Scapuloperoneal Syndrome, Neurogenic, Kaeser Type

A number sign (#) is used with this entry because of evidence that Kaiser-type neurogenic scapuloperoneal syndrome (SCPNK) is caused by heterozygous mutation in the DES gene (125660) on chromosome 2q35.

Clinical Features

Peroneal atrophy is accompanied by bilateral foot drop and talipes equinovarus. Following atrophy of the lower legs, the shoulder girdle is involved. Bulbar involvement is late. Autopsy shows muscular atrophy and involvement of caudal cranial nuclei. Palmer (1932) described a family with 8 persons affected, the earliest having onset about 1800. Davidenkow (1939) suggested that cases reported by Wohlfart (see juvenile muscular atrophy, 253400 and 158600) were the same as those he designated scapuloperoneal amyotrophy.

Kaeser (1965) reported a kindred (kindred F) in which 12 members in 5 generations had neurogenic scapuloperoneal syndrome in an autosomal dominant pattern of inheritance. Age at onset was between 30 and 50 years and followed a slowly progressive course. In the first 3 generations, weakness and atrophy started in the legs and spread to the thighs and pelvic girdle, resulting in paraplegia. In the fifth generation, the atrophies extended to the shoulder girdle, upper arms, neck, face, pharynx, and external eye muscles. Histologic examination at autopsy in 1 patient showed that the atrophies were neurogenic in origin, similar to those in Wohlfart-Kugelberg-Welander muscular atrophy. Kindred F, however, demonstrated significant differences from the cases reported by Davidenkow (1939) and from Wohlfart-Kugelberg-Welander juvenile muscular atrophy. Kaeser (1965) concluded that the scapuloperoneal syndrome is a descriptive term comprising various myopathies, peroneal muscular atrophies, and spinal muscular atrophies.

Emery et al. (1968) and Schuchmann (1970) reported sporadic childhood cases with electromyographic and biopsy evidence of neurogenic disease; motor nerve conduction velocities were borderline or normal, suggesting anterior horn cell pathology. Kazakov et al. (1976) provided a follow-up on the kindred reported by Davidenkow (1939). The disorder in many ways resembled Landouzy-Dejerine facioscapulohumeral muscular dystrophy (158900). There are both myopathic (see 181430) and neurogenic dominant forms of the scapuloperoneal syndrome. Emery (1981) described a large kindred in the West of Scotland. Ferguson-Smith and McKusick (1981) saw a brother and sister who clearly had this disorder. The sister had been diagnosed as having Charcot-Marie-Tooth disease and the brother muscular dystrophy. Their disease was neurogenic scapuloperoneal syndrome.

Tawil et al. (1995) described a 3-generation kindred in which 7 members were affected with neurogenic scapuloperoneal syndrome in which nerve conduction velocities showed evidence of a mild demyelinating polyneuropathy and electromyography demonstrated acute and chronic denervation in both proximal and distal muscles. The proband fulfilled the diagnostic criteria for facioscapulohumeral dystrophy (158900), but none of the other affected members had facial weakness. Linkage to markers on 4q35 was excluded, demonstrating this to be a genetically distinct disorder.

Walter et al. (2007) studied the large, multigenerational kindred first described by Kaeser (1964, 1965) with a peculiar scapuloperoneal distribution of weakness and atrophy, inherited in an autosomal dominant fashion, named scapuloperoneal syndrome type Kaeser. A large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb-girdle (n = 10, 60%), and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia, and gynecomastia were frequent additional symptoms. Affected men seemingly carried a higher risk of sudden, cardiac death as compared to affected women. Histologic and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, mild fibrillar changes with accumulation of desmin.

Molecular Genetics

By genetic analysis of the original kindred described by Kaeser (1964), Walter et al. (2007) found possible linkage to the gene encoding desmin and identified a heterozygous missense mutation of the desmin gene (R350P; 125660.0016) cosegregating with the disorder. Moreover, Walter et al. (2007) found the R350P mutation in 4 unrelated German families, which allowed for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. This study suggested that the clinical and pathologic variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. Walter et al. (2007) suggested that mutations of the desmin gene should be considered early in the diagnostic workup of any adult-onset, autosomal dominant myopathy, even if specific myofibrillar pathology is absent.