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Genetic identity of Marinesco–Sjögren/myoglobinuria and CCFDN syndromes

From the Neuromuscular Unit (Drs. Merlini and Talim), Istituto Ortopedico Rizzoli, Bologna, Italy; Centre for Human Genetics, Edith Cowan University (Drs. Angelicheva and Kalaydjieva, and R. Gooding), Western Australian Institute for Medical Research (Dr. Kalaydjieva), Perth, Australia; Genzentrum (Dr. Lochmüller) and Friedrich-Baur Institut (Drs. Lochmüller, Müller–Felber, and Walter), Ludwig-Maximilians-Universität, München, Germany; and Department of Psychiatry and Behavioral Sciences (Dr. Hallmayer), Stanford University School of Medicine, Palo Alto, CA.

Address correspondence and reprint requests to Dr. Luba Kalaydjieva, Center for Human Genetics, Edith Cowan University, Perth, WA 6027, Australia; e-mail: L.Kalaydjieva{at}ecu.edu.au

Objective and Background: To describe three Gypsy families with Marinesco–Sjögren syndrome (MSS), demyelinating neuropathy, and recurrent episodes of myoglobinuria in five of the six affected subjects. Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder.

Methods: Clinical studies were conducted and linkage and haplotype analyses were performed for the three families. A total of 16 individuals, including the 6 with MSS and 10 unaffected relatives, were genotyped for six polymorphic microsatellite markers from the CCFDN region on 18qter.

Results: Linkage analysis of markers in the 18qter region, where we previously had located the CCFDN gene, produced a lod score of 3.55, demonstrating colocalization of the gene responsible for MSS with demyelinating neuropathy and myoglobinuria with the CCFDN gene. Moreover, the patients with MSS shared the conserved marker haplotype found in CCFDN chromosomes.

Conclusions: These data suggest that Marinesco–Sjögren syndrome with peripheral neuropathy and myoglobinuria, and congenital cataracts facial dysmorphism neuropathy syndrome are genetically identical and are caused by a single founder mutation.

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