Table 3.

Hereditary Spastic Paraplegia: Genes and Distinguishing Clinical Features – X-Linked Inheritance

Gene 1HSP DesignationType of HSPOnsetDistinguishing Clinical FeaturesOtherReferences
GeneReview
or OMIM Entry		Citation
L1CAM SPG1 2ComplicatedInfancy
  • ID
  • Adducted thumbs
  • Corpus callosum hypoplasia
  • Aphasia
  • Obstructive hydrocephalus
Rare L1 Syndrome Jouet et al [1994], Schrander-Stumpel et al [1995], Yamasaki et al [1995], Finckh et al [2000]
PLP1 3SPG2ComplicatedEarly-childhood to juvenile onset
(in manifesting female heterozygotes: onset in 4th-7th decade)
  • Pure HSP phenotype present in early stages; later, other signs emerge
  • Nystagmus
  • Optic atrophy
  • Dysarthria
  • ID
  • Variable degree of leukodystrophy on MRI
 PLP1-Related Disorders Saugier-Veber et al [1994], Cambi et al [1996], Hodes et al [1999], Sivakumar et al [1999]
SLC16A2 SPG22ComplicatedEarly childhood
  • Severe ID
  • Infantile hypotonia
  • Progressive spasticity
  • Ataxia
  • Dystonia
  • ↑ T3 & normal to mildly ↑ TSH
  • ↓ T4 hypomyelination on neuroimaging
  • Rare
  • SPG22 is a proposed designation. 4
  • Also referred to as Allan-Herndon-Dudley syndrome 5
 Allan-Herndon-Dudley Syndrome Dumitrescu et al [2004], Boccone et al [2010]

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HSP = hereditary spastic paraplegia; ID = intellectual disability

1.

Genes are listed alphabetically.

2.

SPG1 is more commonly referred to as MASA syndrome (mental retardation [intellectual disability], aphasia [delayed speech], spastic paraplegia, adducted thumbs). Allelic disorders are X-linked hydrocephalus with stenosis of the aqueduct of Sylvius and X-linked complicated corpus callosum agenesis.

3.
4.

OMIM 300523

5.

Because of the overlap between the clinical phenotype in individuals with SLC16A2 abnormalities and in those with a previously described syndrome, Allan-Herndon-Dudley syndrome (AHDS), Schwartz et al [2005] analyzed SLC16A2 in six families with AHDS. SLC16A2 pathogenic variants were identified in all six; therefore, AHDS is now synonymous with MCT8-specific thyroid hormone cell-membrane transporter deficiency due to pathogenic variants in SLC16A2 (see Allan-Herndon-Dudley Syndrome).

From: Hereditary Spastic Paraplegia Overview

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