Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15

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Abstract

Two separate disorders, autosomal dominant distal spinal muscular atrophy type V (dSMA-V) characterized by marked bilateral weakness in the hands and atrophy of thenar eminence and the first interosseous muscle, and Charcot-Marie-Tooth disease type 2D (CMT2D) characterized by sensory deficits in addition to the upper limb weakness and wasting, have been independently linked to chromosome 7p. We identified a multigenerational Mongolian kindred with 17 members affected with either dSMA-V or CMT2D and mapped both syndromes to the same region on chromosome 7p15. A maximum two-point lod score of 4.74 at recombination fraction zero was obtained with marker D7S474. Tight linkage without recombination was also detected with markers D7S526 and D7S632. A multipoint lod score of 6.07 suggested that the gene is located between markers D7S526 and D7S474. A single conserved haplotype was associated with dSMA-V and CMT2D. Based on informative recombination events, the disease locus was placed between markers D7S516 and D7S1514 within the 7p15 band. Data obtained from this study suggest that a single gene is responsible for both syndromes, dSMA-V and CMT2D, and extend our knowledge of the candidate region.

Introduction

Charcot-Marie-Tooth (CMT) disease is the most frequent type of motor and sensory neuropathy characterized by progressive distal muscle weakness and atrophy with skeletal deformity, diminished or absent deep tendon reflexes and impaired sensation. Based on clinical, electrophysiologic and neuropathologic data, CMT is divided into CMT type 1 (CMT1), a demyelinating peripheral neuropathy showing markedly decreased nerve conduction, CMT type 2 (CMT2), an axonal neuropathy, and distal spinal muscular atrophy (dSMA), a disease of anterior horn neurons 7, 10.

Recent advances in molecular genetics of hereditary neuropathies have helped to locate and characterize genes responsible for distinct types of disease and provide more reliable criteria for classification and diagnosis. CMT1A was mapped to chromosome 17p11.2-p12 and associated with a duplication of a 1.5 megabase DNA fragment that includes the peripheral myelin protein-22 (PMP22) gene [3]. Point mutations in the peripheral myelin protein zero (MPZ) gene on chromosome 1q22 are responsible for CMT type 1B [11]. Disease genes for the CMT2 were mapped to chromosomes 1p36-p35 (CMT2A), 3q13-q22 (CMT2B) and 7p (CMT2D) 1, 12, 17. Genetic linkage was also reported for autosomal dominant dSMA type V (dSMA-V) mapped to chromosome 7p [4], scapuloperoneal SMA localized at 12q24.1-q24.31 [13], and distal hereditary motor neuropathy type II (dSMA type II) mapped to 12q23-q24.1 [25].

The distal form of SMA with upper limb predominance studied in a family from Burgass, Bulgaria [4], and autosomal dominant Charcot-Marie-Tooth axonal neuropathy type 2D (CMT2D) characterized in a family from Iowa [12], had similar phenotypic features such as age of onset in the second or third decade of life, prominent thenar wasting with mild peroneal weakness and atrophy, and very slow progression. The essential difference between the two phenotypes was the presence of reduced sensation for touch, proprioception and vibration in the CMT2D patients and absence of sensory deficits in dSMA-V, except for a slightly reduced vibratory sense in 10% of the patients. Genetic linkage to chromosome 7p was suggested for both dSMA-V and CMT2D phenotypes 4, 12, but the proposed gene locations did not overlap, and the question whether a single gene on chromosome 7p is responsible for these variable phenotypes has not been resolved.

Section snippets

The affected kindred

We have identified a large Mongolian kindred originating from a rural region of Central Mongolia in which 11 members were diagnosed as dSMA-V and six had features of CMT2D. The complete pedigree included 74 persons in five generations (Fig. 1). Genetic studies were approved by Institutional Review Boards of the National Institutes of Health in Bethesda, Maryland, and the Mongolian National Institute of Health in Ulaanbaatar, Mongolia. After obtaining informed consent, 17 affected and 37

Results

To identify the location of the gene responsible for the autosomal dominant dSMA-V and CMT2D in the Mongolian kindred, we first analyzed candidate regions previously shown to harbor genes for phenotypically similar neuropathies. A total of 54 individuals, 17 of them affected, were included in the linkage study. Linkage to loci of CMT subtypes 1A (17p11.2-p12), 2A (1p36-p35) and 2B (3q13-q22), scapuloperoneal SMA (12q24.1-q24.31) and distal hereditary motor neuropathy type II (12q23-q24.1) was

Discussion

Initially, the autosomal dominant dSMA-V in a family from Bulgaria and the autosomal dominant CMT2D in a family from Iowa have been linked to two separate areas on chromosome 7p 4, 12. However, additional genetic studies of the Iowan CMT2D family [21]that became known after this work had been completed, support an overlap with the candidate region for the dSMA-V Bulgarian family. Affected members of the Mongolian kindred presented here had clinical and neurophysiologic features resembling

Acknowledgements

We are grateful to the members of this large kindred for cooperation and participation in this study; Dr Muhar and Mrs Bayambatsoo for support and help in conducting the initial phase of this work at the Mongolian National Institute of Health, Jim Tomlin for assistance with multipoint analysis, Dr Alejandro A. Schaffer for valuable suggestions, and Dr Rachel E. McGuire for sharing the physical mapping results.

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