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Infantile-onset ascending hereditary spastic paralysis
Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a very rare motor neuron disease characterized by severe spasticity of the lower limbs in early life, progression of spasticity to the upper limbs in late childhood, and dysarthria.
ORPHA:293168Classification level: Disorder
The prevalence and incidence of IAHSP are not known. 17 families accounting for at least 30 cases have been reported to date. The disorder has been described in various ethnic groups.
Affected patients are normal at birth and early development is mostly unremarkable. They then develop spastic paraplegia, increased reflexes and sustained lower limb stiffness in the first two years of life. By 7 to 8 years of age they also develop progressive weakness and spasticity extending to the upper limbs. Other signs include dysarthria, dysphagia (sometimes with drooling), and slow eye movements. Most become wheel-chair bound by late childhood or early adolescence and some patients have feeding difficulties (swallowing liquids) starting in the second decade. Subsequently, the disease progresses to severe spastic tetraparesis and a pseudobulbar syndrome may be observed. Cognitive function is generally preserved.
IAHSP appears to be caused by mutations in the ALS2 gene (2q33-q35) encoding alsin, a protein that is abundant in motor neurons. Mutations in this gene are not found in all families with members affected by the disease. Other genes or loci have not been identified to date.
Diagnosis is based on the characteristic features of the disorder and on ascending progression. Electrophysiological studies show severe dysfunction of motor evoked potentials. Somatosensory evoked potentials, electromyography and nerve conduction velocities are normal. Magnetic resonance imaging (MRI) is normal in affected children but brain changes are found in older patients. The diagnosis can be confirmed by molecular genetic testing.
Differential diagnoses include the allelic disorders juvenile primary lateral sclerosis and juvenile amyotrophic lateral sclerosis (see these terms).
Prenatal diagnosis for at-risk pregnancies is possible if the disease-causing mutations have been identified in the family.
IAHSP is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and are therefore asymptomatic carriers. Genetic counseling should be provided to affected families.
Management and treatment
There is currently no specific treatment. Management primarily involves physical and occupational therapy to promote mobility and independence.
The vital prognosis is good with long-term survival in most cases. Quality of life, however, is affected by progressive neurological manifestations and loss of independence.