Pure or complex autosomal dominant spastic paraplegia
-Rare genetic disease
-Rare neurologic disease
Comment:
SPG10 is an autosomal dominant form of hereditary spastic paraplegia caused by mutations in KIF5A, which encodes one of the isoforms of kinesin-1 (KIF5A, KIF5B, and KIF5C) (PMID:22785106).
SPG10 is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or ... SPG10 is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, 118210). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by Goizet et al., 2008 and Crimella et al., 2012).
Reid et al. (1999) reported a large family with autosomal dominant 'pure' hereditary spastic paraplegia. All but a single affected member of the SPG10 family had a symptomatic spastic gait abnormality, in addition to lower limb hyperreflexia, thereby ... Reid et al. (1999) reported a large family with autosomal dominant 'pure' hereditary spastic paraplegia. All but a single affected member of the SPG10 family had a symptomatic spastic gait abnormality, in addition to lower limb hyperreflexia, thereby meeting the Hereditary Spastic Paraplegia Working Group diagnostic criteria for being 'definitely affected' (Fink et al., 1996). The asymptomatic patient was an obligate gene carrier who had bilateral lower-limb hyperreflexia, bilateral extensor plantar responses, and unilateral sustained ankle clonus. One previously asymptomatic affected patient in this family had become symptomatic since an earlier report of the family. The mean age at onset of symptoms was 10.8 +/- 9.6 years (range, 8 to 40 years); the asymptomatic patient was not included in the age-at-onset calculation. Reid et al. (1999) reported an additional family in which linkage to all 5 known loci (including SPG10) was excluded. Fichera et al. (2004) reported a 4-generation family with autosomal dominant SPG10. Clinical data were available for only 4 patients. All had abnormal gait and hyperreflexia of the lower limbs since early childhood. Other features included extensor plantar responses, paresthesias, and pes cavus. Upper limb involvement, urinary urgency, and scoliosis were only observed in the 2 oldest patients who were in their mid-seventies. Blair et al. (2006) reported a large 4-generation family in which 17 individuals had signs of corticospinal tract dysfunction, with spastic gait and reduced vibration sense in the lower limbs. All affected individuals had adult onset of the symptoms between 29 and 44 years of age. Five patients over the age of 60 years also developed a moderate degree of amyotrophy in the lower extremities; 2 also developed mild amyotrophy of the hands. The degree of disability varied: 5 could walk unaided with spastic gait, whereas 4 were wheelchair-dependent; others required an assistive device for walking. Two younger at-risk but asymptomatic individuals had brisk tendon reflexes and extensor plantar responses. Crimella et al. (2012) reported 7 unrelated Italian patients from 5 families with SPG10. In 4 families, the age at onset ranged from 13 to 33 years. In the fifth family, the proband had onset at age 1.2 years, although his father, who also carried the mutation, had only subtle hyperreflexia on examination. Clinical features in all patients included lower limb spasticity, hyperreflexia, and weakness, leading to impaired gait. Most patients also had mild upper limb hyperreflexia and pes cavus. Four patients from 3 families had an axonal sensorimotor peripheral neuropathy, and 2 patients had distal sensory impairment. - Clinical Variability To better define the phenotype and frequency of SPG10, Goizet et al. (2008) sequenced the KIF5A gene in 175 probands with autosomal dominant hereditary spastic paraplegia and 30 patients with sporadic disease in whom mutations in several other SPG-related genes were excluded. Most of the patients were French. Eight different heterozygous pathogenic mutations (see, e.g., 602821.0002; 602821.0005-602821.0007) were found in 8 (4.8%) of 175 families, with a frequency among French families of 5.1% (8 of 156 French families). All of the mutations were located in the highly conserved motor domain. The clinical features of 17 patients from these families were reviewed in detail. Although the age at onset varied, most had onset during the third or fourth decade, and all presented with gait abnormalities resulting from stiffness in the lower extremities. All patients had lower limb hyperreflexia, spasticity, and extensor plantar responses, usually associated with lower limb weakness. Upper limb spasticity and bladder dysfunction were frequent, but not always observed. Sensory disturbances were common: 10 patients (59%) had decreased vibration sense and 9 (53%) had distal hypoesthesia. Disease progression was mild to moderate, and all patients were still able to walk without help even many years after onset. Affected individuals in 7 of the 8 families had a complicated form of SPG with variable additional features, including axonal sensorimotor peripheral neuropathy, severe amyotrophy of the hands, mild to moderate mental retardation, and parkinsonism. One patient had deafness and another had retinitis pigmentosa. There was intrafamilial variability: in 1 family, the proband had a pure form of SPG, whereas his father had only axonal neuropathy and no spasticity. Goizet et al. (2008) concluded that complicated forms of SPG are frequent in patients with KIF5A mutations. Crimella et al. (2012) reported an Italian patient with an axonal sensorimotor peripheral neuropathy consistent with type 2 Charcot-Marie-Tooth disease (CMT). The patient had onset of distal lower limb weakness and fatigability at age 16 years. At age 25, he had lower limb atrophy, pes cavus, ankle weakness, and clumsy gait. Physical examination showed distal atrophy of the lower limbs, mild weakness in the small hand muscles, decreased distal vibration and position senses, and areflexia of the lower limbs. There were no signs of spasticity. Electrophysiologic studies were consistent with an axonal sensorimotor peripheral neuropathy. The patient was 1 of 36 patients (2.7%) with CMT tested for mutations in the KIF5A gene. The findings suggested that axonal neuropathy may represent an extreme end of the spectrum of neurologic disorders associated with KIF5A mutations.
By mutation analysis in the family reported by Reid et al. (1999), Reid et al. (2002) identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A (602821.0001).
In affected members ... By mutation analysis in the family reported by Reid et al. (1999), Reid et al. (2002) identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A (602821.0001). In affected members of a 4-generation family with SPG10, Fichera et al. (2004) identified a heterozygous mutation in the KIF5A gene (602821.0002). In affected members of a large kindred with SPG10, Blair et al. (2006) identified a heterozygous mutation in the KIF5A gene (602821.0003). Notably, all affected members had adult onset of symptoms (average age 36 years). Lo Giudice et al. (2006) identified a heterozygous mutation in the KIF5A gene (602821.0004) in an Italian patient with adult-onset SPG10. Crimella et al. (2012) identified heterozygous mutations (see, e.g., 602821.0006; 602821.0008-602821.0009) in 4 (8.8%) of 45 Italian probands with autosomal dominant spastic paraplegia. A heterozygous mutation was also found in 1 (1%) of 94 patients with sporadic SPG. In 2 families, the disorder was accompanied by axonal sensorimotor peripheral neuropathy. In 1 (2.7%) of 36 patients with CMT tested for mutations in the KIF5A gene, Crimella et al. (2012) identified a de novo heterozygous mutation in the motor domain (G235E; 602821.0009). The findings suggested that axonal neuropathy may represent an extreme end of the spectrum of neurologic disorders associated with KIF5A mutations.