Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7

Marvin Ziegler; Bianca E Russell; Kathrin Eberhardt; Gregory Geisel; Angelica D'Amore; Mustafa Sahin; Harley I Kornblum; Darius Ebrahimi-Fakhari

doi:10.1212/NXG.0000000000000544

Blended Phenotype of Silver-Russell Syndrome and SPG50 Caused by Maternal Isodisomy of Chromosome 7

Neurol Genet. 2020 Dec 29;7(1):e544. doi: 10.1212/NXG.0000000000000544. eCollection 2021 Feb.

Authors

Marvin Ziegler¹, Bianca E Russell¹, Kathrin Eberhardt¹, Gregory Geisel¹, Angelica D'Amore¹, Mustafa Sahin¹, Harley I Kornblum¹, Darius Ebrahimi-Fakhari¹

Affiliation

¹ Department of Neurology and The F.M. Kirby Neurobiology Center (M.Z., K.E., G.G., A.D., M.S., D.E.-F.), Boston Children's Hospital, Harvard Medical School, MA; Department of Functional Neuroanatomy (M.Z.), Institute of Anatomy and Cell Biology, Heidelberg University, Germany; Division of Genetics (B.E.R.), Department of Pediatrics, David Geffen School of Medicine at UCLA; Translational Neuroscience Center (G.G., M.S.), Boston Children's Hospital, Harvard Medical School, MA; and Intellectual and Developmental Disabilities Research Center (H.I.K.), Semel Institute for Neuroscience and Human Behavior and Department of Psychiatry and Biobehavioral Sciences (H.I.K.), David Geffen School of Medicine at UCLA.

Abstract

Objective: Uniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a complex neurodevelopmental disorder was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed.

Methods: A combination of clinical, molecular, and imaging data and functional studies in patient-derived fibroblasts.

Results: We report a 4-year-old female with a blended, complex phenotype of Silver-Russell syndrome (SRS) and hereditary spastic paraplegia type 50 (SPG50) caused by total maternal isodisomy of chromosome 7 (UPiD(7)mat) and a loss-of-function variant in AP4M1 (NM_00472.3: c.59-1G>C, IVS1-1G>C). Functional studies in patient-derived fibroblasts confirmed the loss of adaptor protein complex 4 function. Distinctive facial features, intrauterine growth restriction, short stature, feeding difficulties, and severe gastroesophageal reflux were consistent with SRS. Features associated with SPG50 included early-onset epilepsy, episodes of stereotypical laughter, and thinning of the corpus callosum and ventriculomegaly on brain MRI. Symptoms shared by both syndromes such as developmental delay, short stature, and axial and appendicular hypotonia were also present. Notably, other common manifestations of SPG50 such as microcephaly or spasticity had not developed yet.

Conclusions: This case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity.

Abstract

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