How do you connect a dried blood spot from the heel of a newborn to a life-changing treatment in under a month? The answer to this question is collaboration and expertise. The Georgia Department of Public Health tests every baby in the state for 35 conditions that if treated in the first year of life greatly improves their quality of life and health. Recent additions to the screen are two progressive and life-threatening neurogenetic conditions: X-linked adrenoleukodystrophy and spinal muscular atrophy.
Made famous by the movie “Lorenzo’s Oil”, X-linked adrenoleukodystrophy (X-ALD) is a progressive, X-linked recessive leukodystrophy caused by the deficiency of the adrenoleukodystrophy protein (ALDP) due to mutations in the ABCD1 gene. Missing ALDP results in the inability to transport specific molecules into the peroxisome and break down Very Long Chain Fatty Acids (VLCFA). These VLCFAs accumulate and damage the nervous system’s white matter and adrenal cortex (Moser et al., 2001; Engelen et al., 2012; Steinberg et al., 2015).
The abnormal accumulation of VLCFA results in a spectrum of disease severity that varies in the age of onset of clinical symptoms, rate of progression and neurological impact. It is not possible to predict symptoms based on VLCFA levels or mutation, so the full range of phenotypic expression can vary within the same family or sibship (Moser et al., 2000).
The variable presentation of the disease in males is usually divided into three broad categories: childhood cerebral form (CALD), adrenomyeloneuropathy (AMN) and Addison disease only (Engelen et al., 2012; Steinberg et al., 2015). These three clinical presentations are not mutually exclusive. Approximately 86% of males with X-ALD will develop Addison’s disease or some kind of adrenal insufficiency, often occurring in infants and young children prior to the onset of neurologic symptoms (Dubey et al., 2005).
If undiagnosed, delayed treatment of adrenal insufficiency can lead to death from even minor illnesses. These individuals may later go on to develop the cerebral form or, most often, the AMN form of X-ALD (Steinberg et al., 2015).
In AMN, symptoms most often begin in the late 20s to 30s and include slowly progressive paraparesis, peripheral neuropathy, bowel and bladder disturbance, and sexual dysfunction. Almost all males and most female carriers will develop myelopathy or peripheral neuropathy (Engelen et al., 2014). A portion of individuals with X-ALD, 35-40%, will develop the childhood cerebral form (Mallack et al., 2019 and Moser et al., 2001).
CALD is associated with an inflammatory demyelination of the brain with symptoms beginning between ages 2 and 10 years of age (Mallack et al., 2019 and Moser et al., 2001). Symptoms may initially resemble attention deficit or hyperactivity disorder; however, progressive impairment of cognition, behavior, vision, hearing and motor function follow the initial symptoms and progress rapidly to a vegetative state or death within 2-3 years (Mallack et al., 2019). About 20% of older males with AMN develop cerebral disease (Engelen et al., 2012).
Treatment for all forms of ALD begins with monitoring adrenal function and starting corticosteroid replacement therapy as indicated. Referral to an endocrinologist on diagnosis and monitoring cortisol and ACTH levels every 3-4 months for the first 2 years and then every 4-6 months thereafter is recommended (Regelmann et al., 2018).
In the childhood-onset forms of ALD, signs of the disease can be detected on MRI of the brain prior to the onset of neurologic symptoms, and scoring symptoms have been developed to rate the severity of the disease on MRI from 0 to 34 (Loes et al., 1998). Although still considered experimental and controversial, reduction of the VLCFA hexacosanoic acid (C26:0) by Lorenzo’s oil (a mixture of erucic and oleic acids) may reduce the risk of developing MRI abnormalities and, therefore, childhood cerebral disease (Moser et al., 2007; Engelen et al., 2012). Most centers consider the efficacy unproven and do not recommend the use of the oil.
Hematopoietic stem cell transplantation (HSCT) has been successful in reducing the disease progression in affected boys and adolescents in early stages of ALD who have evidence of early, presymptomatic brain involvement on MRI with a 92-95% survival rate (Peters et al., 2004; Miller et al., 2011). However, in a study of 62 patients who underwent transplant with early CALD, the majority of those with MRI scores of 4.5-9, showed a decline in at least one area of neurocognitive testing post-transplant (Mallack et al., 2019). These studies support the need for early identification and screening for transplant.
More recently, gene therapy has been researched for CALD with promising results. The largest research study on gene therapy in ALD was the STARBEAM study, in which 17 boys with CALD were treated with autologous CD34+ stem cells corrected ex vivo with a lentiviral vector carrying functional ABCD1. After 2 years, 15 of the boys were still alive and without major disabilities. On MRI, brain lesions also stabilized. The results indicate that gene therapy leads to stabilization/halting of clinical symptoms and brain lesions (Mallack et al., 2019). Benefits over HSCT may include no need for a matched donor, the avoidance of graft vs. host and no need for immunosuppression therapy, as the procedure uses autologous stem cells. Research is ongoing for CALD gene therapy, so it is only available at certain centers through a clinical trial.
In all forms of ALD, early identification of the disease and early initiation of monitoring and treatment improves clinical outcomes. As such, early diagnosis is essential. In addition to screening for adrenal insufficiency, screening for cerebral involvement with an MRI of the brain is recommended to begin at 12 months and repeated yearly until age 3. From age 3-12 years old, males should have a screening MRI brain with contrast every 6 months. After age 12, MRIs should be obtained yearly as the risk for CALD decreases (Aidan Jack Seeger Foundation, 2019).
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord and the brain stem nuclei. The onset of weakness ranges from prenatal to adolescence or young adulthood. The muscle weakness is progressive and symmetric with the proximal muscles being affected before the distal muscles (Prior et al, 2000). Individuals with SMA will typically have reduced or absent deep tendon reflexes and hypotonia. The most severe infantile forms are uniformly and rapidly fatal without specific treatment (Muralidharan et al, 2011).
SMA is caused by a deficiency of the SMN protein that is essential for the survival of motor neurons, hence its name survival motor neuron protein. Before 2016, the only available treatments for SMA were nutritional support, physiatry, orthopedic management and ventilator support. While these continue to be important aspects of care for this disease and supportive therapies improve quality and length of life, they do not treat the underlying disease process (Prior et al, 2000).
However, in the last several years, there has been tremendous growth in the availability of disease-modifying therapies for this condition. In late 2016, a treatment for all types of SMA was approved by the U.S. Food and Drug Administration (FDA) called nusinersen (SPINRAZA TM). This drug is delivered intrathecally every 4 months, after a loading period, and functions by increasing the amount of SMN protein the body naturally produces.
In mid-May 2019, the FDA approved the first gene therapy to treat children less than two years of age with spinal muscular atrophy. Onasemnogene abeparvovec (ZOLGENSMA™) is a single-dose, viral-vector therapy delivered through infusion. It functions by providing an additional copy of the DNA that individuals with SMA are born without. These DNA instructions are used by the body to create more copies of the SMN protein.
In August of this year, the FDA approved a third drug for the treatment of SMA for individuals over 2 months of age. Risdiplam (EVRYSDI™) is an oral small molecule therapy, which also functions by encouraging the body to create more SMN protein.
Beginning with SMA mouse models and continuing into human studies, it has been shown that there is a therapeutic window over the first 3 months of life during which increased SMN protein is needed for motor neuron survival and when lacking a substantial denervation occurs (Le, 2011; Farrar, 2017). For patients to derive the maximal benefit from promising new treatments, intervention is almost certainly required before disease manifestations such as muscle weakness and atrophy occur. Based on the availability of an FDA-approved medication and data that found improvements in treated patients, early identification of the disease and early initiation of monitoring and treatment is essential.
Most of us think about newborn screening as a simple test. In reality, an intricate system of dedicated medical professionals are charged with ensuring children move through the screening system quickly and efficiently. The diagram of what it takes to move from a newborn baby’s heel to the first life-impacting treatment looks like a complicated blueprint for a new home build, but at every step, the Georgia Newborn Screening team is there to help.
The Georgia Public Health Laboratory is full of laboratory professionals trained to quickly accession samples from all over the state and begin the multitude of tests immediately. Time-sensitive results are handled with kid gloves to ensure children with high-risk results are moved into the follow-up system in a matter of days.
Upon receipt of these critical results, the hard-working short-term follow-up team of nurses and genetic counselors at the Emory School of Medicine’s Department of Human Genetics immediately reach out to the pediatrician of record. Sometimes that pediatrician is familiar with the family and can quickly bring the family in for evaluation. Sometimes they have yet to meet their newborn patient. Faced with the latter situation, they may feel like they are Ethan Hunt or Jason Bourne racing against time to find the baby at risk and confirm their diagnosis.
Keeping in mind that not all babies with positive newborn screens are actually affected by the genetic condition for which they tested positive, each case is handled with a skillful mix of urgency and reassurance. At the same time the newborn screening follow-up team is working to bring in the baby for evaluation, they are also notifying the genetic counselor, medical geneticist and neurology teams to pave the way for a fast diagnostic process and a caring and comprehensive discussion with the family about how this condition has just changed their lives and what happens next.
Genetic counselors provide a background on the natural history of the disease, evaluate genetic testing options, collect family histories to determine who else might be at increased risk, review inheritance patterns, provide resources and connect the families to other advocates who have taken their journey before them. Medical geneticists, genetic advance practice nurses and neurologists discuss treatment options and how to develop the best care plans. The neurology team organizes the chosen treatment and/or monitoring plan using cutting-edge advancements in imaging and therapy. All together, they try to make a parent’s worst nightmare into a journey in which they can understand and play an active role as things move along.
Both X-ALD and SMA, if not caught very early, can result in profound disability and a shortened life span. The reward for all this hard work? The difference between a baby who moved quickly through this fast-moving collaborative process and one who, just a few years ago, would have presented in our clinics already in the thick of their disease, with very few options in front of them.
1. Aidan Jack Seeger Foundation, “A Parent’s Guide: A Guide to Living with Adrenoleukodystrophy (ALD.)” ALD Newborn Screening, Aidan Jack Seeger Foundation, 2019. https://aldnewbornscreening.org/userFiles/uploads/Resources/ALD_brochure_2020_1-2_DL.pdf
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4. Farrar, M. A., Park, S. B., Vucic, S., Carey, K. A., Turner, B. J., Gillingwater, T. H., … Kiernan, M. C. (2017). Emerging therapies and challenges in spinal muscular atrophy. Annals of Neurology, 81(3), 355–368. http://doi.org/10.1002/ana.24864.
5. FDA press release on nusinersen approval.
Accessed on November 23, 2020.
6. FDA. FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality
https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease. Accessed on November 23, 2020.
7. FDA Approves Oral Treatment for Spinal Muscular Atrophy
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