Advanced Diagnostic System and Introduction of Newborn Screening of Adrenoleukodystrophy and Peroxisomal Disorders in Japan

Abstract

We established a diagnostic system for adrenoleukodystrophy (ALD) and peroxisomal disorders (PD) over 35 years ago in Japan, and have diagnosed 237 families with ALD and more than 100 cases of PD other than ALD using biochemical and molecular analyses. In particular, since the only treatment for the cerebral form of ALD is hematopoietic stem cell transplantation at an early stage of onset, we have developed a protocol for the rapid diagnosis of ALD that can provide the measurements of the levels of very-long-chain fatty acids in the serum and genetic analysis within a few days. In addition, to improve the prognosis of patients with ALD, we are working on the detection of pre-symptomatic patients by familial analysis from the proband, and the introduction of newborn screening. In this review, we introduce the diagnostic and newborn screening approaches for ALD and PD in Japan.

Newborn Screening for X-Linked Adrenoleukodystrophy: Review of Data and Outcomes in Pennsylvania

“…In Japan, X-ALD diagnoses have long occurred through a streamlined diagnostic approach at a single referral center [ 51 ]. That system screened asymptomatic relatives of known X-ALD cases to facilitate presymptomatic diagnosis but ultimately relied on the identification of symptomatic individuals as a starting point [ 51 , 52 ]. In April 2021, a pilot study of NBS for X-ALD in Japan was initiated in which only results from babies with typical male-appearing external genitalia at birth were recorded [ 52 ].…”

“…That system screened asymptomatic relatives of known X-ALD cases to facilitate presymptomatic diagnosis but ultimately relied on the identification of symptomatic individuals as a starting point [ 51 , 52 ]. In April 2021, a pilot study of NBS for X-ALD in Japan was initiated in which only results from babies with typical male-appearing external genitalia at birth were recorded [ 52 ]. Although rare, this presents an interesting challenge in cases of atypically appearing external genitalia or gonadal dysgenesis, both of which can obscure identification of babies with a single X chromosome.…”

Newborn Screen for X-Linked Adrenoleukodystrophy Using Flow Injection Tandem Mass Spectrometry in Negative Ion Mode

“…The previously established C26:0-LPC measurement in DBSs by negative mode LC-MS/MS methods has a satisfactory screening false positive rate, but it takes three minutes to process each specimen [ 27 , 28 , 29 ]. A positive mode LC-MS/MS method was reported with a runtime of two minutes per sample and features a low false positive rate [ 30 , 31 ]. The positive mode FIA-MS/MS method takes fewer than two minutes to process each specimen, but its false positive rate is of concern [ 2 , 23 , 24 ].…”

“…A 3 min, negative mode LC-MS/MS method, introduced in 2012, eliminated detection of these interferences altogether, which has dramatically led to no false positive identifications when a borderline cutoff is employed that triggers repeat DBS collection and testing [ 27 , 28 , 29 ]. Additional LC method optimizations yielded two-minute sample analyses using positive mode LC-MS/MS that maintained low false positive rates similar to New York’s second tier testing [ 30 , 31 ]. Here we report a FIA–MS/MS X-ALD screen using newborn DBSs that is adapted from the negative mode LC-MS/MS assay.…”

High incidence of null variants identified from newborn screening of X-linked adrenoleukodystrophy in Taiwan

“…In some NBS programs, C26:0-LPC is used as the only screening marker, and those with abnormal C26:0-LPC levels were retested before confirmatory tests [ 14 , 15 ]. Others measured both C26:0-LPC and C24:0-LPC and referred those with positive screening results from either test [ 13 , 16 ]. The sequencing of the ABCD1 gene was deemed critical for the diagnosis of ALD [ 17 ] and is included by most NBS programs for confirmatory testing.…”