Family Perspectives on Newborn Screening for X-Linked Adrenoleukodystrophy in California

X-linked adrenoleukodystrophy (ALD) is caused by gene variants in the ABCD1 gene, resulting in a varied clinical spectrum. Males with ALD present with symptoms ranging from isolated adrenal insufficiency and slowly progressive myelopathy to severe cerebral demyelination. Females who are heterozygous for ALD typically develop milder symptoms by late adulthood. Treatment for adrenal insufficiency associated with ALD exists in the form of cortisol, and cerebral ALD may be treated with stem cell transplantation. Currently, there is no treatment for myelopathy. Since 2013, at least 14 states have added ALD to their newborn screening (NBS) panel, including California in 2016. We examined the impact of a positive NBS result for ALD on families in California. Qualitative interviews were conducted with mothers of 10 children who were identified via NBS for ALD. Interviews were transcribed verbatim and analyzed using thematic analysis by two coders. Mothers felt strongly that ALD should be included on California’s NBS panel; however, many expressed concerns over their experience. Themes included stress at initial phone call, difficulty living with uncertainty, concerns regarding mental health support, and desire for more information on disease progression, treatments and clinical trials. Mothers exhibited diverse coping strategies, including relying on faith, information seeking, and maintaining hope. Mothers’ recommendations for healthcare providers included: educating providers making the initial phone call, providing patient-friendly resources, offering information about ongoing research, and streamlining care coordination. Advice for parents of children with ALD focused on staying hopeful and appreciating the time they have with their children. As more states add ALD to their NBS panel, it is important to improve the current model to promote family resiliency and autonomy

Acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male

Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle defect. While hemizygous males typically present with hyperammonemic coma in infancy, reports of rare late-onset presentations exist, with poor outcomes in males up to 58 years old. Relatives with mutations identical to affected patients often remain asymptomatic, and it is likely that environmental and genetic factors influence disease penetrance and expression. Here, we present our investigation of a patient with late-onset presentation, and we emphasize the potential role of environmental and genetic factors on disease expression. The patient was a previously healthy 62-year-old man who developed mental slowing, refractory seizures, and coma over an 8-day period. Interestingly, the patient had recently used home gardening fertilizers and pesticides. Evaluations for drug and alcohol use, infections, and liver disease were negative. Despite aggressive therapy, blood NH3 concentration peaked at 2,050 μM and the patient died from cerebral edema and cerebellar herniation. Analysis of the OTC gene showed a Pro-225-Thr (P225T) change in exon 7, a mutation that has been previously implicated in OTC deficiency. This case illustrates that OTC deficiency can cause acute, severe hyperammonemia in a previously healthy adult and that the P225T mutation can be associated with late-onset OTC deficiency. We speculate that exposure to organic chemicals might have contributed to the onset of symptoms in this patient. This case also emphasizes that persistent hyperammonemia may cause irreversible neurologic damage and that after the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle disorders and other causes of hyperammonemic encephalopathy

Acute fatal presentation of ornithine transcarbamylase deficiency in a previously healthy male.

Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle defect. While hemizygous males typically present with hyperammonemic coma in infancy, reports of rare late-onset presentations exist, with poor outcomes in males up to 58 years old. Relatives with mutations identical to affected patients often remain asymptomatic, and it is likely that environmental and genetic factors influence disease penetrance and expression. Here, we present our investigation of a patient with late-onset presentation, and we emphasize the potential role of environmental and genetic factors on disease expression. The patient was a previously healthy 62-year-old man who developed mental slowing, refractory seizures, and coma over an 8-day period. Interestingly, the patient had recently used home gardening fertilizers and pesticides. Evaluations for drug and alcohol use, infections, and liver disease were negative. Despite aggressive therapy, blood NH(3) concentration peaked at 2,050 muM and the patient died from cerebral edema and cerebellar herniation. Analysis of the OTC gene showed a Pro-225-Thr (P225T) change in exon 7, a mutation that has been previously implicated in OTC deficiency. This case illustrates that OTC deficiency can cause acute, severe hyperammonemia in a previously healthy adult and that the P225T mutation can be associated with late-onset OTC deficiency. We speculate that exposure to organic chemicals might have contributed to the onset of symptoms in this patient. This case also emphasizes that persistent hyperammonemia may cause irreversible neurologic damage and that after the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle disorders and other causes of hyperammonemic encephalopathy