Galactosemia Diagnosis By Whole Exome Sequencing Later In Life

Galactosemia (OMIM:230400) is an inborn neuro-metabolic disorder caused by an alteration in 1 of the 3 enzymes involved in the metabolism of galactose: galactokinase, galactose-1-phosphate-uridylintransferase (GALT), and UDP-galactose 4-epimerase.1 Most of the classic galactosemia patients present during the neonatal period with jaundice, hepatosplenomegaly, hepatocellular failure, poor growth, renal dysfunction, sepsis, and cataracts. Neurological complications include development delay,1 hypotonia, seizures, tremor, ataxia, and progressive cerebellar and extrapyramidal features, such as chorea.2, 3 Here, we report a case of a Caucasian 34-year-old man with an atypical clinical presentation. Past medical history was remarkable for a maternal diagnosis of RH incompatibility. During the first week of life, he presented with a diminished sucking reflex, weight loss, and mild jaundice. Hyperbilirubinemia was treated with phototherapy, and the mother interrupted breastfeeding, resolving jaundice. During the first year, he received a lactose-free diet because of a suspicion of lactose intolerance. The parents first noticed an awkward gait and language delay at 18 and 24 months, respectively. At that moment, he was diagnosed with global developmental delay. Sensorineural hearing loss and myopia appeared at the age of 5, and the ophthalmologic examination revealed no cataracts. The brain magnetic resonance imaging (MRI) showed periventricular deep white matter gliosis. Metabolic causes were studied by determining amino acids and organic acids in plasma and urine, which were normal. Study of Fragile X syndrome and Angelman syndrome were also negative. As a result, a diagnosis of infantile-onset cerebral palsy was made, with no further investigations. The patient underwent special education and had difficulty in carrying out basic activities of daily living. In his teens, the patient developed a disabling hand tremor and received treatment with piracetam and propranolol, without improvement. Behavior disturbances, which appeared in adolescence, were treated with olanzapine. At the age of 32, parents sought medical advice because the patient had developed an intermittent generalized tremor and his gait worsened to the point of needing a wheelchair for outdoors activities. Physical examination (Video 1) revealed microcephaly, social smiling, and severe cognitive impairment. A spastic-ataxic gait with poor balance and a broad walking base were also observed. The patient had “saccadic” pursuit eye movements and intermittent strabismus. There was generalized spasticity with exaggerated osteotendinous reflexes in the upper extremities. A new brain MRI (Fig. 1) showed diffuse white matter signal alteration with moderate cerebellar atrophy, and the electroencephalogram found nonspecific signs. New extensive metabolic investigations revealed a serum elevation of asialo 1.4%; (<0.10) and disialotransferrin 4.10% (0.70–2.80), suspecting a congenital disorder of glycosylation (CDG). However, the clinical exome revealed he was a compound heterozygous for variants c.563A > G (p.Q188R) and c.855G > T (p.K285N) in the GALT gene. A galactosemia diagnosis was made; hence, the patient started a low-galactose diet. After 3 months, sialotransferrin levels dropped by 75% and gait improved slightly. CDG encompasses several diseases with a defect in the N- or O-glycosylation of proteins. CDG disorders display a wide range of clinical manifestations. In this case, given the predominant neurological picture and the alteration in the sialotransferrin profile, CDG type Ia was suspected. CDG Ia is characterized by psychomotor retardation, cerebellar hypoplasia, strabismus, and retinitis pigmentosa. Some cases might also present extra neurological manifestations, such as dysmorphic features.4 Nonetheless, the presence of jaundice and the progressive deterioration of the patient made CDG a less feasible option, despite the alteration in sialotransferrins. Finally, whole exome sequencing confirmed the diagnosis of galactosemia with the variants p.Q188R and p.K285N in the GLA gene. These variants account for 69% to 88% of galactosemia alleles in Caucasians.5 Because galactose is a monosaccharide, galactosemia can secondarily impair glycosylation, with an elevation of sialotransferrin, just like CDG. Several studies have reported an improvement in glycosylation after initiation of a low galactose diet, which can be monitored by measuring N-glycans, which might be a surrogate marker of the disease's evolution.6, 7 Our patient mainly expresses the neurologic manifestations of galactosemia. This fact could be explained because he followed a lactose-free diet during early childhood, protecting him from an abundant galactose source. However, the diet was not enough to avoid neurological complications, because brain tissue might be much more sensitive to toxic metabolites' accumulation.8 This patient was diagnosed in adulthood despite having symptoms since the first week of life. Owing to the remarkable clinical variability, neurometabolic disorders tend to be underdiagnosed. Because some of them might have treatments that could alter the prognosis, neurometabolic disorders should always be considered in children with early developmental delay. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. S.L.P.D.: 1A, 1B, 1C, 3A, 3B D.M.M.: 1A, 1B, 1C, 3A, 3B M.C.G.: 1A, 1B, 1C, 3A, 3B D.M.M.: 1A, 1B, 1C, 3A, 3B J.H.V.: 1A, 1B, 1C, 3A, 3B The authors confirm that the approval of an institutional review board was not required for this work. The patient provided written informed consent for publication of his case history and videos. We affirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.