsy revealed aberrant mRNA lacking exon 3, which predicted a protein lacking 12 amino acids from the COL3 domain of alpha3(IX) collagen. Direct sequencing of genomic DNA confirmed the presence of a splice acceptor mutation in intron 2 of the COL9A3 gene (intervening sequence 2, G-A, -1) only in affected family members. By electron microscopy, chondrocytes from epiphyseal cartilage exhibited dilated rough endoplasmic reticulum containing linear lamellae of alternating electron-dense and electron-lucent material, reflecting abnormal processing of mutant protein. Type IX collagen chains appeared normal in size and quantity but showed defective cross-linking by Western blotting. The novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene. Patients with MED and a waddling gait but minimal radiographic hip involvement should be evaluated for a primary myopathy and a mutation in type IX collagen.

Cartilage↗
PubMed2000

Acute care pediatric electromyography.

The recognition of uncommon pediatric motor unit disorders or unusual clinical presentations of common illnesses, such as Guillain-Barré syndrome (GBS), have increased the need for electromyography (EMG) in childhood critical care units. There are two different clinical sets, one appropriate to newborns and infants and the other to older children. Some illnesses that present as an acute floppy infant are not found in the differential diagnosis of motor unit disorders in the older child or adult. These include spinal muscular atrophy, postvaccine poliomyelitis, intrauterine GBS, infantile botulism, and severe myopathies, such as myotonia dystrophy, and some glycogen storage diseases. An appreciation of the neurophysiological maturational norms is essential to an effective pediatric EMG consultation for children ages 0-3 years. Additionally, the neuromuscular complications of extended intubation and sepsis in children are gaining broader recognition. An increased dialogue between clinical neurophysiologists and pediatric neurologists and intensivists in both neonatal and pediatric intensive care units is essential.

Acute Disease↗
PubMed2000

Diagnosis of pediatric neuromuscular disorders in the era of DNA analysis.

Extraordinary breakthroughs in the molecular pathogenesis of muscle and nerve disease have resulted in an evolving genetic classification of neuromuscular disorders and the development of new diagnostic methods. This remarkable progress has introduced new genetic tests and has changed the indications for use of certain invasive diagnostic procedures in the evaluation of children with presumed disorders of the motor unit. In this review, we present the current diagnostic approach to the more common neuromuscular diseases of infancy and childhood and define the diagnostic role of muscle biopsy and pediatric electromyography/nerve conduction studies in the era of genetic analysis.

Blotting, Southern↗
PubMed2000

Metabolic myopathies: a clinical approach; part II.

Major recent advances in the field of metabolic myopathies have helped delineate the genetic and biochemical basis of these disorders. This progress has also resulted in the development of new diagnostic and therapeutic methodologies. In this second part, we present an updated review of the main nonlysosomal and lysosomal glycogenoses and lipid metabolism defects that manifest with signs of transient or permanent muscle dysfunction. Our intent is to increase the pediatric neurologist's familiarity with these conditions and thus improve decision making in the areas of diagnosis and treatment.

Glycogen Storage Disease↗
PubMed2000

Metabolic myopathies: a clinical approach; part I.

Children and adults with metabolic myopathies have underlying deficiencies of energy production, which may result in dysfunction of muscle or other energy-dependent tissues, or both. Patients with disorders of glycogen, lipid, or mitochondrial metabolism in muscle may present with dynamic findings (i.e., exercise intolerance, reversible weakness, and myoglobinuria) or progressive muscle weakness, or both. In this first part of the review, we present a brief description of energy metabolism in muscle, a simplified overview of the clinical and laboratory evaluation of the patient with suspected metabolic myopathy, and a diagnostic algorithm aimed at predicting the nature of the underlying biochemical abnormality. The goal is to simplify a complex field of neuromuscular disease and thus lead to early recognition and treatment of these disorders.

Adult↗
PubMed1998

Exclusion of the gastrin-releasing peptide receptor (GRPR) locus as a candidate gene for Rett syndrome.

The gene for the gastrin-releasing peptide receptor (GRPR) has been mapped to a candidate region for Rett syndrome (RTT) on the short arm of the X chromosome. The recent report of a translocation that disrupted the gene in an individual with mental retardation and autistic behavior prompted us to examine GRPR as a possible locus for RTT. Genomic polymerase chain reaction amplification of exons followed by single-strand conformation analysis screening in 25 unrelated RTT-affected individuals and by direct sequencing in 12 others has failed to detect any mutation. No gross structural rearrangements were found by Southern analysis of DNA from six unrelated RTT-affected individuals. A high-frequency biallelic polymorphism caused by two single nucleotide substitutions in exon 2 was discovered. The allele frequencies were identical in the RTT population as compared to 100 normal control X chromosomes. This polymorphism will enable future evaluation of the GRPR locus as a candidate for other X-linked mental retardation or neurobehavioral syndromes.

Blotting, Southern↗
PubMed1997

Neuromuscular disorders in the newborn.

The main manifestations of neuromuscular disease in the newborn period are hypotonia and weakness. Infants with severe hypotonia but only marginal weakness usually do not have a disorder of the lower motor unit. These infants may have genetic conditions, metabolic disturbances, congenital heart disease, hypothyroidism, sepsis, or other systemic disorders. Early on, neonates with central nervous system pathology may present with profound hypotonia, decreased reflexes, and moderate to severe but transient weakness. However, they also tend to have seizures, obtundation, cranial nerve signs, or history of perinatal asphyxia.

Humans↗
PubMed1996

Clonal analysis of meningiomas.

Meningiomas are primary brain tumors arising from meningothelial cells. They usually grow slowly and are surgically easy to separate from the brain. A recent clonal analysis of meningiomas, using methylation-sensitive restriction fragment length polymorphisms, suggested a monoclonal origin. Using the same technique but with a highly informative X chromosome probe (M27 beta), we found that 17 (85%) of the 20 meningiomas analyzed were informative. Of the 17 informative tumors, 8 (47%) were monoclonal, 3 (18%) had loss of heterozygosity on the X chromosome, and, unexpectedly, 6 (35%) had a polyclonal pattern. Samples from two areas of one tumor showed a monoclonal pattern and loss of heterozygosity, respectively, on the X chromosome. A review of the histopathological and radiological features of the 17 informative tumors did not help to distinguish the clonal from the polyclonal tumors. We conclude that meningiomas are heterogeneous in clonal composition.

Adult↗