IMPE Abstracts

Pelizaeus-Merzbacher disease (PMD; MIM 312080) is a rare X-linked genetic disorder due to a mutation of PLP-1 located on chromosome Xq22. PMD is a hypomyelinating leukodystrophy that results in progressive neurological disease due to loss of the myelin sheath. Gene duplication of PLP-1 is the most common cause of PMD and results in an excess of PLP-1 that then accumulates in the lysosome and causes hypomyelination and oligodendrocytes apoptosis. Patients often present with delayed motor milestones, nystagmus, ataxia, dystonia, dysarthria, and spasticity in boys. Subclinical Hypothyroidism was reportedly previously by Viera et al (2021) in same-sex twins with PMD at 10 months of age and persisted and subsequently treated with levothyroxine. Untreated congenital hypothyroidism results in intellectual disability and growth retardation and occurs in about 1:2000 to 1:4000 live births. A 21-month male infant was referred to our clinic for failure to thrive with PMD due to PLP-1 gene duplication. Parents reported low energy, dry skin, worsening global developmental delays, poor muscle tone, brittle hair, and constipation. The infant had steady linear growth that peaked at the the 32nd percentile at age 9 months and then subsequently crossed multiple percentile lines to the O.1 percentile with a Z-score of -3.98 at 13 months of age. Past medical history included nystagmus, pectus excavatum, and hypotonia. Newborn screen was normal. After an extensive workup for failure to thrive genetic testing confirmed PMD just before age one. His decreased growth velocity, dry yellowing skin, and developmental delays were attributed to his PMD. Work up for constipation by gastroenterology revealed a TSH was 8.29 mIU/L with Free T4 of 1.1 ng/dL at 17 months of age. Based on his clinical history he was started on 25 mg of levothyroxine. Within six weeks of treatment with levothyroxine his parents reported dramatic improvements in energy, skin color and texture, hair, and resolution of his constipation. Developmentally he began to speak several words for the first time and motor skills improved. Growth velocity improved from pre-treatment rate of 4.8 cm/year to 24 cm/year with improved Z-score of -2.8 after 4 months of treatment. TSH normalized to 1.91 mIU/L with Free T4 of 1.5 ng/dL. This presentation indicates a critical need to evaluate infants with PMD for evolving hypothyroidism after the newborn period and the need for further research to assess the association of hypothyroidism with PLP-1 expression.