Ep143: Newborn Screening for X-linked Adrenoleukodystrophy: Identification of Isodisomy of X in an Affected Female Infant

X-linked Adrenoleukodystrophy (X-ALD) is a rare genetic disorder due to aberrant peroxisomal metabolism of very long chain fatty acids (VLCFAs). The ABCD1 gene is responsible for shuttling VLCFAs into the peroxisomes. Variants within this gene disrupt this process, causing VLCFAs to accumulate at toxic levels within the cells, specifically in the adrenal cortex and central nervous system. The clinical spectrum of X-ALD varies widely and can include childhood cerebral X-ALD (ccALD), adrenomyeloneuropathy (AMN), adrenal insufficiency (also known as Addison’s disease) and asymptomatic forms. X-ALD follows an X-linked pattern of inheritance, and males are more severely affected. Given the availability of comprehensive care guidelines for X-ALD, it is important to identify affected individuals early in life to enact appropriate surveillance. In June 2019 X-ALD was added to the Illinois state newborn screening (NBS) panel. NBS for X-ALD is conducted through measurement of C26:0-lysophosphatidylcholine (LPC) on dried blood spots. Infants with elevated C26:0-LPC (>0.18 umol/L) are referred to a metabolic specialist for further diagnostic evaluation, including VLCFA profile and molecular testing. Since full implementation, our center has been involved in the evaluation and management of 15 NBS patients diagnosed with X-ALD and other peroxisomal disorders, including Zellweger spectrum disorder. Affected males and heterozygous females of X-ALD had C26:0-LPC levels ranging from 0.19-0.44 umol/L, while other peroxisomal disorders had C26:0-LPC levels >0.90 umol/L. We report on a unique case identified in our NBS cohort. A female infant was brought to clinical attention due to elevated C26:0-LPC (0.76, RR: <0.18 umol/L). Follow up VLCFA profile was abnormal (C26:0: 1.600, RR: 0.23±0.09 ug/mL; C24:0/C22:0: 1.727, RR: 0.84±0.10; C26:0/C22:0: 0.104, RR: 0.01±0.004), consistent with a defect in peroxisomal fatty acid oxidation. Molecular testing revealed a homozygous pathogenic variant in ABCD1 (c.1166G>A, p.R389H). Parental testing revealed mother to be heterozygous of the variant; presumed father was negative. A SNP array was obtained, revealing isodisomy of X. Isodisomy is rare a phenomenon whereby an individual inherits two identical copies of one chromosome homologue from a single parent, rather than biparental inheritance. The true incidence of isodisomy is likely underreported, as only individuals with clinical presentations due to imprinting disorders or recessive diseases will have testing sensitive enough to identify this type of uniparental disomy. Isodisomy of X has been observed to cause disease in females with other X-linked disorders (notably, Duchenne Muscular Dystrophy). Per review of the available literature, four females homozygous for a familial variant in ABCD1 have been reported in a large consanguineous family: two females were reported to be asymptomatic, one was reported to have AMN, and the other was deceased by age 11 due to ccALD. Given the likelihood of manifesting disease, our patient has undergone screening according to guidelines for affected male patients in the first two years of life. Adrenal function has revealed normal ACTH and cortisol levels at 2, 10, and 17 months of age. Baseline brain MRI at 16 months was normal. Her growth has been normal up to her most recent visit at 21 months of age. She was enrolled in speech and developmental therapy due to mild developmental delay, unlikely related to X-ALD given age and normal imaging. Her mother is unaffected at age 22 and there is no reported family history of X-ALD, although cascade testing of maternal family members is still in process. Our patient will continue to be followed over time with serial MRI scans and adrenal screening, as per standard of care for affected males. To our knowledge, this is the first reported case of a female with X-ALD due to isodisomy of X. The existing literature on the phenotypic presentation of females with homozygous ABCD1 variants is limited to presentations observed within a single pedigree. In order to ensure comprehensive care, our long-term management strategy for this patient will follow the current guidelines for surveillance in affected males. Population based-screening for X-ALD through the newborn screen will continue to identify unique presentations of this disorder, further enriching the current knowledge base for X-ALD.