Genetic Mapping to 10q23.3-q24.2, in a Large Italian Pedigree, of a New Syndrome Showing Bilateral Cataracts, Gastroesophageal Reflux, and Spastic Paraparesis with Amyotrophy

Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Largo G. Gaslini n. 5, 16148 Genova Quarto, Italy.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/1999; 64(2):586-93. DOI: 10.1086/302241
Source: PubMed


We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.

Download full-text


Available from: Roberto Cusano, Oct 06, 2015
19 Reads
  • Source
    • "As a result, genetic analysis of families with suspected hereditary GOR has been difficult (Katz, 1998). As yet, two forms of dominantly inherited GOR have been identified: GOR with spastic paraparesis, amyotrophy and cataracts linked to chromosome 10q23–q24 (Seri et al., 1999), and a severe paediatric form linked to chromosome 13q14 (Hu et al., 2000). However, none of the previously published GOR families has had sensory neuropathy or cough. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals provided clinical information and blood for genetic analysis. Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex). Other features included throat clearing, hoarse voice, cough syncope and sensorineural hearing loss. Neurophysiological and pathological studies demonstrated a sensory axonal neuropathy. Gastric emptying studies were normal, and autonomic function and sweat tests were either normal or showed distal hypohidrosis. Cough was likely to be due to a combination of denervation hypersensitivity of the upper airways and oesophagus, and prominent GOR. Most affected individuals were shown on 24 h ambulatory oesophageal pH monitoring to have multiple episodes of GOR, closely temporally associated with coughing. Hoarse voice was probably attributable to acid-induced laryngeal damage, and there was no evidence of vocal cord palsy. No other cause for cough was found on most respiratory or otorhinological studies. Linkage to chromosome 3p22-p24 has been found in both families, with no evidence of linkage to loci for known HSN I, autosomal dominant hereditary motor and sensory neuropathy, hereditary GOR or triple A syndrome. These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract.
    Brain 01/2006; 128(Pt 12):2797-810. DOI:10.1093/brain/awh653 · 9.20 Impact Factor
  • Source
    • "We also directly sequenced the HSPB1 gene for 7q11 and the HSPB8 for 12q24 loci. Moreover, since it has been reported that families with complicated autosomal dominant hereditary spastic paraplegia (ADHSP) may present with upper and lower motor neuron dysfunction [5] [10] [11], we performed the linkage analysis to all the known loci for ADHSP to rule out the possibility that our family was affected by ADHSP complicated by peroneal muscular atrophy. Finally a molecular analysis for mutations in Super Oxide Dismutase (SOD1) gene was also performed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Distal hereditary motor neuronopathy is a genetically and clinically heterogeneous disorder. To date, five loci, and their relative genes, have been mapped on chromosomes 7p14, 7q11, 9q34, 11q12 and 12q24, respectively. We describe an Italian family with autosomal dominant distal HMN starting at around 30 years of age with weakness and atrophy of distal leg muscles and pyramidal features. We performed genetic linkage analysis on chromosomes 7p14, 9q34, 11q12 and 12q24. Moreover we sequenced the genes mapped to 7q11 and 12q24. Negative LOD scores excluded linkage to 7p14, 9q34, and 11q12 chromosomes in our family. No mutations were found in genes mapped to 7q11 and 12q24. In addition, because of pyramidal features, we performed the linkage analysis to all the known loci for autosomal dominant hereditary spastic paraparesis. The analysis was negative thus excluding a complicated form of autosomal dominant hereditary spastic paraparesis. These data further confirm a genetic heterogeneity within inherited motor neuronopathy.
    Neuromuscular Disorders 12/2004; 14(11):705-10. DOI:10.1016/j.nmd.2004.07.004 · 2.64 Impact Factor
  • Source
    • "Autosomal dominant inheritance was assumed, with 95% penetrance by the age of 35 years. A disease allele frequency of 0.001 and a phenocopy rate of 0.001 were assumed (Seri et al. 1999). Male and female recombination rates were considered equal. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hereditary sensory neuropathy type I (HSN I) is a group of dominantly inherited degenerative disorders of peripheral nerve in which sensory features are more prominent than motor involvement. We have described a new form of HSN I that is associated with cough and gastroesophageal reflux. To map the chromosomal location of the gene causing the disorder, a 10-cM genome screen was undertaken in a large Australian family. Two-point analysis showed linkage to chromosome 3p22-p24 (Zmax=3.51 at recombination fraction (theta) 0.0 for marker D3S2338). A second family with a similar phenotype shares a different disease haplotype but segregates at the same locus. Extended haplotype analysis has refined the region to a 3.42-cM interval, flanked by markers D3S2336 and D3S1266.
    The American Journal of Human Genetics 10/2003; 73(3):632-7. DOI:10.1086/377591 · 10.93 Impact Factor
Show more