Kemper AR, Brosco J, Comeau AM, Green NS, Grosse SD, Jones E, Kwon JM, Lam WK, Ojodu J, Prosser LA, Tanksley S. Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation. Genet Med. 2016 Jun 23. doi: 10.1038/gim.2016.68. [Epub ahead of print]
The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.
From the article
X-ALD (OMIM 300100) is a peroxisomal disorder caused by mutations in the ABCD1 gene and is estimated to affect approximately 1 in 42,000 males. Additionally, 1 in 28,000 females are estimated to be heterozygous for an ABCD1 mutation.2 The disorder has a broad phenotype and there is no genotype–phenotype correlation, even within families. Data extrapolated from reported incident cases suggest that the most severe form, childhood cerebral ALD (CCALD), affects between 31 and 57% of hemizygous males. CCALD typically presents between 2 and 10 years of age and is associated with rapid neurologic decline; without treatment, death or severe disability typically occurs within approximately 3 years. For boys who have been determined to have CCALD, treatment is HSCT administered at an early stage of progressive brain involvement. Because most boys with X-ALD will not develop CCALD, and because of the risks associated with HSCT, HSCT is reserved for those with a clear diagnosis of CCALD in its early stages.
Most males with CCALD will also develop adrenal insufficiency. If unrecognized, delayed treatment of adrenal insufficiency can lead to death from even minor illnesses. Little is known about how often signs or symptoms of adrenal insufficiency lead to the diagnosis of X-ALD or about the timing of clinical recognition of adrenal insufficiency relative to the development of cerebral involvement. HSCT treatment for CCALD does not treat adrenal hormone insufficiency; therefore, lifelong hormone replacement therapy is required for all X-ALD patients with adrenal insufficiency.
Affected males with or without CCALD may develop progressive spastic paraparesis, sensory ataxia, and other peripheral nerve and spinal nerve involvement, collectively referred to as adrenomyeloneuropathy (AMN). Relatively little is known about the natural history of AMN. Although the literature indicates that the typical age of AMN onset is after age 30, the neurological symptoms may begin to manifest in later childhood or adolescence. Patients with AMN can develop adrenal insufficiency years or even decades before the disease is recognized based on the onset of neurological symptoms. The course of AMN is highly variable; within a mean of 13 years from recognized onset in adults, the rate of death or severe disability is reported to be 12%. Although AMN is not amenable to HSCT, identification and treatment of adrenal insufficiency in these patients can be lifesaving. No studies that characterized the morbidity associated with delayed recognition of adrenal insufficiency in any type of X-ALD were identified.
Heterozygous females can develop symptoms, usually of AMN, in mid- to late adulthood. Although potentially serious, the impact of heterozygous females manifesting some form of X-ALD was not explicitly considered by the Condition Review Workgroup because of the adult onset of symptoms…
A limitation of the evidence reviewed was that no published study directly compared treatment outcomes for individuals detected presymptomatically (e.g., through newborn screening or family history) with those diagnosed symptomatically. Indirect evidence suggests that earlier age of treatment with HSCT is associated with better outcomes. For example, more advanced disease, as indicated by increased white matter pathology found on brain MRI, is associated with worse outcomes following HSCT. Unpublished data in small numbers of subjects suggest that detection through family testing (i.e., presymptomatic identification of a young child who had a relative previously identified with X-ALD), compared with clinical detection resulting from testing based on signs or symptoms, is associated with less cerebral disease at the initiation of HSCT and also with longer survival and improved neurocognitive outcomes…
An important potential harm of X-ALD newborn screening is direct clinical harm related to treatment following early diagnosis. No recent data are available regarding the mortality risk associated with HSCT for X-ALD. However, among studies reporting transplant follow-up at 1 year or later, the overall 1-year risk of mortality following HSCT appears to be approximately 15% or less. The mortality rate is a function of several factors, including the health of the child at the time of HSCT, the type of transplantation performed, the degree of match between donor and recipient, and the treatment regimen used by those performing the HSCT…
In general, HSCT has a significant risk of mortality and morbidity. For example, a case series of 51 infants treated with HSCT between 1992 and 2010 with long-term follow-up found an overall survival rate of 70% after a median follow-up of 8.9 years, and 30% had acute graft-versus-host disease. Although such harms might occur in children with X-ALD regardless of how the condition was detected, some children who would not have undergone transplantation in the absence of screening might undergo HSCT. There is also the potential harm that individuals could receive inappropriate or ineffective treatment…
Although it is too early to assess whether screening in New York has led to improvements in health outcomes, unpublished evidence from other sources suggests that earlier detection of CCALD can improve survival and neurologic function through HSCT. In addition, screening could identify individuals who will develop adrenal insufficiency, which can be asymptomatic and can be treated with cortisol. Challenges include the poor genotype–phenotype correlation and the need to develop an infrastructure for both screening and follow-up care. Harms of screening include false-positive results, overdiagnosis, and the risks associated with HSCT performed earlier than needed.