AP4B1-associated hereditary spastic paraplegia: expansion of phenotypic spectrum related to homozygous p.Thr387fs variant

Krzysztof Szczałuba,Małgorzata Rydzanicz,Hanna Mierzewska,Piotr Stawiński,Rafał Płoski,Joanna Kosińska,Anna Biernacka,Robert Śmigiel,Agnieszka Pollak,Agnieszka Koppolu

doi:10.1007/s13353-020-00552-w

Abstract

Biallelic mutations in the AP4B1 gene, encoding adaptor-related protein complex 4 beta-1 subunit, have been recognized as an important cause of a group of conditions leading to adaptor-related protein complex 4 (AP4)-associated hereditary spastic paraplegia (SPG47). We describe a homozygous, known variant c.1160_1161delCA (p.Thr387fs) that was found in the largest ever group of patients coming from four families. The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of SPG47. Our findings expand phenotypic spectrum of SPG47 to include polymorphic seizures, mild/moderate intellectual disability, and intracerebral cysts as well as point to founder mutation in AP4 deficiency disorders in apparently non-consanguineous Polish families without shared ancestry.

Highlights

The pathogenesis of a number of human disorders has been associated with inefficient bidirectional trafficking of proteins between Golgi apparatus and endosomes (Progida and Bakke 2016)
The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of spastic paraplegia type 47 (SPG47)
All the patients present with hypotonia progressing to spastic paraplegia, microcephaly (4 out of 5), epilepsy (4 out of 5), central nervous system (CNS) defects (4 out of 5), and global developmental delay

Summary

Introduction

The pathogenesis of a number of human disorders has been associated with inefficient bidirectional trafficking of proteins between Golgi apparatus and endosomes (Progida and Bakke 2016). The older one, was born after uneventful pregnancy and delivery with weight 3600 g, occipitofrontal circumference 34 cm, and Apgar score of 10 points The younger sister was born after uneventful pregnancy and delivery with weight 3300 g, occipitofrontal circumference (OFC) 34 cm, and Apgar 9 points due to hypotonia Her psychomotor development was delayed, and at age 9, polymorphic seizures started, mainly during febrile infection. Diagnostic brain imaging was performed twice: at age 3 revealing normal pattern of myelination and apparently no brain anomalies and at 5 years showing relatively mild white matter loss as well as corpus callosum hypoplasia (Fig. 1c). A 12-year-old boy presents with non-progressive spastic paraplegia He can move only with assistance, and he is unable to control his physiological needs. The results of ROH analysis are shown in Supplementary Figure 1

Discussion

Findings

Compliance with ethical standards