A case series of adrenoleukodystrophy in children conceived through in vitro fertilization with an egg donor

Abstract

Objective

To report 3 cases of adrenoleukodystrophy (ALD) in children conceived by in vitro fertilization (IVF) and egg donation.

Design

A case report.

Patient(s)

Patients aged 4–5 years old, evaluated by the University of Minnesota Leukodystrophy Center, who were diagnosed with ALD after being conceived by IVF with oocytes provided by the same donor.

Intervention(s)

One patient received a hematopoietic stem cell transplant from a human leukocyte antigen-matched donor, and 1 patient received autologous lentiviral corrected hematopoietic cells. The disease state in 1 patient was unfortunately too advanced for effective treatment to be administered.

Main Outcome Measure(s)

Progression of disease after diagnosis or treatment was observed by cerebral magnetic resonance imaging and monitoring the development or advancement of any cognitive, adaptive, and motor deficits.

Result(s)

Patients who received a transplant for ALD successfully experienced little to no disease progression at least 6 months to 1 year after treatment.

Conclusion(s)

These 3 cases of transmission of ALD through oocyte donation and IVF highlight the potential need to implement more comprehensive genetic screening of gamete donors to prevent the transfer of rare but severe genetic diseases through IVF. Further, these cases highlight limitations in carrier screening guidelines that limit reportable variants to pathogenic and likely pathogenic variants.

Within women aged 15 to 34 years old, infertility rates are approximately 7%–9%. That rate increases to 25% in women aged 35–39 years old and even further to 30% in women aged 40–44 years old (1). Approximately 21% of couples experiencing infertility will use in vitro fertilization (IVF) as a means to conceive (1). Current anonymous donor carrier screening guidelines, updated in 2021, recommend donor screening for a limited number of genetic disorders, including cystic fibrosis, spinal muscular atrophy, and thalassemias/hemoglobinopathies with unspecified guidance regarding when expanded carrier screening may be appropriate (2). Adrenoleukodystrophy (ALD), an X-linked disorder associated with variants in the ABCD1 gene, is not yet regularly screened for before the collection of donor gametes (2).

A recent update to carrier screening guidance recommends ABCD1 testing as a part of routine screening for pregnant persons and individuals planning pregnancy, advising that pathogenic and likely pathogenic variants be reported (3). Screening recommendations in the setting of gamete donation are less clear. The Food and Drug Administration requirements for gamete donor screening do not include genetic screening, whereas the American Society for Reproductive Medicine advises screening all gamete donors for a select few genetic conditions which does not include ALD, only indicating that “additional expanded carrier screening may also be appropriate” (2).

Adrenoleukodystrophy is a metabolic disorder characterized by an inability to appropriately degrade very long-chain fatty acids (VLCFAs) (4). The VLCFAs accumulate to toxic levels in the cytosol of the cells, particularly affecting the central nervous system, adrenal glands, and the testes, often leading to a neuroinflammatory or demyelinating condition (cerebral ALD, CALD), primary adrenal insufficiency, and primary hypogonadism, respectively (4). Because the variant leading to ALD is inherited in an X-linked manner, males are more affected by ALD. Females with an ALD mutation have a 50% chance of passing down the disease-causing variant with each pregnancy (5). The minimum combined frequency of hemizygotes and heterozygotes for X-ALD in the United States is estimated at 1 in 16,800 (6).

There are 3 different clinical phenotypes of ALD in males: cerebral ALD (CALD), adrenomyeloneuropathy (AMN), and Addison disease. Of the different forms of ALD, childhood CALD accounts for 35% of affected males (4) and is the most severe, with symptoms typically presenting between ages 4 and 8 years (5). Without early diagnosis and treatment, progressive CALD often leads to severe disability and eventually death within 1–2 years (4). Addison disease, also termed primary adrenal insufficiency, often presents in ALD as a consequence of adrenal glands damage, leading to adrenocortical insufficiency and can be life-threatening with a potentially untreated adrenal crisis. Males with ALD are closely monitored for adrenal dysfunction to evaluate if treatment for Addison disease is needed (5).

Females who are heterozygous for ABCD1 mutations and affected males often develop age-related myelopathy, referred to as AMN in males (7). The onset of symptoms is typically after 30 years of age and may include slowly progressive gait difficulties, issues with bladder and bowel control, mild spasticity, as well as possible peripheral neuropathy and neuropathic pain (8). Adrenoleukodystrophy can be diagnosed in males using biochemical or molecular testing of the ABCD1 gene.

Hematopoietic stem cell transplant (HSCT) is currently the only accepted treatment for stabilizing demyelination in CALD (9). However, for HSCT to be the most effective in treating ALD, intervention should occur at an early stage of the disease (Loes < 10 preferably) (10, 11, 12, 13). Previous transplants in advanced CALD patients have led to an increased risk for transplant-related complications, often intensifying the disease progression (10).

Identifying HSCT donors well-matched for human leukocyte antigen alleles is important to decrease risks for graft-versus-host disease and mortality, as has been described elsewhere (14). In addition to standard allogeneic HSCT, there are new prospects for the use of gene therapy to treat ALD. Preliminary results suggested that Lenti-D gene therapy could be used effectively and safely as an alternative to allogeneic HSCT in patients with ALD, eliminating the need for finding a well-matched donor (9).

We report 3 cases of ALD that were transmitted through IVF and egg donation. These cases highlight a potential need for egg donors to undergo more genetic scrutiny for X-linked conditions. Further, these cases highlight limitations of the existing guidelines for carrier screening in general for X-linked conditions in pregnant patients and those making reproductive planning decisions.

Materials and methods

We describe families who presented to the University of Minnesota Leukodystrophy Center with a diagnosis of childhood ALD for workup, diagnosis, and treatment options which were subsequently found to have resulted from oocytes from the same donor. Informed consent was obtained from all parents or guardians and approved by the Committee on the Use of Human Subjects in Research at the University of Minnesota.

Case 1

A 4-year-old boy presented with unilateral exotropia. He and his twin sister had been conceived through in vitro fertilization with an egg donor and were born at 35 weeks gestation but had otherwise been healthy with appropriate development. Exotropia responded partially to patching; however, his parents noted slowly progressive changes to his vision. His depth perception became more impaired and was implicated in accompanying changes to balance and coordination. At 5 years of age, he presented with fever and acute mental status changes and was diagnosed with parainfluenza. While hospitalized, the patient was noted to be agitated with waxing and waning orientation, needing assistance to stand up, and with poor oral intake.

A head computed tomography was performed that showed diffuse white matter disease, suggestive of a leukodystrophy. This was subsequently confirmed with brain magnetic resonance imaging (MRI), which showed hyperintensity in the bilateral parieto-occipital white matter and brain stem with contrast enhancement (estimated Loes score of 14), consistent with CALD (Fig. 1A) (4). Biochemical testing revealed elevated VLCFAs, and genetic testing confirmed a variant of uncertain significance (VUS) in the ABCD1 gene for the sequence variant c.1247C>G, resulting in the predicted amino acid substitution p.Thr416Arg. Adrenal function testing confirmed adrenal insufficiency. His neurologic function score (NFS) was 3 (1 point each for field cuts, delayed auditory processing, and hyperreflexia).

Figure 1.

Axial FLAIR images from 3 different boys showing different severity of disease at the time of CALD diagnosis. A. Extensive involvement of CALD, extending further into the subcortical white matter of the temporal and parietal lobes and into the frontal white matter in patient 1. B. Abnormal signal throughout the splenium of the corpus callosum extending symmetrically into the periventricular parietal white matter in patient 2. C. Faint abnormal signal in the splenium of the corpus callosum (dashed white arrow) in Patient 3.

FLAIR= Fluid attenuated inversion recovery; CALD= cerebral adrenoleukodystrophy.

After the initial hospitalization that led to his diagnosis of ALD, the patient improved, returning almost back to prehospitalization baseline, although his NFS was noted as such: 1 point for field cuts, 1 point for processing, and 1 point for suspected hyperreflexia for a total of 3 points. Because of the advanced stage of his CALD, HSCT was not recommended, and treatment was focused on supportive care. The patient continued to progress neurologically and died approximately 5 months after the initial diagnosis.

Case 2

A 4-year-old boy conceived by in vitro fertilization using a donor egg was evaluated after his parents were notified by their reproductive medicine clinic that another child conceived from the same egg donor was diagnosed with ALD. The child was developmentally normal with only 1 significant health episode of a febrile seizure in the context of left lower lobe pneumonia at age 2. An MRI showed T2 hyperintensities near the corpus callosum, extending into the adjacent parietal white matter and somewhat posteriorly, and contrast enhancement at the leading edge with mild restricted diffusion. The Loes score was 4 with an NFS of zero (Fig. 1B). Testing showed elevated VLCFAs, with additional genetic testing confirming the same ABCD1 gene VUS: c.1247C>G. The patient was diagnosed with early-stage CALD. Other biochemical testing confirmed adrenal insufficiency. Neuropsychological testing showed some difficulty with visual-spatial problem-solving but otherwise preserved function.

The patient was found to be a candidate for HSCT. Approximately 2 months after his diagnosis of CALD, he received a single umbilical cord blood transplant from an 8/8 human leukocyte antigen-matched donor after myeloablative conditioning. Posttransplant, the patient developed mucositis and had a gastrostomy tube placed. This was kept after he also developed an aversion to oral medications. Otherwise, the patient did not experience major transplant complications.

On day 28 after HSCT, an MRI scan showed near complete resolution of gadolinium and minimal T2 progression. On day 42, there was 100% donor chimerism observed in the CD33 fraction and 79% in CD3. An MRI at day 100 after HSCT showed improvements in T2 hyperintensity and diffusion restriction in the splenium of the corpus callosum, the parietal, and the occipital white matter bilaterally and symmetrically. Six months after HSCT, his parents reported that the patient continued to meet developmental milestones, and MRI showed no progression of cerebral disease. An MRI, 1 year after HSCT, showed minimal progression in the left temporoparietal region, as well as symmetric progression extending into the dorsolateral midbrain, and the boy continued to do well neurodevelopmentally.

Case 3

A 5-year-old boy conceived through IVF using an egg donor was tested for ALD after his parents were notified by their reproductive medicine clinic that another child conceived from the same egg donor was diagnosed with ALD. At the time of testing, his parents had some concerns about his neurologic developmental status, as the patient still had urine and stool incontinence. Additionally, the patient’s parents noticed that he had stopped dressing himself because of sensory complaints about clothing textures. They believed he had poor finger strength as well, noticeably when trying to hold pencils or eating utensils. The patient also seemed to have regressed in his independence recently, exhibiting more whiny and clingy behaviors. Retrospectively, at the age of 2, he was hospitalized for dehydration, which his parents believe may have been related to an adrenal crisis, given new concerns about ALD.

Genetic testing found a c.1247C>G (p.Thr416Arg) VUS in the ABCD1 gene. An initial MRI showed baseline subtle T2 hyperintensity in the central portion of the splenium of the corpus callosum without conclusive restricted diffusion or enhancement. The patient was given a Loes score of 1 and an NFS score of 0, but given the lack of contrast enhancement on MRI, he was deemed not to have active CALD (Fig. 1C). A baseline neuropsychologic exam was conducted and found that the patient’s overall intellectual functioning was average, although he did have some weaknesses in working memory and nondominant hand fine motor speed and dexterity.

Shortly after the initial consultation, the patient was hospitalized for an adrenal crisis, with sustained emesis, dehydration, and hypotension. Six months later, a second MRI showed a slight increase in T2 hyperintensity within the center of the splenium. His overall cognitive, adaptive, and motor development was stable; however, he was newly diagnosed with attention deficit hyperactivity disorder.

One year after his initial diagnosis of ALD, the patient was enrolled in the lentiviral gene therapy trial. Overall, his transplant course was uneventful. An MRI at day 30 posttransplant showed an increased size of the T2 hyperintensity in the splenium of the corpus callosum without contrast enhancement or restricted diffusion. At days 60, 100, and 180 posttransplant, his MRIs remained stable.

Discussion

The frequency of hemizygotes and heterozygotes with variants within the ABCD1 gene causing ALD in the United States is estimated at 1 in 16,800 (6). We present 3 distinct cases of carrier transmission of ALD through a single egg donor because of a lack of ABCD1 sequencing before gamete donation and use for IVF. Of the 3 presented cases, 2 patients were diagnosed with CALD.

Early detection of ALD in male patients can allow for life-saving management of adrenal insufficiency and early monitoring for cerebral MRI changes. Compelling research has shown that early diagnosis and intervention improve treatment outcomes after HSCT for patients with CALD (10, 11, 12, 13). Additionally, considering that the goal of treatment is to halt the further development of irreversible neurologic disease (9), these cases further demonstrate the significance of early detection. Because parents were prompted by their current fertility clinic to evaluate their child for ALD before the presentation of major symptoms, 2 of these patients were able to receive treatment during the early stages of the disease and have, thus far, been displaying positive responses to therapy (1 received HSCT, 1 received—gene therapy). It is vital for fertility clinics to have effective methods in place for identifying such situations in which donors are suspected carriers of a genetic disease and inform other potentially affected families in a timely manner.

There have been documented cases of the transfer of other genetic diseases through IVF and egg donation. A case report published in 2021 detailed a patient with Fragile X syndrome who inherited the condition from a clinically unaffected egg donor who was later identified to have a premutation in FMR1 (15). Additionally, in 2014, a case report documented a case of X-linked adrenal hypoplasia congenita in a child conceived by IVF and egg donation (16). Similar reports have also been published regarding children conceived through IVF who were later diagnosed with autosomal recessive disorders, including spinal muscular atrophy, despite reporting no known family history (17, 18). Most investigators called for reconsideration of current screening protocols at fertility clinics for gamete donors (15, 16, 17).

These cases of genetic disorders that were or could have been transferred to individuals through egg donation, in addition to our presented cases, highlight a need to update screening guidelines of gamete donors to strongly advocate for more comprehensive carrier screening for a wide range of genetic conditions similar to carrier screening for individuals pursuing pregnancies with their own gametes. Current American College of Medical Genetics and Genomics guidelines in these cases recommend X-ALD testing be offered to “all pregnant patients and those planning a pregnancy” because of the X-linked inheritance pattern and the prevalence of greater than 1/40,000(3). A recent study demonstrated that expanded carrier screening of gamete donors led to the rejection of 17.6% of donors (19). Roughly half of those rejected carried 1 of the 4 conditions that American Society for Reproductive Medicine guidelines specifically advise should be required or specifically considered for all gamete donors; however, the remaining variants identified in prospective donors would not have been detected based on current screening recommendations (2, 19).

The variant identified in the present cases was initially classified as a VUS—a relatively common occurrence in ALD families because of the high rate of unique, missense variants (43.4%) in these cases (20). This classification complicates the utility of carrier screening for ALD in oocyte donors, as traditional carrier screening only discloses likely pathogenic/pathogenic variants with few exceptions (3). Current guidelines have exceptions suggesting laboratories consider reporting a VUS in a carrier screen when the partner has a known disease-causing variant (21). The same logic should lead to the disclosure of VUS in X-linked disease alleles, especially in conditions with a known incidence of novel missense variants causing disease, because a single variant can cause disease in the offspring. Our cases demonstrate a justification for reporting ABCD1 gene novel, missense variants—which will invariably be classified as VUSs—as a part of carrier screening, especially considering the X-linked inheritance of the disorder, meaning a single variant is sufficient to cause disease in future pregnancies (18).

Conclusion

This study reports 3 cases of ALD in children conceived by IVF and oocyte donation. These cases illustrate gaps in current screening recommendations, highlighting the need for updated recommendations for gamete donor screening. Given the rapid changes occurring in this area of genetic testing, gamete donor screening recommendations should be reviewed regularly, such as on an annual or biannual basis, to maintain clinical relevance. Further, VUS in the ABCD1 gene should be given additional consideration in reporting recommendations given the high incidence of rare, missense variants causing disease and the uniparental origin of the disease. In cases where screening did not occur, and reproductive centers become aware of a child conceived with donor oocytes who has subsequently been diagnosed with an X-linked disorder, a process should be in place for promptly notifying other affected families. These cases also highlight the utility of creating a uniform process for reproductive centers to obtain updated health information on children conceived with donor gametes to determine circumstances when a genetic diagnosis has been made that could impact the health of other children conceived with gametes from the same donor. As our cases demonstrate, prompt action in these circumstances can be critical to the early initiation of life-saving treatment.