RESUMEN
We report three unrelated individuals, each exposed to maternal autoantibodies during gestation and found to have elevated very long-chain fatty acids (VLCFAs) in the newborn period after screening positive by California newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD). Two probands presented with clinical and laboratory features of neonatal lupus erythematosus (NLE); the third had features suggestive of NLE and a known maternal history of Sjogren's syndrome and rheumatoid arthritis. In all three individuals, subsequent biochemical and molecular evaluation for primary and secondary peroxisomal disorders was nondiagnostic with normalization of VLCFAs by 15 months of age. These cases add to the expanding differential diagnosis to consider in newborns who screen positive for ALD via elevated C26:0-lysophosphatidylcholine. Though the pathophysiology of how transplacental maternal anti-Ro antibodies damage fetal tissue is not well-understood, we postulate that the VLCFA elevations reflect a systemic inflammatory response and secondary peroxisomal dysfunction that improves once maternal autoantibodies wane after birth. Additional evaluation of this phenomenon is warranted to better understand the intricate biochemical, clinical, and possible therapeutic overlap between autoimmunity, inflammation, peroxisomal dysfunction, and human disease.
Asunto(s)
Adrenoleucodistrofia , Lupus Eritematoso Sistémico , Humanos , Recién Nacido , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/complicaciones , Tamizaje Neonatal , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/complicaciones , AutoanticuerposRESUMEN
Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5 µM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases. Single and multivariate analysis of NBS data from the 11 cases using Collaborative Laboratory Integrated Reports (CLIR; https://clir.mayo.edu) demonstrated citrulline <1st percentile, C3 > 50th percentile, and C5-OH >90th percentile when compared with reference data, as well as unequivocal separation from proximal UCD cases and false-positive low citrulline cases using dual scatter plots. Five of the eight mothers were symptomatic at the time of their child(ren)'s diagnosis, and all mothers and maternal grandmothers evaluated molecularly and biochemically had a homoplasmic pathogenic variant in MT-ATP6, low citrulline, elevated C3, and/or elevated C5-OH. All molecularly confirmed individuals (n = 17) with either no symptoms (n = 12), migraines (n = 1), or a neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) phenotype (n = 3) were found to have an A or U mitochondrial haplogroup, while one child with infantile-lethal Leigh syndrome had a B haplogroup.
Asunto(s)
Enfermedades Mitocondriales , ATPasas de Translocación de Protón Mitocondriales , Tamizaje Neonatal , Humanos , Recién Nacido , ATPasas de Translocación de Protón Mitocondriales/genética , Enfermedades Mitocondriales/sangre , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Citrulina/sangre , Linaje , Trastornos Innatos del Ciclo de la Urea/diagnósticoRESUMEN
We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12 months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.
Asunto(s)
Adrenoleucodistrofia/sangre , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Genéticas Ligadas al Cromosoma X/sangre , Tamizaje Neonatal , Malformaciones del Sistema Nervioso/sangre , Adrenoleucodistrofia/complicaciones , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/patología , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Pruebas con Sangre Seca , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Lactante , Recién Nacido , Lisofosfatidilcolinas/sangre , Masculino , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/patología , Espectrometría de Masas en TándemAsunto(s)
Infecciones por Coronavirus/complicaciones , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/terapia , Neumonía Viral/complicaciones , Betacoronavirus , COVID-19 , Enfermedades Transmisibles Emergentes/epidemiología , Enfermedades Transmisibles Emergentes/terapia , Infecciones por Coronavirus/epidemiología , Predicción , Humanos , Pandemias , Neumonía Viral/epidemiología , Medición de Riesgo , SARS-CoV-2RESUMEN
Here, we report an individual, eventually diagnosed with HMG-CoA synthase deficiency, who presented with a cyclic vomiting phenotype. HMG-CoA synthase deficiency is a rare disorder affecting ketone body synthesis in which affected individuals typically present at a young age with hypoketotic hypoglycemia, lethargy, encephalopathy, and hepatomegaly, usually triggered by catabolism (e.g., infection or prolonged fasting). This individual presented with recurrent episodes of vomiting and lethargy, often associated with hypoglycemia or hyperglycemia, at 3 years of age. Metabolic labs revealed nonspecific abnormalities in her urine organic acids (showing mild elevation of dicarboxylic acids with relatively low excretion of ketones) and a normal acylcarnitine profile. Given her clinical presentation, as well as a normal upper gastrointestinal series, esophagogastroduodenoscopy with biopsies, and abdominal ultrasound, she was diagnosed with cyclic vomiting syndrome at 3 years of age. Molecular testing completed at 7 years of age revealed a previously reported pathogenic sequence variant (c.1016+1G>A) and a novel likely pathogenic deletion (1.57 kB deletion, including exon 1) within HMGCS2 consistent with HMG-CoA synthase deficiency. This individual's presentation, mimicking cyclic vomiting syndrome, widens the clinical spectrum of HMG-CoA synthase deficiency. In addition, this case highlights the importance of molecular genetic testing in such presentations, as this rare disorder lacks specific metabolic markers.
Asunto(s)
Hidroximetilglutaril-CoA Sintasa , Vómitos , Humanos , Vómitos/etiología , Femenino , Hidroximetilglutaril-CoA Sintasa/genética , Hidroximetilglutaril-CoA Sintasa/deficiencia , Preescolar , Biomarcadores/orina , Biomarcadores/sangre , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/complicaciones , Diagnóstico Diferencial , Acetil-CoA C-Acetiltransferasa/deficiencia , Errores Innatos del Metabolismo de los AminoácidosRESUMEN
The phenotype of individuals with glycogen storage disease (GSD) IX appears to be highly variable, even within subtypes. Features include short stature, fasting hypoglycemia with ketosis, hepatomegaly, and transaminitis. GSD IXÉ2 is caused by hemizygous pathogenic variants in PHKA2, and results in deficiency of the phosphorylase kinase enzyme, particularly in the liver. Like other GSDs, GSD IXÉ2 can present with hypoglycemia and post-prandial lactic acidosis, but has never been reported in a newborn, nor with lactic acidosis as the presenting feature. Here we describe the clinical presentation and course of a newborn boy with profound neonatal lactic and metabolic acidosis, renal tubulopathy, and sensorineural hearing loss (SNHL) diagnosed with GSD IXÉ2 through exome sequencing. Review of the literature suggests this case represents an atypical and severe presentation of GSD IXÉ2 and proposes expansion of the phenotype to include neonatal lactic acidosis and renal tubulopathy.