Lauren Bailey

Severe Cardiomyopathy as the Isolated Presenting Feature in an Adult with Late-Onset Pompe Disease: A Case Report

Many inborn errors of metabolism can cause cardiomyopathy. Cardiomyopathy associated with glycogen storage includes PRKAG2-associated glycogen storage disease (GSD), Danon disease, infantile-onset Pompe disease (GSD II), GSD III, GSD IV, and phosphofructokinase deficiency (Tarui disease or GSD VII).We present a 35-year-old female who presented with cardiomyopathy after a pregnancy complicated by primary hyperparathyroidism. She had enjoyed excellent health until her first pregnancy at age 33. One week postpartum, she developed dyspnea and an echocardiogram revealed left ventricular ejection fraction (LVEF) of 35%. A cardiac MRI was consistent with nonischemic cardiomyopathy with an infiltrative process. Endomyocardial biopsy showed striking sarcoplasmic vacuolization, excess glycogen by PAS staining, and frequent membrane-bound glycogen by electron microscopy, consistent with lysosomal GSD. Acid alpha-glucosidase (GAA) activity in skin fibroblasts was in the affected range for Pompe disease. Sequencing of the GAA gene revealed a paternally inherited pathogenic c.525delT (p.Glu176Argfs*45) and a de novo c.309C>G (p.Cys103Trp) with unknown pathogenicity. Testing of the familial mutations in her daughter indicated that the variants in the proband were in trans. 26-gene cardiomyopathy sequencing panel had normal results thereby excluding GSD III, Danon disease, Fabry disease, and PRKAG2-associated cardiomyopathy. Therefore, results strongly suggest a diagnosis of Pompe disease.Pompe disease has a broad disease spectrum, including infantile-onset (IOPD) and late-onset (LOPD) forms. LOPD typically presents with proximal muscle weakness and respiratory insufficiency in childhood or late adulthood. Our case may represent a very unusual presentation of adult LOPD with isolated cardiomyopathy without skeletal muscle involvement or respiratory failure.

Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32–13 T > G variant

BACKGROUND Individuals with late-onset Pompe disease (LOPD) and the common c.-32-13 T > G variant are widely thought to have milder, adult-onset disease. This belief, and the consequent low suspicion of clinical involvement in children, has led to delays in diagnosis and treatment initiation in patients with early onset of symptoms. Previous reports of LOPD in children do not include description of the early-onset phenotype. This description of signs and symptoms, some of which are subtle and less known, is important to facilitate prompt identification and appropriate treatment in symptomatic children. METHODS Retrospective chart review of a cohort of 84 LOPD patients with the c.-32-13 T > G variant was conducted to identify patients diagnosed clinically (as opposed to through newborn screening) who had clinically documented symptom-onset within the first two years of life. RESULTS Four patients had early onset of symptoms, with age at onset ranging from 10 days to 20 months. Initial symptoms included delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea. Early and characteristic alterations in posture and movement were identified in all patients. Age at diagnosis ranged from 10 months to 26 months. Median age at enzyme replacement therapy (ERT) initiation was 23.5 months. Despite ERT, progression of musculoskeletal involvement and residual muscle weakness was evident in all patients, as evidenced by ptosis, myopathic facies, scoliosis, lumbar lordosis, scapular winging, and trunk and lower extremity weakness. Standardized functional assessments showed gross motor function below age level as measured by the Alberta Infant Motor Scales, the Peabody Developmental Motor Scales-2, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the six-minute walk test. CONCLUSIONS Onset of symptoms including delay in achievement of gross motor milestones, signs of proximal muscle weakness, swallow and feeding difficulties, and sleep apnea in the first two years of life is not uncommon in individuals with LOPD and the c.-32-13 T > G variant. Patients with early-onset disease appear to have a more, rapid and severe progression of disease with persistent residual muscle deficits which partially improve with higher doses of ERT. Careful evaluation for specific and characteristic patterns of posture and movement in patients with this variant is necessary to identify those who have early onset of disease. Increased awareness of the early-onset signs and symptoms may also enable early identification of disease onset in children who are diagnosed through newborn screening.

Combination of exome sequencing and immune testing confirms Aicardi–Goutières syndrome type 5 in a challenging pediatric neurology case

Exome sequencing is increasingly being used to help diagnose pediatric neurology cases when clinical presentations are not specific. However, interpretation of equivocal results that include variants of uncertain significance remains a challenge. In those cases, follow-up testing and clinical correlation can help clarify the clinical relevance of the molecular findings. In this report, we describe the diagnostic odyssey of a 4-year-old girl who presented with global developmental delay and seizures, with leukodystrophy seen on MRI. Clinical evaluation, MRI, and comprehensive metabolic testing were performed, followed by whole-exome sequencing (WES), parental testing, follow-up testing, and retrospective detailed clinical evaluation. WES identified two candidate causative pathogenic variants in SAMHD1, a gene associated with the recessive condition Aicardi–Goutières syndrome (AGS) type 5 (OMIM 612952): a previously reported pathogenic variant NM_015474 c.602T>A (p.I201N), maternally inherited, and a rare missense variant of uncertain significance, c.1293A>T(p.L431F). Analysis of type I interferon-related biomarkers demonstrated that the patient has an interferon signature characteristic of AGS. Retrospective detailed clinical evaluation showed that the girl has a phenotype consistent with AGS5, a rare neurological condition. These results further define the phenotypic spectrum associated with specific SAMHD1 variants, including heterozygous variants in AGS carriers, and support the idea that autoinflammatory dysregulation is part of the disease pathophysiology. More broadly, this work highlights the issues and methodology involved in ascribing clinical relevance to interpretation of variants detected by WES.

Three cases of multi-generational Pompe disease: Are current practices missing diagnostic and treatment opportunities?

Pompe disease (Glycogen storage disease type II, GSDII, or acid maltase deficiency) is an autosomal recessive metabolic myopathy with a broad clinical spectrum, ranging from infantile to late‐onset presentations. In 2015, Pompe disease was added as a core condition to the Recommended Uniform Screening Panel for state newborn screening (NBS). The clinical importance of Pompe disease is evolving with the use of NBS, increasing awareness of the disease, and higher than previously reported disease prevalence; however, current practices miss additional diagnostic and potential treatment opportunities in close relatives of the family proband. In this report, we describe three families with multiple individuals in multiple generations affected by both infantile and late‐onset clinical presentations of Pompe disease. The presence of multi‐generational disease within these families highlights the importance of subsequent risk assessment through medical history and physical examination, with a low threshold for the screening of a probands family members. We recommend enzymology (GAA activity assay) as the first screening method, as opposed to targeted mutation analysis, for at‐risk family members. Given that the initial symptoms of the slowly progressive late‐onset presentation of Pompe disease may be mild or non‐specific, enzymatic testing of all parents of affected infants should be considered.