Hereditary paraganglioma (PGL) is characterized by the development of benign, vascularized tumors in the head and neck. The most common tumor site is the carotid body (CB), a chemoreceptive organ that senses oxygen levels in the blood. Analysis of families carrying the PGL1 gene, described here, revealed germ line mutations in the SDHD gene on chromosome 11q23. SDHD encodes a mitochondrial respiratory chain protein-the small subunit of cytochrome b in succinate-ubiquinone oxidoreductase (cybS). In contrast to expectations based on the inheritance pattern of PGL, the SDHD gene showed no evidence of imprinting. These findings indicate that mitochondria play an important role in the pathogenesis of certain tumors and that cybS plays a role in normal CB physiology.

Objectives To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identified potential endpoints for future treatment trials. Study design Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric MRI, respectively. Liver and spleen volumes, CSF and urine biomarker levels were measured. Results Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing form of MPS IIIA (RP), and 5, a more slowly progressing form (SP). Children with RP plateaued in development by 30 months, followed by rapid regression after 40 to 50 months. Cognitive developmental quotients (DQ) in patients with RP showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with SP had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and CSF and urine HS levels were elevated and relatively constant over time. Conclusions DQ and cortical gray matter volumes are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy.

We present a high resolution radiation hybrid map of human chromosome 11 using 506 sequence tagged sites (STSs) scored on a panel of 86 radiation hybrids. The 506 STSs fall into 299 unique positions (average resolution of about 480 kilobases (kb)) that span the whole chromosome. A subset of 260 STSs (143 positions) form a framework map that has a resolution of approximately 1 megabase between adjacent positions and is ordered with odds of at least 1,000:1. The centromere was clearly defined with pericentric markers unambiguously assigned to the short or long arm. The map contains most genes (125) and expressed sequence tags (26) currently assigned to chromosome 11 and more than half of the STSs are polymorphic microsatellite loci. These markers and the map can be used for high resolution physical and genetic mapping.

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