A recurrent ACAA2 variant causes a dominant syndrome of lipodystrophy, lipomatosis, infantile steatohepatitis, and hypoglycemia
Vinaya Simha, Mary Kate LoPiccolo, Anna Platt, Rebecca J. Brown, Xandria Johnson, Deanna Alexis Carere, Colleen Donnelly, Matthew T. Snyder, Chao Xing, Thomas P. Mathews, Purva Gopal, Stephen C. Ward, Diana R. Tomchick, Anil K. Agarwal, Ralph J. DeBerardinis, Abhimanyu Garg
Vinaya Simha, Mary Kate LoPiccolo, Anna Platt, Rebecca J. Brown, Xandria Johnson, Deanna Alexis Carere, Colleen Donnelly, Matthew T. Snyder, Chao Xing, Thomas P. Mathews, Purva Gopal, Stephen C. Ward, Diana R. Tomchick, Anil K. Agarwal, Ralph J. DeBerardinis, Abhimanyu Garg
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Research Letter Endocrinology Genetics

A recurrent ACAA2 variant causes a dominant syndrome of lipodystrophy, lipomatosis, infantile steatohepatitis, and hypoglycemia

Abstract

Authors

Vinaya Simha, Mary Kate LoPiccolo, Anna Platt, Rebecca J. Brown, Xandria Johnson, Deanna Alexis Carere, Colleen Donnelly, Matthew T. Snyder, Chao Xing, Thomas P. Mathews, Purva Gopal, Stephen C. Ward, Diana R. Tomchick, Anil K. Agarwal, Ralph J. DeBerardinis, Abhimanyu Garg

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Figure 1

Clinical features, pedigrees, MRI, and liver pathology of patients carrying heterozygous p.Glu230Lys ACAA2 variant; conservation of Glu230, schematic of ACAA2 structure, effect of variant on ACAA2 structure, and plasma acylcarnitine levels.

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Clinical features, pedigrees, MRI, and liver pathology of patients carry...
(A) Photographs of 1 male and 3 FPL female patients showing marked loss of extremity fat, especially distally, and lipomatosis in pubic and dorsocervical regions. (B) FPL and IHH pedigrees. Black symbols represent affected individuals heterozygous for the c.688G>A (G/A) ACAA2 variant; white symbols, unaffected individuals (G/G); and gray symbols, possibly having FPL. Age (years) is above symbols. (C) T1-weighted MRI of 3 patients with FPL showing variable loss of extremity fat but excess dorsocervical fat. (D) Liver histopathology of FPL421.3 (age 18 months) showing micro/macrovesicular steatosis (I) and periportal fibrosis with bridging (II), and of IHH100.6 (age 13 months) (III) showing mitochondria with reduced cristae (yellow arrows) by electron microscopy. Original magnification, ×200 (I), ×40 (II), and ×6,000 (III). (E) Multiple species alignment of human ACAA2 showing conservation of Glu230. (F) Schematic of human ACAA2 with conserved regions shown in red boxes. (G) As compared with wild-type ACAA2 (I, II), the electrostatic potential of the CoA binding surface changes due to variant Glu230Lys (III) (red, negative and blue, positive charge) and it fails to form a salt bridge with Lys234 (IV). (H) Plasma long-chain acylcarnitines (median ± SEM) in affected patients (n = 4; blue bars) versus normal controls (n = 8; orange bars). *P < 0.05, **P < 0.01 (Wilcoxon’s rank sum test).