Spastic paraplegia-50 is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (summary by Verkerk et al., 2009).
Verkerk et al. (2009) reported a consanguineous Moroccan family in which 5 sibs had spastic quadriplegic cerebral palsy and severe mental retardation. All 5 presented postnatally with early infantile hypotonia, delayed psychomotor development, strabismus, lack of independent walking, ... Verkerk et al. (2009) reported a consanguineous Moroccan family in which 5 sibs had spastic quadriplegic cerebral palsy and severe mental retardation. All 5 presented postnatally with early infantile hypotonia, delayed psychomotor development, strabismus, lack of independent walking, and severe mental retardation (total IQ of 20). They all developed progressive spasticity of all limbs with generalized hypertonia, hyperreflexia, and extensor plantar responses by the end of the first year of life. Speech was absent or limited. Other features included pseudobulbar signs, such as drooling, stereotypic laughter, and exaggerated jaw jerk. Two patients had microcephaly, most had adducted thumbs, and none had achieved sphincter control. Brain imaging showed ventriculomegaly, white matter abnormalities, and variable cerebellar atrophy. Diffusion tensor imaging indicated that the white matter lesions were related to a combination of axonal disarray and loss of myelin integrity. Seizures were not noted, and there were no clinical signs of cerebellar ataxia. There was minimal progression during 20-year follow-up. One patient died at 17 months of aspiration pneumonia. Postmortem neuropathologic examination showed reduced myelin with significant gliosis and changes in dendritic arborization, consistent with neuroaxonal abnormalities.
By linkage analysis, followed by candidate gene sequencing, of a consanguineous Moroccan family with spastic paraplegia, Verkerk et al. (2009) identified a homozygous mutation in the AP4M1 gene (602296.0001). Verkerk et al. (2009) postulated that the genetic defect ... By linkage analysis, followed by candidate gene sequencing, of a consanguineous Moroccan family with spastic paraplegia, Verkerk et al. (2009) identified a homozygous mutation in the AP4M1 gene (602296.0001). Verkerk et al. (2009) postulated that the genetic defect results in abnormal cycling of glutamate receptors, mimicking glutamate-mediated perinatal white matter injury. Of note, this family also independently segregated the arterial tortuosity syndrome (ATS; 208050). By homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability, Najmabadi et al. (2011) identified homozygosity for a missense mutation in the AP4M1 gene (602296.0002) in affected members of a family (M004) segregating CPSQ3.