Clinical and genetic characterization of AP4B1‐associated SPG47

Abstract

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by degeneration of the corticospinal and spinocerebellar tracts leading to progressive spasticity. One subtype, spastic paraplegia type 47 (SPG47 or HSP-AP4B1), is due to bi-allelic loss-of-function mutations in the AP4B1 gene. AP4B1 is a subunit of the adapter protein complex 4 (AP-4), a heterotetrameric protein complex that regulates the transport of membrane proteins. Since 2011, 11 individuals from six families with AP4B1 mutations have been reported, nine of whom had homozygous mutations and were from consanguineous families. Here we report eight patients with AP4B1-associated SPG47, the majority born to non-consanguineous parents and carrying compound heterozygous mutations. Core clinical features in this cohort and previously published patients include neonatal hypotonia that progresses to spasticity, early onset developmental delay with prominent motor delay and severely impaired or absent speech development, episodes of stereotypic laughter, seizures including frequent febrile seizures, thinning of the corpus callosum, and delayed myelination/white matter loss. Given that some of the features of AP-4 deficiency overlap with those of cerebral palsy, and the discovery of the disorder in non-consanguineous populations, we believe that AP-4 deficiency may be more common than previously appreciated.

Autophagy in childhood neurological disorders

“…Adaptor protein‐4 deficiency syndrome is a subtype of complex HSP caused by autosomal recessive mutations of genes encoding any subunit of adaptor protein‐4 ( SPG47 and SPG52 , *614066, *614067) . Patients exhibit a complex phenotype, including early hypotonia progressing to hypertonia, intellectual disability, and microcephaly.…”

Integrating structural and evolutionary data to interpret variation and pathogenicity in adapter protein complex 4

“…Sivley et al 34,35 developed a program called PathProx that evaluates the relative 3D proximity of a variant to known pathogenic and benign variants. To explore the spatial distribution of variants in AP‐4, we mapped onto the AP‐4 homology model four reported pathogenic variants (curated from the literature) 13–16,36 and six variants annotated as likely pathogenic in ClinVar (Table 3). 32 We also identified 699 likely benign variants in AP‐4 from gnomAD database (Figure 4).…”

“…The complex is expressed ubiquitously in cells, but AP‐4 seems especially important for neurological development 9–12 . Each of the four subunits can harbor mutations that cause hereditary spastic paraplegias (HSPs), 13–16 and current clinical research suggests patients have a specific subtype of HSP called AP‐4 deficiency syndrome 17 . Each AP‐4 gene ( AP4E1/AP4B1/AP4M1/AP4S1 ) is also classified as a spastic paraplegia gene ( SPG51/SPG47/SPG50/SPG52 , respectively).…”

Novel variants in AP4B1 cause spastic tetraplegia, moderate psychomotor development delay and febrile seizures in a Chinese patient: a case report

“…A paternal heterozygous nonsense variant c.1207C > T (p.Gln403*) and a maternal heterozygous frameshift variant c.52_53delAC (p.Cys18Glnfs*7) which resulted in the introduction of a premature termination codon in two different alleles were identified in AP4B1 gene. Ebrahimi-Fakhari et al [5] reported the clinical and genetic characterization of nineteen probands with AP4B1-associated SPG47 including early developmental delay and intellectual disability(100%), delayed motor development(100%), neonatal or infantile hypotonia(100%), delayed speech development(94%), progression to spastic diplegia (89%), loss of independent walking (88%), short stature (57%), thin corpus callosum(73%), delayed myelination or white matter loss(67%), ventriculomegaly(40%). Only half of the patients had epilepsy (47%), especially febrile seizures (3/19).…”

“…Diseasecausing mutations in AP4B1 have been reported in 29 individuals from 22 families. Most of these mutations are homozygous (23/29) [5][6][7][8].…”