Spastic Paraplegia 9b, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-9B (SPG9B) is caused by homozygous or compound heterozygous mutation in the ALDH18A1 gene (138250) on chromosome 10q24.

Heterozygous mutation in the ALDH18A1 gene can cause autosomal dominant spastic paraplegia-9A (SPG9A; 601162).

Description

Autosomal recessive SPG9B is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (summary by Coutelier et al., 2015).

For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).

Clinical Features

Coutelier et al. (2015) reported 6 adult patients from 2 unrelated families (FSP856 from Spain and SR45 from Portugal) with early-onset autosomal recessive complex spastic paraplegia. Four affected individuals in 1 family presented in the first decade (less than 1 year to 7 years of age) with intellectual disability and/or delayed motor development. They had severe spasticity and gait instability associated with hyperreflexia of the upper and lower limbs and extensor plantar responses; 1 lost ambulation at age 30. Three had limb muscle weakness, including 2 with tetraplegia and foot drop. All patients also had mild microcephaly, and 3 had nonspecific dysmorphic facial features. Additional more variable features included postural tremor, dysarthria, mildly decreased vibration sense at the ankles, and urinary symptoms. Two brothers in the other family had onset of severely delayed psychomotor development in the first year of life. As adults, both had lost ambulation due to severe spasticity. They had severe intellectual disability; 1 never acquired speech. One patient likely had cataracts. Brain imaging of 1 patient showed atrophy of the corpus callosum, periventricular white matter abnormalities, and mild cortical atrophy. Both were incontinent. None of the 6 patients had evidence of skin abnormalities. The parents of the Spanish sibs were unaffected; the Portuguese parents were not available for evaluation.

Inheritance

The transmission pattern of SPG9B in the families reported by Coutelier et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 2 unrelated families with autosomal recessive spastic paraplegia-9B, Coutelier et al. (2015) identified homozygous or compound heterozygous missense mutations in the ALDH18A1 gene (138250.0010-138250.0012) affecting conserved residues. The mutations were found by whole-exome or panel sequencing. Functional studies of the variants were not performed.