Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis

Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation1−3. The genetic basis for CIPA is unknown. Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons4. Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF5,6, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals7. We therefore considered the human TRKA homologue as a candidate for the CIPA gene. The mRNA and genomic DNA encoding TRKA were analysed in three unrelated CIPA patients who had consanguineous parents. We detected a deletion-, splice- and missense-muta-tion in the tyrosine kinase domain in these three patients. Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF−TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans. These results also implicate genes encoding other TRK and neurotrophin family members as candidates for developmental defect(s) of the nervous system

Chorioretinal lacuna in the amniotic band syndrome.

The malformations in the amniotic band syndrome (ABS) are due to entrapment of fetal parts by fibrous band in the amniotic sac. Limbs are most commonly affected followed by craniofacial defects in one third of patients. Ocular defects include corneal leukomas and lid colobomas often contiguous with facial clefts, strabismus, hypertelorism, and microphthalmos. Unilateral chorioretinal defects or lacunae are rare findings in the ABS. We report a female infant with such a lacunar defect along with central nervous abnormalities, and discuss the differential diagnosis and the embryopathic implications

A novel X–linked gene, DDP, shows mutations in families with deafness (DFN–1), dystonia, mental deficiency and blindness

In 1960, progressive sensorineural deafness (McKu-sick 304700, DFN-1) was shown to be X-linked based on a description of a large Norwegian pedigree1 . More recently, it was shown that this original DFN-1 family represented a new type of recessive neurodegenerative syndrome characterized by postlingual progressive sensorineural deafness as the first presenting symptom in early childhood, followed by progressive dystonia, spasticity, dysphagia, mental deterioration, paranoia and cortical blindness. This new disorder, termed Mohr-Tranebjasrg syndrome (referred to here as DFN-1/MTS) was mapped to the Xq21.3–Xq22 region2. Using positional information from a patient with a 21-kb deletion in chromosome Xq22 and sensorineural deafness along with dystonia, we characterized a novel transcript lying within the deletion as a candidate for this complex syndrome. We now report small deletions in this candidate gene in the original DFN-1/MTS family, and in a family with deafness, dystonia and mental deficiency but not blindness. This gene, named DDP (deaf-ness/dystonia peptide), shows high levels of expression in fetal and adult brain. The DDP protein demonstrates striking similarity to a predicted Schizosaccharomyces pombe protein of no known function. Thus, is it likely that the DDP gene encodes an evolutionarily conserved novel polypeptide necessary for normal human neurological development