Objective: 1) To develop a registry and natural history study for AP-4-HSP; 2) to define core clinical and radiographic features; 3) to explore genotype-phenotype correlations.

Background: Bi-allelic, loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to four prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1) [1].

Method: A cross-sectional analysis of clinical, imaging and genetic data of individuals enrolled in the AP-4-HSP International Registry. Data were obtained using a standardized questionnaire and rating scales including the Spastic Paraplegia Rating Scale [2], Modified Ashworth Scale [3], Four Stage Functional Mobility Score [4] and the CPCHILD [5].

Results: We report a detailed clinical, radiographic and molecular characterization of 115 patients of 74 families enrolled in the AP-4-HSP International Registry. Age at diagnosis was 9.9 ± 7.1 years (SD, range 0.1- 46 years) and ~70% were born to consanguineous parents. We define a core set of symptoms: Early-onset developmental delay with delayed motor milestones and significant speech delay (54% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia and later tetraplegia; microcephaly (postnatal in most cases); foot deformities; febrile seizures and epilepsy that is refractory in a subset. Dystonia and ataxia develop in a subset of patients with advanced disease. At last follow up 28% of patients ambulated with assistance, 69% were wheelchair-dependent. Key neuroimaging features include a thin corpus callosum (91%), ventriculomegaly (71%), and periventricular white-matter signal abnormalities (66%). Iron deposition and polymicrogyria are found in a small subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 account for the majority of cases. Over 65 unique variants were present, the majority of which are frameshift or non-sense mutations.

Conclusion: Through a cross-sectional analysis we define the core clinical, molecular and radiographic features of AP-4-HSP. We delineate disease progression across the age spectrum and explore genotype-phenotype correlations. These data will define endpoints for future clinical trials.

References: 1. Ebrahimi-Fakhari, D., et al., AP-4-Associated Hereditary Spastic Paraplegia, in GeneReviews((R)), M.P. Adam, et al., Editors. 2018: Seattle (WA). 2. Schule, R., et al., The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology, 2006. 67(3): p. 430-4. 3. Bohannon, R.W. and M.B. Smith, Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther, 1987. 67(2): p. 206-7. 4. Erichsen, A.K., et al., Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain, 2009. 132(Pt 6): p. 1577-88. 5. Narayanan, U.G., et al., Initial development and validation of the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD). Dev Med Child Neurol, 2006. 48(10): p. 804-12.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-clinical-molecular-and-radiographic-spectrum-of-adaptor-protein-complex-4-associated-hereditary-spastic-paraplegia-ap-4-hsp-results-from-the-ap-4-hsp-international-registry/