RESUMEN
X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.
Asunto(s)
Displasia Ectodérmica Hipohidrótica Autosómica Recesiva/tratamiento farmacológico , Ectodisplasinas/uso terapéutico , Animales , Perros , Displasia Ectodérmica Hipohidrótica Autosómica Recesiva/genética , Displasia Ectodérmica Hipohidrótica Autosómica Recesiva/patología , Ectodisplasinas/administración & dosificación , Femenino , Feto/diagnóstico por imagen , Pie , Edad Gestacional , Embarazo , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Sudoración , Resultado del Tratamiento , Ultrasonografía IntervencionalRESUMEN
CASE SERIES SUMMARY: The congenital midline defects of peritoneopericardial diaphragmatic hernia (PPDH) and omphalocele are believed to be related developmental defects, and have both been described in cats and dogs. This case series describes multiple cases of PPDH and omphalocele in related cats. The majority of cats affected with midline defects (PPDH or omphalocele) were male, consistent with previous reports of male overrepresentation. RELEVANCE AND NOVEL INFORMATION: This is the first report of a family of Persian cats affected by PPDH and/or omphalocele. Clinical findings and pedigree information are suggestive of an autosomal recessive mode of inheritance. However, other modes of inheritance cannot be ruled out owing to limited sample size. The findings in this family and previous reports of Persians affected by PPDH warrant further investigation. Based on this information, recommendations for breeding populations of Persians and long-haired cats should include thoracic radiographs to screen for PPDH until a DNA-based genetic test is available.
RESUMEN
Mucopolysaccharidoses are inherited metabolic disorders that result from a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans. Lysosomal glycosaminoglycan accumulation results in cell and organ dysfunction. This study characterized the phenotype and genotype of mucopolysaccharidosis VI in a Great Dane puppy with clinical signs of stunted growth, facial dysmorphia, skeletal deformities, corneal opacities, and increased respiratory sounds. Clinical and pathologic evaluations, urine glycosaminoglycan analyses, lysosomal enzyme assays, and ARSB sequencing were performed. The urine mucopolysaccharide spot test was strongly positive predominantly due to the accumulation of dermatan sulfate. Enzyme assays in leukocytes and tissues indicated a deficiency of arylsulfatase B (ARSB) activity. Histologic examination revealed cytoplasmic vacuoles in many tissues. Analysis of the exonic ARSB DNA sequences from the affected puppy compared to the published canine genome sequence revealed a homozygous nonsense mutation (c.295C>T) in exon 1, replacing glutamine with a premature stop codon (p.Gln99*), predicting no enzyme synthesis. A polymerase chain reaction-based restriction fragment length polymorphism test was established to assist with the clinical diagnosis and breeding of Great Danes. This genotyping test revealed that the clinically healthy parents and some other relatives of the puppy were heterozygous for the mutant allele, but all 200 clinically healthy dogs screened including 15 Great Danes were homozygous for the normal allele. This ARSB mutation is the fourth identified genetic variant causing canine mucopolysaccharidosis VI. Mucopolysaccharidosis VI is the first lysosomal storage disorder described in Great Danes but does not appear to be widespread in this breed.