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Rapid Progressive Leukodystrophy in Early Childhood Appears to Be a New Phenotype of Infantile-Onset Pompe Disease

Alexander Broomfield - Speaker World Symposium 2017Alexander Broomfield, MD

February 18, 2017—San Diego, California—A more aggressive cerebral manifestation of infantile Pompe disease than previously reported appears to be a new phenotype of the disease.

This case report of a preterm infant was reported at the 13th Annual WORLDSymposium, from February 13–18.

Alexander Broomfield, MD, of the Royal Manchester Children's Hospital, UK, explained that while initial 2006 case reports suggested that infantile patients with Pompe disease may suffer delayed myelination, evidence from 2016 suggests that patients may be at risk of a chronic progressive leukodystrophy in late childhood.

Infantile-onset Pompe disease is usually diagnosed at 4–8 months. Muscles appear normal but are limp and weak, preventing infants from lifting their head or rolling over. As the disease progresses, heart muscles thicken and progressively fail. Without treatment, death usually occurs due to heart failure and respiratory weakness.

Infantile-onset Pompe disease usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%), and failure to thrive (50%).

The main clinical findings include floppy baby appearance, delayed motor milestones, and feeding difficulties. Moderate hepatomegaly may be present. Facial features include macroglossia, wide-open mouth, wide-open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone.

Cardiopulmonary involvement is manifested by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias, and evidence of heart failure.

Median age at death in untreated cases is 8.7 months and is usually due to cardiorespiratory failure.

The usual initial investigations include chest X-ray, electrocardiogram, and echocardiography. Typical findings are those of an enlarged heart with nonspecific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10-fold) with lesser elevations of serum aldolase, aspartate transaminase, alanine transaminase, and lactic dehydrogenase.

Diagnosis is made by estimating acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.

Dr. Broomfield and colleagues reported on a preterm infant born at 34 gestational weeks. The child was negative for cross-reactive immunological material, homozygous for the c.2237GgrA p.(Trp746*) mutation.

The child was diagnosed at birth and underwent immunomodulation with rituximab and methotrexate at 36 weeks gestation. Initial development was good, with no antibody formation and walking at 16 months of age.

At age 3 years, 10 months, however, a change in gait with increasing tightness, initially in the left then in both Achilles tendons, was noted. Brain MRI at 4 years of age showed bilateral frontoparietal leukodystrophy involving deep, periventricular and subcortical white matter with sparing of U-fibres and internal capsules.

Over 6 months, this leukodystrophy progressed in extent with new, mild bilateral involvement of the external capsules. Radiological deterioration was matched by increasing distal spasticity of the lower limbs, though as yet no obvious other neurological, respiratory, gastrointestinal, cardiac, or intellectual changes have been seen.

Extensive investigations revealed normal metabolic profiling except for a mildly reduced cerebrospinal fluid tetrahydrofuran (35 nmoL/L [normal range 72–130 nmoL/L]), with normal folate receptor 1[FOLR1], methylene tetrahydrofolate reductase [MTHFR], the proton-coupled folate transporter SLC46A1, dihydrofolate reductase (DHFR), mitochondrial DNA sequencing, and cerebrospinal fluid lactate. JC virus and other infective serological results were normal.

Given wide metabolic and infective profiling, the lack of potential variants on a targeted exome and progression in radiology, Dr. Broomfield concluded that the reported case appears to be potentially a more aggressive cerebral manifestation of infantile Pompe disease than thus far reported. This is a potentially an important consideration for infantile patients with sudden onset of gait abnormalities.

Of note, initial tetrasaccharide profiling of cerebrospinal fluid suggests that such profiling is not a useful biomarker of potential central nervous system involvement.

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Molecular Genetics and Metabolism is a contribution to the understanding of the metabolic basis of disease. The journal publishes articles describing investigations that use the tools of biochemistry and molecular biology for studies of normal and diseased states. In addition to original research articles, occasional minireviews reporting timely advances as well as brief communications and letters to the editor are considered.

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