BCAP31‐associated encephalopathy and complex movement disorder mimicking mitochondrial encephalopathy

Abstract

BCAP31, encoded by BCAP31, is involved in the export of transmembrane proteins from the endoplasmic reticulum. Pathogenic variants in BCAP31 results in global developmental delay, dystonia, deafness and dysmorphic features in males, called deafness, dystonia, and cerebral hypomyelination (DDCH) syndrome. We report a new patient with BCAP3-associated encephalopathy, DDCH syndrome, sensorineural hearing loss, generalized dystonia, and choreoathetosis. This 3.5-year-old boy had microcephaly and failure to thrive within the first 3 months of life. His brain MRI showed bilateral increased signal intensity in globus pallidus at age 3 months raising the suspicion of mitochondrial encephalopathy. His muscle biopsy revealed pleomorphic subsarcolemmal mitochondria collection in electron microscopy. Respiratory chain enzyme activities were normal in muscle. He was enrolled to a whole exome sequencing research study, which identified a hemizygous likely pathogenic truncating variant (c.533_536dup; p.Ser180AlafsX6) in BCAP31, inherited from his mother, who had sensorineural hearing loss and normal cognitive functions. We report a new patient with BCAP31-associated encephalopathy, DDCH syndrome, mimicking mitochondrial encephalopathy. We also report a heterozygous mother who has bilateral sensorineural hearing loss. This patient's clinical features, muscle histopathology, brain MRI features, and family history were suggestive of mitochondrial encephalopathy. Whole exome sequencing research study confirmed the diagnosis of BCAP31-associated encephalopathy, DDCH syndrome.

Genetic landscape of pediatric movement disorders and management implications

“…Abnormal brain MRI of 8 patients is demonstrated in figure 2 . Abnormal brain MRI of 2 patients (patient 4 8 and patient 24 10 ) were reported previously.…”

“…Ten patients had one of the inherited metabolic disorders, including glucose transporter 1 (GLUT1) deficiency (n = 1), neuronal ceroid lipofuscinosis type 2 (n = 2), SURF1 -associated Leigh disease (n = 1), X-linked pyruvate dehydrogenase complex (PDHC) deficiency (n = 1), dilated cardiomyopathy ataxia syndrome (3-methylglutaconic aciduria) due to homozygous DNAJC19 likely pathogenic variant (n = 1), 8 mitochondrial encephalopathy due to mitochondrial ND3 likely pathogenic variant (n = 1), riboflavin transporter type 2 deficiency by homozygous likely pathogenic variant in SLC52A2 (n = 1), mitochondrial 3-hydroxy-3-methylglutaryl (HMG) CoA synthase 2 deficiency (n = 1), PDHC E3 deficiency (n = 1). In the remaining 16 patients, one of the neurogenetic disorders were identified, including STXBP1 -associated epileptic encephalopathy (n = 4) (3 patients were reported previously 9 ), SCN2A -associated epileptic encephalopathy (n = 1), 9 SLC9A6 -associated intellectual disability (Christianson syndrome) (n = 1), 9 CACNA1A -associated epileptic encephalopathy (n = 1), ataxia telangiectasia (n = 2), KCNA2 -associated epileptic encephalopathy (n = 1), CAMTA1 -associated cerebellar ataxia (n = 1), ATP1A3 -associated alternating hemiplegia and dystonia (n = 1), Allan-Herndon-Dudley syndrome (MCT8 - specific thyroid hormone cell membrane transporter deficiency; n = 1), BCAP31 -associated encephalopathy, deafness, dystonia, and cerebral hypomyelination syndrome (n = 1), 10 CTNNB1 -associated encephalopathy (n = 1), and SLC13A5 -associated epileptic encephalopathy (n = 1).…”

BCAP31, a cancer/testis antigen-like protein, can act as a probe for non-small-cell lung cancer metastasis

“…As an evolutionarily conserved molecule, the BCAP31 protein contains three predicted transmembrane segments within its amino terminus 12 , and has been implicated in the sorting of a diverse range of ER membrane proteins, as well as participating in the transportation of various molecules from the ER to the Golgi apparatus 13 . As a substrate of caspase, BCAP31 participates in the crosstalk between ER and mitochondria to regulate apoptosis 14 . After being defined as a novel CTA-like protein, BCAP31 has been correlated with hepatocellular carcinoma and breast cancer 15,16 .…”

De novo mutation and skewed X‐inactivation in girl with BCAP31 ‐related syndrome

“…While whole exome sequencing has been successful in identifying some causal mutations, most cases remain unsolved. Since 2012, multiple groups have reported that males with hemizygous defect in BCAP31 gene on Xq28 involving splicing site mutations, nonsense, or small indels result in severe phenotypes such as deafness, dystonia, and cerebral hypomyelination (DDCH; MIM# 300475) or contiguous ABCD1/DXS1375E deletion syndrome (Albanyan, Al Teneiji, Monfared, & Mercimek‐Mahmutoglu, 2017; Cacciagli et al, 2013; Rinaldi, Van Hoof, Corveleyn, Van Cauter, & de Ravel, 2020; Shimizu et al, 2020; Vittal, Hall, & Berry‐Kravis, 2015; Vittal, Hall, Dames, Mao, & Berry‐Kravis, 2016; Whalen et al, 2019). These phenotypes are also found with microdeletions between SLC6A8 and ABCD1 or partial deletion of SLC6A8 ‐ BCAP31 (Calhoun & Raymond, 2014; van de Kamp et al, 2015; Osaka et al, 2012).…”