A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies.

Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms "AP-4 deficiency syndrome" for this clinically recognizable phenotype. Using whole-exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP-4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition. In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP-4 deficiency, speculating on a possible role of AP-4 complex in eye development.

Genotype-phenotype correlations and expansion of the molecular spectrum of AP4M1-related hereditary spastic paraplegia.

BACKGROUND: Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients. METHODS: We investigated a Greek HSP family using whole exome sequencing (WES). RESULTS: A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI. CONCLUSIONS: We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission.