Spastic Paraplegia 50, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic paraplegia-50 (SPG50) is caused by homozygous mutation in the AP4M1 gene (602296) on chromosome 7q22.

Description

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).

Clinical Features

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.

Tuysuz et al. (2014) reported 4 children from 2 unrelated consanguineous Turkish families with SPG50. The patients had delayed psychomotor development, severe intellectual disability with impaired speech, spastic tetraplegia with hypertonia and inability to walk independently, and infantile-onset seizures. Dysmorphic features included microcephaly, facial hypotonia, bitemporal narrowing, broad nasal bridge with bulbous nose, short philtrum, everted upper lip, wide mouth, and high-arched palate. Brain imaging showed ventriculomegaly and thin corpus callosum; 2 patients had white matter abnormalities.

Inheritance

The transmission pattern of SPG50 in the family reported by Verkerk et al. (2009) was consistent with autosomal recessive inheritance.

Molecular Genetics

By linkage analysis, followed by candidate gene sequencing, in a consanguineous Moroccan family with spastic paraplegia, Verkerk et al. (2009) identified a homozygous splice site 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. 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 (E193K; 602296.0002) in affected members of a family (M004) segregating SPG50.

In affected members of 2 unrelated consanguineous Turkish families with SPG50, Tuysuz et al. (2014) identified 2 different homozygous truncating mutations in the AP4M1 gene (R338X, 602296.0003 and R318X, 602296.0004). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.