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Spastic Paraplegia-47 (AP4B1 related AP-4 deficiency)

  • Background:
    • Hereditary spastic paraplegias (HSP) are a group of disorders characterized by progressive degeneration of the long tracts of the central nervous system, predominantly the corticospinal tracts and dorsal columns. These are among the most heterogeneous disorders in the realm of neurogenetics, with around 70 loci and 60 genes associated with different forms.
  • Clinical Presentation:
    • There are 2 main forms: pure and complicated. Pure HSP patients typically present with lower limb–predominant spasticity and weakness resulting in gait abnormalities. Complicated HSP patients may, in addition, have cognitive impairment, epilepsy, and even visual symptoms.
  • Key Diagnostic Features:
    • MRI findings in HSP can be nonspecific and include thinning of the corpus callosum, predominant spinal cord atrophy, cerebral and cerebellar volume loss, enlarged ventricles, white matter T2 hyperintensities, bilateral T2 hypointense globus pallidus, and thoracic spinal cord hydromyelia. 
    • Ear of the lynx sign: FLAIR hyperintense foci along the frontal horns resembling lynx ears
    • Among the various HSPs, thinning of the entire length of corpus callosum is a distinguishing feature for SPG11 and SPG15.
    • However, when there is splenial predominant thinning of the corpus callosum, asymmetric ventriculomegaly, and incomplete inversion as well as hippocampal thinning, adapter protein 4 (AP4) deficiency syndromes should be considered (such as: SPG 47, 50, 51, and 52). Spinal cord atrophy is rare in this subgroup.
    • A combination of spastic tetraplegia, microcephaly, and severe intellectual disability in addition to these imaging features further points to an “AP-4 deficiency syndrome.” All these clinical features coupled with the imaging features help in accurate prediction of this HSP subgroup.
    • In the clinical picture of lower limb–predominant spasticity, the following differentials need to be considered:
      • Spastic cerebral palsy (evidence of hypoxic ischemic brain injury such as periventricular leukomalacia)
      • Hypomyelinating leukodystrophy (predominant white matter changes).
      • Other HSP variants:
        • SPG 11, 15 (“Ear of lynx” sign)
        • SPG 1 (Marked hydrocephalus)
        • SPG 2 (Multifocal and confluent white matter FLAIR hyperintensities)
        • SPG 4, 6, 8 (Spinal cord atrophy)
  • Treatment:
    • Muscle relaxants such as baclofen, tizanidine, and botulinum can be used to relieve spasticity. Physiotherapy helps in improving and maintaining muscle strength.
May 2, 2024

A 13-year-old girl presents with developmental delay from birth, seizures since 6 months of age, and progressive gait disturbances. On examination she demonstrates spasticity in all 4 limbs (lower limbs > upper limbs), microcephaly, and low intelligence quotient.

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