Clinical characteristics: The spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and pes cavus and other foot deformities. Disease severity is variable among and within families.
Diagnosis/testing: The diagnosis of a BSCL2-related neurologic disorder is established in a proband with characteristic clinical and electrophysiologic features and identification of a heterozygous BSCL2 pathogenic variant on molecular genetic testing.
Management: Treatment of manifestations: Symptomatic treatment includes physiotherapy, orthopedic shoes, and calipers to stabilize gait. Foot deformities may be corrected with surgery.
Prevention of secondary complications: Early regular physiotherapy may prevent contractures.
Surveillance: Annual evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist.
Genetic counseling: BSCL2-related neurologic disorders are inherited in an autosomal dominant manner. Each child of an individual with a BSCL2-related neurologic disorder has a 50% chance of inheriting the pathogenic variant. Penetrance is incomplete, with more than 20% of individuals with the pathogenic variant showing no clinical abnormalities or only minor clinical signs. Prenatal testing for a pregnancy at increased risk is possible in families in which the pathogenic variant is known; however, requests for prenatal testing for adult-onset disorders are not common.
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