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A variant of hereditary spastic paraparesis characterized by spasticity and amyotrophy of the extremities.
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Silver Syndrome; Silver Spastic Paraplegia Syndrome; Spastic Paraplegia 17; Spastic Paraparesis with Amyotrophy of Hands and Feet.
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Named after John R. Silver, a British neurologist, who in 1966 described 12 affected patients from two families with autosomal dominant inherited, familial spastic paraplegia and amyotrophy of the hands. However, the disease had already been described earlier by the German neurologist Ernst A. G. G. von Strümpell in 1880.
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Autosomal dominant, although autosomal recessive transmission has been suggested for some cases. De novo mutations and/or incomplete penetrance may occur in Silver syndrome/SPG17 and should be considered even if only one family member is affected. Approximately one quarter of individuals with a pathogenic mutation remain minimally symptomatic or asymptomatic. The genetic defect is caused by mutations in the Berardinelli-Seip congenital lipodystrophy (BSCL2) gene, which has been mapped to chromosome 11q12-q14. Three heterozygous mutations N88S, S90L and S90W have been described that may result in disruption of N-glycosylation of Seipin, an endoplasmatic reticular protein found in abundance in adipocytes and at synapses in motor neurons and brain. The Seipin mutations result in accumulation of mis- or unfolded protein in the endoplasmic reticulum (ER) and manifests as impaired synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse.
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Based on the family history and the clinical findings of gait disturbances with spastic paraparesis of the legs and severe amyotrophy of the small hand muscles. Confirmation requires molecular genetic testing with documentation of a mutation in the BSCL2 gene.
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The age at the onset of symptoms as well as the clinical manifestations are highly variable (first to seventh decade of life) and progression of the disease is usually slow and normal life expectancy. Spastic gait disturbances are the predominant and often first sign of the disorder and may present as stiffness, cramps, or frequent tripping when walking. Weakness in the hands can also be a presenting symptom. Muscular hypertonia and hyperreflexia of the legs with positive Babinski sign develop gradually and may lead to foot deformities (pes cavus and/or hammer toes) over the course of the disease. However, in some cases, lower limb hypo- or even areflexia was found. The tendon reflexes in the upper extremities are normal. Clinically, three main types of presentations can be distinguished: a) weakness and atrophy of the distal lower limb muscles with or without gradually evolving Babinski sign, with or without distal upper limb muscle involvement later in the course of disease; b) manifestation with primary involvement of the hand muscles, with minimal ...