Beta Propellar Protein-Associated Neurodegeneration: A Rare Cause of Infantile Autistic Regression and Intracranial Calcification

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of single gene disorders with distinguished clinical phenotypes and definitive imaging findings. Beta propeller protein-associated neurodegeneration (BPAN) is a subentity of NBIA with X linked dominant inheritance. In this report, we describe a girl with autistic regression, seizures, intracranial calcification, iron accumulation in substantia nigra, and globi pallidi, and diagnosis of BPAN was established based on the identification of previously described disease causing variant in WD repeat domain 45 (WDR45) gene encoding for β propeller protein. This is the first genetically proven case from India. BPAN is an underrecognized disorder and must be considered as a differential diagnosis in children with atypical Rett features and should be enlisted among the causes for autistic regression and intracranial calcification. Pediatricians must be aware of this rare entity for establishing early diagnosis, prognostication, and genetic counseling. Treatment is usually supportive. More research is needed to explore drugs in the management of BPAN that can facilitate the autophagy and promotes cytoprotection.

Keywords

BPAN - autistic regression - intracranial calcification - brain iron accumulation

Author's Contribution

Sangeetha Yoganathan, Venkateswaran Rajaraman, and Maya Thomas provided clinical care to the patient. Sangeetha Yoganathan prepared the initial report. Gautham Arunachal and Sumita Danda established the molecular diagnosis and revised the report. Sniya Valsa Sudhakar prepared the images and revised the report. The report was critically reviewed by Maya Thomas. All authors approved the final report.

• References

• 1 Haack TB, Hogarth P, Kruer MC , et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am J Hum Genet 2012; 91 (6) 1144-1149
• 2 Haack TB, Hogarth P, Gregory A, Prokisch H, Hayflick SJ. BPAN: the only X-linked dominant NBIA disorder. Int Rev Neurobiol 2013; 110: 85-90
• 3 Hayflick SJ, Kruer MC, Gregory A , et al. β-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. Brain 2013; 136 (Pt 6): 1708-1717
• 4 Okamoto N, Ikeda T, Hasegawa T , et al. Early manifestations of BPAN in a pediatric patient. Am J Med Genet A 2014; 164A (12) 3095-3099
• 5 Ichinose Y, Miwa M, Onohara A , et al. Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN). Neurol Clin Pract 2014; 4 (2) 175-177
• 6 Van Goethem G, Livingston JH, Warren D, Oojageer AJ, Rice GI, Crow YJ. Basal ganglia calcification in a patient with beta-propeller protein-associated neurodegeneration. Pediatr Neurol 2014; 51 (6) 843-845
• 7 Saitsu H, Nishimura T, Muramatsu K , et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet 2013; 45 (4) 445-449 , e1
• 8 Dusi S, Valletta L, Haack TB , et al. Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation. Am J Hum Genet 2014; 94 (1) 11-22
• 9 Wu YW, Hess CP, Singhal NS, Groden C, Toro C. Idiopathic basal ganglia calcifications: an atypical presentation of PKAN. Pediatr Neurol 2013; 49 (5) 351-354
• 10 Tennison MB, Bouldin TW, Whaley RA. Mineralization of the basal ganglia detected by CT in Hallervorden-Spatz syndrome. Neurology 1988; 38 (1) 154-155
• 11 Goldberg W, Allen N. Nonspecific accumulation of metals in the globus pallidus in Hallervorden-Spatz disease. Trans Am Neurol Assoc 1979; 104: 106-108
• 12 Paudel R, Li A, Wiethoff S , et al. Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy. Acta Neuropathol Commun 2015; 3 (1) 39