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Biomedical subjects

M D Ludman

Publications and source records attributed to M D Ludman.

At least 19 recordsLinked to original sources
PubMed1997

Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families.

We describe a large Acadian kindred including 8 Alstrom Syndrome (AS) patients, with an age range of 4 to 26 at the time of clinical assessment. The affected subjects come from 5 nuclear families within this kindred. The phenotype includes early childhood retinopathy, progressive sensorineural hearing loss, truncal obesity, and acanthosis nigricans. In addition, hyperinsulinemia and hypertriglyceridemia with normal cholesterol levels were observed in most affected individuals tested. Non-insulin dependent diabetes mellitus and growth retardation appear to be age-related manifestations that occur post-adolescence. Younger affected children are not overtly hyperglycemic and are normal or above average height for age. Although the AS patients in kindred 1 presumably carry the same mutation, many manifestations of the disease are variable. For example, of the 8 children in the Acadian kindred, 4 have scoliosis, 2 have had infantile cardiomyopathy, 2 are hypothyroid, 1 has had hepatic dysfunction and is hypertensive, and 4 have developed asthma. Seven subjects described in this kindred exhibit developmental delay. One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested. The clinical data from this large Acadian kindred, together with information obtained from 4 additional AS patients in 3 unrelated kindreds, confirm and extend clinical observations previously described. In addition, the Acadian kindred with multiple affected individuals, probably arising from a common founder, should allow for identification of the chromosomal localization of a gene causing AS.

Abnormalities, Multiple↗
PubMed1997

Metachromatic leucodystrophy in three families from Nova Scotia, Canada: a recurring mutation in the arylsulphatase A gene.

Metachromatic leucodystrophy (MLD) is a lysosomal storage disease resulting from a deficiency of arylsulphatase A. We have identified a child with infantile onset MLD who is homozygous for an A212V mutation, a mutation previously reported but not further characterised. We have introduced this mutation into an arylsulphatase A expression vector by site directed mutagenesis. Transient expression of this mutant plasmid in COS cells yields very low levels of arylsulphatase A activity consistent with the patient's phenotype. The arylsulphatase A pseudodeficiency also segregates in this family causing difficulty in interpreting enzyme levels in the absence of DNA data. Two other patients from the same province, also carrying the A212V allele, have juvenile and adult onset MLD and are heterozygous for P426L ("A" allele) and I179S alleles respectively, known late onset alleles.

Adult↗
PubMed1996

A case-control study of fluctuating dermatoglyphic asymmetry as a risk marker for developmental delay.

In traits which are normally bilaterally symmetrical, asymmetries may arise as a result of genomic or environmental stress. Such asymmetries are called fluctuating asymmetry. Symmetry is known to be decreased in a variety of disorders of developmental origin, and thus could potentially serve as a risk marker for disorders with a developmental component. We examined this idea by conducting a case-control study of 49 developmentally delayed children and 51 controls. Using two dermatoglyphic characters as a measure of symmetry (finger print concordance and A-B triradial ridge count difference), we found odds ratios of 2.32 (95% CI 0.65-3.17) and 2.11 (95% CI 0.57-3.27); depending on which character was measured. These results suggest that fluctuating asymmetry may have potential as a risk marker for developmental disorders, and that this area of research warrants further research.

Case-Control Studies↗
PubMed1996

Fluctuating asymmetry and disorders of developmental origin.

Environmental and/or genetic stresses may cause a breakdown in developmental homeostasis, resulting in increased bilateral asymmetry of morphological traits. The degree of these deviations (termed "fluctuating asymmetry") is thought to correlate with the severity of the stress. If these stresses also play a role in the appearance of developmental disorders, then increased morphological asymmetry may serve as a risk marker for disorders of developmental origin. This would be possible if 1) the environmental stress that caused a breakdown in developmental stability also contributed to the appearance of the disorder, and/or 2) the genetic predisposition (liability) to the disorder and increased susceptibility to fluctuating asymmetry have a common cause. Although a number of authors have reported associations between increased fluctuating asymmetry and disorders of presumed developmental origin, the usefulness of fluctuating asymmetry as a risk marker has not been established. One obstacle to this assessment is the lack of odds ratios reported by previous authors.

Child↗
PubMed1995

Successful treatment of painful crises of Fabry disease with low dose morphine.

Fabry disease is an X-linked disorder characterized in childhood by angiokeratoma, corneal opacities, and pain. At age 7 years our patient began experiencing an intermittent intense "burning" sensation within his feet and hands (acroparesthesias). Treatment with aspirin, acetaminophen, acetominophen with codeine, and phenytoin was unsuccessful. Carbamazepine and phenytoin reduced the frequency and duration of painful crises to 3-4 times annually. A treatment plan was developed consisting of a low-dose morphine infusion with increasing dosage until pain was relieved. Over the subsequent 28 months, we have had experienced treating 7 crises with morphine given as 0.06 mg/kg IV push, followed by a continuous infusion of 0.02 mg/kg/hr with amitriptyline 0.25 mg/kg at bedtime. Pain control is immediate, with the infusion gradually tapered after 24 hours.

Amitriptyline↗
PubMed1994

Fabry disease: twenty-three mutations including sense and antisense CpG alterations and identification of a deletional hot-spot in the alpha-galactosidase A gene.

Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from mutations in the alpha-galactosidase A gene at Xq22.1. To determine the nature and frequency of the molecular lesions causing the classical and milder variant Fabry phenotypes, and for precise carrier detection in Fabry families, the alpha-galactosidase A coding and flanking intronic sequences from 23 unrelated Fabry hemizygotes were analyzed. In patients with the classic phenotype, 16 new missense and nonsense mutations and four small exonic gene rearrangements were identified: C52S, C56F, E59K, L89R, R100K, R112H, L131P, A143P, G144V, C172Y, D244N, N272K, A288D, W81X, Q99X, Q157X, R301X, 25del1, 333del18, 358del6, and 1020del1. The R112H mutation at a CpG dinucleotide resulted in residual activity and a mild variant phenotype while the R112C lesion caused the classic disease manifestations, defining a genotype/phenotype correlation for sense and antisense mutations at the same CpG dinucleotide. In addition, two complex rearrangements, each involving two mutational events, occurred in classic hemizygotes. Both rearrangements resulted in missense mutations that did not change the reading frame. Notably, three of the deletions occurred within 11 codons in exon 2, thereby defining a 'hot-spot' for deletions. These studies revealed that most mutations in the alpha-galactosidase A gene causing Fabry disease were private, that codons 111-122 defined a deletion hot-spot, and that different substitutions of the same codon resulted in markedly different disease phenotypes.

Amino Acid Sequence↗
PubMed1993

Schimke immuno-osseous dysplasia: case report and review.

We report on a patient with Schimke immunoosseous dysplasia, an autosomal recessive disorder, and review nine patients from the literature. Manifestations include spondyloepiphyseal dysplasia, lymphopenia, signs of defective cellular immunity, and progressive renal disease. This is the first patient known to have the additional findings of thrombocytopenia and microdontia.

Child, Preschool↗
PubMed1993

Hypomandibular faciocranial dysostosis: another case and review.

We report on a third case of hypomandibular faciocranial dysostosis and review the literature. Manifestations include craniosynostosis, prominent eyes, deficient midface and zygomatic arches, short nose with anteverted nares, protruding lower face, minute oral aperture, persistent buccopharyngeal membrane, and severe mandibular hypoplasia. In contrast to coronal synostosis found in the 2 earlier cases, our patient had multiple sutural synostosis. The 2 affected sibs reported earlier suggest the possibility of autosomal recessive inheritance. However, gonadal mosaicism for a dominant mutation or an undetected microdeletion must also be considered at this early stage in the delineation of this disorder.

Abnormalities, Multiple↗
PubMed1993

Longitudinal study of the early electroretinographic changes in Alström's syndrome.

We obtained serial electroretinograms in four patients aged between 6 months and 5 years with Alström's syndrome and studied the early stages of the severe retinopathy that is characteristic of that disease. The weak electroretinographic signals found at age 6 months demonstrate a severe early cone dysfunction; one year later the cone activity is undetectable. The rod component of the electroretinogram is initially normal but can rapidly deteriorate to become undetectable as early as 5 years of age. These unusual electroretinographic findings are pathognomonic of Alström's syndrome and different from other cone-rod dystrophies or other syndromes with similar phenotypes such as Bardet-Biedl, Laurence-Moon, and Cohen syndromes.

Child, Preschool↗
PubMed1990

Mesomelic dysplasia with absence of fibulae and hexadactyly: Nievergelt syndrome or new syndrome?

Mesomelic dysplasia is a form of short-limb dwarfism characterized by disproportionate shortness of the middle segment of all limbs. Included in this category of skeletal disorders is the Nievergelt syndrome, which typically manifests a rhomboidal shape of the tibiae and fibulae, an unusual foot deformity, radioulnar synostosis, and dysplasia of the elbow and knee joints. We describe a patient with mesomelic dysplasia with findings suggestive of the Nievergelt syndrome and with absence of fibulae and hexadactyly.

Abnormalities, Multiple↗
PubMed1989

Resting energy expenditure in Gaucher's disease type 1: effect of Gaucher's cell burden on energy requirements.

The resting energy expenditure (REE; kcal/d) of 25 patients with Gaucher's disease type 1 was determined by indirect calorimetry. The average observed REE for the group was approximately 44% greater (P less than .01) than that predicted (predicted REE) for these patient's age, sex, height, and weight. The increased caloric requirements of these patients was manifested by a height-for-age less than or equal to the fifth percentile in seven of nine growing children and a muscle mass of less than the fifth percentile in 15 of 19 patients studied. The excess REE (observed REE--predicted REE) for individual Gaucher's disease type 1 patients was directly related to their liver volume as estimated from radionuclide scans and to the mass of the spleen as measured at splenectomy. The relationship between spleen mass and excess REE was demonstrated by an average 22.0% decrease in REE following splenectomy in five patients. Based on these data, the metabolic rate of the splenic tissue removed from the patients was calculated to be 96.8 kcal/d/kg, about twofold to threefold less than that of normal splenic tissue. These findings indicate that the elevated REE observed in these patients resulted from the large mass of Gaucher's cells, which although individually hypometabolic, were cumulatively an excessive metabolic burden. Furthermore, they suggest that indirect calorimetry may be a quantitative tool for measuring disease progression and the effect of therapeutic intervention in Gaucher's disease type 1.

Adolescent↗
PubMed1989

Gaucher disease: fate of the splenic remnant after partial splenectomy--a case of rapid enlargement.

In Gaucher disease, partial splenectomy has been suggested for alleviating the complications of splenomegaly as well as for avoiding the immunologic compromise and potential acceleration of bony and hepatic involvement that may follow total splenic resection. However, the fate of the splenic remnant has been reported rarely. A subtotal splenectomy (85%) was performed in a 19-month-old girl with rapidly progressing Gaucher disease and massive splenomegaly (12% of body weight). Within 3 months, the splenic remnant had increased four-fold in size. Previous reports indicated only three Gaucher patients had significant enlargement of the splenic remnant after partial splenectomy. These findings indicate that splenomegaly may recur rapidly in Gaucher disease following partial splenectomy.

Female↗