eP005: Complex glycerol kinase deficiency and X-linked intellectual disability


      Glycerol kinase deficiency (GKD) is caused by pathogenic variants of the GK gene on chromosome Xp21. Three forms of GKD are recognized, characterized as infantile, juvenile, and adult forms. While the juvenile and adult forms are recognized as isolated GKD, the infantile form manifests itself as part of the Xp21.3 contiguous gene deletion syndrome, also known as complex GKD. This syndrome is composed of genes associated with Duchenne muscular dystrophy (DMD), X-linked congenital adrenal hypoplasia (NR0B1), and intellectual disability (IL1RAPL1).

      Case presentation

      A 2-year-old male born to a primigravida mother, uncomplicated pregnancy and birth, birth weight of 7lbs 7oz, and uneventful postnatal period, presented to the genetics clinic with a history of global developmental delay. There was also a family history of developmental delay and intellectual disability in the patient’s mother and sister. Significant findings on examination included a startling appearance, absent eyebrows and temporal thinning, high forehead, frontal bossing, and axial hypotonia. Laboratory findings included elevated creatine kinase (CK) of 14809 units/L (reference range 27-160 units/L), aspartate aminotransferase (AST) of 307 (reference range 20-60 units/L) and alanine aminotransferase (ALT) 265 units/L (reference range 15-45 units/L) , and elevated triglycerides at 683 mg/dL (reference range 44-157 mg/dL). Organic acid analysis by gas chromatography-mass spectrometry (GC-MS) and chromosomal microarray was performed for further evaluation. Organic acid analysis showed abnormal accumulation of glycerol. Chromosomal microarray detected a 4.2 Mb deletion of Xp21.3p21.1(29296579_33551038), including complete copies of GK, DMD, and NR0B1 genes as well as multiple exons of IL1RAPL1. This confirmed his glycerol kinase deficiency (GKD) as part of the Xp21.3 contiguous gene deletion syndrome.


      Our patient’s presenting and ongoing symptoms were related to his chromosomal abnormality, however, may have been identified earlier through a urine organic acid screen. Testing of affected family members was also recommended. In addition, he will require continuous follow-up with a multidisciplinary team including genetics, metabolic dietician, developmental pediatrics, speech, and physical therapies, endocrinology, and neuromuscular specialties. This case demonstrates the importance of educating providers who care for those with developmental delays, that metabolic screening is still an integral part of the initial workup. In addition, these screens may help prevent delays in diagnosing and managing treatable genetic conditions.