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McMaster University, Department of Pediatrics, Division of Genetics, McMaster Children's Hospital, Hamilton, Ont.Queen's University, Department of Pediatrics, Kingston Health Sciences Centre, Kingston General Hospital, Kingston, Ont.
We report a case of atypical classic galactosemia diagnosed after ophthalmologic examination revealed bilateral cataracts at age 7 years.
We report a full-term female born to healthy, nonconsanguineous parents by elective Caesarean delivery weighing 10 pounds, 3 ounces; the uneventful pregnancy and delivery occurred before implementation of galactosemia newborn screening. She was initially breastfed but within the first few days of life developed poor feeding, vomiting, and significant weight loss. Investigations over the subsequent 2 months included a normal abdominal ultrasound and specifically demonstrated no hepatomegaly. A soy-based formula with dietary lactose restriction was initiated after which symptoms promptly resolved. She was diagnosed with failure to thrive secondary to suspected milk allergy, although confirmatory testing was never conducted. An ophthalmologic assessment was completed at age 2 years because of an older sister with amblyopia and was unremarkable, specifically with no evidence of cataract. Later that year, her younger brother (age 4 months) was diagnosed with galactosemia after presenting with feeding difficulty. Examination revealed hepatomegaly and bilateral cataracts. He was diagnosed with galactosemia based on undetectable erythrocyte galactose-1-phosphate uridyltransferase (GALT) enzyme activity, decreased erythrocyte GALT levels (0.3 umol/hr/g Hb) and increased erythrocyte galactose-1-phosphate (GAL1P) levels (130 ug/g Hb). He was heterozygous for 2 different GALT gene mutations: c.292G>A, p.Asp98Asn and c.377+7A>C (IVS4+7 A>C). The family as a whole initiated a galactose-free diet out of convenience for accommodating the brother's dietary needs.
At age 7 years, our patient's parents became concerned due to poor academic performance and vision issues in school. She was prescribed glasses for hyperopic astigmatism by an optometrist, who referred her for a repeat ophthalmologic assessment. She was found to have mild bilateral cataracts with best corrected visual acuity (BCVA) 20/25 OD and 20/30 OS. Due to her learning disability, cataracts, and the galactosemia family history, GALT activity, GAL1P levels, and mutation analysis were ordered. The results revealed undetectable GALT enzyme activity consistent with a diagnosis of galactosemia. Erythrocyte GAL1P (26 ug/g Hb) and erythrocyte galactose (<4.9 ug/g Hb) levels were normal. Genetic testing confirmed she had the same heterozygous GALT mutations as her brother.
At the time of diagnosis our patient was on a relatively galactose-restricted diet, consuming occasional dairy products with no adverse symptoms. She was 85th percentile for height and 99th percentile for weight. Liver function tests and abdominal ultrasounds were normal. She was diagnosed with a mild learning disability, considered consistent with a diagnosis of galactosemia. There was no evidence of premature ovarian failure on examination by gynecology and she has since continued to develop appropriately, achieving menarche.
Most recent ocular examination at age 15 years revealed stable, mild bilateral nuclear and posterior subcapsular cataracts (Fig. 1), with bilateral high astigmatism and BCVA 20/30 OD and 20/20 OS.
Galactosemia is an autosomal recessive inherited metabolic disorder, caused by GALT) impairment. The incidence ranges from 1:30 000 to 1:60 000 live births; in Ontario the incidence is approximately 1:60 000 (www.newbornscreening.on.ca/en/disease/galactosemia).
Typically within hours of galactose ingestion, infants with galactosemia develop life-threatening complications, including feeding intolerance (76%), failure to thrive (29%), and hepatocellular damage (89%) often leading to jaundice and hepatomegaly but can also cause abnormal liver function tests and coagulation disorders. Escherichia coli sepsis is a major concern in these infants.
Untreated infantile cataract affects normal visual development and leads to blindness, often requiring lensectomy. Once a galactose-free diet is instituted, there is typically prompt resolution of acute neonatal complications and cataracts can often be prevented and reversed. However, a galactose-free diet does not prevent the long-term complications of developmental delay and primary ovarian failure. Untreated, galactosemia can lead to liver failure, seizures, sepsis, and death; however, how much galactose restriction is required is controversial.
GAL1P levels have been associated with poorer long-term outcomes; therefore, measuring GAL1P levels on galactose-restricted diets may help estimate risk of developing long-term complications, but the evidence is conflicting.
Diagnosis is based on clinical symptoms and confirmed by GALT deficiency biochemical assay and GALT gene molecular analysis.
In our patient the suspected diagnosis of milk allergy was supported by the presenting gastrointestinal symptoms, response to dietary change, and lack of typical examination findings for galactosemia. Furthermore, the maintenance of a galactose-restricted diet into childhood may have masked development of overt manifestations of galactosemia; a similar case was reported by Della Casa et al.
In our case, newborn screening for galactosemia was introduced after the younger brother's diagnosis. Newborn screening for galactosemia is now available in many countries and is based on evaluation of GALT activity and (or) total galactose levels.
Screening allows early diagnosis and treatment, although some patients present clinically in the first few days of life before screening results are available, at times with life-threatening sepsis and liver failure.
Another form of galactosemia, Duarte variant galactosemia, is typically asymptomatic or presents with very mild symptoms and signs.
Although our patient presented with a very mild course, the detected variants in this case are not among those previously reported in Duarte galactosemia, and our patient's testing demonstrated undetectable GALT enzyme activity, a finding inconsistent with the reduced, but not absent, GALT enzyme activity of Duarte variant.
Furthermore, the same genetic mutations presented with severe disease in her brother. The milder presentation of her symptoms relative to her brother may be the result of avoiding milk consumption from an early start in life, due to her suspected milk allergy.
Our case represents an atypical case of classic galactosemia with a mild phenotypic presentation with ocular findings only later in childhood. It also demonstrates that variable expression may be found within a single family and suggests that even apparently asymptomatic older siblings should be considered for testing as they may be at risk. This case highlights the importance of considering galactosemia as a cause of childhood cataract even if the presentation is later than expected or without classic symptoms and signs.